Non-pegylated liposomal doxorubicin plus cyclophosphamide as first-line therapy in elderly women with HER2 negative metastatic breast cancer.

Background: The use of anthracyclines in metastatic breast cancer (MBC) is limited by cumulative dose-dependent cardiotoxicity mostly in elderly women with comorbidities. The aim of this observational retrospective study was to evaluate the efficacy of non-pegylated liposomal doxorubicin (Myocet®) and cyclophosphamide in elderly women as HER2 negative first-line MBC treatment. Methods: 84 elderly women >70 years of age (median age 78 years) with MBC HER2 negative were enrolled. Performance Status in 58 patients was ECOG-0 and in 26 patients was ECOG-1. Results: The drug was well tolerated, with overall response rates were >40%, median overall survival was 16.2 months (95%CI:14.6-18.8) and median progression free survival was 5.8 months (95%CI:4.4-8.6). Hematologic toxicity with neutropenia was the most frequent adverse event, but the treatment was well tolerated maintained a manageable cardiotoxicity. Conclusion: Non-pegylated liposomal doxorubicin may represent a valid therapeutic option in first-line for elderly patients with HER/2 negative MBC improving survival, anti-tumor response rate and de-creases cardiotoxicity.

NEPA (netupitant/palonosetron) for the antiemetic prophylaxis of nausea and vomiting induced by chemotherapy (CINV) with Folfirinox and Folfoxiri even during the COVID-19 pandemic: a real-life study.

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.

Use of Eribulin mesylate as second-line therapy in elderly patients with HER/2 negative metastatic breast cancer (MBC): efficacy, tolerability and Quality of Life.

OBJECTIVE: Eribulin mesylate (Halaven®) is a non-taxane inhibitor of microtubule indicated as monotherapy in patients with metastatic breast cancer (MBC), which progresses after anthracycline and taxanes therapy. In this retrospective observational study, we want to evaluate the efficacy of Eribulin in elderly women with MBC pretreated with anthracyclines and taxanes. PATIENTS AND METHODS: 40 elderly patients > 70 years of age were enrolled, and the median age was 76 years (range 70-82). Overall survival (OS), Progression Free Survival (PFS), Objective Response Rate (ORR) were primary endpoints, tolerability, carcinoembryonic antigen levels 15.3 (Ca 15.3), before and after treatment, and Quality of Life (QoL) were secondary endpoints. RESULTS: Eribulin treatment was well tolerated, produced a good level of disease control, a manageable toxicity profile and a significant impact on QoL. Median OS was 12.8 months and median PFS was 3.2 months. A significant correlation was observed between reduction of Ca 15.3 and PFS with a value of 0.59 (p = 0.002). CONCLUSIONS: Despite a limited number of patients and a modest manageable toxicity, Eribulin is a chemotherapy treatment that has showed to be an effective and well-tolerated therapeutic option in elderly patients with MBC. Further analysis should focus on the elderly patients in our setting of study.

Nivolumab in metastatic melanoma: good efficacy and tolerability in elderly patients.

Background: Nivolumab is an anti-PD-1 antibody that restores the antitumour immune function of T cells, blocking the binding of PD-1 with its ligand PD-L1. PD-1 is expressed on T cells and interacts with PD-L1 on tumour cells. The PD-1-PD-L1 link inhibits T cell activation. In metastatic melanoma, PD-1-PD-L1 binding plays a critical role, and the advent of the immune checkpoint inhibitor nivolumab has delivered new and effective treatment options with proven clinical benefit. In the present study, we evaluated the efficacy of nivolumab in elderly patients with metastatic melanoma. Methods: The study enrolled 55 elderly patients (75 years of age and older) with a diagnosis of metastatic melanoma. Primary endpoints of the study were progression-free survival (pfs) and the objective response rate; secondary endpoints were overall survival, reduction in serum lactate dehydrogenase (ldh) from before to after treatment, and tolerability. Results: Nivolumab was well tolerated and resulted in good disease control, with a manageable toxicity profile and significant clinical benefit. The duration of pfs was 5.1 months (95% confidence interval: 3.5 months to 6.8 months). A significant correlation was observed between reduction in serum ldh and pfs: 0.60 (95% confidence interval: 0.28 to 0.86; p = 0.002). Conclusions: Nivolumab is an immunotherapy treatment that has proved to be an effective and well-tolerated therapeutic option in elderly patients with metastatic melanoma.

Tailoring the optical properties of MoS2 and WS2 single layers via organic functionalization.

Tailoring the structural and electronic properties of 2D materials is fundamental to boost their use in a wide range of technological applications. In this paper, by means of first principles simulations, we show how methyl functionalization of MoS2 and WS2 monolayers can be employed to change their energy gap, tune their optoelectronic properties and modify the relative stability of their structural phases (or polytypes). In particular for both compound monolayers, we find that the most stable semiconducting H phase becomes metallic upon methyl functionalization, while in the metastable T' phase the band gap increases as a function of the -CH3 coverage; correspondingly the phase stability is reversed and the on-set of the optical absorption is blue-shifted.

Distinctive features of tumor-infiltrating γδ T lymphocytes in human colorectal cancer.

γδ T cells usually infiltrate many different types of cancer, but it is unclear whether they inhibit or promote tumor progression. Moreover, properties of tumor-infiltrating γδ T cells and those in the corresponding normal tissue remain largely unknown. Here we have studied features of γδ T cells in colorectal cancer, normal colon tissue and peripheral blood, and correlated their levels with clinicopathologic hallmarks. Flow cytometry and transcriptome analyses showed that the tumor comprised a highly variable rate of TILs (5-90%) and 4% γδ T cells on average, with the majority expressing Vδ1. Most Vδ1 and Vδ2 T cells showed a predominant effector memory phenotype and had reduced production of IFN- Î³ which was likely due to yet unidentified inhibitory molecules present in cancer stem cell secretome. Transcriptome analyses revealed that patients containing abundant γδ T cells had significantly longer 5-year disease free survival rate, suggesting their efficacy in controlling tumor at very early stage.

Risk Perception and Psychological Distress in Genetic Counselling for Hereditary Breast and/or Ovarian Cancer.

Oncological Genetic Counselling (CGO) allows the identification of a genetic component that increases the risk of developing a cancer. Individuals' psychological reactions are influenced by both the content of the received information and the subjective perception of their own risk of becoming ill or being a carrier of a genetic mutation. This study included 120 participants who underwent genetic counselling for breast and/or ovarian cancer. The aim of the study was to examine the relation between their cancer risk perception and the genetic risk during CGO before receiving genetic test results, considering the influence of some psychological variables, in particular distress, anxiety and depression. Participants completed the following tools during a psychological interview: a socio-demographic form, Cancer Risk Perception (CRP) and Genetic Risk Perception (GRP), Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer (DT). The data seem to confirm our hypothesis. Positive and significant correlations were found between the observed variables. Moreover, genetic risk perception determined an increase in depressive symptomatology and cancer risk perception led to an increase in anxious symptomatology, specifically in participants during cancer treatment. The present results suggest the importance of assessing genetic and cancer risk perception in individuals who undergo CGO, to identify those who are at risk of a decrease in psychological well-being and of developing greater psychological distress.

Ramucirumab and its use in gastric cancer treatment.

The inhibition of the mechanisms of tumor neo-angiogenesis represents a milestone that in the last 10 years has seen the advent of numerous molecules to target action against the vascular endothelial growth factor (VEGF). More recently, new molecules have been developed that inhibit tumor spread by the blockade of specific VEGF receptors (VEGFRs), thereby preventing the binding of a ligand to its receptor and the cascade of proliferative events downstream. Ramucirumab is a fully humanized IgG1 monoclonal antibody that performs its action by blocking the isoform 2 of the VEGF receptor (VEGFR-2). Numerous preclinical and clinical studies have demonstrated its activity in several solid tumors, demonstrating a remarkable efficacy in terms of progression-free survival and overall survival in addition to a favorable toxicity profile. This review analyzes in detail the role of ramucirumab in the treatment of advanced gastric and gastroesophageal junction cancers.

Zn vacancy induced green luminescence on non-polar surfaces in ZnO nanostructures.

Although generally ascribed to the presence of defects, an ultimate assignment of the different contributions to the emission spectrum in terms of surface states and deep levels in ZnO nanostructures is still lacking. In this work we unambiguously give first evidence that zinc vacancies at the (1010) nonpolar surfaces are responsible for the green luminescence of ZnO nanostructures. The result is obtained by performing an exhaustive comparison between spatially resolved cathodoluminescence spectroscopy and imaging and ab initio simulations. Our findings are crucial to control undesired recombinations in nanostructured devices.

Targeted therapies in hepatocellular carcinoma.

The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various new target drugs are under developed and other biological treatments normally indicated in other malignancies are under investigation also for HCC. These strategies aim to target the different biological pathways implicated in HCC development and progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugs with standard treatments to achieve improvement in overall survival and quality of life.

Piezoelectric properties of zinc oxide nanowires: an ab initio study.

Nanowires made of materials with non-centrosymmetric crystal structures are expected to be ideal building blocks for self-powered nanodevices due to their piezoelectric properties, yet a controversial explanation of the effective operational mechanisms and size effects still delays their real exploitation. To solve this controversy, we propose a methodology based on DFT calculations of the response of nanostructures to external deformations that allows us to distinguish between the different (bulk and surface) contributions: we apply this scheme to evaluate the piezoelectric properties of ZnO [0001] nanowires, with a diameter up to 2.3 nm. Our results reveal that, while surface and confinement effects are negligible, effective strain energies, and thus the nanowire mechanical response, are dependent on size. Our unified approach allows for a proper definition of piezoelectric coefficients for nanostructures, and explains in a rigorous way the reason why nanowires are found to be more sensitive to mechanical deformation than the corresponding bulk material.

The molecular changes driving the carcinogenesis in Barrett's esophagus: which came first, the chicken or the egg?

Esophageal adenocarcinoma originates from columnar metaplastic epithelium of the distal esophagus. Various steps for this carcinogenetic process are known. Before the onset of high-grade dysplasia and adenocarcinoma, endoscopic surveillance is possible. However, because of the high cost of long-term surveillance, predictive factors for cancer are being evaluated to identify subjects with metaplasia who have a higher risk of developing malignancy. Molecular changes seem suitable for this purpose, but could require a high resource expenditure. While trying to identify the best predictive factors for cancer risk, molecular changes and differences in miRNA expression profile between the various steps leading to cancer could help to clarify Barrett's carcinogenesis. In this attempt to find a molecular explanation for the onset of esophageal adenocarcinoma, it is still difficult to understand whether the molecular changes are causes or effects of the neoplastic phenotypic modifications.

A quantum-mechanical study of the adsorption of prototype dye molecules on rutile-TiO2(110): a comparison between catechol and isonicotinic acid.

In this work we present a theoretical investigation of the attachment of catechol and isonicotinic acid to the rutile-TiO(2)(110) surface. These molecules can be considered as prototypical dyes for use in Grätzel type dye sensitised solar cells (DSCs) and are often employed as anchoring groups in both organic and organo-metallic sensitisers of TiO(2). Our study focuses on determining the lowest energy adsorption mode and discussing the electronic properties of the resultant hybrid interface by means of density functional theory (DFT) calculations using the hybrid exchange (B3LYP) functional. We find that both molecules adsorb dissociatively at the TiO(2) surface giving a type II (staggered) heterojunction. Compared to isonicotinic acid, catechol, due to the greater hybridisation of its molecular orbitals with the states of the substrate, is seen to enhance performance when employed as an anchoring group in dye sensitised solar cells.

Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance?

BACKGROUND: Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. PATIENTS AND METHODS: We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. RESULTS: Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). CONCLUSION: Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options.

MicroRNAs in colorectal cancer stem cells: new regulators of cancer stemness?

Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called 'cancer stem cells' (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy.

Docetaxel plus prednisone in patients with metastatic hormone-refractory prostate cancer: an Italian clinical experience.

AIMS AND BACKGROUND: We investigated the efficacy of docetaxel plus prednisone in Italian patients with metastatic hormone-refractory prostate cancer (mHRPC). METHODS: Twenty four patients with mHRPC received docetaxel 75 mg/m2 every 3 weeks plus prednisone 5 mg twice daily for up to six cycles. The primary endpoint was efficacy measured by a reduction in serum prostate specific antigen (PSA) levels and measurable disease. Evaluation of toxicity, quality of life and reduction of pain were secondary endpoints. RESULTS: PSA response was seen in 18 patients (75%). We observed a partial response in 2 patients (8.3%), stable disease in 10 patients (41.7%), and disease progression in 12 patients (50%). Severe neutropenia was reported in 12.5% of patients. CONCLUSIONS: Treatment with docetaxel every three weeks is an effective and well tolerated therapeutic option in patients with mHRPC.

Hsp10, Hsp70, and Hsp90 immunohistochemical levels change in ulcerative colitis after therapy.

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by damage of large bowel mucosa and frequent extra-intestinal autoimmune comorbidities. The role played in IBD pathogenesis by molecular chaperones known to interact with components of the immune system involved in inflammation is unclear. We previously demonstrated that mucosal Hsp60 decreases in UC patients treated with conventional therapies (mesalazine, probiotics), suggesting that this chaperonin could be a reliable biomarker useful for monitoring response to treatment, and that it might play a role in pathogenesis. In the present work we investigated three other heat shock protein/molecular chaperones: Hsp10, Hsp70, and Hsp90. We found that the levels of these proteins are increased in UC patients at the time of diagnosis and decrease after therapy, supporting the notion that these proteins deserve attention in the study of the mechanisms that promote the development and maintenance of IBD, and as biomarkers of this disease (e.g., to monitor response to treatment at the histological level).

In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients.

The potent anti-tumour activities of gammadelta T cells have prompted the development of protocols in which gammadelta-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vgamma9Vdelta2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vgamma9Vdelta2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers emerged, as seven patients who failed to sustain Vgamma9Vdelta2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vgamma9Vdelta2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatment-refractory patients with advanced breast cancer.