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Genetically targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK-positive LMs, one with Gorham Stout disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly targeted therapies for LMs., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Pancreatic and periampullary cancers pose significant challenges in oncological care due to their complexity and diagnostic difficulties. Global experiences underscore the crucial role of multidisciplinary collaboration and centralized care in improving patient outcomes in this context. Recognizing these challenges, Lombardy, Italy's most populous region, embarked on establishing pancreas units across its territory to enhance clinical outcomes and organizational efficiency. This initiative, driven by a multistakeholder approach involving the Lombardy Welfare Directorate, clinicians, and a patient association, emphasizes the centralization of complex care in high-volume hospitals, adopting a hub-and-spoke model and a multidisciplinary approach. This article outlines the process and criteria set forth for pancreas unit implementation, aiming to provide a structured framework for enhancing pancreatic cancer care. Central to this initiative is the establishment of structured criteria and minimal requirements, not only for surgery but also for other essential components of care, ensuring a comprehensive approach to pancreatic cancer management. The Lombardy model offers a structured framework for enhancing pancreatic cancer care, with potential applicability to other regions and countries seeking to improve their cancer care infrastructure., Competing Interests: Declaration of competing interest The following authors declare conflict of interest: Other authors declare no conflicts of interest, (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Folliculotropic mycosis fungoides (FMF) is a rare cutaneous malignancy that can be mistaken for inflammatory diseases, such as discoid lupus erythematosus (DLE), due to the variability of histopathological findings., Methods: This study aims to provide dermatopathologists with evidence-based histopathologic criteria to distinguish DLE from FMF by reporting overlapping and distinguishing microscopic features. Forty-three biopsies from patients with a confirmed diagnosis of DLE or FMF were graded for the presence or absence of 18 histopathologic features., Results: The main histopathologic findings present in nearly all DLE and FMF biopsies were folliculocentric and folliculotropic patterns. Comedones, granulomas, and folliculitis were not prominent. Follicular hyperplasia, follicular plugging, interstitial mucin, lichenoid/interface dermatitis, and plasma cells were significantly more common in DLE biopsies, while follicular mucinosis and eosinophils were significantly more common in FMF samples. Cytologic atypia ranged from none to mild in DLE and mild to moderate in FMF. Rarely, both sets of biopsies contained epidermotropism, spongiosis, or peri-eccrine infiltration., Conclusion: While many histopathological features present in DLE overlap with features found in FMF, such as folliculocentrism and folliculotropism, significant differences do exist. Therefore, when diagnosing FMF, it is important to follow established criteria that differentiate this malignancy from inflammatory conditions such as DLE., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In addition to "classic" and eosinophilic subtype, chromophobe renal cell carcinoma (RCC) is well-known to demonstrate various morphological patterns including adenomatoid, microcystic, pigmented, multicystic, papillary, neuroendocrine-like, and small cell-like, all of which are important to appreciate for accurate diagnosis. Herein, we expand on a unique chromophobe RCC morphology not previously described consisting of tumor cells with extensive stromal retraction, mimicking upper urothelial tract micropapillary carcinoma (MPC). Twelve MPC-like chromophobe RCC nephrectomies were reviewed with clinicopathological features recorded; molecular testing was performed on 7 of 12 tumors. Patients were mostly men (n=10) with a mean age of 65 years. Mean tumor size was 6.4 cm with pathological stage distribution as follows: 4 (33%) T1a, 2 (17%) T1b, 1 (8%) T2b, and 3 (25%) T3a. The extent of MPC-like chromophobe RCC foci ranged from 10% to 40% (mean=26%; there was no correlation between the extent of MPC-like chromophobe RCC foci and tumor stage). Other chromophobe RCC morphological patterns were not identified. When performed, all (100%) tumors depicted prototypic chromophobe RCC staining pattern of KIT positivity/KRT7 positivity. Molecular showed 6 of 7 (86%) with multiple chromosomal losses. Clinically significant mutations were identified in NF1, TP53, FLCN (likely somatic), CHEK2, and ZFHX3 genes. Follow up available in 9 patients showed no evidence of disease (mean=23 months). Although the etiology behind the extensive stromal retraction in our tumors is unknown, this may likely be artifactual in nature. Nonetheless, it is important to include MPC-like chromophobe RCC in the spectrum of "variant" morphologies to avoid diagnostic pitfalls from micropapillary carcinoma., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A significant proportion of men with prostate cancer will experience biochemical recurrence (BCR), which is characterized by an elevation in prostate-specific antigen (PSA) levels after receiving treatment with curative intent. Imaging plays an important role in the management of patients with BCR. It can help identify sites of recurrence to determine the most appropriate management strategies, ranging from salvage treatment for local recurrences to systemic treatments for those with advanced, distant disease. PET/CT with prostate-specific membrane antigen (PSMA)-radioligands is the most sensitive method for the detection of prostate cancer recurrence, with significantly higher cancer detection rates compared to conventional imaging techniques such as bone scan and computed tomography, even at lower PSA levels. Nevertheless, interpretation of PSMA PET/CT images can be challenging, particularly for the evaluation of local recurrence due to urinary activity that can mimic or mask the presence of cancer. Furthermore, some prostate cancers may not express PSMA and have false negative results. Multiparametric prostate MRI is an excellent method for the evaluation of local recurrence and can overcome some of the limitations of PSMA PET/CT. In this review, we discuss the role of imaging in managing patients with prostate cancer BCR and describe the potential benefits of MRI in the PSMA-radioligand imaging era, emphasizing the assessment of local recurrence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Osteosarcoma is the most common malignant bone tumour with limited treatment options and poor outcomes in advanced metastatic cases. Current immunotherapies show limited efficacy, highlighting the need for novel therapeutic approaches. Systemic immune activation by Toll-like receptor 4 (TLR4) immunostimulants has shown great promise; however, current TLR4 agonists' toxicity hinders this systemic approach in patients with osteosarcoma., Methods: We compared the antitumour effect of lipopolysaccharides (LPS) with that of an innovative chemically detoxified TLR4 agonist (Lipo-MP-LPS) in a syngeneic metastatic osteosarcoma mouse model. Lipo-MP-LPS exhibited an optimal safety and solubility profile for systemic administration at an effective dose. We evaluated tumour growth, lung metastases, and immune cell infiltration in wild-type and TLR4-mutant mice and performed selective immunodepletion., Results: Lipo-MP-LPS exhibited antitumour effects against localised osteosarcoma tumours and lung metastases, like those of natural LPS. Lipo-MP-LPS promoted CD8 + T cells and M1 macrophages infiltration in primary tumours and CD8 + T cells in metastases, with an M1-phenotype macrophage shift. The Lipo-MP-LPS antitumour effects were found to depend on TLR4 and CD8 + T cells, but not on macrophages., Conclusion: Lipo-MP-LPS inhibited tumour growth and lung metastasis of osteosarcoma by promoting CD8 + T cell infiltration, indicating its therapeutic potential for advanced osteosarcoma., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval: The Institutional Review Board of the Kyushu University Hospital approved the study protocol (approval number: A24-037-0)., (© 2025. The Author(s).)

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3). COL6A3 levels were strongly increased by body mass index and increased coronary artery disease risk. Notably, the carboxyl terminus product of COL6A3, endotrophin, drove this effect. COL6A3 was highly expressed in disease-relevant cell types and tissues. Finally, we found that body fat reduction could reduce plasma levels of COL6A3-derived endotrophin, indicating a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effects of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target., Competing Interests: Competing interests: J.B.R. has served as an advisor to GlaxoSmithKline and Deerfield Capital. J.B.R.’s institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline, and Biogen for projects unrelated to this research. J.B.R. is the CEO of 5 Prime Sciences ( www.5primesciences.com ), which provides research services for biotech, pharma and venture capital companies for projects unrelated to this research. T.L., Y.C. and V.F. are employees of 5 Prime Sciences. The remaining authors declare no competing interests., (© 2025. The Author(s).)

A case of cutaneous adnexal neoplasm with unusual squamoid morphology and harboring an in frame ACTB::ZMIZ2 fusion transcript was recently described. Herein, we report a second case of adnexal carcinoma harboring similar morphology and an identical in frame ACTB::ZMIZ2 fusion transcript. This 2.2-cm mass was removed from the axilla of a 17-year-old woman. Microscopic examination revealed a large nodular and infiltrative tumor invading the dermis composed of sheets and nests frequently centered by large areas of keratinization. Molecular investigation revealed an in frame ACTB::ZMIZ2 fusion transcript. Clustering analysis revealed close proximity of this case with the ACTB::ZMIZ2-fused adnexal tumor previously reported. Herein, we report a second case of adnexal tumor with ACTB::ZMIZ2 fusion arising in a young adult suggesting that ACTB::ZMIZ2 fusion might be a defining genetic event, specific of a rare and previously undescribed adnexal tumor entity., Competing Interests: Declarations. Ethical approval: Local Ethics Committee in Human Research, Tours, France; No. ID RCB2009-A01056-51. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Anal melanoma is a rare malignancy, accounting for 0.4% to 1.6% of all melanomas. Its atypical presentation, low incidence, and non-specific symptoms make it a challenging diagnosis, which can lead to delayed treatment with an unfavorable impact on clinical outcomes. Treatment should be multidisciplinary and may include surgical resection with adjuvant therapy, chemotherapy, and radiotherapy. We present the case of a male patient who presented to the emergency department due to foreign body sensation and transanal bleeding. The patient underwent an anal exploration under anesthesia, where a hyperpigmented canal-dependent tumor lesion with extension into the perianal skin was found. After a wide local excision, histopathological study confirmed the diagnosis of invasive nodular melanoma. The patient was discharged without complications for follow-up and management in the outpatient medical oncology clinic., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2025.)

To examine the effect of DBS of the lateral hypothalamic area (LHA) on age-related memory changes, neuronal firing from CA1, oxidative stress, and the expression of Hsp70, BDNF, and synaptophysin. 72 male rats were randomly allocated into 6 equal groups: a) normal young group (8 W), b) sham young group, c) DBS young group, d) normal old group (24 months), e) sham old group and f) DBS old group. Memory tests (passive avoidance and Y maze), oxidative stress markers (MDA, catalase, and GSH) and expression of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin were measured by the end of the experiment. Also, in vivo recording of the neuronal firing of the CA1 region in the hippocampus was done. Old rats show significant decline in memories, antioxidant genes (Nrf2 and HO-1), antioxidants (GSH and catalase), Hsp70, BDNF, and synaptophysin with significant increase in MDA in hippocampus (p < 0.05) and DBS for LHA caused a significant improvement in memories in old rats, with significant rise in fast gamma and theta waves in CA1 region in old rats (p < 0.05). This was associated with a significant increase in antioxidants (GSH and CAT), antioxidant genes (Nrf2, HO-1), Hsp70, BDNF, and synaptophysin with significant reduction in MDA in hippocampus (p < 0.05). DBS for LHA ameliorates the age-induced memory decline. This might be due to increase in fast gamma in CA1, attenuation of oxidative stress, upregulation of Nrf2, HO-1, Hsp70, BDNF, and synaptophysin in the hippocampus., Competing Interests: Declarations. Ethics: The study was approved by the IRB committee, Mansoura Faculty of Medicine (Code ##RP.19.09.41). Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Synovial osteochondromatosis is a relatively rare condition of the hand. We present a rare case of a locked finger in a paediatric patient with synovial osteochondromatosis, in which a tumourous lesion was continuous with the flexor tendon and trapped proximal to the A1 pulley. After resection of the tumour and synovium, no recurrence was observed over a 6-month follow-up period. Synovial osteochondromatosis in the hand or fingers can lead to swelling and limited range of motion; however, symptom progression is usually slow. Moreover, it is uncommon for an extra-articular tumour to cause a sudden onset of locking symptoms without prior warning signs. Comprehensive excision of the synovium is essential, and ongoing observation for recurrence is necessary during follow-up. Level of Evidence: Level V (Therapeutic).

Background: Tumor microvasculature is an important component of the tumor microenvironment (TME), and it has been reported that tumor microvasculature induces TME to become immunosuppressive via vascular endothelial growth factor. However, the significance of this in adenocarcinoma with epidermal growth factor receptor (EGFR) common mutations has not been fully investigated., Methods: We analyzed 262 patients with adenocarcinoma harboring EGFR common mutations who underwent surgery at Kyushu University Hospital between 2006 and 2021. Microvessel density (MVD) was calculated by CD34 immunohistochemistry. Patients were categorized into high and low MVD status, which was compared with the clinicopathological characteristics., Results: A total of 136 (51.9%) patients had L858R mutation, and 126 (48.1%) had Exon 19 Del. Regarding MVD status; 133 patients (50.8%) were classified as high and 129 (49.2%) as low. Fisher's exact test revealed a significant association of high MVD status with high CD8+ tumor infiltrating lymphocytes (TILs) (p = 0.0187), low GZMB+ TILs (p = 0.0019), and high Foxp3+ TILs (p = 0.0003). On multivariate analysis, MVD status was significantly associated with Foxp3+ TILs and GZMB+ TILs. Fisher's exact test also revealed that tumors with L858R mutation had a high MVD status (p = 0.0136) compared with tumors with deletions of exon 19 (Exon 19 Del), and multivariate analysis revealed that L858R mutation was significantly associated with high MVD status., Conclusions: In adenocarcinomas harboring EGFR common mutations, abundant tumor microvasculature might induce the TME to be immunosuppressive. Tumors with L858R mutation compared with Exon 19 Del might be more likely to form an immunosuppressive TME owing to the abundance of tumor microvasculature., (© 2025. Society of Surgical Oncology.)

Exosome markers, CD63 and CD81, belong to the tetraspanin family and are expressed in solid tumors. It has been reported that these tetraspanin family members are prognostic factors in some cancers. However, the expression of CD63 and CD81 in pathological breast cancer specimens has not been reported. It has been reported that CD63 promotes the proliferation of breast cancer cells in vitro through yes-associated protein (YAP). Therefore, in this study, the expression of tetraspanin family members, particularly CD63, CD81, and YAP were investigated in breast cancer tissue, by immunohistochemistry, to clarify the relationship between clinicopathological factors and prognosis. The number of CD63 and YAP double-positive breast cancer cells was significantly higher in patients with pathological T factor (pT) status (p = 0.030) and tended to be higher in patients with pathological N factor (pN) status (p = 0.054). Furthermore, the number of CD81 and YAP double-positive breast cancer cells was significantly higher in patients with histological grade (p = 0.015), pT status (p = 0.001), and Ki67 expression (p = 0.049), and tended to be higher in patients with pN status (p = 0.062) and TNM stage (p = 0.052). In addition, CD63 and YAP double-positive breast cancers and CD81 and YAP double-positive breast cancers were associated with shorter disease-free and breast cancer-specific survival, respectively. In conclusion, CD63 and YAP, and CD81 and YAP may serve as potential prognostic biomarkers in patients with breast cancer., Competing Interests: Declarations. Conflict of interest: All authors declare that they have no conflict of interest. Ethical approval: This study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of Tohoku University (2020–1-656)., (© 2025. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive orphan hematopoietic malignancy characterized by cutaneous and systemic hematologic involvement. BPDCN is frequently misidentified, but early, accurate diagnosis is critical to extending patient survival using tagraxofusp, a first-in-class CD123-targeted therapy, and increasing their chances of receiving a potentially curative stem cell transplantation. Cases of BPDCN in countries of the Gulf Cooperation Council are lower than the extrapolated incidence from other geographic locations due to lack of awareness of key diagnostic features, lack of consensus on the minimal phenotype for diagnosis, and lack of local immunohistochemistry testing facilities, contributing to underdiagnosis in this region. Practical recommendations, a streamlined diagnostic panel, and suggested multidisciplinary approaches based on expert experience regarding diagnostic and clinical challenges specific to this region, and a review of the literature are presented here to facilitate diagnosis of BPDCN in this region by primary care physicians, dermatologists, and hematologists.

Malignant colonic neuroendocrine tumours are rare. Even more uncommon is their occurrence in the left colon. They also infrequently occur in males and young adults. We describe a rare case of poorly differentiated neuroendocrine carcinoma of the descending colon in a 32-year-old male who presented with signs of intestinal obstruction. He later had exploratory laparotomy and tumour resection with 5 cm gross tumour margins and Hartman-type colostomy and completed six cycles of Etoposide and Carboplatin combination. He has been tumour- and symptom-free for 36 months. Even though rare, neuroendocrine tumours should be an important differential of all colonic tumours, irrespective of the patient's age and sex, and surgeons should have a high index of suspicion for them. Although they most commonly occur in the right colon (cecum), they can also be found in the descending colon, where they can present with intestinal obstruction. Tumour resection with 5 cm gross tumour margins and Hartman-type colostomy can be handy. Etoposide and Carboplatin combination can improve overall survival in complicated World Health Organization (WHO) stage 3 neuroendocrine carcinoma with regional lymph node involvement, and generally poor prognosis, but without evidence of distant metastasis, and relatively fair performance index. Younger patients with neuroendocrine carcinomas may benefit better from platinum-based chemotherapy., (Copyright © 2024 Nigerian Medical Association.)

G protein-coupled receptors (GPCRs), critical for cellular communication and signaling, represent the largest cell surface protein family and play important roles in numerous pathophysiological processes. Consequently, GPCRs have become a primary focus in drug discovery efforts. Beyond their traditional G protein-dependent signaling pathways, GPCRs are also capable of activating alternative signaling mechanisms, including G protein-independent signaling, biased signaling, and signaling crosstalk. A particularly novel signaling mode employed by these receptors is GPCR transactivation, which enables cross-communication between GPCRs and other receptor types. Intriguingly, GPCR transactivation by distinct GPCRs has also been identified. In this review, I provide an overview of the known GPCR transactivation mechanisms and explore recently uncovered GPCR transactivation mediated by adhesion-class GPCRs (aGPCRs). These aGPCR-GPCR transactivation processes regulate unique cell type-specific functions, offering an exciting opportunity to develop therapies that precisely modulate specific GPCR-mediated biological effects.

Background: Soft tissue tumors (STTs) in adolescents are relatively rare, and their characteristics and behavior have not been well studied in this age group. The aim of this study was to describe the clinicopathologic patterns of STTs in adolescents aged 10-19 years according to the 2020 WHO classification., Method: A 10-year retrospective cross-sectional study of 632 surgical samples from adolescents was conducted at a tertiary health facility to determine the frequency, histological patterns and characteristics of STTs in this population. The data were analyzed via SPSS 23., Results: STTs accounted for 12.5% of all histologically diagnosed lesions in adolescents, with a mean age of 15 ± 2.9 years, 54.4% occurring in females and 35.4% in middle adolescents. The majority (64.56%) of STTs were benign, while malignant and intermediate-grade neoplasms accounted for 25.32% and 10.13%, respectively. Vascular tumours were the most common, followed by adipocytic and fibroblastic/myofibroblastic tumours, with hemangiomas being the most common. The most prevalent symptom was a painless mass (82.3%), with the head and neck (25.3%) being the most commonly involved body site. Most of the STTs patients presented within the first two years of occurrence (36.7%, n = 29/79). However, age, age group and sex were not significantly associated with the WHO grades of these STTs., Conclusion: This study provided valuable insights into the characteristics and behavior of STTs in adolescents, highlighting the importance of early diagnosis and management. These findings suggest that adolescent STTs affect females more than males , involve the head and neck more and are more benign, with vascular tumours being the most common type of STT in this age group., Competing Interests: Declarations. Ethics approval and consent to participate: This study utilized anonymized archived human tissues and was conducted in accordance with the World Medical Association’s Helsinki Declaration and the National Health Research Ethics Committee guidelines. The study protocol was reviewed and approved by NAUTH Human Research Ethics Committee (NAUTH HREC), Nnewi (Reference: NAUTH/CS/66/VOL.14/VER3/134/2021/036). As the study did not involve direct contact with human subjects, consent to participate was deemed unnecessary by the NAUTH HREC. A hospital permit (Reference: NAUTH/CS/66B/VOL.2/153) was also obtained from NAUTH management before commencement of this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

BACKGROUND Primary cardiac malignancies are extremely rare, with an incidence of 0.07% on autopsy series. Primary sarcomas represent up to 95% of malignant neoplasms, with myxofibrosarcomas accounting for only 10%. Around 90% of patients present with unspecific symptoms and a tumor with polypoid appearance on imaging, thus frequently receiving a misdiagnosis of myxoma. CASE REPORT A 65-year-old man presented with abrupt chest pain, blood pressure of 130/80 mmHg, and heart rate of 180 beats/min. Electrocardiogram showed atrial fibrillation, and imaging revealed a polypoid tumor on the atrioventricular septum obstructing the mitral valve. The tumor was removed and sent for histopathological evaluation, revealing a multinodular pattern with spindled hypocellular areas and hypercellular areas featuring pleomorphic cells. The mitotic count was 11 in 10 high-power fields, and necrosis was present in less than 50% of the tumor area. Tumor cells were calretinin and MDM2 negative and CD34 positive. Heterologous elements, necrosis and hemorrhage, were noted. Considering these findings, this tumor was classified as intermediate-grade myxofibrosarcoma. CONCLUSIONS Due to the rarity of myxofibrosarcomas, evidence for optimal diagnostic and therapeutic management is limited. Despite being frequently polypoid, seemingly benign tumors on imaging, the extent of infiltration at their base is usually deep. Their innocent appearance can hinder adequate presurgical planning, leading to suboptimal resections. We present the example of a seemingly benign tumor as a potential pitfall in evaluating cardiac neoplasms, highlighting the importance of histopathological and immunohistochemical evaluation in their correct characterization, in order to offer the best follow-up and adjuvant treatment, when needed.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for this journal and was not involved in the editorial review or the decision to publish this article.

A rare autopsy case of malignant transcription factor E3 (TFE3)-rearranged perivascular epithelioid cell tumor (PEComa)-like neoplasm is presented. An 84-year-old woman manifested multiple cerebral infarctions and repetitive embolic events in the supra mesenchymal artery (SMA), and the presence of a mobile mass in the heart's left ventricle was also revealed. Tumoral lesions were also found in a pelvic space and a right pleural cavity, and a biopsy was performed from one of the disseminated tumor masses in the right pleura. Pathological diagnosis of TFE3-rearranged PEComa-like neoplasm was defined based on the evidence of partial expression of Melan A, and strong nuclear expression of TFE3 and by detection of the Xp11.2 locus split signal with FISH. A post-mortem analysis via autopsy revealed the widespread intravascular tumors in the heart's left ventricle, supra mesenchymal vein (SMV), and partial vein. The left intraventricular tumoral mass was associated with thrombus and fibrine, and thrombotic emboli were also found in SMA, SMV, and left pulmonary arteries. Interestingly, organ-based tumor invasion accompanying desmoplastic reactions was hardly seen. The small intestine was perforated, likely due to ischemia, which resulted in suppurative peritonitis and sepsis. This was thought of as the direct cause of death. This is the first report of a precise autopsy investigation of TFE3-rearranged PEComa-like neoplasm. Tumoral localization was mostly intravascular or disseminative in the pleural cavity. Given the limited understanding of this tumoral pathophysiology, this case offers valuable insights for prompt diagnosis and effective treatment strategies., Competing Interests: Declaration of competing interest There is no conflict of interest to declare., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background:  Accurately matching the correct fascicles in a ruptured mixed nerve is critical for functional recovery. This study investigates the use of transcranial magnetic stimulation (TMS) to differentiate motor and sensory fascicles in a mixed nerve., Methods:  In all 40 rats, the median nerve in the left upper arm was evenly split into three segments. The rats were separated into two groups. In Group A (20 rats), the segment with the highest amplitude during TMS was selected as the motor neurotizer and transferred to the musculocutaneous nerve. In Group B (20 rats), only the medial one-third segment was selected and transferred without using TMS. The results were compared using grooming tests, nerve electrophysiological studies, muscle tetanus contraction force measurements, muscle weight, and axon counts at 16 weeks., Results:  The grooming test showed that Group A performed significantly better than Group B at 12 and 16 weeks postoperatively. Tetanic muscle contraction force measurements also revealed that Group A had significantly better outcomes than Group B. However, electrophysiological testing, muscle weight, and axon counts showed no significant differences between the two groups., Conclusion:  This study suggests that TMS can be used to distinguish motor fascicles from sensory fascicles in a mixed nerve. It is desirable to apply this technique intraoperatively to differentiate motor and sensory fascicles for appropriate nerve matching and to select the motor fascicles as a motor neurotizer for functioning free muscle innervation in human mixed nerve injury., Competing Interests: None declared., (Thieme. All rights reserved.)

BACKGROUND Studies using transgenic mouse models have demonstrated that estrogen is necessary for the development of cervical cancer, particularly in tissues responsive to estrogen. Estrogen also protects cervical cancer cells from apoptosis, suggesting its role in the survival and persistence of cancer cells. CASE REPORT An 84-year-old woman with diabetes mellitus, hypertension, and stage III chronic renal failure was diagnosed with cervical squamous cell carcinoma, FIGO stage IB2. She underwent complete concurrent chemoradiotherapy, but central recurrence was found 9 months later. However, instead of salvage chemotherapy, substitutionary anti-estrogens were given due to her poor medical condition and advanced age. Complete remission was noted after tamoxifen therapy. Since the cervical cancer relapsed again 40 months after tamoxifen use, the anti-estrogen therapy was shifted to letrozole. The SCC-Ag level decreased dramatically after letrozole therapy, and disease stability was achieved until 29 months afterward. After 5 years and 9 months of anti-estrogen use only, the patient died due to noncancer-related pneumonia and heart failure. CONCLUSIONS This report demonstrates the tumor-stabilizing and therapeutic effect of anti-estrogens in the treatment of squamous cervical carcinoma. Further clinical trials are warranted to evaluate the efficacy of anti-estrogen therapy in cervical cancer patients.

Extramammary Paget disease (EMPD) is a rare skin cancer that typically occurs in the anogenital area of older people. Since efficacy of treatments for metastatic or unresectable EMPD remains poor, development of a novel therapeutic approach is strongly desired. However, the lack of EMPD models has hampered investigation of EMPD. Here we investigated whether trophoblast cell surface antigen 2 (TROP2) could be a promising therapeutic target for EMPD. We retrospectively collected 108 samples from 54 patients with primary and metastatic EMPD from 10 Japanese institutions, and compared TROP2 expression between primary and metastatic lesions of each paired sample. In vitro assays were performed using a newly established EMPD cell line, KS-EMPD-1. TROP2 was strongly and homogeneously expressed in patient tissues, regardless of primary or metastatic lesions. The KS-EMPD-1 cells were treated with a TROP2-targeted antibody-drug conjugate (ADC), sacituzumab govitecan, and it significantly reduced cell viability in a dose-dependent manner compared with that of the cells treated with sacituzumab alone. Knockdown of TROP2 reduced cell viability and cell migration, and caused slight upregulation of the apoptosis-related factors, together with downregulation of the epithelial-to-mesenchymal transition-related factors. These findings suggest that a TROP2-targeted ADC may be a promising treatment option for unresectable EMPD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Oxidative stress prompts breast cancer cells to adapt by raising the lethal threshold and enhancing the antioxidant mechanism, thereby enabling survival and continuous proliferation that facilitates tumor progression. Nrf2 and 8-OHdG are indicative of oxidative stress activity and impact the progression of breast cancer. We aimed to analyze the expression of Nrf2 and 8-OHdG in various T stages of breast cancer in our hospital., Methods: This observational study employed a cross-sectional design and included patients with invasive breast carcinoma of no special type diagnosis from histopathology examination who underwent modified radical mastectomy without neoadjuvant chemotherapy at Dr. Soetomo General Academic Hospital between January 2019 and December 2022. Medical records and paraffin blocks that met these criteria were obtained. 8-OHdG and Nrf2 were assessed using immunohistochemistry., Result: There was no significant difference and correlation between 8-OHdG (p=0.578) and Nrf2 (p=0.694) expression with various T stages of IBC-NST and no significant correlation between 8-OHdG/Nrf2 expression and T stage (p=0.242 and 0.625 respectively)., Conclusion: Consistent expression of 8-OHdG and Nrf2 in various T stages of breast cancer represents a continuation of the oxidative stress process in breast cancer that is not influenced by the tumor size. The existence of consistent oxidative stress at all tumor sizes (T stage) stimulates breast cancer cells to continue proliferating.

Background: Helicobacter pylori bacteria colonize the gastric mucosa and contribute to the occurrence and development of gastrointestinal diseases. According to the WHO, H. pylori bacteria are considered class I carcinogen., Objectives: To detect Helicobacter pylori organisms by IHC expression of anti-H. Pylori antibodies in the explanted   liver tissue; and enlarged perihepatic lymph nodes of cirrhotic liver; to detect any relation between the presence of the organism and histopathological findings in the liver tissue., Materials and Methods: This retrospective cross-sectional study included forty cases of cirrhotic patients with decompensated end-stage liver, recruited for liver transplantation based on combined clinical, radiological, and histological data. Samples were immunohistochemically analyzed for anti-H-Pylori antibodies to detect Helicobacter pylori organisms in the explanted liver tissue and enlarged perihepatic lymph nodes. The presence of the organism was correlated with clinic-pathologic variables., Results: Eighty-five percent (34 cases) and seventy percent (28 cases) of cases were positive for anti-H-Pylori antibodies in the liver and lymph nodal tissues, respectively. More than eighty percent (14 cases) and half of the studied cases (8 cases) showed dysplasia in liver tissue expressing anti-H-Pylori-antibody in the liver tissue and the lymph nodes, respectively. All HCC cases expressed anti-H-Pylori antibody in the liver tissue and the lymph nodes. The relation between anti-H-Pylori antibody expression in lymph nodes and the presence of dysplasia or HCC in liver tissue was statistically significant (p-value = 0.037 and p-value = 0.041 respectively)., Conclusion: Our results conclude that there is a pathogenic role of extra-gastric H-Pylori colonization in lymph nodal tissue and in liver tissue, and it may be preventable by treating H. pylori, especially if treatment can be started very early.

Pregnancy has fascinated immunologists ever since Peter Medawar's observation that reproduction runs contrary to the founding tenets of immunology. During healthy pregnancy, maternal B cells interact with antigens of the foreign conceptus (placenta and fetus) yet do not elicit rejection. Instead, robust and redundant fetomaternal tolerance pathways generally prevent maternal B cells and antibodies from harming the placenta and fetus. Fetomaternal tolerance is not absolute, and unfortunately there exist several pregnancy complications that arise from breaks therein. Here, important historic and recent developments in the field of fetomaternal tolerance pertaining to maternal B cells and antibodies are reviewed. General rules from which to conceptualize humoral tolerance to the placenta and fetus are proposed. Significant but underexplored ideas are highlighted and topics for future research are suggested, findings from which are predicted to provide insight into the fundamental nature of tolerance and bolster efforts to combat immune-mediated pregnancy complications.

Background: Hepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS., Methods: In total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined., Results: A high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006)., Conclusions: The HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflicts of interest. Ethical approval: This study was conducted in accordance with the principles of the Declaration of Helsinki. It was approved by the Medical Human Investigation Committee of Kyushu University (institutional Review Board no. 20476). Informed consent was obtained from all patients., (© 2024. The Author(s).)

Background: Cluster of differentiation 155 (CD155) is expressed in many tumor types. CD155 is involved in the immune avoidance of tumor cells and contributes to tumor development and progression. Therefore, CD155 is a novel target for cancer immunotherapy. The clinical significance of CD155 expression in lung squamous cell carcinoma (LUSC) has not been fully elucidated., Materials and Methods: We performed a retrospective analysis of 264 patients with surgically resected LUSC. Immunohistochemistry was used to evaluate CD155 expression. The association of CD155 expression with clinicopathological features and clinical outcomes was assessed. We also analyzed the relationship between CD155 expression and programmed cell death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes., Results: Among the 264 patients, 137 patients (51.9%) were classified in the high CD155 expression group. High CD155 expression was significantly associated with pleural invasion, vascular invasion, PD-L1 positivity, and high CD3, CD4, and CD8 expressions. In multivariate analysis, the presence of pleural invasion and PD-L1 positivity were independent predictors of high CD155 expression. Kaplan-Meier curve analysis showed that high CD155 expression was significantly associated with shorter disease-free survival and overall survival. In multivariate analysis, high CD155 expression was an independent poor prognostic factor for overall survival, but not for disease-free survival. Subgroup analyses revealed that the prognostic effect of CD155 expression was observed in the PD-L1 positive group but not the PD-L1 negative group., Conclusion: Our analysis revealed that high CD155 expression significantly predicted poor prognosis in patients with surgically resected LUSC, especially in patients with PD-L1-positive tumors., Competing Interests: Declarations. Conflict of interest: The authors have no conflict of interest., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: Cases involving invasive cervical root resorption (ICRR) in oncological patients are rare, in addition, follow-up of these patients has not yet been reported in the literature., Objective: This study aims to present a literature review and report a case of denosumab as a possible cause of ICRR in a patient with breast cancer with 2 years of follow-up., Case Report: A 39-year-old female with a history of luminal breast cancer was treated with denosumab semiannually for osteopenia with discontinuation 1 year ago. Oral examination revealed areas of ICRR lesions on two mandibular teeth. The patient presented irreversible pulpitis on the lower left first molar (#19). The lower right first premolar (#28) was asymptomatic, and the resorption cavity was restricted to the tooth crown. Cone-beam computed tomography (CBCT) established the ICRR 2Bp and 2Ad diagnosis in teeth #19 and #28, respectively. Periodontal surgery and a nonsurgical root canal were performed in the molar and restorative treatment was performed in the premolar. Two years after treatment, both teeth were functional and asymptomatic, and probing was within normal limits (< 3 mm) without bleeding. Periapical radiographic examination revealed no progression of resorption nor new lesions., Conclusions: This article highlights a rare adverse effect of an antiresorptive therapy, unfamiliar to most clinicians and specialists. In addition, it emphasizes that the early diagnosis and follow-up of ICRR are relevant and can provide successful treatment, avoiding infections and extractions., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Aims: Melanomas are recognised for their remarkable morphological plasticity. Some tumours may lose conventional features and/or acquire non-melanocytic characteristics, referred to as undifferentiated, dedifferentiated and transdifferentiated melanoma. Despite this phenotypical variability, melanomas typically maintain their cancer driver aberrations, affecting genes such as BRAF, NRAS and NF1. Currently, little is known about whether the DNA methylation profile follows the loss or change of differentiation or is retained despite extensive morphological transformation., Methods and Results: In this study we analysed 11 melanoma cases, comprising six males and five females, with a median age of 67 years, including five undifferentiated, four trans-differentiated and two de-differentiated melanomas. Undifferentiated and trans-differentiated tumours either arose in a patient with known melanoma and/or presented in the groin/axilla with molecular alterations consistent with melanoma. Cases with heterologous differentiation resembled chondrosarcoma, osteosarcoma, angiosarcoma and rhabdomyosarcoma both morphologically and immunohistochemically, while undifferentiated tumours resembled undifferentiated pleomorphic sarcoma. Methylome profiling was performed, and unsupervised clustering analysis revealed nine cases (five undifferentiated, three trans-differentiated and one de-differentiated) to cluster closely together with conventional melanomas from a reference set. Two cases clustered separately with a distinct group of conventional melanomas exhibiting H3K27me3 loss., Conclusions: Despite loss of differentiation and phenotypical plasticity, methylation patterns seem to be retained in undifferentiated, de-differentiated and trans-differentiated melanomas and represent useful diagnostic tools to enhance diagnostic precision in these diagnostically challenging cases., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Competing Interests: Disclosures: ABS, RM, JJARB, GYL, JF, and AJS have no relevant disclosures. SRM is a consultant for C2/Pentax and STERIS. GYL reports consulting fees from ALIMENTIV outside the submitted work. JMP has agreements with Astellas Pharma, Inc and serves on the Scientific Medical Board of AdvoCare International, LLC.

Purpose: This study aimed to assess the efficiency of artificial intelligence (AI) in the detection of visceral pleural invasion (VPI) of lung cancer using high-resolution computed tomography (HRCT) images, which is challenging for experts because of its significance in T-classification and lymph node metastasis prediction., Methods: This retrospective analysis was conducted on preoperative HRCT images of 472 patients with stage I non-small cell lung cancer (NSCLC), focusing on lesions adjacent to the pleura to predict VPI. YOLOv4.0 was utilized for tumor localization, and EfficientNetv2 was applied for VPI prediction with HRCT images meticulously annotated for AI model training and validation., Results: Of the 472 lung cancer cases (500 CT images) studied, the AI algorithm successfully identified tumors, with YOLOv4.0 accurately localizing tumors in 98% of the test images. In the EfficientNet v2-M analysis, the receiver operating characteristic curve exhibited an area under the curve of 0.78. It demonstrated powerful diagnostic performance with a sensitivity, specificity, and precision of 76.4% in VPI prediction., Conclusion: AI is a promising tool for improving the diagnostic accuracy of VPI for NSCLC. Furthermore, incorporating AI into the diagnostic workflow is advocated because of its potential to improve the accuracy of preoperative diagnosis and patient outcomes in NSCLC., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Introduction: This study examined factors that affected sentinel lymph node (SLN) identification of patients with endometrial cancer having a preoperative estimation of low recurrent risk., Methods: This study included 97 patients with endometrial cancer who attempted to identify SLN using a uterine cervical injection of technetium-99 m phytate under laparoscopic or robotic-assisted surgery at our institute. A preoperative single photon emission computed tomography (SPECT) and intraoperative gamma probe were used to detect hot nodes. Multiple clinical factors, including age, body mass index (BMI), and so on, were investigated for their association with SLN mapping failure., Results: Among 97 cases, SPECT failed to detect SLN unilaterally in 38 cases (39%) and on both sides in 9 cases (9%). Meanwhile, the gamma probe failed to detect SLN unilaterally in 23 cases (24%) and on both sides in 3 cases (3%). While only age was significantly associated with SLN detection failure using the SPECT detection system, both age and BMI were significantly associated with SLN detection failure using the gamma probe detection system. When limiting to the preoperative SLN detection failure cohort of 47 cases, there was a strong association between intraoperative SLN detection failure and BMI, but not age., Conclusion: The SLN biopsy system was effectively applied to patients with endometrial cancer who underwent minimally invasive surgery (MIS). Attempts to improve SLN identification in older patients and those with obesity are warranted to obtain maximum benefits of MIS for low- or medium-risk cases., (© 2025 The Author(s). Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

NTRK-rearranged spindle cell neoplasm is a group of tumors characterized by NTRK1/2/3 gene fusion. Recently, tumors with other kinase fusion genes were reported to exhibit similar morphologies. Herein, we discuss an adult-onset soft tissue tumor with similar histologic patterns as kinase gene fusion-related tumors but with BRAF and NRAS mutations. A female in her 40s had a 40 mm tumor with an unclear border in the soft tissue of her foot joint. Short spindle-shaped tumor cell proliferation with abundant capillaries and collagen fiber bundles were observed. The tumor infiltrated the subcutaneous adipose tissue, exhibiting a lipofibromatosis-like pattern. Immunohistochemically, the tumor cells coexpressed CD34, S-100, and BRAF V600E. Whole-exome sequencing revealed BRAF p.V600E and NRAS p.Q61K mutations. Since BRAF activation occurs in BRAF fusion gene tumors and BRAF mutations, they could share a similar mechanism in tumorigenesis. This case suggests the further expansion of kinase-related spindle cell tumors., (© 2024 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Introduction: Ancillary testing on cytopathology and other small biopsy specimens is crucial for diagnosis and provides critical information to clinicians. Testing is dependent on preanalytic factors and would benefit from standardization of specimen collection protocols across laboratories. To assess institutional practices and areas of need for evidence-based standards, we surveyed current practices across cytopathology laboratories., Materials and Methods: A twelve-question electronic survey was distributed to American Society of Cytopathology (ASC) members through email, social media, and the ASC from January 8, 2024 to March 1, 2024. Survey responses were tabulated., Results: Of 294 respondents, 257 (87%) completed at least 10/12 questions. Formalin-fixed, paraffin-embedded cell blocks (CBs) are utilized for immunohistochemistry, molecular testing, and in situ hybridization by 89%, 84%, and 71% of respondents, respectively. For fine needle aspirations, no collection medium is utilized by a majority of respondents. In contrast, 61% utilize no collection medium for fluids; 64% predominantly utilize liquid-based preservatives for other exfoliative specimens. For CB preparation, 58% of respondents use coagulating agent; 67% use no fixative before formalin. The two most significant factors limiting clinical utility of ancillary testing in cytology specimens are low cellularity and lack of validation (49% and 23% of respondents, respectively)., Conclusions: There is wide variation in current practices among laboratories, reflecting lack of consensus. Although laboratories utilize different collection media for different specimen types, for CB utilization, current survey results are similar to those reported previously. ASC has convened a task force to facilitate specimen standardization and minimize variability among preanalytic factors., (Copyright © 2024 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy-which might be, instead, pathogenically related to adenosine triphosphate deficiency., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is challenging to treat because of its lack of specific molecular targets. The IMMUNOPEG study aimed to evaluate a novel structured method for interpreting TNBC immunohistochemistry specimens processed with VENTANA PD-L1 (SP142) assay. The study involved 10 pathologists who evaluated 50 different immunohistochemistry specimens of TNBC with programmed death ligand 1 (PD-L1) expression considered challenging and that were previously evaluated by the scientific committee, using the NAVIFY Digital Pathology platform. Initially, the overall percent agreement (OPA) was 74%, with a negative percent agreement (NPA) of 68.2% for samples classified as negative, and a positive percent agreement (PPA) of 94.5% for positive samples. After training on the method, the OPA improved significantly to 81.6%, with the NPA increasing to 80.5% and the PPA decreasing to 85.5%. The mean percentage of the tumor area occupied by PD-L1-stained immune cells decreased from 2.5% to 1.6% post-training, approaching to the scientific committee's consensus of 1.029%. The study found that the pathologists' confidence in their assessments increased significantly when using the structured method, which was found to be easy to use by 9 out of 10 pathologists. All pathologists agreed that the structured method was useful for assessing PD-L1 expression. The study suggests that this method has potential value in interpreting challenging cases of PD-L1 immunohistochemistry (IHC) in TNBC. Further refinement and a training protocol may be necessary to enhance the method's efficiency. The potential for generalizing this structured method to other IHC procedures and pathologies warrants additional research., Competing Interests: V.P. has received fees as consultant, participated in advisory boards and/or received travel grants from Sysmex, Roche, MSD, AstraZeneca, Bayer, Exact Sciences, and Daiichi-Sankyo. M.A.M. has received travel grants and fees for having participated in scientific meetings from Roche and MSD. M.G.-R. has received fees as consultant, participated in advisory boards and/or received travel grants from Sysmex, Roche, MSD, and Hologic. D.H. has received fees as consultant, participated in advisory boards and/or received travel grants from Sysmex, AstraZeneca, and Daiichi-Sankyo. M.J.N. has received fees as consultant, participated in advisory boards, and/or received travel grants from Roche. M.L.S.-B. has received fees as travel grants from Sysmex and Roche. L.G. and I.R. have received honoraria from Roche Farma S.A. F.R. has received fees as consultant, participated in advisory boards, and/or received travel grants from Roche, MSD, BMS, AstraZeneca, Lilly, Astellas, Daiichi-Sankyo, AbbVie, GSK, Novartis, Merck, Agilent, Sophia Genetics, Menarini, Amgen, Janssen. The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

GLI1-altered mesenchymal tumors have recently emerged as a distinctive group of neoplasms characterized by GLI1 fusions or amplifications. Although there is clearly metastatic potential, the clinicopathologic features predicting for metastasis are currently unknown. Herein, we present 6 cases of GLI1-altered mesenchymal tumors with multiomics analysis. The median patient age was 50 years (range, 3-68 years). They arose from the extremities and trunk (2/6), head and neck region (2/6), and gastrointestinal tract (2/6). Histologically, they featured uniform round to ovoid cells with nested architecture and a rich vascular network. One case displayed abundant multinucleated giant cells. All stained positive for GLI1 (5/5) and CD56 (6/6). Molecularly, they featured GLI1 fusion (5/6) and amplification (1/6). Fusion partners included ACTB (3/5), TXNIP (1/5), and novel TUBA1B (1/5). Multiomics analysis revealed they possessed distinct expression and epigenomic profiles. All the 6 cases had follow-up information, with 5 of them having no evidence of disease at a median follow-up of 30 months (range, 17.3-102 months), and 1 case being died of disease with regional neck lymph node and bilateral lung metastasis at 81.5 months of follow-up. By incorporating cases reported in the literature, we analyzed clinicopathologic features of a total of 167 cases predictive of malignant behavior. We found that size ≥6 cm and mitotic count ≥5 per 10 high-power fields are predictive of metastasis. Cases with both high-risk features had significantly poorer survival. This study expands the literature database of GLI1-altered mesenchymal tumors and identifies features that can be used for risk stratification., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Background: In Japan, there are currently no general guidelines for the treatment of primary malignant bone tumors. Therefore, the Japanese Orthopaedic Association established a committee to develop guidelines for the appropriate diagnosis and treatment of primary malignant bone tumors for medical professionals in clinical practice., Methods: The guidelines were developed in accordance with "Minds Clinical Practice Guideline Development Handbook 2014″ and "Minds Clinical Practice Guideline Development Manual 2017". The Japanese Orthopaedic Association's Bone and Soft Tissue Tumor Committee established guideline development and systematic review committees, drawing members from orthopedic specialists leading the diagnosis and treatment of bone and soft tissue tumors. Pediatricians, radiologists, and diagnostic pathologists were added to both committees because of the importance of multidisciplinary treatment. Based on the diagnosis and treatment algorithm for primary malignant bone tumors, important decision-making points were selected, and clinical questions (CQ) were determined. The strength of recommendation was rated on two levels and the strength of evidence was rated on four levels. The recommendations published were selected based on agreement by 70% or more of the voters., Results: The guideline development committee examined the important clinical issues in the clinical algorithm and selected 22 CQs. The systematic review committee reviewed the evidence concerning each CQ and a clinical value judgment was added by experts. Eventually, 25 questions were published and the text of each recommendation was determined., Conclusion: Since primary malignant bone tumors are rare, there is a dearth of strong evidence based on randomized controlled trials, and recommendations cannot be applied to all the patients. In clinical practice, appropriate treatment of patients with primary malignant bone tumors should be based on the histopathological diagnosis and degree of progression of each case, using these guidelines as a reference., (Copyright © 2024. Published by Elsevier B.V.)