Acral lentiginous melanoma histotype predicts outcome in clinical stage I-II melanoma patients: an International multicenter study.

BACKGROUND: In the American Joint Committee on Cancer (AJCC) classification, acral lentiginous melanoma (ALM) histotype ALM is not included as an independent prognostic factor; in small series its negative prognostic impact on disease-free survival (DFS) and overall survival (OS) has been linked to the greater Breslow thickness (BT). PATIENTS AND METHODS: The study was carried out at four referral melanoma centers (three Italian and one Polish). Clinical consecutive patients with stage I-II melanoma, who were diagnosed, treated, and followed up between January 1998 and March 2018 in annotated specific databases were included. RESULTS: Overall, 6734 were evaluable, 4349 with superficial spreading melanoma (SSM), 2132 with nodular melanoma (NM), and 253 with ALM. At univariable analysis, a statistically significant worse DFS [hazard ratio (HR) 2.72, 95% confidence interval (CI) 2.24-3.30; P < 0.001] and OS (HR 2.67, 95% CI 2.15-3.32; P < 0.001) were found in patients with ALM compared with SSM. Similarly, the NM histotype was associated with a worse prognosis compared with the SSM histotype (DFS: HR 2.29, 95% CI 2.08-2.52; P < 0.001 and OS: HR 2.21, 95% CI 1.99-2.46; P < 0.001). At multivariable analysis, after adjusting for age, sex, BT, ulceration, and the sentinel lymph node status, a statistically significant worse DFS [adjusted HR (aHR; ALM versus SSM) 1.25, 95% CI 1.02-1.52; P = 0.028] was confirmed for patients with ALM. For patients with NM, instead, no impact of histology was found in terms of DFS [aHR (NM versus SSM) 1.04, 95% CI 0.93-1.15; P = 0.513] and OS [aHR (NM versus SSM) 0.96, 95% CI 0.86-1.08; P = 0.548]. CONCLUSIONS: ALM is associated with a worse long-term DFS. Our results could have important clinical implications for patients' stratification in future clinical trials and the incorporation of ALM histotype in the new AJCC classification as an independent prognostic factor.

FOXO1 is a TXN- and p300-dependent sensor and effector of oxidative stress in diffuse large B-cell lymphomas characterized by increased oxidative metabolism.

Molecular profiling has led to identification of subtypes of diffuse large B-cell lymphomas (DLBCLs) differing in terms of oncogenic signaling and metabolic programs. The OxPhos-DLBCL subtype is characterized by enhanced mitochondrial oxidative phosphorylation. As increased oxidative metabolism leads to overproduction of potentially toxic reactive oxygen species (ROS), we sought to identify mechanisms responsible for adaptation of OxPhos cells to these conditions. Herein, we describe a mechanism involving the FOXO1-TXN-p300 redox-dependent circuit protecting OxPhos-DLBCL cells from ROS toxicity. We identify a BCL6-dependent transcriptional mechanism leading to relative TXN overexpression in OxPhos cells. We found that OxPhos cells lacking TXN were uniformly more sensitive to ROS and doxorubicin than control cells. Consistent with this, the overall survival of patients with high TXN mRNA expression, treated with doxorubicin-containing regimens, is significantly shorter than of those with low TXN mRNA expression. TXN overexpression curtails p300-mediated FOXO1 acetylation and its nuclear translocation in response to oxidative stress, thus attenuating FOXO1 transcriptional activity toward genes involved in apoptosis and cell cycle inhibition. We also demonstrate that FOXO1 knockdown in cells with silenced TXN expression markedly reduces ROS-induced apoptosis, indicating that FOXO1 is the major sensor and effector of oxidative stress in OxPhos-DLBCLs. These data highlight dynamic, context-dependent modulation of FOXO1 tumor-suppressor functions via acetylation and reveal potentially targetable vulnerabilities in these DLBCLs.

Efficacy of neoadjuvant hypofractionated radiotherapy in patients with locally advanced myxoid liposarcoma.

BACKGROUND: Myxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas (STS). The use of preoperative hypofractionated radiotherapy 5 × 5 Gy for five consecutive days, and then immediate surgery in patients with locally advanced STS showed a good local control rate. The main objective of our work was to assess the efficacy of hypofractionated radiotherapy in preoperative setting in patients with locally advanced primary MLPS. METHODS: From February 1999 to March 2014, 32 patients with primary MLPS were treated with preoperative hypofractionated radiotherapy for 5 consecutive days followed by immediate surgery (median dose 5 × 5 Gy). Median size of the tumor 10.5 cm. In one patient the tumor was located on the upper extremity, the other (31 patients) had their tumors located on the lower extremity. RESULTS: In 90% patients histologically negative surgical margins (R0) were obtained. 34% patients had distant recurrence of the disease, local recurrence was found in 9.3% of the patients. 5-year local relapse-free survival rate was 90% and overall survival was 68%. In all analyzed surgical specimens the radiotherapy response features (hyalinization, fibrosis, paucicelularity, hemorrhages, dilatation of vessels) were detected. We have not found statistically significant differences in terms of OS and LRFS for RCC component, tumor grade, BCL2, TP53, postsurgery necrosis and tumor size. In postradiotherapy specimens significantly higher positivity of TP53 expression was detected as compared to primary biopsies. CONCLUSION: Combined therapy with hypofractionated radiotherapy followed by immediate surgery seems to be effective therapy in MLPS demonstrating good local control and pathological response to therapy.