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Soft tissue sarcomas comprise a heterogeneous group of neoplasms. Although soft tissue malignancies make up only 2% of adult cancers, classification based on histomorphology presents a diagnostic challenge. Characterisation of soft tissue sarcomas by molecular analysis is rapidly evolving to improve diagnostic accuracy and develop targeted therapies. This review highlights the advances in molecular techniques, including current next-generation sequencing-based assays (fusion detection by RNA sequencing, targeted/whole exome sequencing, microRNA profiling), as well as emerging methods (liquid biopsies, DNA methylation profiling, single-cell molecular profiling and next-generation immunohistochemistry) for future clinical applications.

The emergence of the circular economy (CE) paradigm is a key driver in steering industrial sectors towards sustainability. The formulation of a robust circularity strategy depends on a comprehensive assessment, which is closely related to the overarching goal of managing the transition to circularity. The initial phase of transition within the healthcare sector reinforces the need to seamlessly integrate CE principles. It is therefore imperative to define and carefully monitor indicators that will help assess and improve sustainability, operational efficiency, supply chain resilience and stakeholder satisfaction, including both consumers and patients. The primary objective of this research is to prioritize relevant performance indicators that will be critical in measuring the effectiveness of the transition to a circular economy within the healthcare supply chain. To achieve this objective, the study employs the Analytic Hierarchy Process (AHP), a well-established methodology known for its effectiveness in solving complex multi-criteria challenges. The AHP is used to prioritize performance indicators that facilitate the management of the circular economy transition in the healthcare supply chain. The focus is on improving the quality of care, optimizing delivery efficiency, and emphasizing environmental sustainability within the healthcare paradigm. The methodological framework includes the identification of key main criteria covering environmental, social, economic, and logistical dimensions. These criteria are further refined with the inclusion of 14 sub-criteria, resulting in a list of 16 key performance indicators (KPIs). Additionally, the study proposes an alternative business model advocating for the implementation of the Circular Supply Chain Operation Reference Model (circular SCOR). This model offers a perspective for rapid change in supply chain processes towards circular transition within the healthcare system. The final stage of the research involves verifying the results through sensitivity analysis and correlation mapping of the indicator results with the Circular SCOR model. This process helps organizations refine their performance measurement protocols, enhancing their capacity for effective evaluation and strategic decision-making within the circular economy framework. This comprehensive approach enables healthcare organizations to proactively contribute to a more sustainable and environmentally conscious future while maintaining a focus on quality care for patient well-being.

To achieve a balance between rightsholders and the public in the age of generative AI (GenAI), it is necessary to redefine the concept of public interest in copyright law. This equilibrium is critical because it guarantees that rightsholders are rewarded for their work while also allowing for the dissemination and access of knowledge along with cultural expression. Additionally, redefining the concept of public interest in copyright could address emerging issues such as fair use, open access and the democratization of information in the digital age.The article examines how public interest in copyright would look in the development of GenAI by using Virginia Held’s typology of public interest theory as the sole compass to address the question. The article finds that public interest in copyright could be adjusted to protect rightsholders, sustain cultural production and simultaneously accommodate the development of GenAI by first balancing the preponderance of individual interest or being supported by the preponderance of numbers and empirical terms; second, by making it consistent with individuals’ overall interests and being agreed upon by the polity; and third, by judging the public interest in copyright on ‘valid judgment’ and normative content, where the judgment is based.While different typologies may be used to conceptualize public interest, the article suggests that it is important to explicitly identify what copyright law seeks to achieve and to balance the rights of creators with the public’s interest in accessing creative works. This could be achieved through evidence-based analysis, agreement among individuals without conflicts and normative content based on the morality of society.

Despite a wide spectrum of clinical presentations, including primary or secondary, most angiosarcomas are considered high grade. One exception is primary breast angiosarcoma, where historically, histologic grading has shown to predict outcome using the Rosen 3-tier system. However, more recent studies have challenged this concept suggesting that even in this specific clinical context angiosarcomas should be considered high grade. This study aimed to critically reevaluate the impact of histologic grade in a clinically uniform cohort managed at a single institution using a newly proposed grading system. Our study included 49 primary breast angiosarcomas diagnosed during 1994 to 2022 (median follow-up: 33 mo), classified as low grade (29%), intermediate grade (20%), and high grade (51%), based on mitotic count, extent of solid components, and necrosis. At last follow-up, 22% patients developed locoregional recurrences, 63% distant metastases, and 47% patients died of disease. As patients with low and intermediate-grade angiosarcomas had relatively similar outcomes, our cohort was further analyzed using a 2-tier system (low grade and high grade). Targeted-DNA next-generation sequencing (505 cancer gene panel) performed in 11 cases found KDRmutations in 78% and PIK3CAmutations in 44% of high-grade lesions. Histologic grade, by either 3-tier or 2-tier grading systems, had a strong impact on survival, with the 2-tier system being an independent predictor of disease-specific survival and overall survival. Based on 2-tier system, the 5-year overall survival was 38% for high-grade angiosarcoma and 74% for low-grade angiosarcoma. PIK3CAmutations alone or concurrent with KDRalterations were identified in angiosarcomas with worse prognosis.

TRAF7somatic mutations are rare and have been reported in meningiomas, intraneural perineuriomas, and mesotheliomas. Triggered by an index case of an unclassified low-grade mesenchymal tumor with TRAF7mutation as the only genetic alteration, we searched our files and identified 2 additional cases with similar features. The tumors arose in 2 females and 1 male, aged 63 to 75 years old (median: 67 y). They were infiltrative deep soft tissue masses involving the shoulder, chest wall, and thigh, measuring 7.0 to 9.1 cm in greatest dimensions. One tumor was locally aggressive, and 2 were associated with lung and bone metastases. The tumors displayed alternating fibrous and myxoid stroma with mild to moderate cellularity and consisted of uniform spindle cells with open chromatin, inconspicuous nucleoli and scant cytoplasm. Significant mitotic activity or necrosis were not present. However, the metastatic tumor of 1 case showed an epithelioid morphology and brisk mitotic activity. Immunohistochemically, the tumors showed nonspecific and focal smooth muscle actin or CD34 expression. By DNA sequencing, all 3 cases harbored TRAF7missense mutations involving the C-terminal WD40 domains as the only somatic mutations, showed nonrecurrent focal copy number alterations, and were negative for gene fusions by targeted RNA sequencing. On methylation profiling, the tumors clustered with the undifferentiated sarcoma and myxofibrosarcoma methylation classes and were distinct from morphologic mimics. On follow-up (5 to 36 mo), 2 patients died of disease following aggressive chemotherapeutic regimens. We describe a novel TRAF7-mutated mesenchymal tumor characterized by aggressive clinical behavior despite the histologic appearance of a low-grade fibromyxoid spindle cell tumor.

Background: To utilize EQ-5D in economic evaluations, a societal-based value set is needed. To date, no value sets exist for any EQ-5D instrument in Pakistan. Previous EQ-5D studies conducted in Pakistan ‘borrowed’ health preferences developed in other countries. However, for a value set to be valid for Pakistani population, it should represent the preferences of the Pakistani population, and culture and living standards of Pakistan. Objective: The aim of this study was to derive a Pakistani EQ-5D-3L value set. Methods: A moderately representative sample aged 18 years and over was recruited from the Pakistani general population. A multi-stage stratified quota method with respect to ethnicity, gender, age and religion was utilized. Two elicitation techniques, the composite time trade-off (cTTO) and discrete choice experiments (DCE) were applied. Interviews were undertaken by trained interviewers using computer-assisted face-to-face interviews with the EuroQol Portable Valuation Technology (EQ-PVT) platform. To estimate the value set, a hybrid regression model combining cTTO and DCE data was used. Results: A total of 289 respondents who completed the interviews were included for the analysis. The hybrid model correcting for heteroskedasticity without a constant was selected as the final model for the value set. It is shown that being unable to do usual activities (level 3) was assigned the largest weight, followed by mobility level 3, self-care level 3, pain/discomfort level 3 and anxiety/depression level 3. The worst health state was assigned the value − 0.171 in the final model. Conclusions: A Pakistani country-specific EQ-5D-3L value set is now available. The availability of this value set may help promote and facilitate health economic evaluations and health-related quality-of-life (HRQoL) research in Pakistan.

Indonesia is well-known for its tuna production. To enrich its tuna processes and expand it to export markets, it is important for tuna industry players in Indonesia to have an assessment system for their processes. The study aims to develop guidelines for export quality frozen tuna for Indonesia tuna players. Data collection was done in Nizam Zachman Oceanic Fishing Port, one of the biggest ports in Indonesia. Critical activities in each of four key areas (catching, transporting, storing and processing) were identified by open questionnaires to tuna experts. The collected data was then cleansed and grouped as critical activities, and used as fuzzy input variables into a fuzzy expert system. The model was validated using analytical hierarchy process (AHP). The proposed FES model was then used as assessment tool for Indonesia tuna industry players in evaluating their processes to establish whether they are ready to serve export markets.

Pleomorphic liposarcoma (PLPS) is a highly aggressive sarcoma comprising variable numbers of pleomorphic lipoblasts mixed with undifferentiated pleomorphic sarcoma (UPS)-like areas. Morphologic variants, such as myxofibrosarcoma-like or epithelioid, may cause diagnostic confusion, especially on a core biopsy, but there are few data on the prognostic significance of these features. A total of 120 PLPS biopsies and resection specimens were reviewed and catalogued based on the presence of myxofibrosarcoma-like, UPS-like, and epithelioid foci, in 10% increments. The clinical parameters were collected. Cases occurred in 75 males and 45 females, ranging from 8 to 98 years (median, 62.5 y). Cases arose in the extremities (n=72), trunk (n=32), head/neck (n=10), bone (n=4), mediastinum (n=1), or viscera (colon polyp, n=1). Of those with known depth (n=81), 40 were intramuscular, 34 were subcutaneous, and 7 arose in the dermis. Their sizes ranged from 1 to 24.5 cm (median, 7 cm). Of the patients with ≥1 month of follow-up (n=70), 5 had recurrence and 15 had metastasis. The 5-year overall survival and event-free survival rates were 66.2% and 63.1%, respectively. Tumors ≥5 cm had inferior overall survival compared with tumors <5 cm. The presence of epithelioid areas was also statistically significant in terms of poorer overall survival and event-free survival, while tumors with ≥50% undifferentiated pleomorphic-like areas had better overall survival. There was a trend towards poorer outcomes in tumors with necrosis (≥1%). PLPS is an aggressive adipocytic malignancy that is most commonly present in the extremities of older adults. The morphologic features of these tumors are diverse, and they may be mistaken for UPS or myxofibrosarcoma, carcinoma, and melanomas, particularly on biopsies. Tumor size, necrosis, and epithelioid morphology are associated with adverse prognosis.

SMARCB1biallelic inactivation resulting in SMARCB1/INI1 deficiency drives a wide range of malignancies, including many mesenchymal tumors. However, the specific types of SMARCB1alterations and spectrum of cooperating mutations among various types of sarcomas has not been well investigated. We profiled SMARCB1genetic alterations by targeted DNA sequencing and fluorescence in situ hybridization (FISH) in a large cohort of 118 soft tissue and bone tumors, including SMARCB1-deficient sarcomas (78, 66%): epithelioid sarcomas, epithelioid peripheral nerve sheath tumors, poorly differentiated chordomas, malignant rhabdoid tumors, and soft tissue myoepithelial tumors, as well as non-SMARCB1-deficient sarcomas (40, 34%) with various SMARCB1genetic alterations (mutations, copy number alterations). SMARCB1 loss by immunohistochemistry was present in 94% SMARCB1pathogenic cases. By combined sequencing and FISH assays, 80% of SMARCB1-deficient tumors harbored homozygous (biallelic) SMARCB1loss, while 14% demonstrated heterozygous SMARCB1loss-of-function (LOF) alterations, and 6% showed no demonstrable SMARCB1alterations. FISH and sequencing were concordant in the ability to detect SMARCB1loss in 48% of cases. Epithelioid sarcomas most commonly (75%) harbored homozygous deletions, while a subset showed focal intragenic deletions or LOF mutations (nonsense, frameshift). In contrast, most soft tissue myoepithelial tumors (83%) harbored SMARCB1nonsense point mutations without copy number losses. Additionally, clinically significant, recurrent co-occurring genetic events were rare regardless of histotype. By sequencing, extended 22q copy number loss in genes flanking the SMARCB1locus (22q11.23) occurred in one-third of epithelioid sarcomas and the majority of poorly differentiated chordomas. Poorly differentiated chordomas and soft tissue myoepithelial tumors showed significantly worse overall and disease-free survival compared to epithelioid sarcomas. Overall, SMARCB1LOF alterations predominate and account for SMARCB1 protein loss in most cases: majority being biallelic but a subset were heterozygous. In contrast, SMARCB1alterations of uncertain significance can be seen in diverse sarcomas types and does not indicate a SMARCB1-deficient entity.

Myxoid pleomorphic liposarcoma (MPLPS) is a recently described and extremely rare subtype of liposarcoma with a predilection for the mediastinum. However, the genomic features of MPLPS remain poorly understood. We performed comprehensive genomic profiling of MPLPS in comparison with pleomorphic liposarcoma (PLPS) and myxoid/round cell liposarcoma (MRLPS). Of the 8 patients with MPLPS, 5 were female and 3 were male, with a median age of 32 years old (range 10–68). All except one were located in the mediastinum, with invasion of surrounding anatomic structures, including chest wall, pleura, spine, and large vessels. All cases showed an admixture of morphologies reminiscent of PLPS and MRLPS, including myxoid areas with plexiform vasculature admixed with uni- and/or multivacuolated pleomorphic lipoblasts. Less common features included well-differentiated liposarcoma-like areas, and in one case fascicular spindle cell sarcoma reminiscent of dedifferentiated LPS. Clinically, 4 experienced local recurrence, 4 had distant metastases and 5 died of disease. Compared to PLPS and MRLPS, patients with MPLPS had worse overall and progression-free survival. Recurrent TP53mutations were present in all 8 MPLPS cases. In contrast, in PLPS, which also showed recurrent TP53mutations (83%), RB1and ATRXlosses were more common. MRLPS was highly enriched in TERTpromoter mutations (88%) and PI3K/AKT pathway mutations. Copy number profiling in MPLPS revealed multiple chromosomal gains with recurrent amplifications of chromosomes 1, 19 and 21. Importantly, allele-specific copy number analysis revealed widespread loss of heterozygosity (80% of the genome on average) in MPLPS, but not in PLPS or MRLPS. Our findings revealed genome-wide loss of heterozygosity co-existing with TP53mutations as a characteristic genomic signature distinct from other liposarcoma subtypes, which supports the current classification of MPLPS as a stand-alone pathologic entity. These results further expand the clinicopathologic features of MPLPS, including older age, extra-mediastinal sites, and a highly aggressive outcome.

To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS::CREBtranslocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1/FUSfusion partners—ATF1, CREB1, and CREM—and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERTpromoter and CDKN2Amutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/Bhomozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF, CDH19, PARVB, and PFKPwas found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4and XAF1were differentially upregulated and hypomethylated in AFH but not CCS. Unsupervised clustering of methylation profiles revealed that CREB family translocation-associated tumors form neighboring but tight, distinct clusters. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS::CREBtranslocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.

Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB(formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFBgene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFBfusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.

The mandatory carbon reduction guidelines and regulations in Indonesia encourage all industrial sectors particularly the petroleum industry to implement decarbonization programs by systematically reducing carbon emissions as part of climate action. Unlike existing carbon emission studies in the petroleum industry, the literature lacks studies on the decarbonization patterns. In addition, the effectiveness of carbon mitigation in the upstream oil and gas field has not been studied so far. This study developed short panel data models to understand the current decarbonization efforts and patterns during 2015–2018. The results indicate that the considered variables are significantly impactful in carbon reduction with different coefficient patterns. It is suggested to associate decarbonization with oil and gas production and highlight energy efficiency optimization to stabilize production. The impact of financial, human, and administrative resources on the supporting facility is critical for executing sustainable carbon mitigation projects.

The vast majority of peatlands in Southeast Asia are located in Indonesia. They are currently classified as degraded and at risk of fire. Fire prevention and the restoration of degraded peatlands have therefore been part of the national government's agenda for the last two presidential terms. With the immense pressure of anthropogenic challenges, interventions to restore degraded peatlands and prevent fire combine biophysical and socioeconomic considerations. This paper explores the implementation of community-focused interventions and participatory processes in fire prevention, peatland restoration and sustainable livelihood improvement in Bengkalis Regency, Riau Province. We used Participatory Action Research (PAR) and an Institutional Analysis and Development (IAD) framework to foster an on-the-ground and inclusive process for behavioral changes that result in not using fire in agricultural land preparation and to advance awareness of and participation in restoring degraded peatlands. Our findings reveal that PAR, with an IAD framing, can catalyze change. Four critical aspects are required for this: (a) demand for the intervention; (b) adequate political support; (c) community participation, leadership, social capital and local institutions; and (d) business models for sustainable livelihood transitions. This paper provides lessons on scientifically driven and evidence-based participatory processes for restoration.

Hydroxyapatite is known as HAp, Ca10(PO4)6(OH)2, commonly used in orthopedics since it resembles the inorganic portion of human bone. Calcium, Ca and phosphorous, P are the main components of HAp, with Ca/P molar ratio of 1.67 capable of promoting bone growth. Large quantities of by-product waste from fisheries factories have a negative effect on the environment. Hence, this research was carried out to obtain biological natural HAp derived from fishery factory waste black tilapia fish bones. As a result, fish bone can be a low-cost source of HAp and important contributions in biomedical applications. To remove meat and other impurities, black tilapia fish bones were boiled at 100 °C followed by milling to produce a fine powder. The powder was calcined at 600 °C and 800 °C for 3 hours. Characterizations were done by using X-ray diffraction (XRD) for mineralogy, Scanning Electron Microscopy (SEM) for morphology and Energy Dispersive Spectroscopy, EDX for element analysis. The XRD results showed the existence of derived HAp, which was consistent with standard HAp. The raw samples tended to have denser and less porous microstructures than calcined samples were shown in SEM results. EDX results showed the chemical composition of Ca and P with present of magnesium, Mg and sodium, Na as their traces elements. The samples' Ca/P molar ratio was found to be higher than the stoichiometric HAp, >1.67. Thus, the findings show that producing calcium and phosphorus from fishery wastes is a viable option for biomedical applications with the present of trace elements to help accelerates bone growth.

Extraction of the natural halal hydroxyapatite (HAp) from fish scale (Black Tilapia) was produced by calcining of raw fish scale at 600 °C and 800 °C. The produced powders were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM) equipped with an Energy Dispersive Spectroscopy, (EDX). The crystallite size, cell parameters, strain and crystallinity of the raw fish scale and derived HAp calcined powder were observed from the XRD results. By increasing the calcination temperature, the average crystallite size HAp amount increased and close to the pure HAp (JCPDS: 9-432). SEM analysis showed the raw fish scale surface morphology contains collagen fiber compared with boiled and after calcination of the powder samples. The calcined fish scale powders at 800°C morphology was discovered embraced of hexagonal fragments form. The EDX investigation exposed that the fish scale from HAp powder calcined at temperature 600 °C contain a high amount of magnesium and sodium compared to the powder that was calcined at 800 °C.

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20–78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3gene fusions: majority with YAP1exon 1 fused to TFE3exon 4 (88%), or less commonly, TFE3exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4–360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.

CD34-negative solitary fibrous tumors (SFTs) are rare and have not been comprehensively studied. We retrospectively reviewed all cases of SFT confirmed with STAT6 immunohistochemistry and/or STAT6gene fusion between 2013 and 2020 and collected pertinent clinicopathologic parameters. Of a total of 244 cases, 25 (10%) lacked CD34 expression by immunohistochemistry. Compared with CD34-positive SFT, CD34-negative SFT are more likely to arise in the head and neck area (32% vs. 24%, P=0.02) and present as metastatic disease (28% vs. 1%, P<0.0001). A significantly higher percentage of CD34-negative SFT exhibit high-grade cytologic atypia (hypercellularity, round cell or anaplastic morphology, nuclear pleomorphism, etc.) (48% vs. 22%, P=0.0073). There are no significant differences in the distributions of age, sex, tumor size, mitotic count, tumor necrosis, or risk stratification between CD34-negative and CD34-positive SFT. In addition, only 56% of CD34-negative SFT display a typical hemangiopericytoma-like vascular pattern. Special histologic features among CD34-negative SFT include prominent alternating hypercellular or fibrous and hypocellular myxoid areas with curvilinear vessels mimicking low-grade fibromyxoid sarcoma, pulmonary edema-like microcystic changes, and prominent amianthoid collagen fibers. In conclusion, compared with their CD34-positive counterparts, CD34-negative SFT is more likely to present as metastatic disease, show high-grade nuclear atypia, and lack the characteristic hemangiopericytoma-like vasculature, posing a unique diagnostic challenge. The use of STAT6 immunohistochemistry and/or molecular studies may be prudent in soft tissue tumors that appear CD34 negative and lack conventional SFT histopathologic characteristics.

Cancer of unknown primary (CUP) refers to metastatic tumors for which the primary tumor of origin cannot be determined at the time of diagnosis, despite extensive clinicopathologic investigations. Molecular profiling is increasingly able to predict a probable primary tumor type for CUP when clinicopathologic workup is inconclusive. Numerous studies have explored the use of various molecular profiling techniques for identification of site/tissue of origin of CUP. These techniques include gene expression profiling utilizing microarray, reverse transcriptase polymerase chain reaction, RNA-sequencing, somatic gene mutation profiling with next-generation DNA sequencing, and epigenomics including DNA methylation profiling. Despite the generally poor prognosis of CUP, a minority of patients can expect to benefit from targeted therapy despite being agnostic to the tissue of origin. Studies have explored the use of various molecular profiling techniques to predict prognostic and therapeutic biomarkers, with the goal of improving outcome for patients with CUP. However, discordant results between non-randomized and randomized clinical trials in evaluating tumor-type specific therapies raise uncertainties of the benefits of molecularly-predicted tissue of origin-based treatment in routine clinical use. Nevertheless, the current overall trend is in favor of using molecular tools to refine the diagnosis and clinical management of patients with CUP. More large-cohort, randomized prospective studies are needed to assess and validate the utility and feasibility of molecular profiling to uncover potentially targetable genetic alterations. These efforts will also yield further biological insights into the biology and pathogenesis of CUP (Graphical Abstract).

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALKrearrangements. The six cases involved two females and four males, aged 18–84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALKfusions with FLNA(3 cases), MYH10(2 cases), and HMBOX1(1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2–18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term “superficial ALK-rearranged myxoid spindle cell neoplasm”.

Last month's first virtual summit of the Quadrilateral Security Dialogue - commonly known as the Quad - signified the growing cooperation among its four members: the United States, Australia, Japan, and India. ASEAN's attempt to get ARF participants sitting at the same table and discussing regional security concerns will not be easy when Indo-Pacific security architecture is dominated by the Quad, the members of which are powerful countries outside Southeast Asia. [Extracted from the article]

Intravascular lobular capillary hemangioma (ILCH), or intravascular pyogenic granuloma, is relatively rare and likely underrecognized. We reviewed all ILCH cases from our institution confirmed pathologically from 2006 to 2019. Immunostains for smooth muscle actin and Wilms tumor 1 were performed on all cases and prior immunohistochemical stains were reviewed. Forty cases were identified (22 females; 18 males) with a median age of 53 years (range: 13 to 85 y). Clinically, all were well-circumscribed, stable to slow-growing raised/cystic skin lesions ranging from 1 to 40 mm. Most were located on the upper extremities (n=18), followed by head and neck (n=16). Vascular lesions were suspected clinically in one third. Of the consultation cases, provided differential diagnoses included Masson tumor, other hemangiomas, and vascular tumors of intermediate malignancy. The common histologic features were a well-circumscribed, lobular proliferation of closely packed capillaries with central ectatic vessels. The surrounding vascular wall was well-visualized in only half of the cases. About 30% of the cases were mitotically active (mean: 8 to 9 mitotic figures/10 HPFs), and 34% showed mild to moderate cytologic atypia. Hobnail features were present in 40% of cases. All cases were diffusely and strongly positive for Wilms tumor 1. Smooth muscle actin stains highlighted pericytes in all cases. Of the 20 cases with clinical follow-up (median: 40 mo), none recurred. ILCH commonly involves the upper extremities and a vascular tumor is suspected clinically in the minority. Mitotic activity and cytologic atypia, when present, can cause confusion with more aggressive vascular tumors. Recognition of this entity is essential as it is a benign lesion with no risk of recurrence following limited local excision.

Pulmonary carcinoid tumors are relatively uncommon and have an indolent clinical course. The role of histologic grading and cell proliferation as measured by a Ki-67 index in predicting long-term recurrence in carcinoid tumors of the lung is not defined. We report the largest single-institution study of carcinoid tumors and correlate histologic grade and Ki-67 index with clinical outcome. We reviewed all surgical lung resection cases from 1995 to 2016 with a diagnosis of primary carcinoid tumor. We collected clinicopathologic parameters, including tumor size, nodal status, histologic pattern, presence of lymphovascular invasion, mitotic count, %Ki-67 positive cells (Ki-67 index) using a digital algorithm, time to tumor recurrence, and staged these tumors based on the 8th edition of TNM Staging. The final cohort consists of 176 carcinoid tumor cases with complete data: 165 (94%) were typical carcinoids and 11 (6%) were atypical carcinoids. The Ki-67 index is significantly increased in atypical versus typical carcinoids and in higher stage disease. Only the Ki-67 index and not the histologic patterns or lymphovascular invasion status was a significant predictor of tumor recurrence on multivariate analysis among all pulmonary carcinoid tumors and within typical carcinoid tumors alone. A Ki-67 index cutoff of 5% offered the optimal combination of sensitivity and specificity in predicting long-term recurrence based on the receiver operating characteristic curve. In addition, stratifying pulmonary carcinoid tumors based on a 3-tier histologic grading system (grade 1: typical carcinoids with Ki-67 index ≤5%, grade 2: typical carcinoids with Ki-67 index >5%, and grade 3: atypical carcinoids regardless of Ki-67 index) significantly correlated with likelihood of tumor recurrence. Finally, we propose an integrated staging system unique to pulmonary carcinoid tumors by keeping the original TNM stage for grade 1 tumors, but upstaging grade 2 tumors to stage II, and grade 3 tumors to stage III.

Interoperability is an important property for different systems to be integrated. It provides interfaces from multiple data sources to support data and information integrity between various information systems. This study was aimed to: 1) designed an interoperable component to integrate several sub-systems into a centralised data centre; 2) developed a prototype based on the design to be used within an existing data centre system. Both purposes were done to support data integration as required by implementing ETL process, crypto-post, and REST service. This work has provided the solution of data integration model between information systems running on HTTP protocol. The integration model used both synchronous and asynchronous schemes. The methodology that was used in this research was research and development with agile SCRUM framework. The SCRUM framework was used to manage all processes of the development workflow before the production release. The result of the SCRUM framework implementation was burn down process chart and the retrospective logs. It shown the effectiveness of teamwork during the development and the release phases. There were three stages of testing that had been conducted consisted of white box and black box testing, followed by the performance verification.