Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road.

Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.

Immunotherapy and brain metastasis in lung cancer: connecting bench side science to the clinic.

Brain metastases (BMs) are the most common form of intracranial malignant neoplasms in adults, with a profound impact on quality of life and traditionally associated with a dismal prognosis. Lung cancer accounts for approximately 40%-50% of BM across different tumors. The process leading to BMs is complex and includes local invasion, intravasation, tumor cells circulation into the bloodstream, disruption of the blood-brain barrier, extravasation of tumor cells into the brain parenchyma, and interaction with cells of the brain microenvironment, among others. Once the tumor cells have seeded in the brain parenchyma, they encounter different glial cells of the brain, as well as immune cells. The interaction between these cells and tumor cells is complex and is associated with both antitumoral and protumoral effects. To overcome the lethal prognosis associated with BMs, different treatment strategies have been developed, such as immunotherapy with immune checkpoint inhibitors, particularly inhibitors of the PD-1/PD-L1 axis, which have demonstrated to be an effective treatment in both non-small cell lung cancer and small cell lung cancer. These antibodies have shown to be effective in the treatment of BM, alone or in combination with chemotherapy or radiotherapy. However, many unsolved questions remain to be answered, such as the sequencing of immunotherapy and radiotherapy, the optimal management in symptomatic BMs, the role of the addition of anti-CTLA-4 antibodies, and so forth. The complexity in the management of BMs in the era of immunotherapy requires a multidisciplinary approach to adequately treat this devastating event. The aim of this review is to summarize evidence regarding epidemiology of BM, its pathophysiology, current approach to treatment strategies, as well as future perspectives.

Associations amongst genes, molecules, cells, and organs in breast cancer metastasis.

This paper is a cross fertilization of ideas about the importance of molecular aspects of breast cancer metastasis by basic scientists, a pathologist, and clinical oncologists at the Henry Ford Health symposium. We address four major topics: (i) the complex roles of lymphatic endothelial cells and the molecules that stimulate them to enhance lymph node and systemic metastasis and influence the anti-tumor immunity that might inhibit metastasis; (ii) the interaction of molecules and cells when breast cancer spreads to bone, and how bone metastases may themselves spread to internal viscera; (iii) how molecular expression and morphologic subtypes of breast cancer assist clinicians in determining which patients to treat with more or less aggressive therapies; (iv) how the outcomes of patients with oligometastases in breast cancer are different from those with multiple metastases and how that could justify the aggressive treatment of these patients with the hope of cure.

Safety and efficacy of avelumab plus carboplatin in patients with metastatic castration-resistant prostate cancer in an open-label Phase Ib study.

BACKGROUND: Single-agent PD-1/PD-L1 inhibitors have shown limited efficacy in unselected mCRPC. The evidence of a survival benefit with sipuleucel-T and ipilimumab, provides a rationale to study further increasing immunogenicity in mCRPC through combinations. METHODS: Safety and efficacy avelumab plus carboplatin was investigated in a single-arm Phase Ib study in mCRPC, progressing to at least one taxane and one androgen-receptor inhibitor. The primary endpoint was safety. Secondary endpoints included PSA/radiographic responses, progression-free survival (PFS) and overall survival (OS). Germline/somatic mutation analysis was performed. RESULTS: In total, 26 patients were included. Patients were heavily pretreated: 76.9% received ≥3 and 42.3% ≥4 prior lines. A DNA damage repair (DDR) alteration was found in three patients (11.5%). The safety profile was acceptable with 73% Grade 3-4 treatment-related adverse events. PSA response rate ≥50% was seen in 7.7% of patients. The objective response rate was 17.6%, including one complete response (5.9%). Two of these responders had a known DDR alteration (one BRCA2, one ATM). The median response duration was 6 months. Median radiographic PFS was 6.6 months (95% CI 4.28-9.01), and median OS 10.6 months (95% CI 6.68-NR). CONCLUSIONS: Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.

Acquired Mechanisms of Resistance to Osimertinib-The Next Challenge.

EGFR-mutated tumors represent a significant percentage of non-small cell lung cancer. Despite the increasing use of osimertinib, a treatment that has demonstrated an outstanding clinical benefit with a tolerable toxicity profile, EGFR tumors eventually acquire mechanisms of resistance. In the last years, multiple mechanisms of resistance have been identified; however, after progressing on osimertinib, treatment options remain bleak. In this review, we cover the most frequent alterations and potential therapeutic strategies to overcome them.

Incidence of complications associated to bile duct stents, in patients with advanced cancer: a single-center experience.

BACKGROUND: Pancreatic cancer (PCa) and biliary tract carcinomas (BTCa) have high morbidity and mortality rates. Bile duct obstruction (BDO) develops in approximately 65-75% of PCa at diagnosis, delaying the administration of optimal treatment. In patients not candidates for surgery, BDO is usually treated through the endoscopy-guided placement of self-expanding stents in the bile duct. METHODS: In this retrospective study, we sought to describe clinical characteristics and outcomes of a cohort of patients with BDO of malignant origin who underwent biliary stent placement (BSP), with a special focus regarding complications developed after the procedure. Patients with PCa, BTCa, colon cancer, lung cancer, gastric cancer, and ovarian cancer who underwent BSP from 2014 to April 2019 at our institution were included in this cohort. Demographic and clinicopathologic characteristics were collected. Statistical analysis stratified according to ECOG performance status. Specific information regarding stent material (metallic vs. plastic), as well as incidence and type of complications derived from BSP, was also recorded. RESULTS: One hundred fifteen patients were included. The median age was 72 years. Sixty-six patients (57%) had PCa. All patients presented hyperbilirubinemia, which decreased after the procedure in 111 (96%) patients. Complications were observed in 44 (38%) patients, most of which 33 (75%) were infections. The median time to the complication was 1 month. The mean overall survival (OS) in our study was 20.3 weeks. CONCLUSION: BSP effectively decreased hyperbilirubinemia in patients with BDO; however, the procedure associated a significant rate of infectious complications, which can further compromise an effective anti-cancer therapy as well as optimal palliative strategies.

Prognostic factors and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer treated with immune checkpoint blockage.

Our aim was to describe the incidence and characteristics of immune-related adverse events (irAEs) in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and to evaluate their impact on outcome. All cases of NSCLC patients treated with ICIs in the second-line setting between December 2015 and May 2018 were evaluated. Seventy patients were included. Mean age was 65.9 years, and the majority of male (n = 53, 75.7%), with PS of 0-1 (n = 62, 88.6%) treated with nivolumab (n = 51; 72.9%). Thirty-one patients (44.3%) experienced an AE, 5 (7.1%) were grades 3-4. Median OS in patients with AE was 30.1 months (95% CI, 16.7-43.5) compared with 5.1 months (95% CI, 1.2-9.0) in cases without AE (log-rank test: p = 0.010). The adjusted HR for OS was 0.46 (95% CI, 0.25-0.86) for the irAE occurrence and 3.60 (95% CI, 1.56-8.32) for PS 2-3 group. The development of irAEs was associated with improved patient outcome.

Prehispanic Functional Foods and Nutraceuticals in the Treatment of Dyslipidemia Associated to Cardiovascular Disease: a Mini-Review.

Dyslipidemia is an important modifi able risk factor for cardiovascular and metabolic diseases, which are responsible for a large number of mortality and disability cases around the globe. Different strategies have been used within the treatment of dyslipidemia, including lifestyle modifi cations, pharmacologic therapy, as well as functional foods and nutraceuticals. Functional foods have been used worldwide since ancient times, particularly, the prehispanic civilizations utilized several as medicinal foods. In the current pandemic of dyslipidemia as well as the nutritional transition, particularly in Latin America, the use of native functional foods represents an attractive target for the treatment and/ or prevention of these conditions. In this mini-review, evidence regarding different functional foods such as cacao, amaranth, chia, nopal, spirulina, as well as their nutraceutical compounds, including fl avonoids, omega-3 PUFAs, fi ber, prebiotics, lovastatin, c-phycocyanin, among others, and their mechanism of action are presented and discussed. Although such foods certainly are considered as attractive potential agents to target dyslipidemia thus decrease the associated cardiometabolic risk, we conclude that for most of the presented functional foods there is currently not enough evidence to support its recommendation and every-day use.

New Dietary Supplements for Obesity: What We Currently Know.

Obesity and its associated cardiometabolic alterations currently are considered an epidemic; thus, their treatment is of major importance. The cornerstone for such treatment involves therapeutic lifestyle changes; however, the vast majority of cases fail and/or significant weight loss is maintained only in the short term because of lack of compliance. The popularity of dietary supplements for weight management has increased, and a wide variety of these products are available over the counter. However, the existing scientific evidence is insufficient to recommend their safe use. Hence, the purpose of this article is to review the clinical effects, proposed mechanism of action, and safety profile of some of the new dietary supplements, including white bean extract, Garcinia cambogia, bitter orange, Hoodia gordonii, forskolin, green coffee, glucomannan, ß-glucans, chitosan, guar gum, and raspberry ketones.

Variability of apparent diffusion coefficients in metastatic small cell lung carcinoma: comparisons between-within normal tissue and liver metastases.

In recent years, the use of diffusion weighted MRI (DW-MRI) has increased for the diagnosis of focal liver lesions (FLLs). DW-MRI may help in the differentiation of benign and malignant FLLs by measuring the apparent diffusion coefficient (ADC) values. Unfortunately, liver metastases present different histopathologic features with variable MRI signals within each lesion; this histologic variability explains the intra- and inter-lesion variations of ADC measurements. We present the case of a 64-year-old female with diagnosis of liver metastasis from small cell lung carcinoma admitted to the emergency unit due to symptoms of inappropriate antidiuretic hormone secretion. Quantitative comparison of two liver MRI, on admission and 2-months after transcatheter arterial chemoembolization showed persistence of the hyperintense metastatic lesions with significant difference in the ADC values in the with-in metastatic lesions (p = 0.001) and between normal tissue and liver metastases only at the end of treatment (p < 0.001). Several publications state that DWMRI is capable to predict the response to chemotherapy in malignant tumors, the histologic variability of liver metastasis and their response to different treatments is reflected in intra- and inter-lesion variations of ADC measurements that might delay an accurate imaging diagnosis. We present evidence of this variability, which might encourage prospective clinical trials that would define better cut-off values, would help understand the ADC biological behaviour, and would reach consensus about the best acquisition parametersfor this promising quantitative biomarker.

Obesity, Metabolic Syndrome, and Dietary Therapeutical Approaches with a Special Focus on Nutraceuticals (Polyphenols): A Mini-Review.

More than half of all global deaths in 2010 were related to non-communicable diseases, including obesity, cancers, diabetes, and cardiovascular illnesses. It has been suggested that the alarming increase in the incidence of cardiovascular disease is the epidemiologic result of a nutrition transition characterized by dietary patterns featuring an increase in the intake of total fat, cholesterol, sugars, and other refined carbohydrates, concomitant with low consumption of polyunsaturated fatty acids and fiber. Although traditional dietary approaches have proven successful as part of the treatment for obesity and cardiometabolic derangements within clinical trial scenarios, they lack effectiveness in the long term, mainly due to poor compliance. Research has thus turned its attention to nutraceutics, nutrients that have the ability to modulate physiological and pathophysiological molecular mechanisms, thus resulting in favorable health outcomes. Polyphenols have been considered as among the bioactive molecules as they are thought to yield beneficial effects by exerting antioxidant activity; however, there are other--and even more robust--metabolic pathways through which polyphenols enhance cardiovascular health, such as via promoting vasodilatory, anti-atherogenic, antithrombotic, and anti-inflammatory effects. No standard dose has yet been determined, as the effects greatly vary among polyphenols and food sources; thus, there is an imperative need to generate more evidence in order to support dietary recommendations aimed at the prevention and therapeutics of obesity and its associated cardiometabolic diseases.