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Introduction The 2015 dengue outbreak in southern Taiwan caused substantial mortality. We analyzed the causes of death among these patients. Materials and methods This retrospective study was conducted at a medical center in Tainan from August 2015 to December 2015. Dengue was diagnosed based on the detection of serum dengue NS1 antigen, IgM, or viral RNA in the blood. Causes of death were retrieved from chart reviews by three clinicians. Results There were 4488 cases of dengue in the study hospital, with an in-hospital fatality rate of 1.3% (60 cases). The mean age of the 60 fatal cases was 73 years, among whom 90% were aged ≥65 years. Twenty-eight (46.7%) patients died of severe dengue, and 29 (48.3%) deaths were possibly related to dengue. Of the latter, 24 (40%) died of secondary infections. Thirteen cardiac arrest events, including out-of-hospital (5 events) and in-hospital (8) cardiac arrests in the emergency department, occurred during the dengue epidemic. Seven (53.8%) patients did not receive medical aid before the event. Of the 40 deaths that occurred within one week after hospitalization, 60% died of severe dengue. In contrast, 50% of 20 deaths that occurred one week after hospitalization were related to hospital-acquired infections, mainly pneumonia. Conclusion Of 60 fatal cases, with a predominance of elderly patients, deaths were related to severe dengue within the first week after admission and secondary infections thereafter. The absence of medical care before cardiac arrest events highlights the importance of health education for warning signs of dengue.

Background: Among the individuals with hematological malignancy (HM) complicated with Clostridioides difficile infection (CDI), the variables associated with in-hospital mortality and recurrence of CDI were investigated. Material and methods: Including adults with HM and those without malignancy suffering from CDI from January 2015 to December 2016 in three hospitals in Taiwan. Results: Totally 314 patients including 77 with HM and 237 patients without malignancy were included. HM patients more often had low leukocyte counts (

Background Clostridium difficile infections (CDIs) cause significant mortality and morbidity. Critically ill patients are susceptible to CDIs and tend to have severe CDIs, and their clinical presentations are not merely diarrhea. Materials and methods From September 2017 to March 2018, the adults with CDIs in the ICUs were included. Fecal specimens with positive results of glutamate dehydrogenase assay were cultured for C. difficile, and toxinotyping and ribotyping for available C. difficile isolates were done. The CDI cases were categorized into the diarrheal group and ileus group. Difficult-to-treat cases with the presentations of life-threatening complications (bowel perforation or bacteremia), toxic megacolon, and refractory diarrhea, were analyzed. Results Totally 23 cases, including 6 cases of ileus and 17 of diarrhea, were included. Overall, the incidence of CDI in the ICUs was 10.7 cases per 10,000 patient-days. The ileus group tended to have more severe presentation, shorter ICU stay, higher ICU mortality, and receive initial intravenous metronidazole therapy. Severe and fulminant CDIs accounted for 65.2% (15 cases). The ICU mortality rate was 39.1%, but only one death was directly related to CDI (4.3%). Of nine (39.1%) difficult-to-treat cases, there was only one isolate of RT611 with tcdC deletion and cdtA/cdtB from a case with toxic megacolon. No hypervirulent isolates of RT027 or 078 were detected. Conclusion Severe CDIs in the ICU were not rare. Clinicians should be aware of abdominal symptoms and signs other than diarrhea, such as ileus, to make timely diagnosis and management of CDI.

Clostridioides difficile (C. difficile) infection (CDI) is the most common cause of antibiotic-associated diarrhea and one of the common infections in healthcare facilities. In recent decades, ther...

Background Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Hospitalized patients were at risk of C. difficile-associated diarrhea (CDAD). However the risk factors of CDAD in patients with different hospitalization period are not clear. Material and methods A prospective investigation was conducted in medical wards of a district hospital in southern Taiwan, from January 2011 to January 2013. We arbitrary divided patients into two groups: hospitalized for at most 14 days and 15–30 days, and analyzed their risk factors for CDAD. Results Overall 451 patients were enrolled. The multivariable analysis of 19 (8.0%) patients developing CDAD within 14 days' hospital stay and 216 patients hospitalized for ≤ 14 days without CDAD showed malignancy (odds ratio [OR] 7.15, 95% confidence interval [CI] 1.82–28.09; P = 0.005), prior cephalosporin (OR 10.8, 95% CI 1.3–93.9; P = 0.03) and proton pump inhibitor (PPI; OR 7.1, 95% CI 2.1–24.7; P = 0.002) therapy were independently related to CDAD (Table 3), but hypertension (OR 0.2, 95% CI 0.1–0.7; P = 0.01) was reversely related to CDAD. However, of 9 (4.2%) patients developing CDAD later (15–30 days' hospital stay) and 207 patients with longer hospitalization (15–30 days) but free of CDAD, malignancy (OR 14.0, 95% CI 1.6–124.9; P = 0.02) and underlying diabetes mellitus (OR 20.5, 95% CI 2.9–144.9; P = 0.002) were independent risk factors of CDAD. Conclusion Risk factors for CDAD among hospitalized patients varied by the duration of hospital stay. Intervention strategies to prevent CDAD may be different in terms of hospital stay duration.

The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis, and gene expression profiling were carried out, followed by in silico analyses, cell line study, and immunohistochemical validation. Using gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p = 0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in low-grade GISTs (p 0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p 0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss.

Aims USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST). Methods and results Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs> 50 mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC. Conclusion MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a uterine mesenchymal tumor defined histologically by showing sex cord-like growth patterns, such as sheets, nests, trabeculae, cords, or tubules, with/without Sertoli-like or Leydig-like components, and immunohistochemically by exhibiting variable sex cord markers in addition to epithelial, myogenic, and sex hormone markers. Recent years have seen the emergence in UTROSCT of novel fusion genes that involve key genes in sex hormone pathways, including ESR1 and GREB1 as the 5' partner, and (co)activator oncogenes, particularly NCOA1-3, as the 3' partner. While the identification of similar fusions in the majority of cases serves as a strong argument for UTROSCT to be a distinct entity, there is no denying significant clinicopathologic heterogeneity within the disease spectrum, which might to some extent correlate with the different fusion types. The current review gives a summary of the recently identified fusions in UTROSCT, along with their possible clinicopathologic relevance. Also discussed are unsolved issues including the relationship between UTROSCT and so-called GREB1-rearranged uterine sarcoma as well as other uterine mesenchymal tumors harboring similar fusions.

Aims Intracranial myxoid mesenchymal tumors (IMMTs) with fusions between EWSR1/FUS and CREB transcription factors have morphologic overlap with myxoid angiomatoid fibrous histiocytoma (mAFH) and myoepithelial tumor/carcinoma (MET/MEC). We aimed to study the clinicopathologic and genetic spectrum of extracranial IMMT-like tumors and their relationships with mAFH and MET/MEC. Methods Twelve extracranial tumors harboring EWSR1/FUS-CREB fusions across different histologic groups were characterized using RNA sequencing, FISH and/or RT-PCR. Results There were 4 IMMT-like neoplasms, 3 MET/MECs, and 5 mAFHs from the tibia (n=1), oral cavity (n=2), and soft tissues (n=9; 5 in the extremities), harboring EWSR1-ATF1 in 4 cases, FUS-CREM and EWSR1-CREM in 2 each, and EWSR1-CREB1 in 2. Multinodular growth, reticular/cording/trabecular arrangements, myxocollagenous matrix, and lymphocytic infiltrates variably prevailed among the 3 groups. mAFHs were characterized by cells with syncytial cytoplasm. IMMT-like neoplasms and MET/MECs shared cells with distinct boundaries, but only MET/MECs expressed GFAP and/or S100. MUC4 and ALK were expressed in some IMMT-like neoplasms (2/4; 2/4) and mAFH (2/5; 1/5). Pan-TRK reactivity was observed in two IMMT-like neoplasms with upregulated NTRK3 mRNA and one MEC. Local recurrences, typically ≥ 12 months postoperatively, developed in 2/3 IMMT-like neoplasms, 1/2 MET/MECs, and 0/4 mAFHs with follow-up. No definite associations were found between fusion types and histology, immunoprofile or outcome. Conclusions We demonstrated the similarities and differences among 3 extracranial myxocollagenous tumor groups sharing EWSR1/FUS-CREB fusions. Oral IMMT-like neoplasms harboring FUS-CREM or EWSR1-ATF1 and FUS-CREM-positive

The importance of the detection of relevant toxins or toxin genes to diagnose Clostridioides difficile infection (CDI) or the prediction of clinical outcomes of CDI has been emphasized in recent years. Although stool culture of C. difficile is not routinely recommended in the era of nonculture methods as the preferred tools for CDI diagnosis, the clinical significance of toxigenic C. difficile growth (tCdG) in stool cultures was analyzed. A clinical study was conducted in medical wards of Tainan Hospital, Ministry of Health and Welfare, in southern Taiwan. Diarrheal adults with fecal glutamate dehydrogenase and C. difficile toxin between January 2013 and April 2020 were included. Of the 209 patients with CDI, 158 (75.6%) had tCdG found in stool cultures, and the rest (51, 24.4%) had no tCdG in stool. Only prior ceftazidime or ceftriaxone therapy was independently associated with no tCdG in stool (odds ratio [OR] 2.17, P = 0.02). Compared to the patients with tCDG in stool, those without tCdG in stool experienced treatment success more often (97.1% versus 67.0%, P

Probiotic supplements have been used to decrease the gut carriage of antimicrobial-resistant Enterobacterales through changes in the microbiota and metabolomes, nutrition competition, and the secretion of antimicrobial proteins. Many probiotics have shown Enterobacterales-inhibiting effects ex vivo and in vivo. In livestock, probiotics have been widely used to eradicate colon or environmental antimicrobial-resistant Enterobacterales colonization with promising efficacy for many years by oral supplementation, in ovo use, or as environmental disinfectants. In humans, probiotics have been used as oral supplements for infants to decease potential gut pathogenic Enterobacterales, and probiotic mixtures, especially, have exhibited positive results. In contrast to the beneficial effects in infants, for adults, probiotic supplements might decrease potentially pathogenic Enterobacterales, but they fail to completely eradicate them in the gut. However, there are several ways to improve the effects of probiotics, including the discovery of probiotics with gut-protection ability and antimicrobial effects, the modification of delivery methods, and the discovery of engineered probiotics. The search for multifunctional probiotics and synbiotics could render the eradication of “bad” Enterobacterales in the human gut via probiotic administration achievable in the future.

Psychosocial stressors - life events that challenge social support and relationships - represent powerful risk factors for human disease; included amongst these events are relocation, isolation and displacement. To evaluate the impact of a controlled psychosocial stressor on physiology and underlying molecular pathways, we longitudinally studied the influence of a 28-day period of quarantine on biomarkers of immune signalling, microbial translocation, glycaemic health and blood transcriptome in the wild-born vervet monkey. This event caused a coordinated, mostly transient, reduction of circulating levels of nine immune signalling molecules. These were paralleled by a massive dysregulation of blood transcriptome, including genes implicated in chronic pathologies and immune functions. Immune and inflammatory functions were enriched among the genes downregulated in response to stress. An upregulation of genes involved in blood coagulation, platelet activation was characteristic of the rapid response to stress induction. Stress also decreased neutrophils and increased CD4 + T cell proportions in blood. This model of psychosocial stress, characterised by an immune dysregulation at the transcriptomic, molecular and cellular levels, creates opportunities to uncover the underlying mechanisms of stress-related diseases with an immune component, including cardiovascular diseases and susceptibility to infections.

Soft tissue tumors with GLI1 gene fusions or amplifications have been recently described as a unique pathologic entity with an established risk of malignancy. We herein expand these findings by investigating a cohort of 11 head and neck lesions with GLI1 alterations, including 8 from the tongue, for their clinicopathologic and molecular features. The tumors commonly affected males in their 30s (male:female ratio 2.7:1; range: 1 to 65). Tumors showed a multinodular growth pattern, nested architecture separated by a delicate, arborizing vascular network, monotonous round to ovoid nuclei, and clear cytoplasm. Tumor protrusion into vascular spaces was common. Genetic alterations were investigated by fluorescence in situ hybridization and/or targeted RNA sequencing. Seven tumors harbored GLI1 fusions with the following partners: ACTB (n=4), PTCH1 (n=2), or MALAT1 (n=1). The remaining 4 cases showed coamplifications of GLI1 with CDK4 and MDM2 genes. Tumors were commonly positive for S100 protein and CD56. CDK4, MDM2, and STAT6 were positive in GLI1-amplified tumors. Two of 6 patients with available follow-up (1 each with GLI1 amplification and PTCH1-GLI1 fusion) developed distant metastases. Both tumors showed a high mitotic index and tumor necrosis. The head and neck region, particularly tongue, is a common location for GLI1-related mesenchymal tumors. Although a morphologic overlap was noted with the previously reported "pericytoma with t(7,12) translocation," often occurring in the tongue, our findings expand the original findings, to include a more variable immunophenotype, propensity for late distant metastases, and alternative mechanisms of GLI1 oncogenic activation, such as various GLI1 fusion partners or GLI1 coamplifications with MDM2 and CDK4 genes.

Background: In Southeast Asia, Japanese encephalitis (JE) is an important cause of viral encephalitis which may cause severe neurological sequelae. JE affects mostly children; therefore, clinical presentations and prognosis of adult JE patients are seldom addressed. This study aimed to describe the clinical characteristics and prognostic factors for the outcome of adult JE patients. Methods: Medical records of adult JE patients with acute encephalitis syndrome during 2001–2018 from five medical centers in southern Taiwan were reviewed. Clinical characteristics, brain images, and prognostic factors for outcomes were analyzed. Patients were divided into the good outcome (GO) group and poor outcome (PO) group according to their Glasgow Coma Scale (GCS) scores (GCS >8 vs. ≤ 8) at discharge. Results: Sixty-eight patients (men, 61.8%; median age, 50 years) were included. Summer is the epidemic season, and the number of cases peaked in June. The most common symptoms at initial presentation were altered consciousness and fever (both 94.1%), followed by headache (51.4%). The most commonly involved brain regions were thalamus (55.7%) and basal ganglion (37.7%). The median GCS score at nadir was 8, and the median time from onset to nadir was five days. Fifty-two patients were included in the GO group, while 16 were included in the PO group. On multivariate analysis, flaccidity, rigidity, and elevated CSF protein level were identified as independent prognostic factors for PO. Conclusion: Initial clinical presentations of abnormal muscle tone including flaccidity, rigidity and high CSF protein levels are independent prognostic factors for PO in adult JE patients. Keywords: Adult, Japanese encephalitis, Outcome, Prognostic factor

Cherry hemangioma is the most common hemangioma in adult life. Neoplastic and non-neoplastic theories had both been proposed for its pathogenesis, but its nature is still poorly understood. We noted a significant subset of anastomosing hemangiomas and congenital hemangiomas harbored a population of small capillaries surrounded by a perivascular hyaline layer, reminiscent of the vessels seen in cherry hemangioma. Both anastomosing hemangioma and congenital hemangioma harbor recurrent mutations in exon 5 of GNAQ and its paralogues. In this study, we analyzed 68 cherry hemangiomas and 17 cherry hemangioma-like hemangiomas exhibiting additional non-classical features including markedly dilated, cavernous vessels, and/or a deep component extending to the deep dermis. By Sanger sequencing, GNAQ, GNA11, and GNA14 exon 5 mutations were identified in 12, 4, and 32 cherry hemangiomas, respectively, and 5, 3, and 3 cherry hemangioma-like hemangiomas, respectively. MassARRAY analysis detected mutations (including exon 2 GNAQG48V mutations) in additional 8 cherry hemangiomas and 3 cherry hemangioma-like hemangiomas. Overall, the cherry hemangiomas and cherry hemangioma-like hemangiomas had equal GNA mutation rates (82%), and GNA14 and GNAQ mutations were present in approximately half of cherry hemangiomas and cherry hemangioma-like hemangiomas, respectively. All mutations were mutually exclusive. KRASG12V mutation was also detected in one cherry hemangioma-like hemangioma without GNA mutations. In summary, our study demonstrated recurrent GNA14/GNAQ/GNA11 mutations were present in the majority of this very common hemangioma and established its neoplastic nature. Our results also expanded the morphological spectrum of GNA-mutated hemangiomas to include tumors composed of cavernous-like vessels and indicated GNA14 was the most commonly mutated gene in vascular tumors.

In this study, we aimed to present the clinicopathologic and molecular features of a distinct group of hemangioma with GNA mutations that exhibited prominent thrombosis and organization changes with florid intravascular endothelial cell proliferation that we provisionally termed "thrombotic hemangioma with organizing/anastomosing features." Twenty-six cases were included. No sex predilection was seen (male:female=13:13). Patients' age ranged from 17 to 89 years (median: 51 y). All but 1 occurred in the skin whereas the remaining tumor involved the neck soft tissue. Remarkably, the majority (18) occurred in the lower abdominal/inguinal regions. Histologically, thrombotic hemangioma with organizing/anastomosing features were circumscribed tumors composed of variably sized and congested thin-walled vessels. The most striking features were prominent thrombosis and organization with florid intravascular endothelial cell proliferation. The proliferating endothelial cells exhibit a streaming pattern with focal anastomosing-like feature resembling anastomosing hemangioma. The stroma was sclerotic or hyalinized but could also be myxoid/edematous. Other features included vessels with nuclear hobnailing and perivascular hyalinization, cherry hemangioma-like component, cavernous-like or sinusoidal hemangioma-like areas, Masson hemangioma-like feature, and spindle cell fascicular pattern. Mitotic activity was usually low and nuclei were bland but 2 tumors exhibited moderate nuclear atypia and higher mitotic activity. Extramedullary hematopoiesis and hyaline globules were not identified. Genetically, by Sanger sequencing and MassARRAY analysis, mutually exclusive GNAQ, GNA11, and GNA14 exon 5 mutations were identified in 15, 5, and 2 tumors, respectively, with a combined mutation rate of 85% (22/26). In conclusion, we described a distinct group of hemangioma and expanded the clinicopathologic features of GNA-mutated hemangiomas.

Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma, characterized by a distinctive epithelioid phenotype in a densely sclerotic collagenous stroma, that shows frequent MUC4 immunoreactivity and recurrent gene fusions, often involving EWSR1 gene. A pathogenetic link with low-grade fibromyxoid sarcoma (LGFMS) has been suggested, due to cases with hybrid morphology as well as overlapping genetic signature. However, a small subset of SEF is negative for MUC4 and lacks the canonical EWSR1/FUS gene rearrangements. Triggered by the identification of recurrent YAP1-KMT2A gene fusions by RNA sequencing in 3 index cases of MUC4-negative, EWSR1/FUS fusion-negative SEF, we further investigated a cohort of 14 similar SEF cases (MUC4-negative, EWSR1/FUS fusion-negative) by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction, and/or DNA-based massively parallel sequencing (MSK-IMPACT) for abnormalities in these genes. Three additional SEFs with KMT2A gene rearrangements and one additional case with YAP1 gene rearrangements were identified by FISH. In addition, one case with YAP1-KMT2A and one with KMT2A-YAP1 fusion were detected by reverse transcription-polymerase chain reaction and MSK-IMPACT, respectively. As a control group, 24 fibromyxoid spindle cell tumors, diagnosed or suspected as fusion-negative LGFMS, were also tested for YAP1 and KMT2A abnormalities by FISH, but none were positive. The YAP1/KMT2A-rearranged SEF group affected patients ranging from 10 to 86 years old (average and median: 45) of both sexes (4 females, 5 males). The tumors involved somatic soft tissues with a wide distribution, including extremities, trunk, neck, and dura. Histologically, the tumors showed variable cellularity, with monotonous ovoid to epithelioid tumor cells and hyalinized collagenous background typical of SEF. More than half of the cases showed infiltrative borders, within fat or skeletal muscle. No LGFMS component was identified. All tumors were negative for MUC4 and had an otherwise nonspecific immunophenotype. Of the 6 cases with available follow-up information, 2 had local recurrences, and 2 developed soft tissue and/or bone metastases, including 1 of them died of the disease.

Myoepithelial tumors of soft tissue are uncommon neoplasms characterized histologically by spindle to epithelioid cells arranged in cords, nests, and/or reticular pattern with chondromyxoid to hyaline stroma, and genetically by rearrangement involving EWSR1 (among other less common genes) in about half of the cases. The diagnosis often requires immunostaining to confirm myoepithelial differentiation, most importantly the expression of epithelial markers and S100 protein and/or GFAP. However, there are cases wherein the morphology is reminiscent of myoepithelial tumors, while the immunophenotype falls short. Here, we report 2 highly similar myoepithelioma-like tumors arising in the hands of young adults. Both tumors were well-demarcated and composed of alternating cellular areas with palely eosinophilic hyaline stroma and scattered acellular zones of densely eosinophilic collagen deposition. The tumor cells were mainly epithelioid cells and arranged in cords or small nests. Vacuolated cells encircling hyaline matrix globules were focally prominent. A minor component of nonhyaline fibrous nodular areas composed of bland spindle cells and rich vasculature was also observed. Perivascular concentric spindle cell proliferation and perivascular hyalinization were present in some areas. The tumor cells were positive for CD34 and epithelial membrane antigen (focal) by immunostaining, while largely negative for cytokeratin, S100, GFAP, p63, GLUT1, and claudin-1. By RNA sequencing, a novel OGT-FOXO3 fusion gene was identified in case 1 and confirmed by reverse transcription polymerase chain reaction and fluorescence in situ hybridization in both cases. Sharing the unusual clinicopathologic features and the novel fusion, these 2 cases probably represent a distinct tumor entity, whose relationship with myoepithelial tumors and tumorigenic mechanisms exerted by the OGT-FOXO3 fusion remain to be studied.

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5'-ESR1/GREB1 and 3'-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

Aims Spindle cell/sclerosing rhabdomyosarcomas (SC/SRMS) feature spindled and/or rounded rhabdomyosarcomatous cells within variably hyalinised stroma. Only 30-67% of SC/SRMSs harbour neomorphic MYOD1 p.L122R mutations, indicating heterogeneity in this RMS type. We compared MYOD1-mutant and non-mutant cases to characterise the histological and genetic spectrum of mutated SC/SRMS. Methods and results Seventeen RMSs with spindled, sclerosing or hybrid histology were sequenced to identify MYOD1 and PIK3CA mutations and reappraised to assess histological features and myogenic immunophenotypes. Twelve SC/SRMSs harboured MYOD1 mutations, including homozygous p.L122R (n = 8), heterozygous p.L122R (n = 3) and heterozygous p.E118K (n = 1). MYOD1-mutant tumours affected nine females and three males aged 8-64 years (median = 22.5), had a median size of 4.2 cm (range = 2-22) and involved the head and neck (n = 7), extremities (n = 4) and mediastinum (n = 1). Fascicular/spindle histology was predominant in four cases, including one with heterologous lipoblasts in focally myxoid stroma. Four sclerosing cases mainly comprised rounded cells, including one with multinucleated tumour cells. Four cases were histologically hybrid. The only PIK3CA (p.H1047R) mutation was detected in a predominantly spindled MYOD1-p.L122R-mutated case, but not in its laser-microdissected lipoblast-containing area. All MYOD1-mutant cases exhibited diffuse MYOD1 expression but patchy myogenin reactivity. At final follow-up (median = 13.5 months), recurrences (n = 4), metastases (n = 2) or both (n = 1) occurred in seven MYOD1-mutant cases; one had died of disease. Five non-mutated cases were reclassified as spindle embryonal (n = 3), dense embryonal (n = 1) and unclassifiable (n = 1) RMSs. Conclusion MYOD1-mutant RMSs are uncommonly mutated with PIK3CA and behave aggressively with an expanded morphological and genetic spectrum, including lipoblastic differentiation, multinucleated cells and the alternative p.E118K mutation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus of the family Coronaviridae, causes coronavirus disease 2019 (COVID-19), an influenza-like disease that chiefly infects the lungs through respiratory transmission. The spike protein of SARS-CoV-2, a transmembrane protein in its outer portion, targets angiotensin-converting enzyme 2 (ACE2) as the binding receptor for the cell entry. As ACE2 is highly expressed in the gut and pulmonary tissues, SARS-CoV-2 infections frequently result in gastrointestinal inflammation, with presentations ordinarily ranging from intestinal cramps to complications with intestinal perforations. However, the evidence detailing successful therapy for gastrointestinal involvement in COVID-19 patients is currently limited. A significant change in fecal microbiomes, namely dysbiosis, was characterized by the enrichment of opportunistic pathogens and the depletion of beneficial commensals and their crucial association to COVID-19 severity has been evidenced. Oral probiotics had been evidenced to improve gut health in achieving homeostasis by exhibiting their antiviral effects via the gut–lung axis. Although numerous commercial probiotics have been effective against coronavirus, their efficacies in treating COVID-19 patients remain debated. In ClinicalTrials.gov, 19 clinical trials regarding the dietary supplement of probiotics, in terms of Lactobacillus and mixtures of Bifidobacteria and Lactobacillus, for treating COVID-19 cases are ongoing. Accordingly, the preventive or therapeutic role of probiotics for COVID-19 patients can be elucidated in the near future.

Intimal sarcomas simultaneously involving the right atrium and the inferior vena cava are rare. We report an advanced cardiac intimal sarcoma in the right atrium of a 19-year-old man that was complicated by tumor-related inferior vena cava thrombosis. We initially performed partial tumor resection and vena cava thrombectomy to resolve the circulatory obstruction, because complete resection was difficult due to the invading malignancy and an unclear margin. The patient received adjuvant chemo- and radiotherapy along with anticoagulant therapy. After 3 months, the border of the residual sarcoma was clear, and the patient underwent a secondary complete sarcoma excision (including that of the right atrium) and a suprahepatic vena cava reconstruction. At the 2-year follow-up, there was no tumor recurrence. We conclude that aggressive treatment and a staged complete resection can lead to improved outcomes for advanced cardiac intimal sarcoma with poor prognosis.

BackgroundRespiratory viruses can be detected in 18.3% to 48.9% of critically ill adults with severe respiratory tract infections (RTIs). The present study aims to assess the clinical significance of respiratory viruses in pragmatically selected adults in medical intensive care unit patients and to identify factors associated with viral respiratory viral tract infections (VRTIs).MethodsWe conducted a prospective study on critically ill adults with suspected RTIs without recognized respiratory pathogens. Viral cultures with monoclonal antibody identification, in-house real-time polymerase chain reaction (PCR) for influenza virus, and FilmArray® respiratory panel were used to detect viral pathogens. Multivariable logistic regression was applied to identify factors associated with VRTIs.ResultsSixty-four (40.5%) of the included 158 critically ill adults had respiratory viruses detected in their respiratory specimens. The commonly detected viruses included influenza virus (20), followed by human rhinovirus/enterovirus (11), respiratory syncitial virus (9), human metapneumovirus (9), human parainfluenza viruses (8), human adenovirus (7), and human coronaviruses (2). The FilmArray® respiratory panel detected respiratory viruses in 54 (34.6%) patients, but showed negative results for seven of 13 patients with influenza A/H3 infection. In the multivariable logistic regression model, patient characters associated with VRTIs included those aged < 65 years, household contact with individuals with upper RTI, the presence of fever, cough with sputum production, and sore throat.ConclusionsRespiratory viruses were not uncommonly detected in the pragmatically selected adults with critical illness. Selective multiplex PCR testing for respiratory viruses is a practical strategy, and the detection rate could be further improved in selected patient population.

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials. Significance: These findings propose CDK1 as a novel cell-cycle–independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.

Detection of disseminated tumor cells (DTCs) in bone marrow is an established negative prognostic factor. We isolated small pools of (~20) EPCAM-positive DTCs from early breast cancer patients for genomic profiling. Genome-wide copy number profiles of DTC pools (n = 45) appeared less aberrant than the corresponding primary tumors (PT, n = 16). PIK3CA mutations were detected in 26% of DTC pools (n = 53), none of them were shared with matched PTs. Expression profiling of DTC pools (n = 30) confirmed the upregulation of EPCAM expression and certain oncogenes (e.g., MYC and CCNE1), as well as the absence of hematopoietic features. Two expression subtypes were observed: (1) luminal with dual epithelial–mesenchymal properties (high ESR1 and VIM/CAV1 expression), and (2) basal-like with proliferative/stem cell-like phenotype (low ESR1 and high MKI67/ALDH1A1 expression). We observed high discordance between ESR1 (40%) and ERRB2 (43%) expression in DTC pools vs. the clinical ER and HER2 status of the corresponding primary tumors, suggesting plasticity of biomarker status during dissemination to the bone marrow. Comparison of expression profiles of DTC pools with available data from circulating tumor cells (CTCs) of metastatic breast cancer patients revealed gene expression signatures in DTCs that were unique from those of CTCs. For example, ALDH1A1, CAV1, and VIM were upregulated in DTC pools relative to CTCs. Taken together, analysis of pooled DTCs revealed molecular heterogeneity, possible genetic divergence from corresponding primary tumor, and two distinct subpopulations. Validation in larger cohorts is needed to confirm the presence of these molecular subtypes and to evaluate their biological and clinical significance., Genetics: two subtypes of disseminated tumor cells in bone marrow Tumor cells found in the bone marrow of women with early-stage breast cancer constitute molecularly distinct populations that could impact patient outcomes and treatment responses. Mark Jesus Magbanua and coworkers from the University of California, San Francisco, USA, performed genome-wide copy number variation analysis, expression profiling on 64 cancer-related genes and screened for PIK3CA mutations in pools of tumor cells isolated from bone marrow aspirates of patients undergoing surgery. These disseminated tumor cells (DTCs) contained fewer genomic abnormalities on average than their corresponding primary tumors, although the DTCs often acquired oncogenic mutations in PIK3CA. Expression profiling revealed two distinct subtypes of DTCs, both of which were different from circulating tumor cells found in the bloodstream. Further studies are needed to evaluate the biological and clinical significance of this molecular and genomic heterogeneity in DTCs.

Yuan-Pin Hung,1–3,* Pei-Jane Tsai,4,* Yuan-Ti Lee,5,6 Hung-Jen Tang,7 Hsiao-Ju Lin,1–3 Hsiu-Chuan Liu,1 Jen-Chieh Lee,2 Bo-Yang Tsai,4 Po-Ren Hsueh,8 Wen-Chien Ko2,9,10 1Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 3Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Institute of Medicine and School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 6Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 7Department of Internal Medicine, Chi-Mei Hospital, Tainan, Taiwan; 8Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 9Center of Infection Control, National Cheng Kung University Hospital, Tainan, Taiwan; 10Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan *These authors contributed equally to this work Objectives: The information of antimicrobial susceptibility, toxin gene, and ribotype distribution of toxigenic Clostridium difficile isolates in Taiwan remain limited. Patients and methods: The study was conducted from January 2015 to December 2016 in 5 hospitals in Taiwan. Adults aged ≥20 years with a hospital stay for >5 days were included, and those with colectomy or intestinal infection due to other enteropathogens were excluded. Multiplex PCR was used to detect tcdA, tcdB, cdtA, cdtB, and tcdC deletions, and antimicrobial susceptibility for metronidazole, vancomycin, doxycycline, and tigecycline was investigated. Ribotypes of those isolates with tcdC deletion and tcdA+/tcdB+ were determined. Results: Of 1112 C. difficile isolates collected from adults at 5 hospitals, 842 were toxigenic, including 749 (89.0%) tcdA+/tcdB+ isolates and 93 (11.0%) tcdA−/tcdB+. Of the toxigenic isolates, 76 (9.0%) had a tcdC deletion and were cdtA+/cdtB+, indicative of hypervirulence, and RT078 lineage, including RT126, RT127, and RT078, predominated (n=53, 76.3%). Similar to the susceptibility data in Asia countries, metronidazole or vancomycin resistance was rare, noted in 1.2% or 2.1%, respectively. Reduced doxycycline susceptibility (minimum inhibitory concentration [MIC] of ≥8 mg/L) was more common among RT078 lineage than non-RT078 lineage (75.9%, 44/58 vs 6.0%, 47/784; P

Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5' ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.

Giant cell tumors of bone are locally aggressive bone neoplasms with a predilection for young adults. Histologically, they are composed of histiocytoid to spindled mononuclear cells, admixed with numerous large osteoclastic giant cells. Giant cell tumors of soft tissue are rare tumors that bear striking histological resemblance to giant cell tumors of bone and might be regarded as a soft tissue analog thereof. Point mutations of the H3F3A gene (coding for a histone H3.3 protein) at the Gly34 codon, mostly G34W resulting from a GGG>TGG nucleotide change, have recently been identified in a vast majority of giant cell tumors of bone. To delineate the possible pathogenic linkage between both tumor types, we analyzed the H3F3A genotypes in a series of 15 giant cell tumors of soft tissue by Sanger sequencing and found no mutation in any case. We then sequenced cognate histone H3 genes with an identical nucleotide sequence ('GGG') at the codon Gly34, including the H3F3B, H3F3C, HIST2H3A, HIST2H3C, and HIST2H3D genes, and no somatic mutation was detected. These results reveal that giant cell tumors of soft tissue are probably genetically distinct from their bone counterparts and suggest that they might be pathogenically unrelated. Given the prominence of non-neoplastic cells in these tumors and the limitations of the current study, however, analyses using more sensitive techniques might be required to solve the issue.

The purpose of this study was to investigate the efficacy of targeting peptides chemotherapy to overcome adverse event in the conventional chemotherapy for human hepatocellular carcinoma. Previously we reported several cancer-targeting peptides that bind specifically to cancer cells and their vascular endothelia: L-peptide (anti-cancer cell membrane), RLLDTNRPLLPY; SP-94-peptide (anti-hepatoma cell membrane), SFSHHTPILP; PC5-52-peptide (anti-tumor endothelia), SVSVGMKPSPRP; and control peptide, RLLDTNRGGGGG. In this study, these peptides were linked to liposomal iron oxide nanoparticles to localize the targeted tumor cells and endothelia, and to dextran-coated liposomal doxorubicin (L-D) to treat nonobese diabetic severe combined immunodeficient mice bearing hepatoma xenografts. Our results showed that L-peptide-linked liposomal doxorubicin could inhibit tumor growth with very mild adverse events. Use of the control peptide led to a decrease in the xenograft size but also led to marked apoptotic change in the visceral organ. In conclusion, L-peptide-linked liposomal doxorubicin, SP-94-peptide, and PC5-52-peptide can be used for the treatment of hepatoma xenografts in nonobese diabetic severe combined immunodeficient mice with minimal adverse events.

Background Mesenchymal chondrosarcoma (MCS) is a rare malignant variant of chondrosarcoma with a high tendency of recurrence and metastasis. Intradural extramedullary spinal MCS is exceedingly rare and usually found in pediatric patients. Herein, we present an elderly patient with primary intradural extramedullary spinal MCS. Relevant literatures are reviewed to disclose characteristics of intradural extramedullary spinal MCS. Case presentation A 64-year-old female presented with urinary difficulty and tightness of upper back preceding progressive weakness of right lower extremity. Magnetic resonance imaging revealed an intradural extramedullary tumor at the level of 3rd thoracic vertebra. This patient underwent total tumor resection and then received adjuvant radiotherapy. Histopathological examination showed that the tumor composed of spindle and round cells with high nucleocytoplasmic ratio accompanied by scattered eosinophilic chondroid matrix. Along with immunohistochemical findings and the existence of HEY1-NCOA2 fusion transcript, the diagnosis of MCS was confirmed. Neurologic deficit recovered nearly completely after surgery. No evidence of local recurrence or distant metastasis was found 5 years after treatments. Including the current case, a total of 18 cases have been reported in the literature with only one case with local recurrence and one case of mortality. The current case was the eldest patient diagnosed with primary intraspinal MCS in the literature. Conclusions MCS rarely appears in the intradural space of the spine. In contrast to classic MCS, treatment outcome of primary intradural extramedullary spinal MCS is usually excellent as total tumor resection is commonly achievable. Adjuvant radiotherapy may reduce local recurrence and chemotherapy may be associated with fewer recurrences especially for unresectable tumors. Electronic supplementary material The online version of this article (10.1186/s12891-019-2799-2) contains supplementary material, which is available to authorized users.

Giant cell-rich lesions represent a heterogeneous group of tumors and non-neoplastic lesions, usually arising in bone, which harbor varying number of reactive osteoclastic-type multinucleate giant cells as a common feature. Among these entities, some are confined to the head and neck region (e.g., central giant cell granuloma and mimicking lesions, i.e., peripheral giant cell granuloma and cherubism) or show a relative predilection for this region (e.g., aneurysmal bone cyst and brown tumor of hyperparathyroidism), while others are rare but associated with distinct underlying disease (e.g., giant cell tumor of bone) or histology (e.g., tenosynovial giant cell tumor of the temporomandibular joint and phosphaturic mesenchymal tumor of the jaws) when occurring in the head and neck. Collectively, these lesions pose great challenge in the pathologic diagnosis, which often requires combinatory assessment from the clinical, histopathologic, and/or molecular aspects. This review provides a summary of pertinent clinical and pathologic features and an update of recent molecular and genetic findings of these entities. The considerations in differential diagnosis as well as the effects of the emerging therapeutic RANKL-antagonizing antibody denosumab will also be addressed.

Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origin (i.e., osteoblastic or chondroblastic precursors), those existing in soft tissue tumors more often denote a metaplastic phenomenon and reflect the diversity of differentiation these tumors can display. While many soft tissue tumor types can occasionally harbor metaplastic bone or cartilage as an incidental component or heterologous differentiation, in some other tumor types, the production of these matrices is a frequent and distinctive, if not diagnostic, feature. This review focuses on the latter tumor types where emerging immunohistochemical and molecular evidence has significantly improved our understanding of their respective pathogenesis and histopathological spectra. These tumor types include ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, synovial chondromatosis, soft tissue chondroma, calcifying aponeurotic fibroma, giant cell tumor of soft tissue, myositis ossificans and related diseases, mesenchymal chondrosarcoma, and extraskeletal osteosarcoma.

Anastomosing hemangioma (AH) is a distinct benign vascular tumor that may be histologically confused with an angiosarcoma. Recently, recurrent GNAQ and GNA14 mutations were identified in AH. GNA11, another paralogue of GNAQ and the one that shows the highest degree of homology to GNAQ, has not yet been found to be mutated in AH. In this study, we investigated the clinicopathological and molecular features of 26 AHs. By Sanger sequencing and MassARRAY analysis, mutually exclusive mutations in exon 5 of GNAQ, GNA11, and GNA14 were identified in 10, 5, and 5 tumors, respectively, of the 22 investigated tumors, with an overall mutation rate of 91%. No notable differences in the clinicopathological features were observed between GNAQ-, GNA11-, or GNA14-mutated tumors. Our results implicated GNA11 mutations, as well as previously known mutations of its paralogues GNAQ and GNA14, as essential drivers in the pathogenesis of AH.

Aims MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. Methods and results Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as ‘variant adenosarcomas’), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three ‘variant adenosarcomas’ harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1–SUZ12 or JAZF1–PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated ‘variant adenosarcomas’ showed distinctive morphological features, including ‘fibromyomatous’ cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. Conclusions These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.

ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1-FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1-FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1-FGFR1 and FN1-FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary fibrous tumors (positive in 40%), chondroblastomas (40%), and giant cell tumors of bone (38%), suggesting a possible role for FGFR1 immunohistochemistry in the diagnosis of phosphaturic mesenchymal tumor. With the exception of one case reported in our prior study, none of the remaining tumors resembling phosphaturic mesenchymal tumor had either fusion type or expressed significant FGFR1. Our findings provide insight into possible mechanisms underlying the pathogenesis of phosphaturic mesenchymal tumor and imply a central role of the FGF1-FGFR1 signaling pathway. The novel FN1-FGF1 protein is expected to be secreted and serves as a ligand that binds and activates FGFR1 to achieve an autocrine loop. Further study is required to determine the functions of these fusion proteins.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a morphologically distinctive lesion. Although the clinical course of SANT is benign, its reactive or neoplastic nature remains to be clarified. Furthermore, some investigators have suggested that SANT is related to IgG4 sclerosing lesion or inflammatory pseudotumor with stromal cells positive for Epstein-Barr virus (EBV). In this study, we assessed 22 cases of SANT derived from adult women. Clinical data and follow-up information were obtained by chart review. Immunohistochemical studies for IgG4, IgG, and CD21 stains and in situ hybridization to detect EBV-encoded small RNAs were performed. We also assessed genomic DNA extracted from paraffin-embedded tissue for human androgen-receptor α gene analysis using conventional and methylation-specific polymerase chain reaction methods. The median patient age was 41.5 years (range, 25 to 82 y). Most (77%) patients presented with a single mass that was detected incidentally (59%). The mean size of the lesions was 3.8 cm (range, 1.0 to 9.0 cm). Clinical symptoms correlated with multiple lesions (P=0.043) but not lesional size (P=0.637) or location in the spleen (hilum vs. periphery, P=0.696). None of the cases had evidence of IgG4-related disease or recurred after splenectomy. The mean number of IgG4 cells was 27.7 (range, 4 to 125), and the mean IgG4/IgG ratio was 16.4% (range, 1.6% to 55.7%) with only 2 cases being >40%. Cases with higher IgG4 cells did not correlate with inflammatory pseudotumor-like morphology. No lesions were positive for EBV-encoded small RNAs, and almost all cases with informative results (n=19) showed a polyclonal pattern. We conclude that SANT is a polyclonal, reactive lesion rather than a neoplasm.

Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin tissue. In conclusion, we identified frequent chromosome 12q amplifications, including loci containing potential pharmacological targets. Global chromosomal instability and chromothripsis were more frequent in cases with sarcomatous overgrowth. To our knowledge, this is the first time that evidence of chromothripsis has been demonstrated in paraffin-embedded clinical tissues and in adenosarcomas.

Solitary fibrous tumors (SFTs) are rare soft-tissue tumors that often occur in body cavities, especially the pleural space. A subset of SFTs is histologically malignant and tends to metastasize; rarely, they may induce paraneoplastic syndromes. Doege–Potter syndrome is paraneoplastic hypoglycemia induced by oversecretion of unprocessed insulin-growth factor-2. While localized SFTs are treated mainly by surgery, the standard therapy for metastatic SFTs is lacking. Here, we present a case with metastatic malignant SFT and Doege–Potter syndrome, which was treated initially by dacarbazine and bevacizumab with a period of good clinical response.

11507 Background: For advanced LPS and LMS, the two most common histologies in soft tissue sarcoma, there are limited treatment options that readily balance efficacy and toxicity. Patients (pts) treated with E had an improved median overall survival (OS) in a phase III randomized study compared to dacarbazine but with an unsatisfactory 4% objective response rate (ORR). Early studies of L, a multi-targeted anti-angiogenic inhibitor, had suggested efficacy in sarcoma pts. We hypothesized that the combination of anti-angiogenic agent and chemotherapy could potentiate treatment benefit and aimed to explore the safety and efficacy of L + E in advanced LMS and LPS. Methods: LEADER was a single-arm phase Ib/II study for advanced adult LMS and LPS pts who had received no more than 2 lines of systemic chemotherapy. The phase Ib part (starting dose: L 18mg/day, E 1.1mg/m2) had been reported and the recommended phase 2 dose (RP2D) was determined at L 14mg/day and E 1.1mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was ORR by RECIST 1.1, secondary endpoints included ORR by Choi criteria, progression-free survival (PFS), 6-month PFS rate, and OS. With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 13 and 27 pts, respectively. Results: As of Jan 22, 2020, 20 pts (F/M 13/7) had been treated with at least one cycle of L + E; 14 were LMS (5 uterine, 9 non-uterine) and 6 were LPS (4 dedifferentiated, 2 myxoid round cell). The median age was 51 (range 29-73); the median lines of treatment(s) received before enrollment was 1 (range 0-3). 18 pts were evaluable for primary endpoint: the ORR by RECIST 1.1 was 27 % (5/18) (95% CI 10-53%). The ORR by Choi criteria was 67 % (12/18) (95% CI 41-87%). With 8 PFS events, the median PFS and 6-month PFS rate was 56 weeks (95% CI 25-not reached) and 72%, respectively. There were no OS events. The ORRs by RECIST 1.1 between different L starting doses were not significantly different (18mg 33% (2/6) vs 14mg 25% (3/12), p = 0.7). 15 pts experienced at-least one grade (gr) 3 or 4 adverse event (AE); gr 3 or 4 AEs occurred in > 1 pts included (% of phase Ib, % of phase II pts) hypertension (n = 4) (67%, 0%); hand-foot-syndrome (n = 4) (50%, 7%), proteinuria (n = 3) (0%, 25%), febrile neutropenia (n = 2) (17% vs 5%), neutropenia (n = 6) (50% vs 25%). The RP2D was associated with overall lower gr3/4 AEs except for proteinuria. Conclusions: L + E had shown promising efficacy in advanced LMS and LPS. L at 14mg/day had a better AE profile without compromising activity. The exploratory biomarker study of LEADER is ongoing. Clinical trial information: NCT03526679 .

Introduction. The 2015 dengue outbreak in southern Taiwan caused substantial mortality rates in the elderly. We analyzed here the causes of death among adults with dengue. Methods. The retrospective study was conducted at a medical center in Tainan from the 1st of August to 31th of December in the year 2015. The detection of the dengue NS1 antigen IgM or viral RNA in patients' blood were used to diagnose dengue. Clinical courses and causes of death were retrieved from chart reviews by two intensivists. Results. There were 4,488 cases of dengue diagnosed in the study hospital, and these cases had an in-hospital case fatality rate of 1.34% (60 cases). Of these, the mean age was 73 years and gender did not predict outcome. Twenty-eight (46.7%) cases died of severe dengue, and 29 (48.3%) deaths were possibly caused by dengue-related complications, which were mostly secondary infections (24 cases). Most of the families of fatal case (70%) signed do-not-resuscitate (DNR) orders prior to the patients' death. When the dengue epidemic peaked, 13 cardiac arrest events, including out-of-hospital (5 events) and in-hospital (8) cardiac arrests at the emergency department, occurred within four weeks of the dengue epidemic. Notably, in half (7) of these cases, the patients did not search for medical aid prior to experiencing cardiac arrest. Of the 40 cases that had early death (occurring within one week after hospitalization), 60% died of severe dengue. In contrast, 50% of the 20 deaths that occurred later than one week after hospitalization were related to hospital-acquired infections, mainly pneumonia. Conclusion. The elderly that experience dengue fever may die of severe dengue early or die of secondary infections later. Cardiac arrests can also occur unpredictably at the first aids, which highlight the need of professional and patient education regarding the danger signs that are related to severe dengue in an epidemic setting.