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The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: Fondazione Luigi Maria Monti IDI-IRCCS (RC), Regulatory noncoding RNAs (ncRNAs) are a class of RNAs transcribed by regions of the human genome that do not encode for proteins. The three main members of this class, named microRNA, long noncoding RNA, and circular RNA play a key role in the regulation of gene expression, eventually shaping critical cellular processes. Compelling experimental evidence shows that ncRNAs function either as tumor suppressors or oncogenes by participating in the regulation of one or several cancer hallmarks, including evading cell death, and their expression is frequently deregulated during cancer onset, progression, and dissemination. More recently, preclinical and clinical studies indicate that ncRNAs are potential biomarkers for monitoring cancer progression, relapse, and response to cancer therapy. Here, we will discuss the role of noncoding RNAs in regulating cancer cell death, focusing on those ncRNAs with a potential clinical relevance.

During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanisms to repress p73-mediated cell death. Moreover, p73 isoforms may promote cancer growth by enhancing an anti-oxidative response, the Warburg effect and by repressing senescence. Thus, we speculate that the role of p73 in tumorigenesis can be ambivalent and hence, requires new therapeutic strategies that would specifically repress the oncogenic functions of p73, while keeping its tumor suppressive properties intact.

Background Several studies described post-operative irritative symptoms after laser enucleation of prostate, sometimes associated with urge incontinence, probably linked to laser-induced prostatic capsule irritation, and potential for lower urinary tract infections We aimed to evaluate the efficacy of a suppository based on Phenolmicin P3 and Bosexil (Mictalase®) in control of irritative symptoms in patients undergoing thulium laser enucleation of prostate (ThuLEP). Methods In this single-center, prospective, randomized, open label, phase-III study, patients with indication to ThuLEP were enrolled (Dec2019–Feb2021—Institutional ethics committee STS CE Lazio approval no.1/N-726—ClinicalTrials.gov NCT05130918). The report conformed to CONSORT 2010 guidelines. Eligible patients were 1:1 randomized. Randomization defined Group A: patients who were administered Mictalase® suppositories twice a day for 5 days, then once a day for other 10 days; Group B: patients who did not receive Mictalase® (“controls”). Study endpoints were evaluated at 15 and 30 days postoperation. Primary endpoint included evaluation of effects of the suppository on irritative symptoms by administering IPSS + QoL questionnaire. Secondary endpoint included evaluation of effects on urinary tract infections by performance of urinalysis with urine culture. Results 111 patients were randomized: 56 in Group A received Mictalase®. Baseline and perioperative data were comparable. At 15-days, no significant differences were found in terms of IPSS + QoL scores and urinalysis parameters. A significant difference in the rate of positive urine cultures favored Group A (p = 0.04). At 30-days follow-up, significant differences were found in median IPSS score (6 [IQR 3–11] versus 10 [5–13], Group A vs B, respectively, p = 0.02). Urinalysis parameters and rate of positive urine cultures were not significantly different. Conclusions The present randomized trial investigated the efficacy of Mictalase® in control of irritative symptoms and prevention of lower urinary tract infections in patients undergoing ThuLEP. IPSS improvement 30-days postoperation was more pronounced in patients who received Mictalase®. Lower rate of positive urine culture favored Mictalase® group 15-days postoperatively. Trial registration The clinical trial has been registered on ClinicalTrials.gov on November 23rd, 2021—Registration number NCT05130918.

Serine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole‐genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan‐Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine‐learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning., Since the publication of The Cancer Genome Atlas data in 2013, the advances in the sequencing techniques allowed us to study cancer through whole‐genome sequencing and multiomics approaches. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine learning approaches will be the next step towards personalized approaches for cancer medicine.

The development of the sequencing technologies allowed the generation of huge amounts of molecular data from a single cancer specimen, allowing the clinical oncology to enter the era of the precision medicine. This massive amount of data is highlighting new details on cancer pathogenesis but still relies on tissue biopsies, which are unable to capture the dynamic nature of cancer through its evolution. This assumption led to the exploration of non-tissue sources of tumoral material opening the field of liquid biopsies. Blood, together with body fluids such as urines, or stool, from cancer patients, are analyzed applying the techniques used for the generation of omics data. With blood, this approach would allow to take into account tumor heterogeneity (since the circulating components such as CTCs, ctDNA, or ECVs derive from each cancer clone) in a time dependent manner, resulting in a somehow “real-time” understanding of cancer evolution. Liquid biopsies are beginning nowdays to be applied in many cancer contexts and are at the basis of many clinical trials in oncology.

Chron’s Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn’s disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a TH1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence.

Here we review the development of tivantinib, a selective oral inhibitor of c-MET. The initially identified dose and schedule for clinical use was 360 mg twice daily. Biological considerations and early results suggested its activity against hepatocellular carcinoma after progression on sorafenib. The results of randomized Phase II study in this setting have already been reported; while in the overall population, the risk of progression was reduced by 36% (HR: 0.64; 90% CI: 0.43-0.94; p = 0.04), in the pre-defined MET-high population median overall survival (7.2 vs 3.8 months; p = 0.01), median time to progression (2.7 vs 1.4 months; p = 0.03) as well as disease control rate (50 vs 20%), were increased by tivantinib. During study conduction, tivantinib dose was amended to 240 mg twice daily, due to a high incidence of neutropenia, without losing clinical efficacy. Presently, a global Phase III trial is being conducted.

Aim: Sunitinib is an orally active multi-targeted tyrosine kinase inhibitor that exerts its antitumor effects primarily through the selective inhibition of VEGF. Novel targeted therapies such as sunitinib have transformed the treatment of advanced metastatic renal cell carcinomas, particularly those with clear cell histology. Here, our experience in patients with non-clear cell kidney cancer treated as part of the sunitinib Expanded Access Program is reported. Materials & methods: This was a retrospective assessment of 21 patients with non-clear cell renal cell carcinoma who were treated with oral sunitinib 50 mg/day in repeated 6 weekly cycles (4 weeks on and 2 weeks off). Disease assessment and physical examination were recorded at baseline and tumor assessments were performed every 3 months, according to Response Evaluation Criteria In Solid Tumors. The primary outcome measure was progression-free survival. Results: Patients received an average of 6.38 cycles of sunitinib; one patient was classified as a complete responder and two as partial responders. The overall response rate was 14.3% and clinical benefit was attained by 52.4%. The median progression-free survival was 4.1 months while median overall survival was 14.6 months. In general, sunitinib was well tolerated and only three patients experienced a grade 3 toxicity, which resolved with dosage reduction. Conclusion: As expected, sunitinib exerted lower antitumor activity in patients with non-clear cell renal cell carcinoma than was achieved in the general population with metastatic kidney cancer. However, responses (one complete and two partial) were documented and clinical benefit was observed in more than half of all patients.

Objectives: This study included a cohort of advanced renal cell carcinoma patients treated with sunitinib. Since resistance to sunitinib may be mediated through angiogenic cytokines other than VEGF, we measured the circulating levels of three pro-angiogenic cytokines: basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and interleukin (IL)-6. Methods: Cytokines were measured at baseline and on the first day of each treatment cycle until progression in 85 advanced kidney cancer patients treated with sunitinib using a quantitative sandwich enzyme immunoassay (ELISA) technique. Results: Even though no statistically significant differences in the titers of the three cytokines were observed between baseline and the time of progression in the whole patient cohort, in 45.3, 46.6, and 37.3% of the patients a more than 50% increase between baseline and the time of progression was shown in circulating IL-6, bFGF, and HGF, respectively. Furthermore, this increase was more than 100% in 37.3, 44, and 30.6% of the patients, respectively. We also demonstrated that, in these patients, cytokines tended to increase and to remain high immediately before progression. Conclusions: In a large percentage of kidney cancer patients, progression is preceded by a significant increase in pro-angiogenic cytokines other than VEGF.

Aim: To evaluate the effect of sorafenib on the glucose tolerance and diabetic status of patients with metastatic renal cell carcinoma (RCC) or advanced hepatocellular carcinoma (HCC). Materials & methods: Eighty patients with metastatic RCC or advanced HCC received 400 mg sorafenib twice daily for an average of approximately 8 and 5 months, respectively; 22 had diabetes mellitus and three had prediabetes. Results: One of 55 nondiabetic patients, and one of three patients with impaired fasting glucose or impaired glucose tolerance developed diabetes mellitus, one of 12 patients on oral antihyperglycemic agents switched to insulin and no patient treated with insulin needed to increase their dose. Conclusion: Sorafenib has the potential to be a feasible and safe treatment option for patients with advanced HCC or metastatic RCC and comorbid diabetes mellitus or prediabetes.

The multikinase inhibitors Sunitinib and Sorafenib not only inhibit angiogenesis and tumor growth, but also have the potential of interacting with the function of the immune system.Presently available data seem to suggest that Sorafenib may exert immune suppressive effects, whilst the effects of Sunitinib are not so clear, being immune stimulatory in the vast majority - but not all - the studies reported.Trials of combination of these multikinase inhibitors with different types of immune manipulation - and cellular therapies in particular - should be rationally designed taking into account all these complex effects, which ultimately deserve further insights.

The multikinase inhibitors Sunitinib and Sorafenib not only inhibit angiogenesis and tumor growth, but also have the potential of interacting with the function of the immune system. Presently available data seem to suggest that Sorafenib may exert immune suppressive effects, whilst the effects of Sunitinib are not so clear, being immune stimulatory in the vast majority - but not all - the studies reported. Trials of combination of these multikinase inhibitors with different types of immune manipulation - and cellular therapies in particular - should be rationally designed taking into account all these complex effects, which ultimately deserve further insights.

Store-operated Ca2+entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+levels within the endoplasmic reticulum (ER) Ca2+reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca2+store, but not by InsP3-dependent Ca2+release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI). Neither Gd3+nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors.

The term “angiogenic switch” describes one of the earlier events of tumorigenesis, that occurs when the balance between proand anti-angiogenic factors shifts towards a pro-angiogenic outcome. This leads to the transition from a microscopic indolent lesion to a macroscopic and vascularised primary tumor, that may eventually metastasize and spread to distant sites. The molecular mechanisms underlying such a critical step in the carcinogenetic process have been extensively investigated. Both local endothelial cells (ECs) and endothelial progenitor cells (EPCs), recruited from bone marrow, have been implicated in the angiogenic switch, which is ultimately triggered by a plethora of growth factors released by cancer cells, pivotal among which is vascular endothelial growth factor (VEGF); indeed, VEGF both activates ECs nearby the growing tumor, and leads to EPC mobilization into the circulation. In kidney, in particular, the frequent mutation of the Von Hippel Lindau tumor suppressor gene leads to an overproduction of pro-angiogenic factors which makes this neoplasm quite sensitive to antiangiogenic drugs. However, it is now evident that the use of VEGF(Rs) inhibitors in everyday clinical practice is not as effective as observed in murine models. The investigation of alternative signaling pathways involved in the angiogenic switch is, therefore, imperative in order to induce tumor regression whereby preventing harmful drawback consequences. Ca 2+ entry across the plasma membrane has long been known to stimulate mature ECs to undergo angiogenesis. Recent work from several groups worldwide has then outlined that members of the Transient Receptor Potential (TRP) super-family of cationic channels and Orai1 provide the pathway for such proangiogenic Ca 2+ signal. In addition, Canonical TRP 1 (TRPC1) and Orai1 channels control proliferation and tubulogenesis in both normal EPCs and EPCs isolated from peripheral blood of tumor patients. As a consequence, TRP channels and Orai1 might serve as novel molecular targets to develop alternative and more effective strategies of angiogenesis inhibition.

In the 5th century B.C., Zeno of Elea offered arguments that led to conclusions contradicting what we all know from our experience. The arguments were paradoxes for the ancient philosophers and it took centuries to demonstrate that they were not true. For example, in his Achilles and the tortoise paradox, fast running Achilles races to catch a slower tortoise that has a head start; so, if Achilles hopes to overtake the tortoise, he must run first to the place where the tortoise presently is, but by the time he arrives there, it would have crawled to a new place, so then Achilles must run to this new place, but the tortoise meanwhile will have crawled on, and so forth Achilles will never catch the tortoise, concludes Zeno. From this well known paradox, it appears clearly that from wrong premises come wrong conclusions, something that for years has affected our perception of the role of immunotherapy in kidney cancer.

Renal cell carcinoma (RCC) accounts for the 3% of all solid tumors. Despite continuous improvement in the therapy regimen, less has been achieved in terms of enabling an earlier diagnosis: the neoplasia usually reveals its presence at an advanced stage, obviously affecting prognosis. The most frequent sites of secondary disease are shown to be lungs (50–60%), bone (30–40%), liver (30–40%) and brain (5%); while the head and neck district seems to account for less than 1% of patients with primary kidney lesion. We report here the case of a 70-year old man who presented with acute renal failure due to abdominal recurrence of RCC 18 years post nephrectomy. After a few months of follow up without any systemic therapy due to the renal impairment, the patient presented a vascularized tongue lesion that was demonstrated to be a secondary localization of the RCC. This lesion has, therefore, been treated with microsphere embolization to stop the frequent bleeding and to lessen the unbearable concomitant symptoms it caused, such as dysphagia and pain. A tongue lesion that appears in a RCC patient should always be considered suspect and a multidisciplinary study should be conducted both to assess whether it is a metastasis or a primary new lesion and to understand which method should be selected, if necessary, to treat it (surgery, radiation or embolization). Lingual metastasis should be examined accurately not only because they seem to implicate a poor prognosis, but also because they carry a burden of symptoms that not only threatens patients’ lives but also has a strong impact on their quality of life.

BACKGROUND:Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain tumor vascularisation and promote the metastatic switch. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca(2+) entry (SOCE), which is activated by a depletion of the intracellular Ca(2+) pool, regulates the growth of human EPCs, where is mediated by the interaction between the endoplasmic reticulum Ca(2+)-sensor, Stim1, and the plasmalemmal Ca(2+) channel, Orai1. As oncogenesis may be associated to the capability of tumor cells to grow independently on Ca(2+) influx, it is important to assess whether SOCE regulates EPC-dependent angiogenesis also in tumor patients. METHODOLOGY/PRINCIPAL FINDINGS:The present study employed Ca(2+) imaging, recombinant sub-membranal and mitochondrial aequorin, real-time polymerase chain reaction, gene silencing techniques and western blot analysis to investigate the expression and the role of SOCE in EPCs isolated from peripheral blood of patients affected by renal cellular carcinoma (RCC; RCC-EPCs) as compared to control EPCs (N-EPCs). SOCE, activated by either pharmacological (i.e. cyclopiazonic acid) or physiological (i.e. ATP) stimulation, was significantly higher in RCC-EPCs and was selectively sensitive to BTP-2, and to the trivalent cations, La(3+) and Gd(3+). Furthermore, 2-APB enhanced thapsigargin-evoked SOCE at low concentrations, whereas higher doses caused SOCE inhibition. Conversely, the anti-angiogenic drug, carboxyamidotriazole (CAI), blocked both SOCE and the intracellular Ca(2+) release. SOCE was associated to the over-expression of Orai1, Stim1, and transient receptor potential channel 1 (TRPC1) at both mRNA and protein level The intracellular Ca(2+) buffer, BAPTA, BTP-2, and CAI inhibited RCC-EPC proliferation and tubulogenesis. The genetic suppression of Stim1, Orai1, and TRPC1 blocked CPA-evoked SOCE in RCC-EPCs. CONCLUSIONS:SOCE is remodelled in EPCs from RCC patients and stands out as a novel molecular target to interfere with RCC vascularisation due to its ability to control proliferation and tubulogenesis.

4575 Background: Immunotherapy still remains the only treatment which proved able to induce long-lasting complete responses in aRCC. The aim of the present study was to evaluate the feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous CTLs pulsed with patient-derived tumor cells in heavily pre-treated subjects with aRCC. Methods: This study was performed in accordance with local regulations on the production of cell derivatives; local Ethical Committee approval was obtained on a named patient basis, after obtaining each patient’s informed consent. CTLs were generated stimulating CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with fresh autologous tumor cells in the presence of IL-12 and IL-7; these specific anti-tumor CTLs were expanded and then reinfused after a lymphodepleting chemotherapy with CTX and fludarabine, followed by s.c. administration of low-dose IL-2. Disease status was assessed after every two re-infusions. Eight patients were enrolled, 6 with a clear cell RCC, 1 with a papillary RCC, and 1 with a mixed, papillary and collecting ducts, RCC. All patients have been previously treated with a median of 5 prior treatment lines; the median time between diagnosis of aRCC and tumor biopsy was 55 months (15-185). Results: Six of the 8 enrolled patients have produced suitable tumor cell lines, and 5 of them had been already re-infused with tumor-specific CTLs. All patients received at least 2 CTL infusions (range: 2-5+); mean of totally infused CTLs was 10.7 x 109(range: 4-26.6). All CTLs infusions were well tolerated, with no evidence of autoimmune reactions. In terms of antitumor activity, one patient achieved a partial response, 3 had a slowly progressing disease, and one patient is still not evaluable; furthermore, in 3 patients disease-related symptoms improved. Conclusions: Our preliminary results suggest that immunotherapy with autologous CTLs pulsed ex-vivo with patient-derived tumor cells is feasible and safe in heavily pre-treated aRCC patients. Signs of activity were recorded, suggesting the need to further expand this cohort of patients.