BACKGROUND: Dedifferentiation occurs in approximately 10% of atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLPS), primarily in retroperitoneal or deep-seated tumors, conferring metastatic potential. Superficial dedifferentiated liposarcoma (sDDLPS) is rare, and its progression and natural history are poorly documented.
METHODS: We performed a 15-year retrospective review of our pathology database to identify cases of DDLPS in the skin or subcutaneous tissue. Diagnosis of primary sDDLPS required evidence of non-lipogenic sarcoma in the skin or subcutis, with concurrent ALT/WDLPS and/or MDM2 amplification.
RESULTS: We identified 14 cases of DDLPS involving skin or subcutis: 7 primary sDDLPS and 7 secondary lesions (3 from recurrent deep DDLPS and 4 from metastasis). Primary sDDLPS cases (4 females, 3 males; median age: 74) mainly presented as undifferentiated spindle cell or pleomorphic sarcoma. Tumor grades were grade 2 (5 cases) and grade 3 (2 cases), with three cases also showing grade 1 areas. MDM2 amplification was confirmed in 6 sDDLPSs for which FISH was successfully performed. Follow-up available for 6 sDDLPS patients showed 2 local recurrences, treated with re-excision and radiation therapy, with all disease-free at last follow-up (5-126 months). Of the 7 secondary cases, 2 had ongoing disease after multiple recurrences, 1 was disease-free, and all 4 with cutaneous metastasis died of disease (follow-up range: 24-263 months).
CONCLUSIONS: These findings emphasize the importance of distinguishing between primary sDDLPS and secondary lesions due to their distinct prognoses. Metastasis or superficial extensions from deep DDLP correlate with a considerably worse prognosis than those originating in superficial tissues.

OBJECTIVE: Amidst the rarity of High-grade transformation (HGT) in adenoid cystic carcinoma (ACC), this study offers unprecedented insights into its aggressive nature and clinical implications.
METHODS: A 1:1 match comparison between 23 HGT patients and non-HGT counterparts was extracted from 412 ACC cases, focusing on dissecting distinctive clinicopathological features and prognostic outcomes.
RESULTS: The predominant sites of HGT were the sinonasal and lacrimal glands (30.4% each). Notably, the solid subtype was the most prevalent pattern within HGT, accounting for 69.6% of cases. Compared to non-HGT, the HGT cohort exhibited significantly higher rates of lymph node metastasis (39.1% vs. 8.7%; P < 0.05), perineural invasion (60.9% vs. 26.1%; P < 0.05), and increased Ki-67 proliferation index (35.0% vs. 10.0%; P < 0.05). Moreover, HGT regions typically showed reduced or absent p63 expression, along with high-grade pathomorphology. HGT was associated with increased recurrence (55.0%) and distant metastasis (78.3%), leading to an average survival of 35.9 months and a 3-years mortality rate of 35.0%. Overall and progression-free survival rates were significantly decreased in the HGT group.
CONCLUSIONS: This study represents the largest single-center cohort of HGT cases to our knowledge, highlighting its frequent occurrence in the sinonasal and lacrimal glands and association with poorer outcomes. The findings support classifying HGT in ACC as Grade 4, reflecting its severity.

In this study, we present six cases of epithelioid dedifferentiated liposarcoma to further characterize its clinical and pathological features. The patients are all adult men with age at presentation ranging from 46 to 64 years (median 58.5 years). The patients presented with nonspecific symptoms of retroperitoneal mass, intermittent dull pain or discomfort. None of the patients had any prior history of a primary tumor. Radiological examinations revealed the presence of ill-demarcated heterogenous mass located in the deep soft tissue, including retroperitoneum (4 cases), pelvis and trunk (1 case each). Grossly, they appeared as solid tumors with focal areas of necrosis being presented in 2 cases. Histologically, all tumors were characterized by sheets of epithelioid cells that displayed marked cellular atypia and brisk mitotic activity. Variable portion of atypical lipomatous tumor/well-differentiated liposarcoma was present in 3 cases. By immunohistochemistry, the high-grade epithelioid component in all 6 cases showed strong and diffuse nuclear staining of MDM2, CDK4 and P16, with partial expression of AE1/AE3 in 3 cases. Fluorescence in situ hybridization analysis revealed high-level amplification of MDM2 in all 6 cases, with co-amplification of CDK4 in 3 cases. Follow up information showed that two patients died of the disease within one year despite multidisciplinary treatment. Due to the striking epithelioid appearance, this rare variant of dedifferentiated liposarcoma may be confused with undifferentiated epithelioid sarcoma, poorly differentiated carcinoma, mesothelioma or other malignancies with epithelioid phenotype. The study presented herein further highlights the aggressive clinical behavior of this unique tumor type. For patients with advanced disease, CDK4 inhibitor may provide an optional targeted treatment.

Chondrocyte-based cell therapy to repair cartilage has been used for >25 years despite current limitations. This work presents a new treatment option for cartilage lesions.
High-quality hyaline cartilage microtissues called Cartibeads are capable of treating focal chondral lesions once implanted in the defect, by complete fusion of Cartibeads among themselves and their integration with the surrounding native cartilage and subchondral bone.
Controlled laboratory study.
Cartibeads were first produced from human donors and characterized using histology (safranin O staining of glycosaminoglycan [GAG] and immunohistochemistry of collagen I and II) and GAG dosage. Cartibeads from 6 Göttingen minipigs were engineered and implanted in an autologous condition in the knee (4 or 5 lesions per knee). One group was followed up for 3 months and the other for 6 months. Feasibility and efficacy were measured using histological analysis and macroscopic and microscopic scores.
Cartibeads revealed hyaline features with strong staining of GAG and collagen II. High GAG content was obtained: 24.6-µg/mg tissue (wet weight), 15.52-µg/mg tissue (dry weight), and 35 ± 3-µg GAG/bead (mean ± SD). Histological analysis of Göttingen minipigs showed good integration of Cartibeads grafts at 3 and 6 months after implantation. The Bern Score of the histological assay comparing grafted versus empty lesions was significant at 3 months (grafted, n = 10; nongrafted, n = 4; score, 3.3 and 5.3, respectively) and 6 months (grafted, n = 11; nongrafted, n = 3; score, 1.6 and 5.1).
We developed an innovative 3-step method allowing, for the first time, the use of fully dedifferentiated adult chondrocytes with a high number of cell passage (owing to the extensive amplification in culture). Cartibeads engineered from chondrocytes hold potential as an advanced therapy medicinal product for treating cartilage lesions with established efficacy.
This successful preclinical study, combined with standardized manufacturing of Cartibeads according to good manufacturing practice guidelines, led to the approval of first-in-human clinical trial by the ethics committee and local medical authority. The generated data highlighted a promising therapy to treat cartilage lesions from a small amount of starting biopsy specimen. With our innovative cell amplification technology, very large lesions can be treated, and older active patients can benefit from it.

BACKGROUND: Low-grade osteosarcomas, namely parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LGCOS), occasionally dedifferentiate into high-grade malignancy, referred to as dedifferentiation in low-grade osteosarcoma (DLOS). This study aimed to elucidate the clinicopathologic features of DLOS, which are poorly described to date due to the extreme rarity of the disease.
METHODS: A total of 33 patients with DLOS were included. Clinical characteristics, including the diagnostic accuracy of tumor biopsy, multimodal treatments, and clinical course, were retrospectively reviewed. Univariate analysis was performed to identify prognostic factors associated with overall survival (OS) and metastasis-free survival (MFS).
RESULTS: The tumor subtypes comprised 10 cases (30.3%) of LGCOS and 23 cases (69.7%) of POS. The timing of dedifferentiation was synchronous in 25 (75.8%) and metachronous in 8 (24.2%) patients. The rates of preoperative diagnosis of DLOS were 40.0% and 65.4% for core needle biopsy and incisional biopsy, respectively. All patients underwent surgery and 25 patients received perioperative chemotherapy. Of the 13 patients who received neoadjuvant chemotherapy, 11 exhibited a poor histological response. The 5-year OS and MFS rates were 88.1% and 77.7%, respectively. Univariate analysis revealed that local recurrence was associated with poor OS (P < 0.01) and MFS (P < 0.01). Perioperative chemotherapy did not affect OS or MFS.
CONCLUSIONS: The diagnostic accuracy of tumor biopsy for DLOS was lower than that for bone sarcomas, as reported previously. In contrast to conventional osteosarcomas with high chemosensitivity, both histological responses and survival analysis revealed low efficacy of chemotherapy for DLOS.

The factorial structure of schizophrenia symptoms has been much debated but little is known on its degree of unicity, specificity as well as its dynamic over time. Symptom differentiation is a phenomenon according to which patients\' symptoms could differentiate from one another during illness to form more independent, distinct dimensions. On the contrary, symptom dedifferentiation is an increase in the correlations between those symptoms over time. The goal of this study was to investigate symptom differentiation or dedifferentiation over time in recent onset psychosis using the Positive and Negative Syndrome Scale.
A confirmatory factor analysis model based on the consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia was estimated on seven different time points over a three-year period. A general factor capturing common variance between every symptom was also included. Explained common variance was computed for the general factor and each specific factor.
Three hundred and sixty-two recent onset psychosis patients were assessed. Results showed no evidence for either symptom differentiation or dedifferentiation over time. Specific symptoms accounted for >70 % of the variance suggesting a high degree of specificity of the symptomatology.
Overall, this study adds support for a highly multidimensional approach to clinical symptom assessment with an explicit focus on depression. The premise behind the staging approach being inherently one-dimensional, implications for further research is discussed.

The efficacy of listening comprehension is presumably sustained over the life span, contradicting the stereotype of universal cognitive decline. It is thus worth investigating whether and how the preserved auditory semantic function is supported by affected or unaffected neural mechanism with age. To investigate this issue, 22 younger and 21 older Japanese adults were imaged in a 3 Tesla MRI scanner while performing an auditory semantic-tone task. Results showed that (a) relative to younger adults, older participants had preserved accuracy and slowed responses, underpinned by weakened interconnectivity and largely unchanged activation and laterality; (b) older adults with superior performance developed increased regional left-lateralization and stronger interregional connectivity within the domain-general networks; (c) these age-related or performance-related cortical reorganizations were largely consistent with neurocognitive aging models that were supported by age-sensitive cognitive domains, suggesting that these models might also be accountable for relatively age-intact cognitive functions such as auditory semantic processing.

Age-related decline in motor function is associated with over-activation of the sensorimotor circuitry. Using a multimodal MEG-fMRI paradigm, we investigated whether this neural over-recruitment in old age would be related to changes in movement-related beta desynchronization (MRBD), a correlate of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and whether it would characterize compensatory recruitment or a reduction in neural specialization (dedifferentiation). We used MEG to assess age-related changes in beta band oscillations in primary motor cortices, fMRI to localize age-related changes in brain activity, and the Finger Configuration Task to measure task performance during overt and covert motor processing: motor execution (ME) and motor imagery (MI). The results are threefold: first, showing age-related neuroplasticity during ME of older adults, compared to young adults, as evidenced by increased MRBD in motor cortices and over-recruitment of sensorimotor areas; second, showing similar age-related neuroplastic changes during MI; and finally, showing signs of dedifferentiation during ME in older adults whose performance negatively correlated with connectivity to bilateral primary motor cortex. Together, these findings demonstrate that elevated MRBD levels, reflecting greater GABAergic inhibitory activity, and over-activation of the sensorimotor network during ME may not be compensatory, but rather might reflect an age-related decline of the quality of the underlying neural signal.

Cancer recurrence has remained a significant challenge, despite advances in therapeutic approaches. In part, this is due to our incomplete understanding of the biology of cancer stem cells and the underlying molecular mechanisms. The phenomenon of differentiation and dedifferentiation (phenotypic switching) is not only unique to stem cells but it is also observed in several other organisms, as well as evolutionary-related microbes. Here, we propose the use of a primitive eukaryotic unicellular organism, Acanthamoeba castellanii, as a model to study the molecular mechanisms of cellular differentiation and dedifferentiation.

BACKGROUND: Altered glycosylation associated with hepatocellular carcinoma (HCC) is well documented. However, few reports have investigated the association between dedifferentiation and glycosylation. Therefore, the aim of this study was to analyze glycosylation associated with dedifferentiation of HCC within the same nodule and to investigate glycosyltransferase related to the glycosylation.
METHODS: We analyzed resected HCC specimens (n = 50) using lectin microarray to comprehensively and sensitively analyze glycan profiles, and identify changes to glycosylation between well- and moderately-differentiated components within the same nodule. Moreover, we performed immunohistochemical staining of mannosyl(α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (MGAT1), which is an essential glycosyltransferase that converts high-mannose glycans to complex- or hybrid-type N-glycans.
RESULTS: Four lectins from Narcissus pseudonarcissus agglutinin (NPA), Concanavalin A, Galanthus nivalis agglutinin, and Calystegia sepium agglutinin were significantly elevated in moderately-differentiated components of HCC compared with well-differentiated components, and all lectins showed binding specificity to high-mannose glycans. Therefore, these structures were represented to a greater extent in moderately-differentiated components than in well-differentiated ones. Immunohistochemical staining revealed significantly increased NPA expression and decreased MGAT1 expression in moderately-differentiated components. Low MGAT1 expression in moderately-differentiated components of tumors was associated with intrahepatic metastasis and had tendency for poor prognosis.
CONCLUSIONS: Dedifferentiation of well-differentiated HCC is associated with an increase in high-mannose glycans. MGAT1 may play a role in the dedifferentiation of HCC.