Mixed neuroendocrine non-neuroendocrine tumors:The quest for evidence

Mixed neuroendocrine non-neuroendocrine neoplasms(MiNENs)are rare mixed tumors containing both neuroendocrine and non-neuroendocrine components that occupy at least 30%of the whole tumor.Biologically,both components appear to derive from an identical cellular precursor undergoing early dual differentiation or late transdifferentiation.While our understanding of MiNENs has improved in recent years,many areas of uncertainty remain.In this context,setting diagnostic criteria capable of capturing the continuum of disease biology while providing clinically meaningful information in terms of prognosis and response to treatments appears vital to advance the field and improve patients’outcomes.Evidence is needed to generate robust classification schemes,and multi-institutional cooperation will likely play a crucial role in building adequately powered cohorts to address some of the most pressing questions discussed in this Editorial.What is the minimum representation for each component needed to define MiNENs?How can the epidemiology of MiNENs change according to different diagnostic definitions?How can we generate the clinical evidence nee-ded to optimize the management of MiNENs?

Medical treatment of unresectable hepatocellular carcinoma: Going beyond sorafenib

Even though Sorafenib has radically changed the natural history of those hepatocellular carcinoma patients who are not amenable for curative treatments, further therapeutic improvements are badly needed. As it was for Sorafenib, our increasingly refined understanding of the complex mechanisms underlying HCC carcinogenesis are the starting point for the future development of such treatments. Presently, a number of molecularly targeted agents are in different stages of development for this once orphan cancer. Indeed, several pathways are presently being explored to identify potentially active drugs, including epidermal growth factor receptor, vascular endothelial growth factor/vascular endothelial growth factor receptors, mammalian target of rapamycin, phosphatidyl-inositol-3-kinase/Akt, insulin growth factor, Aurora kinase, Wnt/β-catenin, retinoic acid receptor and hepatocyte growth factor/C-Met. This review is aimed at addressing the results obtained so far with these newer drugs, also considering the challenges we shall face in the near future, including the issue of response evaluation and identification of predictive/ prognostic biomarkers.

Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

First-line pazopanib in patients with advanced non-clear cell renal carcinoma:An Italian case series

BACKGROUND Non-clear cell(ncc)metastatic renal-cell carcinoma(RCC)has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart.New systemic combination therapies have emerged for metastatic RCC(mRCC),but the pivotal phase III trials excluded patients with nccRCC,which constitute about 30%of metastatic RCC cases.AIM To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup.METHODS The present study is a multicenter retrospective observational analysis aiming to assess the activity,efficacy,and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting.RESULTS Overall,48 patients were included.At the median follow-up of 40.6 mo,the objective response rate was 27.1%,the disease control rate was 83.3%,and the median progression-free survival and overall survival were 12.3(95%confidence interval[CI]:3.6-20.9)and 27.7(95%CI:18.2-37.1)mo,respectively.Grade 3 adverse events occurred in 20%of patients,and no grade 4 or 5 toxicities were found.CONCLUSION Pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.

Renal cell carcinoma and viral infections:A dangerous relationship?

Virus-related cancers in humans are widely recognized,but in the case of renal cancer,the link with the world of viruses is not clearly established in humans,despite being known in animal biology.In the present review,we aimed to explore the literature on renal cell carcinoma(RCC)for a possible role of viruses in human RCC tumorigenesis and immune homeostasis,hypothesizing the contribution of viruses to the immunogenicity of this tumor.A scientific literature search was conducted using the PubMed,Web of Science,and Google Scholar databases with the keywords“virus”or“viruses”or“viral infection”matched with(“AND”)“renal cell carcinoma”or“kidney cancer”or“renal cancer”or“renal carcinoma”or“renal tumor”or“RCC”.The retrieved findings evidenced two main aspects testifying to the relationship between RCC and viruses:The presence of viruses within the tumor,especially in non-clear cell RCC cases,and RCC occurrence in cases with pre-existing chronic viral infections.Some retrieved translational and clinical data suggest the possible contribution of viruses,particularly Epstein-Barr virus,to the marked immunogenicity of sarcomatoid RCC.In addition,it was revealed the possible role of endogenous retrovirus reactivation in RCC oncogenesis,introducing new fascinating hypotheses about this tumor’s immunogenicity and likeliness of response to immune checkpoint inhibitors.

Clinical resistance predictors to first-line VEGFR-TKI monotherapy for metastatic renal cell carcinoma: a retrospective multicenter real-life case series

Aim:For many years,systemic treatment of metastatic Renal Cell Carcinoma(mRCC)was based on sequential targeted agent monotherapies.In this real-life case series,we evaluated easily accessible clinical factors useful for disease course prediction.Methods:We exploited patients'clinical pathological characteristics and systemic treatment outcomes in a real-world population of 365 mRCC patients who received sequential monotherapies in the targeted therapy era,and we identified an early progressors subpopulation,resistant to first-line VEGFR-TKI monotherapy in less than 6 months.Results:Early progressors(n=124)show a far worse OS compared with patients progressing beyond the sixth month of therapy(13.5 vs.44.8 months,P-value<0.0001,HR=0.41,95%CI:0.29-0.53).However,these patients did not show far worse performance in second and third-line settings compared to first-line responders.In the univariate analysis,IMDC risk class,sarcomatoid features,and Systemic Inflammation Index(SII)were correlated with first-line therapy Progression-Free Survival(PFS1).In multivariate analysis,variables correlated with first-line outcome were IMDC risk class,histotype,and number of metastatic sites at the diagnosis.Conclusion:Real-world data can contribute to developing easy-to-use prognostic factors associated with refractory disease that could support clinicians in identifying the most appropriate treatment strategy for each patient.

Recent advances in the frontline treatment of metastatic renal cell carcinoma

We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma,and to provide criteria-though often subjective-which could be used for treatment selection,by means of a critical review of the results of novel trials of immune-based combinations,coupled with personal considerations and experiences.To date,5 immune-based combinations have been tested within large phase III trials;four of them yielded a significant overall survival benefit(Ipilimumab+Nivolumab,Pembrolizumab+Axitinib,Nivolumab+Cabozantinib and Pembrolizumab+Lenvatinib),while the combination of Avelumab+Axitinib,although reaching study primary endpoint,determined just a significant progression-free survival benefit.In terms of safety,the excess of adverse events is overall counterbalanced to the higher activity of the combinations.Overall,all the discussed immune-based combinations were ultimately approved by different regulatory authorities,and are indeed included in the most important international guidelines.Waiting for longer follow-ups and more mature trial data,as well as for real-world experiences,in the absence of validated biomarkers,our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons,personal preferences,and experience.