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Abstract Objectives We aimed to test the hypothesis that in retroperitoneal dedifferentiated liposarcoma (DDLS) the presence of the dedifferentiated (DD) component at the resection margin is associated with adverse outcome. Methods We retrospectively searched the archive for primary resections of retroperitoneal DDLS performed at our institution between 1990 and 2017. Slides were rereviewed for diagnosis, Fédération Nationale des Centres de Lutte Contre le Cancer grade, myogenic differentiation, and the presence of the well-differentiated (WD) or DD component at the resection margin. The medical records were reviewed for patient age, sex, tumor size, tumor focality, adjuvant/neoadjuvant therapy, local recurrence, distant metastases, local recurrence-free survival (LRFS), overall survival (OS), and follow-up duration. Results The presence of the DD component at the resection margin was associated with worse LRFS compared with cases without the DD component at the margin (P = .002). However, OS was not significantly affected (P = .11). Conclusions LRFS is significantly shorter in cases with the DD component at the margin compared with cases without DD tumor at the margin, while there is no association with OS. We recommend reporting the presence or absence of DD tumor at the margin in retroperitoneal DDLS, as it adds meaningful prognostic information.

Retroperitoneal soft tissue sarcomas comprise a relatively rare entity with incidence rates of less than 1% of all malignancies. The surgical treatment of these tumors is challenging. We present a case of a 70-year-old patient who underwent radical surgery at the Department of Surgical Oncology at the University Hospital in Pleven for giant dedifferentiated liposarcoma. The patient presented with cachexia, anemia, dull abdominal pain, and a huge abdominal mass. After ultrasound and CT, the tumor was assessed as resectable. The removed tumor mass weighed 5.7 kg. Nowadays, complete resection of such tumors remains the most important predictive factor for local recurrence and overall survival.

Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade 3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (p = 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (p = 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2–3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Perineural invasion (PNI) has emerged as a key pathological feature and be considered as a poor prognostic factor in cervical cancer. However, the underlying molecular mechanisms are largely unknown. Here, PNI status of 269 cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) samples were quantified by using whole‐slide diagnostic images obtained from The Cancer Genome Atlas. Integrated analyses revealed that PNI was an indicative marker of poorer disease‐free survival for CESC patients. Among the differentially expressed genes, ADCYAP1 were identified. Clinical specimens supported that high expression of PACAP (encoded by ADCYAP1) contributed to PNI in CESC. Mechanistically, PACAP, secreted from cervical cancer cells, reversed myelin differentiation of Schwann cells (SCs). Then, dedifferentiated SCs promoted PNI by producing chemokine FGF17 and by degrading extracellular matrix through secretion of Cathepsin S and MMP‐12. In conclusion, this study identified PACAP was associated with PNI in cervical cancer and suggested that tumour‐derived PACAP reversed myelin differentiation of SCs to aid PNI.

Endometrial cancer (EC) is one of the most common gynecologic cancers worldwide. There were 417,367 newly diagnosed cases and 97,370 deaths due to this disease worldwide in 2020. The incidence rates have increased over time, especially in countries with rapid socioeconomic transitions, and EC has been the most prevalent gynecologic malignancy in Taiwan since 2012. The new EC molecular classifications of The Cancer Genome Atlas (TCGA) Research Network include clear-cell carcinoma, serous carcinoma, and carcinosarcoma, while undifferentiated/dedifferentiated EC (UDEC) is not mentioned, and most previous clinical trials for EC have not included UDEC. UDEC is rare, has an aggressive growth pattern, tends to be diagnosed at an advanced stage, and is resistant to conventional chemotherapy. In this review, case series or case reports on the clinical features and genomic/epigenetic and expression profiles on UDEC data are summarized in order to identify potential molecular targets for current and future research.

Introduction Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive subtype of soft tissue sarcoma, characterized by limited treatment options and poor prognosis. Despite surgical resection being the only potentially curative treatment for localized DDLPS, the recurrence rate remains high, and systemic chemotherapy, typically anthracycline-based, shows limited efficacy in advanced stages. While immune checkpoint inhibitors (ICIs) have shown promise in various sarcoma subtypes, including DDLPS, their role as a first-line treatment remains unclear. Methods We conducted a systematic meta-analysis to evaluate the efficacy of ICIs in treating patients with DDLPS. A total of 25 studies encompassing 245 patients were included. Data on overall response rate (ORR), progression-free survival, and grade III–V treatment-related adverse events were analyzed. We assessed treatment efficacy based on the line of therapy and treatment regimens, including ICI monotherapy, dual ICI therapy, and ICI combinations with other modalities. Results The pooled ORR for all ICI-based treatments was 7%. First-line ICI therapy yielded a significantly higher ORR of 22%, compared to 4% in later-line treatment. The combination of ICI with anthracyclines demonstrated the highest ORR of 52%. In contrast, ICI regimens combined with trabectedin or other agents showed limited efficacy. Sensitivity analysis confirmed the stability of results, and publication bias was not detected. Conclusion This meta-analysis supports the potential role of ICIs, particularly in combination with anthracyclines, as a first-line therapeutic strategy for DDLPS. These results provide a foundation for future prospective studies aimed at optimizing immunotherapy approaches for this rare and challenging malignancy.

BackgroundPolymorphonuclear neutrophils (PMNs) are the main effector cells in inflammatory responses and play multiple roles in thyroid cancer (TC). PMNs contain and release a plethora of mediators, including granular enzymes [e.g., myeloperoxidase (MPO), pentraxin-3 (PTX3) and matrix metalloproteinase-9 (MMP-9)], and neutrophil extracellular traps (NETs). The aim of this study was to evaluate NETs and neutrophil-derived mediators as possible biomarkers in TC patients.Methods20 patients with differentiated thyroid cancer (DTC), 26 patients with dedifferentiated thyroid cancer (De-DTC), 26 patients with multinodular goiter (MNG) and 22 healthy controls (HCs) were recruited. Serum concentrations of free DNA (dsDNA), nucleosomes, citrullinated histone H3 (CitH3) and MPO-DNA complexes were evaluated as NET biomarkers. Neutrophil-related mediators such as MPO, PTX3, MMP-9, CXCL8, and granulocyte-monocyte colony-stimulating factor (GM-CSF) were measured by ELISA.ResultsSerum levels of all four NET biomarkers were increased in DeDTC patients compared to HCs. CitH3 serum levels were selectively increased in both DeDTC and DTC patients compared to HCs and MNG patients. MPO-DNA complexes and nucleosomes were selectively increased only in DeDTC patients compared to HCs and MNG patients. Moreover, MPO-DNA complexes were selectively increased in DeDTC patients compared to DTC patients also. MPO circulating levels were selectively increased in the DeDTC patient subgroup compared to HCs. Circulating levels of PTX3, MMP-9 and GM-CSF were increased in DTC and DeDTC patients compared to HCs. Nucleosomes positively correlated with dsDNA, CitH3, MPO and CXCL8. MPO-DNA complexes positively correlated with dsDNA, CitH3, CXCL8, MPO and nucleosome levels. Moreover, three out of the four NET biomarkers (i.e., dsDNA, nucleosomes and MPO-DNA complexes) were increased in elderly patients compared to young patients and in patients with metastatic disease at diagnosis compared to non metastatic patients. Nucleosomes were higher in males compared to females.ConclusionMPO-DNA complexes, nucleosomes and, to some extent, CitH3 levels seem to correlate with malignancy and severity of progressive TC. Moreover, serum concentrations of PMN-related mediators (MPO, PTX3, GM-CSF) were increased in TCs compared to MNG and HCs.

Over the last several years, the systemic treatment landscape for dedifferentiated liposarcoma (DDLPS) has notably expanded. Historically, systemic therapy options have been limited to cytotoxic chemotherapy agents, including doxorubicin, ifosfamide, gemcitabine, and docetaxel, that were shown to have efficacy in unselected populations of patients with soft tissue sarcomas. More recently, however, there have been phase II and III trials establishing clinical benefit of the cytotoxic agents trabectedin and eribulin along with the tyrosine kinase inhibitor pazopanib in patients with advanced liposarcoma and DDLPS. Additionally, there are several investigational targeted therapies that have incorporated advances in the understanding of DDLPS disease biology, exploiting the fact that nearly all such tumors include highly amplified expression of MDM2 and CDK4. Recent clinical trials have supported the benefit of the CDK4 inhibitor abemaciclib and the nuclear export inhibitor selinexor and support continued development of anti-MDM2 therapies, with particular attention to the bone marrow toxicity and resultant thrombocytopenia that has thus far limited their use. In contrast, the checkpoint inhibitors pembrolizumab and nivolumab remain of questionable benefit, although these immunotherapy drugs may have a role when combined with other therapeutic agents. Ongoing phase III trials will clarify the role of these novel agents. Future directions include directly comparing current standard-of-care options and newer therapies, developing synergistic combinations of novel agents, and evaluating their role in patients with localized DDLPS.