miR-93-5p Suppresses Ovarian Cancer Malignancy and Negatively Regulate CCND2 By Binding To Its 3’UTR Region

Ovarian cancer is the most lethal gynecological cancer worldwide, but the underlying mechanism of ovarian cancer malignancy acquirement is largely unknown. miRNA is ubiquitously implicated in disease especially in cancer initiation and progression. In current study, we firstly detected the expression level of miR-93-5p in ovarian cancer patient samples and conducted a survival analysis. Our data revealed miR-93-5p is a favorable prognostic factor but is downregulated in ovarian cancer patients. Secondly, CCK8 assay wound healing assay and flow cytometry-based cell cycle analysis and apoptotic cell analysis were performed respectively to study the function of miR-93-5p. Functional analysis show miR-93-5p promotes ovarian cancer malignancy in term of cell proliferation, migration but reduce cell death. Bioinformatic analysis showed Cyclin-D2(CCND2) is a candidate gene of miR-93-5p with the binding site in its 3’UTR region. Furthermore, quantitive-PCR and western blot were utilized to measure miR-93-5p, CCND2 levels in tissues samples and cell lines. Our data suggested miR-93-5p is negatively correlated to the level of CCND2 mRNA and protein. Finally, Luciferase report assay was conducted, and we demonstrated miR-93-5p reduces CCND2 expression by binding to the 3’UTR region. Our study revealed the function of miR-93-5p in ovarian cancer malignancy and declaimed CCND2 as a target of miR-93-5p.

Dermatological toxicity of EGFR inhibitors: pathogenetic rationale and an algorithm for acne-like rash correction

Therapy with epidermal growth factor receptor (EGFR) inhibitors is inevitably accompanied by the phenomena of dermatological toxicity. Being, on the one hand, a favorable prognostic factor for the effectiveness of anticancer therapy, these adverse events are one of the most frequent indications for treatment withdrawal. This article presents the clinical characteristics of a wide spectrum of dermatological adverse events, as well as the pathogenetic rationale for their correction. Algorithms for prescribing of external and systemic therapy based on the assessment of severity of skin lesions and skin appendages involvement are presented.

Occult Nodal Metastasis Defined by PET-CT Identifies a Unique Clinical Subtype of Lung Cancer: A Retrospective Multicenter Study

PurposeTo investigate the surgical prognosis and efficacy of adjuvant therapy in non-small cell lung cancer (NSCLC) with occult lymph node metastasis (ONM) defined by positron emission tomography-computed tomography (PET-CT).MethodsA total of 3537 NSCLC patients receiving surgical resection were included in this study. The prognosis between patients with ONM and evident nodal metastasis, ONM patients with and without adjuvant therapy were compared, respectively.ResultsONM was associated with significantly better prognosis than evident nodal metastasis whether for patients with N1 (5-year OS: 56.8% versus 52.3%, adjusted p value=0.267; 5-year RFS: 44.7% versus 33.2%, adjusted p value=0.031) or N2 metastasis (5-year OS: 42.8% versus 32.3%, adjusted p value=0.010; 5-year RFS: 31.3% versus 21.6%, adjusted p value=0.025). In ONM population, patients receiving adjuvant therapy yielded better prognosis comparing to those without adjuvant therapy (5-year OS: 50.1% versus 33.5%, adjusted p value<0.001; 5-year RFS: 38.4% versus 22.1%, adjusted p value<0.001). ConclusionsONM defined by PET-CT identifies a unique clinical subtype of lung cancer, ONM is a favorable prognostic factor whether for pathological N1 or N2 NSCLC and adjuvant therapy could provide additional survival benefits for ONM patients.

Vitiligo-Specific Soluble Biomarkers as Early Indicators of Response to Immune Checkpoint Inhibitors in Metastatic Melanoma Patients

Background: Immunotherapy with checkpoint inhibitors strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select patients who would respond to this therapy is of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of immunotherapy and a favorable prognostic factor for overall survival, we analyzed known soluble biomarkers of vitiligo to validate them as early indicators of response to checkpoint inhibitors in metastatic melanoma.Methods: Fifty-seven patients with metastatic melanoma receiving anti-PD-1 checkpoint inhibitor immunotherapy were enrolled. Patient sera and plasma were evaluated for vitiligo biomarkers at pre-treatment and after 1 and 3 months of therapy. Patients were divided and analyzed according to the best overall response to treatment. Characteristic vitiligo proteins were analyzed by ELISA, while expression of circulating microRNAs, distinctive of vitiligo, was determined using real-time RT-PCR.Results: Basal serum CD25 levels were higher in stable and responder melanoma patients and remained higher during the first 3 months of anti-PD-1 therapy compared to non-responder patients. The chemokine CXCL9 was absent in non-responder patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responder compared to non-responder patients. Finally, higher levels of miR-19b, miR-25 and miR-16 were observed after 1 month of therapy in plasma of stable and responder compared to non-responder patients.Conclusions: Serum levels of CD25 and CXCL9 before and during the first months of treatment could represent biomarkers of response to anti-PD-1 immunotherapy in metastatic melanoma patients. Plasmatic miR-19b, miR-25 and miR-16 could also represent possible early biomarkers of response to anti-PD-1 treatment, but they must be validated in a higher number of patients.

Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy

BackgroundPancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. Immunotherapy has achieved success in the treatment of multiple malignancies. However, the efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. In this research, we aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy.MethodsA training cohort of 149 PDAC samples from The Cancer Genome Atlas (TCGA) with mRNA expression data was analyzed. By means of non-negative matrix factorization (NMF), we virtually dissected the immune-related signals from bulk gene expression data. Detailed immunogenomic and survival analyses of the immune molecular subtypes were conducted to determine their biological and clinical relevance. Validation was performed in five independent datasets on a total of 615 samples.ResultsApproximately 31% of PDAC samples (46/149) had higher immune cell infiltration, more active immune cytolytic activity, higher activation of the interferon pathway, a higher tumor mutational burden (TMB), and fewer copy number alterations (CNAs) than the other samples (all P &lt; 0.001). This new molecular subtype was named Immune Class, which served as an independent favorable prognostic factor for overall survival (hazard ratio, 0.56; 95% confidence interval, 0.33-0.97). Immune Class in cooperation with previously reported tumor and stroma classifications had a cumulative effect on PDAC prognostic stratification. Moreover, programmed cell death-1 (PD-1) inhibitors showed potential efficacy for Immune Class (P = 0.04). The robustness of our immune molecular subtypes was further verified in the validation cohort.ConclusionsBy capturing immune-related signals in the PDAC tumor microenvironment, we reveal a novel molecular subtype, Immune Class. Immune Class serves as an independent favorable prognostic factor for overall survival in PDAC patients.

High PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor in urothelial carcinoma

Aims: To explore the prognostic value of high PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC) in urothelial carcinoma (UC). Patients & methods: 162 UC specimens were evaluated for PD-L1 expression on TIIC and TC with the SP263 assay. High PD-L1 expression was defined as ≥25% staining. Results: High PD-L1 expression on TC in UC patients with stage T1–4 disease was associated with poor overall survival. However, high PD-L1 expression on TIIC in UC patients with stage T1–4 disease revealed favorable disease-free and overall survival; more significant differences were observed in patients with stages T2–4. Multivariate analysis revealed that high PD-L1 expression on TIIC was an independent prognostic predictor for better disease-free and overall survival. Conclusion: High PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in UC.

Nicht kleinzelliges Lungenkarzinom: Die Rolle immunassoziierter unerwünschter Ereignisse im Hinblick auf die Prognose und Wirksamkeit bei Patienten unter Immuntherapie

<b>Purpose:</b> The development of immune-related adverse events (irAEs) in patients undergoing immunotherapy has been reported to be a favorable prognostic factor in several studies. We aimed to examine the correlation between irAEs and prognosis in patients with non-small cell lung cancer (NSCLC) and further reveal the patient characteristics associated with response to immunotherapy among treatment responders who developed irAEs. <b>Methods:</b> We retrospectively enrolled 80 patients with NSCLC who received immunotherapy at Shinshu University Hospital between February 2016 and February 2020. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and those without irAEs. We examined the prognostic factors associated with PFS and OS using univariate and multivariate Cox proportional-hazards models. We further analyzed the patients who developed irAEs by classifying them into responders and non-responders. <b>Results:</b> Twenty-five patients developed irAEs. The median PFS and OS of the patients with irAEs were significantly longer than those of the patients without irAEs (6.8 vs. 1.9 months, <i>p</i> &#x3c; 0.001, and 37.8 vs. 8.1 months, <i>p</i> &#x3c; 0.001, respectively). Multivariate analysis associated with PFS and OS indicated that the development of irAEs was an independent favorable prognostic factor. Among the patients developing irAEs, the responder group had a significantly higher incidence of multiple irAEs than the non-responder group (41.7 vs. 0.0%, <i>p</i> = 0.009). <b>Conclusion:</b> Our findings revealed that the development of irAEs was associated with clinical benefits in NSCLC patients who received immunotherapy. In particular, patients with multiple irAEs might have good prognoses.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.