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Extracellular Vesicle- MDM2 -DNA as a Potential Liquid Biopsy Biomarker for Disease Identification in Retroperitoneal Liposarcoma.

OBJECTIVE: We aimed to assess the levels of MDM2 -DNA within extracellular vesicles (EVs) isolated from the serum of retroperitoneal liposarcoma (RLS) patients versus healthy donors, as well as within the same patients at the time of surgery versus postoperative surveillance visits. To determine whether EV- MDM2 may serve as a possible first-ever biomarker of liposarcoma recurrence. BACKGROUND: A hallmark of well-differentiated and dedifferentiated (WD/DD) retroperitoneal liposarcoma is elevated MDM2 due to genome amplification, with recurrence rates of >50% even after complete resection. Imaging technologies frequently cannot resolve recurrent WD/DD-RLS versus postoperative scarring. Early detection of recurrent lesions, for which biomarkers are lacking, would guide surveillance and treatment decisions. METHODS: WD/DD-RLS serum samples were collected both at the time of surgery and during follow-up visits from 42 patients, along with sera from healthy donors (n=14). EVs were isolated, DNA purified, and MDM2 -DNA levels determined through q-PCR analysis. Nonparametric tests were employed to compare EV- MDM2 DNA levels from patients versus the control group, as well as the time of surgery versus postsurgery conditions. RESULTS: EV -MDM2 levels were significantly higher in WD/DD-RLS than controls ( P =0.00085). Moreover, EV- MDM2 levels were remarkably decreased in WD/DD-RLS patients after resection ( P =0.00036), reaching values comparable to control group ( P =0.124). During postoperative surveillance, significant increases of EV- MDM2 were observed in some patients, correlating with computed tomography scan evidence of recurrent or persistent postresection disease. CONCLUSIONS: Serum EV- MDM2 may serve as a potential biomarker of early recurrent or postoperatively persistent WD/DD-RLS, a disease currently lacking such determinants.

Humans

Blockade of interleukin-6 (IL-6) signaling in dedifferentiated liposarcoma (DDLPS) decreases mouse double minute 2 (MDM2) oncogenicity via alternative splicing.

Effective therapies for retroperitoneal (RP) dedifferentiated liposarcoma (DDLPS) remain unavailable. Loco-regional recurrence occurs in >80% of cases; 5-year disease-specific survival is only 20%. DDLPS is especially prevalent in the retroperitoneum and abdomen; evaluation of the DDLPS microenvironment in these high-fat compartments appears pertinent. Adipose is a main supplier of interleukin-6 (IL6); excessive activation of IL6 signal transducer glycoprotein 130 (GP130) underlies the development of some diseases. The role of GP130 pathway activation remains unstudied in DDLPS, so we examined the role of microenvironment fat cell activation of the IL6/GP130 signaling cascade in DDLPS. All DDLPS tumors and cell lines studied expressed elevated levels of the GP130-encoding gene IL6ST and GP130 protein compared to normal tissue and cell line controls. IL6 increased DDLPS cell growth and migration, possibly through increased signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) activation, and upregulated mouse double minute 2 (MDM2). GP130 loss conveyed opposite effects; pharmacological blockade of GP130 by SC144 produced the MDM2 splice variant MDM2-ALT1, known to inhibit full length MDM2 (MDM2-FL). Although genomic MDM2 amplification is pathognomonic for DDLPS, mechanisms driving MDM2 expression, regulation, and function beyond the MDM2:p53 negative feedback loop are poorly understood. Our findings suggest a novel preadipocyte DDLPS-promoting role due to IL6 release, via upregulation of DDLPS MDM2 expression. Pharmacological GP130 blockade reduced the IL6-induced increase in DDLPS MDM2 mRNA and protein levels, possibly through enhanced expression of MDM2-ALT1, a possibly targetable pathway with potential as future DDLPS patient therapy.

Proto-Oncogene Proteins c-mdm2

Transabdominal lumbar approach (TALA) versus retroperitoneal approach for robot-assisted renal surgery: a prospective randomised controlled trial.

PURPOSE: Common robotic nephrectomy approaches access the kidney via transperitoneal (TP) or retroperitoneal (RP) routes, each with distinct trade-offs. We developed the transabdominal lumbar approach (TALA), combining advantages of both accesses with improved visualisation and strategic trocar placement, and compared it with conventional RP in a prospective randomised controlled trial using technique-oriented intraoperative endpoints. METHODS: In this single-centre, prospective, open-label RCT, 40 patients were randomised to TALA (n = 18) or conventional RP (n = 22). Eligible patients were ≥ 18 years with a renal tumour or non-functional kidney requiring robot-assisted total or partial nephrectomy. Exclusions included prior surgery on the affected kidney, renal vein tumour thrombus, and pregnancy. Both groups were followed for 30 days. The primary endpoint was time from first skin incision to renal artery identification. RESULTS: TALA achieved a median time saving of 16 min compared to conventional RP (38 vs. 54 min, p = 0.001). Perioperative safety was comparable between groups, with three patients (7.5%) experiencing Clavien-Dindo grade III-IV complications. CONCLUSIONS: TALA met its primary endpoint with a significantly shorter time to renal artery identification than conventional RP access, and improving perceived surgical exposure and instrument handling.

Humans

Diagnostic Accuracy of Circulating Tumor DNA to Predict Retroperitoneal Histology in Patients Treated With Retroperitoneal Lymph Node Dissection for Testicular Germ Tumor.

Testicular germ cell tumor (GCT) has survival rates exceeding 90% and thus contemporary research has focused on reducing morbidity. While chemotherapy is efficacious, long-term effects are significant. Primary retroperitoneal lymphadenectomy (P-RPLND) has been offered, and postchemotherapy lymphadenectomy (PC-RPLND) is considered, based on residual node size, to reduce overtreatment. A significant number of patients have necrosis in the retroperitoneum and are thus overtreated. Circulating tumor DNA (ctDNA) may be used to determine which patients would benefit from RPLND. This retrospective analysis sought to determine the performance of ctDNA to detect retroperitoneal GCT only, teratoma only, and GCT/teratoma. All patients had a ctDNA obtained preoperatively and at 3, 6, and 12 months postoperatively. Ninety-two patients underwent P or PC-RPLND. The sensitivity, specificity, and positive predictive values (PPVs) and negative predictive values (NPVs) for detecting active GCT/teratoma in the entire cohort were 60%, 87%, 96%, and 30%, respectively. For GCT only these were 85%, 75%, 73%, and 86%. For teratoma only, these were 31%, 34%, 23%, and 43%. These findings indicate that patients with a positive ctDNA likely harbor active GCT and/or teratoma, as suggested by a PPV of 96%. Future studies may use whole-genome ctDNA assays to improve detection of teratoma and incorporate ctDNA into surveillance protocols.

Humans