Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer.

Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1-4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7-11. Treatment combining 1 mg kg-1 nivolumab with 3 mg kg-1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy. METHODS: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response. RESULTS: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab. CONCLUSIONS: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).

Resistance to hormone therapy in breast cancer cells promotes autophagy and EGFR signaling pathway.

Breast cancer is the leading cause of cancer deaths for women worldwide. Endocrine therapies represent the cornerstone for hormone-dependent breast cancer treatment. However, in many cases, endocrine resistance is induced with poor prognosis for patients. In the current study, we have developed MCF-7 cell lines resistant to fulvestrant (MCF-7Fulv) and tamoxifen (MCF-7Tam) aiming at investigating mechanisms underlying resistance. Both resistant cell lines exerted lower proliferation capacity in two-dimensional (2-D) cultures but retain estrogen receptor α (ERα) expression and proliferate independent of the presence of estrogens. The established cell lines tend to be more aggressive exhibiting advanced capacity to form colonies, increased expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and heterodimerization of ERBB family receptors and activation of EGFR downstream pathways like MEK/ERK1/2 and PI3K/AKT. Tyrosine kinase inhibitors tested against resistant MCF-7Fulv and MCF-7Tam cells showed moderate efficacy to inhibit cell proliferation, except for lapatinib, which concomitantly inhibits both EGFR and HER2 receptors and strongly reduced cell proliferation. Furthermore, increased autophagy was observed in resistant MCF-7Fulv and MCF-7Tam cells as shown by the presence of autophagosomes and increased Beclin-1 levels. The increased autophagy in resistant cells is not associated with increased apoptosis, suggesting a cytoprotective role for autophagy that may favor cells' survival and aggressiveness. Thus, by exploiting those underlying mechanisms, new targets could be established to overcome endocrine resistance.NEW & NOTEWORTHY The development of resistance to hormone therapy caused by both fulvestrant and tamoxifen promotes autophagy with concomitant apoptosis evasion, rendering cells capable of surviving and growing. The fact that resistance also triggers ERBB family signaling pathways, which are poorly inhibited by tyrosine kinase inhibitors might attribute to cells' aggressiveness. It is obvious that the development of endocrine therapy resistance involves a complex interplay between deregulated ERBB signaling and autophagy that may be considered in clinical practice.

A plain language summary of the CheckMate 649 study: nivolumab in combination with chemotherapy compared to chemotherapy alone for untreated advanced or metastatic cancer of the stomach or esophagus.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the 1-year results of a clinical research study known as CheckMate 649 published in The Lancet in June 2021. The 2-year results on the participants' health and overall quality of life from the same study are in a second publication in Nature in March 2022. Until recently, chemotherapy was the only first treatment option for people with advanced or metastatic gastroesophageal adenocarcinoma who had not been treated before. Patients receiving chemotherapy lived on average for less than 1 year. Nivolumab is an immunotherapy that works by activating a person's immune system to fight back against cancer cells. The goal of CheckMate 649 was to find out if the combination of nivolumab and chemotherapy would help patients with advanced or metastatic gastroesophageal adenocarcinoma live longer and without their cancer getting worse. WHAT WERE THE RESULTS?: Results from the final analysis are reported here. Of 1581 people who took part in the study, 789 received nivolumab and chemotherapy and 792 received chemotherapy. Researchers found that, on average, participants who received nivolumab and chemotherapy lived longer overall than those who received chemotherapy alone. The length of time participants lived without their cancer getting worse was also longer on average with nivolumab and chemotherapy than chemotherapy treatment alone. However, more participants in the nivolumab and chemotherapy group had side effects than those in the chemotherapy group. The three most common side effects in both types of treatment were nausea (urge to vomit), diarrhea and peripheral neuropathy. Participants who received nivolumab and chemotherapy had a lower risk of their cancer symptoms worsening and reported that they were 'less bothered' from side effects of treatment than those receiving chemotherapy alone. WHAT DO THE RESULTS MEAN?: The nivolumab and chemotherapy combination is considered a new standard treatment option and is approved in several countries as a treatment for adults who have not been treated before for their advanced or metastatic gastroesophageal cancer based on results from CheckMate 649. Clinical Trial Registration: NCT02872116 (ClinicalTrials.gov).

An Insight into the Arising Role of MicroRNAs in Hepatocellular Carcinoma: Future Diagnostic and Therapeutic Approaches.

Hepatocellular carcinoma (HCC) constitutes a frequent highly malignant form of primary liver cancer and is the third cause of death attributable to malignancy. Despite the improvement in the therapeutic strategies with the exploration of novel pharmacological agents, the survival rate for HCC is still low. Shedding light on the multiplex genetic and epigenetic background of HCC, such as on the emerging role of microRNAs, is considered quite promising for the diagnosis and the prediction of this malignancy, as well as for combatting drug resistance. MicroRNAs (miRNAs) constitute small noncoding RNA sequences, which play a key role in the regulation of several signaling and metabolic pathways, as well as of pivotal cellular functions such as autophagy, apoptosis, and cell proliferation. It is also demonstrated that miRNAs are significantly implicated in carcinogenesis, either acting as tumor suppressors or oncomiRs, while aberrations in their expression levels are closely associated with tumor growth and progression, as well as with local invasion and metastatic dissemination. The arising role of miRNAs in HCC is in the spotlight of the current scientific research, aiming at the development of novel therapeutic perspectives. In this review, we will shed light on the emerging role of miRNAs in HCC.

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.

BACKGROUND: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone. METHODS: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116. FINDINGS: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified. INTERPRETATION: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients. FUNDING: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.

Immunotherapy for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a 2021 update.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

Low concentrations of bisphenol A promote the activation of the mitochondrial apoptotic pathway on Beta-TC-6 cells via the generation of intracellular reactive oxygen species and mitochondrial superoxide.

Τhe natural history of type 2 diabetes mellitus is characterized by a progressive loss of pancreatic beta cell function and insulin resistance. Bisphenol A (BPA) is an endocrine-disrupting chemical that is used widely in industry; people are exposed to BPA and its products daily. Studies have delineated that BPA alters the function of pancreatic beta cells. Herein, we examined the effect of low doses of BPA on pancreatic beta cell viability and apoptosis and we tried to elucidate the mechanisms involved in these processes. Beta-TC-6 (ATCC® CRL-11506™) cells were cultured with a medium containing the following dilutions of BPA: 0.002, 0.02, 0.1, 0.2, 2 µΜ up to 72 h. We examined the viability and adenosine triphosphate (ATP) levels of cells. Then, we measured apoptosis, cell cycle, and insulin levels. We quantified the levels of proteins implicated in the mitochondrial pathway of apoptosis; and finally, we quantified the intracellular reactive oxygen species and mitochondrial superoxide. We found that the exposure of Beta-TC-6 cells to BPA results in a decrease in cell viability, ATP levels, and an increase in insulin levels. We found an increase in apoptosis levels and a decrease in cell cycle levels. In addition, we provide evidence of the levels of apoptotic proteins. Finally, we found an increase in the cellular reactive oxygen species and mitochondrial superoxide production. Exposure to low concentrations of BPA triggers the mitochondrial pathway of apoptosis via the generation of intracellular reactive oxygen species and mitochondrial superoxide on Beta-TC-6 cells in a dose-dependent way.

Immune Microenvironment and Immunotherapeutic Management in Virus-Associated Digestive System Tumors.

The development of cancer is a multifactorial phenomenon, while it constitutes a major global health problem. Viruses are an important factor that is involved in tumorigenesis and is associated with 12.1% of all cancer cases. Major examples of oncogenic viruses which are closely associated with the digestive system are HBV, HCV, EBV, HPV, JCV, and CMV. EBV, HPV, JCV, and CMV directly cause oncogenesis by expressing oncogenic proteins that are encoded in their genome. In contrast, HBV and HCV are correlated indirectly with carcinogenesis by causing chronic inflammation in the infected organs. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as several growth factors, cytokines, and other tumor-secreted molecules that play a key role in tumor growth, progression, and migration, while they are closely interrelated with the virus. The presence of T-regulatory and B-regulatory cells in the tumor microenvironment plays an important role in the anti-tumor immune reaction. The tumor immune microenvironments differ in each type of cancer and depend on viral infection. The alterations in the immune microenvironment caused by viruses are also reflected in the effectiveness of immunotherapy. The present review aims at shedding light on the association between viruses and digestive system malignancies, the characteristics of the tumor immune microenvironment that develop, and the possible treatments that can be administered.

Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer-Current Treatment Options and Future Perspectives.

Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules.

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1-2% of gastrointestinal neoplasms. About 75-80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5-10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10-15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

Combinatorial Treatment of Tinzaparin and Chemotherapy Can Induce a Significant Antitumor Effect in Pancreatic Cancer.

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.

Are cystic fibrosis mutation carriers a potentially highly vulnerable group to COVID-19?

Undoubtedly, the new SARS-CoV-2 virus poses a grave health threat, plaguing the health and socio-economic sectors. COVID-19 disease must be treated quickly and effectively as soon as possible. The main axes in this direction are establishing vaccines, drugs, diagnostic tests, as well as identifying the most vulnerable groups. Probably, there is a correlation between COVID-19 and cystic fibrosis. Our interest is focused on cystic fibrosis carriers that, due to limited tests, remain undetectable. There is an activation of the inflammatory response in the carriers, as well as in cystic fibrosis patients. First of all, a striking similarity lies between the inflammatory response in COVID-19 and cystic fibrosis carriers. Notably, ACE-2 plays the same role in both cases and a similar geographical distribution is observed in both diseases. In conclusion, we suggest that cystic fibrosis mutation carriers are potential members of a certain vulnerable group and the detection of such mutations in the population might be vital for the prevention of SARS-CoV-2 virus, and more specifically to limit its serious complications.

Inhibition of c-MET increases the antitumour activity of PARP inhibitors in gastric cancer models.

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Activation of c-MET increases tumour cell survival through the initiation of the DNA damage repair pathway. PARP is an essential key in the DNA damage repair pathway. The primary role of PARP is to detect and initiate an immediate cellular response to single-strand DNA breaks. Tumours suppressor genes such as BRCA1/2 are closely associated with the DNA repair pathway. In BRCA1/2 mutations or deficiency status, cells are more likely to develop additional genetic alterations and chromosomal instability and can lead to cancer. In this study, we investigate the role of c-MET and PARP inhibition in a gastric cancer model. We exploited functional in vitro and in vivo experiments to assess the antitumour potential of co-inhibition of c-MET (SU11274) and PARP (NU1025). This leads to a reduction of gastric cancer cells viability, especially after knockdown of BRCA1/2 through apoptosis and induction of γ-Η2ΑΧ. Moreover, in AGS xenograft models, the combinatorial treatment of NU1025 plus SU11274 reduced tumour growth and triggers apoptosis. Collectively, our data may represent a new therapeutic approach for GC thought co-inhibition of c-MET and PARP, especially for patients with BRCA1/2 deficiency tumours.

Autophagy and salivary gland cancer: A putative target for salivary gland tumors.

Salivary gland carcinomas are a group of heterogeneous tumors of different histological subtypes, presenting relatively low incidence but the entire variable of types. Although novel treatment options for salivary gland carcinomas patients' outcomes have improved, the treatment of this type of cancer is still not standardized. In addition, a significant number of patients, with a lack of optimal treatment strategies, have reduced survival. In the last two decades, a plethora of evidence pointed to the importance of autophagy, an essential catabolic process of cytoplasmatic component digestion, in cancer. In vitro and in vivo studies highlight the importance of autophagy in salivary gland carcinomas development as a tumor suppressor or promoter mechanism. Despite the potential of autophagy in salivary gland carcinomas development, no therapies are currently available that specifically focus on autophagy modulation in salivary gland carcinomas. In this review, we summarize current knowledge and clinical trials in regard to the interplay between autophagy and the development of salivary gland carcinomas. Autophagy manipulation may be a putative therapeutic strategy for salivary gland carcinomas patients.

Alveolar bone histological necrosis observed prior to extractions in patients, who received bone-targeting agents.

OBJECTIVE: We reported the alveolar bone histology prior to dental extractions in cancer patients, who received bone-targeting agents (BTA). SUBJECTS AND METHODS: Fifty-four patients were included. Patients underwent extractions, and bone biopsies were taken. RESULTS: Extractions were performed due to pain, swelling, purulence, fistula, and numbness, not responding to treatment, in 40 patients (group A); extractions due to asymptomatic, non-restorable teeth, were performed in 14 patients (group B). Complete alveolar jaw bone histological necrosis was observed in 28 of 40 (70%) patients of group A and none of group B (p < .001). The development of clinical osteonecrosis (MRON) was assessed in 44 patients; 10 patients, who were also treated with Low Level Laser Treatments-LLLT, were excluded from this analysis, as the alternative therapies were a confounding factor. Twelve patients, with alveolar bone histological necrosis prior to extraction, developed medication-related osteonecrosis of the jaw (MRONJ) compared with two patients with vital or mixed vital/non-vital bone (p < .0007). BTAs >1 year and concurrent targeted therapy were also significantly associated with MRONJ (p = .016 and p = .050). CONCLUSION: Pain, swelling, purulence, fistula, and numbness were significantly associated with complete bone histological necrosis prior to extractions and increased MRONJ development. Research is justified to explore whether histological necrosis represents an early stage of osteonecrosis.

The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL.

The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK's involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging.

The Impact of Angiogenesis in the Most Common Salivary Gland Malignant Tumors.

Salivary gland carcinomas (SGCs) represent a group of rare tumors, with complete surgical resection being the main treatment option. Therapeutic armory for cases of locally aggressive, recurrent, and/or metastatic SGCs, though, remains poor since they exhibit high rates of resistance to systematic therapy. Angiogenesis is considered one of the contemporary hallmarks of cancer and anti-angiogenic factors have already been approved for the treatment of several cancer types. This review aims to summarize, in a histotype-specific manner, the most current available data on the angiogenic factors implicated in SGC angiogenesis, in order to highlight the differences between the most common SGC histotypes and the factors that may have a potential role as therapeutic targets.

Androgen Receptor in Breast Cancer-Clinical and Preclinical Research Insights.

The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.

Combining RANK/RANKL and ERBB-2 targeting as a novel strategy in ERBB-2-positive breast carcinomas.

BACKGROUND: ERBB-2 is overexpressed in about 20% of breast cancers (BCs), indicating poor prognosis. The receptor activator of nuclear factor-κB (RANK) pathway is implicated in ERBB-2 (+) BC. The purpose of this study was to elucidate the underlying molecular mechanism of this interaction and the beneficial impact of dual targeting of RANK and ERBB-2 pathways. METHODS: We used SKBR3, MCF7, MDA-MB-453, and BT-474 human BC cell lines. We examined RANK and RANKL expression using RT-PCR, Western blot, and immunofluorescence. The evaluation of RANK expression in a cohort of BC patients was performed using immunohistochemistry. The interaction between RANK and ERBB family members was detected using proximity ligation assay (PLA), which enables the visualization of interacting proteins. We used inhibitors of both pathways [trastuzumab (T), pertuzumab (P), denosumab (D)]. NF-κB pathway activation was studied using Western blot. Cell growth and viability was evaluated using XTT, flow cytometry, and clonogenic assay. For cell migration evaluation, scratch assay was performed. Data were analyzed by one-way ANOVA. RESULTS: Cell lines express RANK and RANKL. RANK immunostaining was also detected in human BC tissue samples. RANK receptor dimerizes with ERBB family members. RANK/ERBB-2 dimer number seems to be associated with ERBB-2 expression (SKBR3, 5.4; BT-474, 8.2; MCF7, 0.7; MDA-MB-453, 0.3). RANK/ERBB-2 dimers were decreased in the presence of the inhibitors D, T, and P, while they were increased after RANKL (R) treatment in SKBR3 (m, 5.4; D, 1.2; T, 1.9; DT, 0.6; TP, 1; DTP, 0.4; R, 11.8) and BT-474 (m, 8.2; D, 3.1; T, 4.3; DT, 0.7; TP, 3.4; DTP, 3.2; R, 11.6). Combination targeting of SKBR3 further decreased NF-κB pathway activation compared to single targeting. In SKBR3, RANKL and ERBB-2 blockage resulted in reduced cell proliferation, increased apoptosis, and lower metastatic potential compared to mock cells (m) and reversed values in RANKL presence. The combination treatment of SKBR3 with D, T, and P had an advantage in functional traits compared to single targeting. Denosumab suppressed NF-κB signaling and diminished proliferation rate in MDA-MB-453 cells. MCF7 did not correspond to inhibitors. CONCLUSIONS: The results indicate a novel physical and molecular association between ERBB-2 and RANK pathways that affects ERBB-2 (+) BC growth. We also present data suggesting that the combination of anti-ERBB-2 agents and RANKL inhibitors have a potential direct anti-tumor effect and should be further tested in certain BC patients.