The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.

Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study.

BACKGROUND: cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. METHODS: The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. RESULTS: From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. CONCLUSIONS: This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

Combination of immunotherapy, radiotherapy and denosumab as the best approach even for NSCLC poor prognosis patients: a case report with strong response, prolonged survival and a review of literature.

Non-Small Cell Lung Cancer (NSCLC) with bone metastasis and poor performance status has the worst prognosis even in strong PD-L1 expression patients. Treatment approach includes immuno- or chemo-immunotherapy, Radiotherapy (RT) and Bone-Targeted Therapy (BTT) but there is insufficient data to suggest the best time to use each of them, alone or in combination. Using an integrated and synergistic treatment strategy with immunotherapy, radiotherapy, and Denosumab as BTT is probably the best treatment planning for metastatic NSCLC for both good and poor performance status patients, although more data are needed to confirm this approach. Here we describe an interesting case report on patient with extensive bone involvement from NSCLC and PS >2 treated simultaneously with radiotherapy, immunotherapy and BTT, achieving an excellent clinical benefit, radiological and metabolic complete response, as a sort of Lazarus effect. We analyzed our result comparing with currently published data about radio-immunotherapy or immunotherapy and BTT combination even though there is no published experience about integration of all 3 treatments. Approval studies often do not represent real-world experience (RWE), so we analyzed data from both RWE and clinical trials.

Look at This Swelling: Retroauricular Mass as Atypical Progression in Long-Survivor Endometrial Endometrioid Adenocarcinoma.

Endometrial endometrioid adenocarcinoma is the most common histology in gynecological malignancies. Most women present loco-regional relapsing or peritoneal and liver involvement within three years from diagnosis. However long-survivor patients may be affected by atypical disease evolutions. Here we describe an extremely rare case of retroauricular metastasis in a patient affected by endometrial endometrioid adenocarcinoma, who had a total abdominal hysterectomy and bilateral salpingo-oophorectomy six years earlier and subsequent salvage surgery three years later for loco-regional relapsed disease.

[Abiraterone acetate: a novel therapeutic option in hormone-refractory prostate cancer]. / Una nuova opzione terapeutica nel carcinoma prostatico ormonorefrattario.

Until recently, only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer. With approvals of sipuleucel-T, cabazitaxel, and abiraterone acetate, all based on improvement in overall survival, the scenary for management of men with metastatic prostate cancer has dramatically changed. Abiraterone acetate was developed to specifically inhibit cytochrome P450 (CYP)17A1, which is an essential enzyme in the biosynthesis of testosterone. In the phase III, the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration-resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile, which was generally similar to that of the placebo plus prednisone group. However, adverse events resulting from elevated mineralocorticoid levels because of CYP17A1 inhibition, fluid retention and oedema, hypokalaemia, hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone.

[Retroperitoneal schwannoma: a case report]. / Un caso di schwannoma retroperitoneale.

Schwannomas are degenerate peripheral nerve sheath tumors that very rarely occur in the retroperitoneum. They are usually benign than malignancy is very rare and is usually observed in patients with von Recklinghausen disease. We report a case of female adult patient who presented with vague abdominal discomfort. The preoperative diagnosis was difficult and the treatment was complete surgical excision. The patient is with no evidence of recurrence more than four years after surgery.

Second-line intra-arterial chemotherapy in advanced pancreatic adenocarcinoma.

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Phase II study of neoadjuvant concurrent chemioradiotherapy with oxaliplatin-containing regimen in locally advanced rectal cancer.

UNLABELLED: The purpose of this phase II trial was to assess tolerance and efficacy of the combination of radiation, fluorouracil and oxaliplatin as neoadjuvant treatment in locally advanced rectal cancer. Between March 2001 and August 2004 , 28 patients M/18 F/10 with locally advanced rectal cancer were entered in our study. All the patients underwent to the Radiotherapy with a total dose was 45 Gy and concurrent chemotherapy with Oxaliplatin 80 mg/mq G1 on weeks 1,3,5 followed by five day continuous infusion of 5-Fluorouracile 300 mg/mq on five consecutive weeks. Surgery was planned 5 weeks later. Surgery was performed in all patients after a mean interval time of 5 weeks. Side effects and toxicity included grade II sec WHO diarrhea and grade II mucositis , grade I-II dysuria and skin reaction Downstaging to T0-2N0 was achieved in 18 patients (65%) with 4 (15%) achieving a pathologically complete response. CONCLUSIONS: Such a combined preoperative chemioradiotherapy and oxaliplatin-containing regimen is well tolerated with non increase in surgical toxicity. The good response rate observed warrants its use in further clinical trials.

[Thrombotic thrombocytopenic purpura in patient with metastatic occult adenocarcinoma. A case report]. / Un caso di porpora trombotica trombocitopenica in paziente con adenocarcinoma metastatico.

In the past two decades, in addition to idiopathic thrombotic thrombocytopenic purpura (TTP) more cases of secondary TTP have been identified, perhaps due to an enthusiasm for cure potential with an availability of exchange-plasmapheresis. An early diagnosis is important, because the evaluation of patients with suspected thrombotic thrombocytopenic purpura is difficult since the diagnostic criteria, thrombocytopenia, microangiopathic haemolytic anemia and no other clinically apparent etiology are not specific.

[Neuroendocrine features of prostatic tumors: state of the art]. / Aspetti neuroendocrini del tumore della prostata: stato dell'arte.

Neuroendocrine (NE) differentiation in prostate cancer has received much attention recently because it has been found to be associated with androgen independence and shortened patient survival in some studies. The present review focuses on morphogenics origins of NE cells, growth properties and the androgen receptor status and relationship between NE-secreted products and regulation of angiogenesis and apoptosis.