Developing Target Therapies Research Articles

Survivin/BIRC5 as a novel molecular effector at the crossroads of glucose metabolism and radioresistance in head and neck squamous cell carcinoma.

Metabolic reprogramming and abnormal glucose metabolism are hallmarks of head and neck squamous cell carcinoma (HNSCC). Certain oncogenes can promote cancer-related metabolic changes, but understanding their crosstalk in HNSCC biology and treatment is essential for identifying predictive biomarkers and developing target therapies. We assessed the value of survivin/BIRC5 as a radioresistance factor potentially modulated by glucose for predicting therapeutic sensitivity and prognosis of HNSCC in a cohort of 32 patients. Additionally, we conducted in vitro experiments to explore the role of survivin/BIRC5 in glucose metabolism concerning radiation response. Tumoral BIRC5 expression is associated with serum glucose and predicts locoregional disease-free survival and lower BIRC5 mRNA levels are associated with better outcomes. Upregulation of BIRC5 by radiation depends on glucose levels and provokes a pro-tumoral and radioresistant phenotype in surviving cells. Survivin/BIRC5 might be independently associated with the risk of recurrence in patients with HNSCC.

Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction.

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility.

Development of combination strategies for focal adhesion kinase inhibition in diffuse gastric cancer.

e16057 Background: Diffuse gastric cancer (DGC) is an aggressive and frequently lethal pathological subtype of gastric cancer (GC). Since DGC often lacks genomic aberrations that indicate clear candidate therapeutic targets, it has been challenging to develop target therapies for this GC subtype. Our previous study highlighted the contribution of focal adhesion kinase (FAK) in the tumorigenesis of DGC, and the potential for small molecule FAK inhibitors to have efficacy in DGC. Currently, FAK inhibitors are under active clinical evaluation in several tumor types. To date, FAK inhibitor monotherapy has been tolerated in the clinic, but has shown only modest clinical efficacy in cancer treatment, which inspired us to explore targets for the combination with FAK inhibitors in DGC. Methods: We constructed the engineered murine DGC model of Cdh1-/- RHOAY42C/+ organoids, with Cdh1 (E-Cadherin) loss and RHOA Y42C mutation, in our previous study. Using this DGC organoids model, we performed genome-scale libraries of open reading frames (ORF) screen to identify candidate mechanisms of resistance to FAK inhibitors (defactinib or PF-573228). For the top hits found in ORF screen, further validations were performed in Cdh1-/- RHOAY42C/+ organoids and human DGC cell lines of NUGC4 and SNU668 to check whether they could function as candidates for the combination with FAK inhibitors. Besides, we used Digiwest, a high-throughput protein analysis assay, to investigate pathway alterations of Cdh1-/- RHOAY42C/+ organoids treated with FAK inhibitors (defactinib or PF-573228). We then explored whether the activated pathways were the candidates for the drug combination. Zero Interaction Potency (ZIP) model was used to measure the synergistic effect between the drugs. The combination strategies were also tested in vivo. Results: We identified that cyclin-dependent kinase 6 (CDK6) promotes FAK inhibitors (defactinib and PF-573228) resistance according to ORF screen, and CDK4/6 inhibitor, Palbociclib, enhances the efficacy of defactinib for DGC models. Furthermore, we demonstrated that FAK inhibitors (defactinib and PF-573228) treatment in DGC models leads to compensatory activation of MAPK pathway in DGC, and the RAF/MEK dual inhibitor VS-6766 effectively enhances the antitumor efficacy of FAK inhibitors in vitro and in vivo. Conclusions: These data suggest that combinations of FAK inhibitors with MAPK inhibitors or CDK4/6 inhibitors are promising treatment strategies for DGC that warrant further testing in clinical trials.

The Advent of Omics Sciences in Clinical Trials of Motor Neuron Diseases.

The “omics revolution” has totally changed the scientific research approach and is contributing to the development of personalized therapies. In motor neuron diseases (MNDs), a set of complex, multifactorial, late-onset and chronic neurodegenerative diseases, the use of multi-omics approaches in clinical trials is providing new opportunities to stratify patients and develop target therapies. To show how omics science is gaining momentum in MNDs, in this work, we review the interventional clinical trials for MNDs based on the application of omics sciences. We analyze a total of 62 clinical trials listed in the ClinicalTrials database where different omics approaches have been applied in an initial phase, for diagnosis or patient selection, or in subsequent stages to cluster subjects, identify molecular signatures or evaluate drugs security or efficacy. The rise of omics sciences in clinical experimentation of MNDs is leading to an upheaval in their diagnosis and therapy that will require significant investments and means to ensure the correct and rapid evolution of personalized medicine.

Epidemiology and Molecular Profile of Mucosal Melanoma: A Population-Based Study in Southern Europe.

Simple SummaryThere are few population-based studies focused on the epidemiology of mucosal melanoma, a rare neoplasm. Its poor prognosis, the different etiology from cutaneous melanoma and the lack of effective treatment beyond corrective surgery, make the knowledge of the mutational profile of this type of cancer a useful tool in understanding its natural history and also for the investigation of new target therapies. The aim of our population-based study is to analyze the incidence and survival of mucosal melanoma, which mainly arises from the head and neck sphere, genitourinary tract and rectal area, and to carry out the mutational analysis of selected cases. We used the Girona Cancer Registry database, which registered all cancer cases in Girona, a province of Spain in southern Europe, during the period of 1994–2018.Background: Mucosal melanoma is a rare neoplasm on which few epidemiological population-based studies have been published. A good surgical approach is the standard treatment, but the prognosis is worse than that of skin melanoma. The analysis of mucosal melanoma’s mutational profile can help to develop target therapies in advanced disease or adjuvant settings. Methods: We analyzed the database of the Cancer Registry of Girona, a region located in the north-east of Spain, in the period of 1994–2018. We selected cases of primary invasive melanoma, excluding those located in the skin, eye, central nervous system and an unknown primary site. Epidemiological analysis included incidence and survival. Mutational profile analysis was performed with a custom gene panel. Results: Forty-two patients were identified: 14 (33%) had vulvar-vaginal melanoma, 15 (35.7%) had rectal melanoma, 12 (28.6%) had melanoma located in the head and neck sphere and 1 male patient had a urethral melanoma. European age-standardized incidence rates for vulvar-vaginal, rectal and head and neck melanoma were 0.09, 0.1 and 0.09 cases/100,000 inhabitant-years, respectively. Five-year observed survival rates were 37.5%, 20% and 25% for these types of cancers. NRAS Q61 was the most frequent mutation found. Conclusion: Our study confirms the steady incidence and low survival of mucosal melanomas in a region of southern Europe. NRAS and NF1 play a role in the molecular landscape of mucosal melanoma. MEK and PI3K/mTOR inhibitors could be reasonable treatment options and are being studied in clinical trials.

COVID-19 Pathophysiology and Clinical Effects on Multiple Organ Systems - A Narrative Review

Patients with comorbidities including Hypertension (HTN), Diabetes Mellitus (DM), Chronic Obstructive Pulmonary Disease (COPD), Asthma, Obesity, Cardiovascular Disease (CVD), Chronic Kidney Disease (CKD), and those who are immunocompromised are prone to more severe complications of COVID-19 and a higher rate of hospitalizations. In the United States, around 94% of COVID-19 deaths had an average of 2.6 additional conditions or causes per death. In a summary report published by the Chinese Centre for Disease Control and Prevention of 72,314 cases, case-fatality rate was elevated among those with preexisting comorbid conditions—10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for HTN, and 5.6% for cancer. The COVID-19 pandemic continues to threaten people and healthcare systems globally and therefore the global economy. Currently, there is no cure or vaccine for COVID-19 and there is an urgent need to develop target therapies as we continue to learn more about this novel virus. Without therapeutic interventions, much of how we contain the viral spread is prevention through mitigation strategies (social distancing, face masks, supportive care). Early suspicion of COVID-19 symptoms with radiological and laboratory assessments may play a major role in preventing severity of the COVID-19. With this literature review we aim to provide review of pathophysiology of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its clinical effects on multiple organ systems.

Role of modern radiotherapy in managing patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement (e.g., stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated.

Cyclin D1 and Chemotherapy Response

Cyclin D1 is a protein that plays a role in the transition from the G1 to S phase of the cell cycle. Cyclin D1 expression has been found to increase in various malignancies and, in many studies, was associated with tumor growth, stage, lymph node involvement, distant metastases, and poor prognosis. Until now, studies on the association of cyclin D1 expression level with chemotherapy response have shown different results. An in-depth understanding of the cell cycle will allow doctors to develop target therapies that work when specific interventions are carried out at certain stages. Some studies reported that cyclin D1 expression was inversely related to chemotherapy response, while others showed opposite results. A significant number of studies have attempted to elucidate this ambiguous effect of cyclin D1. The suggested mechanism involves the difference of cancer cell types, the effect of chromosome instability in a few malignancies, trigger to an excessive DNA repair protein expression stimulus, and the response to DNA damage severity. The ambiguous effect of cyclin D1 towards chemotherapy was thought to arise from the difference in tumor type, chemotherapy agents used, and cell damage severity caused by cytostatics as per different research works. More in-depth research with parallel evaluation of other possible mechanisms such as DNA repair should elucidate the reason behind the inconsistent findings.

Lipid Metabolism and Relevant Disorders to Female Reproductive Health

Lipids are essential components of cells that participate in metabolic and endocrine regulation and reproductive functions. The main organs where lipid regulation takes place are the liver and adipose tissue. Besides, when each tissue specific action cannot be exerted, it could lead to several endocrine-metabolic disorders closely related to PCOS, such as non-alcoholic fatty liver disease (NAFLD) and obesity. This work aims to discuss the impact of lipid alterations on metabolic and reproductive health. Therefore, this review focus on the importance of carrying out an integrated study of the molecular pathways affected in PCOS for developing target therapies. Lipids play a major role in PCOS pathogenesis. In this regard, failures in lipid regulation, synthesis, and/or homeostasis contribute to metabolic and reproductive abnormalities, such as those seen in PCOS. Several lipid pathways and regulators are altered in this pathology, leading to dysfunctions that worsen reproductive functions. Therefore, there are several treatments to manage dyslipidemias. Non-pharmacological therapies are considered a first line treatment being the pharmacological treatments a second line option. The best treatment to improve the lipid profile is a lifestyle intervention, a combination of hypocaloric diet and exercise. Regarding pharmacological therapies, a combination of fibrate and statins would be the most recommended drugs. Still, in PCOS women, treatment with metformin or TZDs not only modulates the lipid metabolism, but also improves the ovulation. Also, metformin with lifestyle interventions has positive effects on the metabolic and reproductive features of PCOS patients.

Utility of Circulating Tumor DNA in Different Clinical Scenarios of Breast Cancer.

Simple SummaryThis review is focused on the concept of a specific type of “liquid biopsy”, circulating cell-free tumor DNA (ctDNA). It explores the advantages and limitations of using this technique and the latest advances of using it in different clinical scenarios of breast cancer: early, metastatic, and locally advanced disease. It provides the latest advances in this area applied to clinical research and clinical practice, as well as the importance of the collaboration between clinicians and laboratory teams to fully grasp the potential of ctDNA in a precision medicine era. Breast cancer is a complex disease whose molecular mechanisms are not completely understood. Developing target therapies is a promising approach. Therefore, understanding the biological behavior of the tumor is a challenge. Tissue biopsy in the metastatic setting remains the standard method for diagnosis. Nevertheless, it has been associated with some disadvantages: It is an invasive procedure, it may not represent tumor heterogeneity, and it does not allow for treatment efficacy to be assessed or early recurrences to be detected. Analysis of circulating tumor DNA (ctDNA) may help to overcome this as it is a non-invasive method of monitoring the disease. In early-stage disease, it can detect early recurrences and monitor tumors’ genomic profiles, identifying the emergence of new genetic alterations which can be related to tumor-acquired resistance. In the metastatic setting, the analysis of ctDNA may also allow for the anticipation of clinical and radiological progression of the disease, selection of targeted therapies, and for a photogram of tumor heterogeneity to be provided. It may also detect disease progression earlier in locally advanced tumors submitted to neoadjuvant treatment, and identify minimal residual disease. ctDNA analysis may guide clinical decision-making in different scenarios, in a precision medicine era, once it acts as a repository of genetic tumor material, allowing for a comprehensive mutation profiling analysis. In this review, we focused on recent advances towards the implementation of ctDNA in a clinical routine for breast cancer.

Functional characterization of uveal melanoma oncogenes.

Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11 or rarely CYSLTR2 or PLCβ4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2->GNAQ/11->PLCβ act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/YAP pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the Gαq subunit or the upstream receptor. Our findings highlight the GNAQ/11->PLCβ->PKC->MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Gαq pathway mutations.

Immunological basis of virus-host interaction in COVID-19.

COVID‐19 is a complex new viral disease, in which a strict balance between anti‐viral immune response and the ensuing organ inflammation has a critical role in determining the clinical course. In adults, compelling evidence exists indicating that an uncontrolled inflammatory response ("cytokine storm") is pivotal in determining disease progression and mortality. Children may rarely present with severe disease. Modulating factors related to the host's genetic factors, age‐related susceptibility, and the capability to mount appropriate immune responses might play a role in control virus load at an early stage and regulating the inflammatory reaction. Elucidating these mechanisms seems crucial in developing target therapies according to patient's age, immunologic status, and disease evolution in COVID‐19.

Abstract IA16: The Halifax Project: Can a chemical mixture be a virtual carcinogen?

Abstract We live in a mixture of chemicals that has literally been created during our lifetimes. The possibility that this mixture might be carcinogenic has never been assessed systematically. Concurrent with the spread of this chemical mixture, cancer has changed. For example, there is more breast cancer and it occurs earlier in life for the same mutations. This increase has been attributed to artifacts and overdiagnosis. However, the increase started long before mammograms (Doll and Peto, Oxford Mono 1981), and Anderson et al. (JCO 2010) found similar increased invasive breast cancer in men—for whom the explanations that blame women do not apply. The Halifax Project used a Hallmarks of Cancer framework to ask whether the mixture of chemicals in which we live, or some part of it, might—together as a mixture—act as a virtual carcinogen even though not one of the chemicals was considered a carcinogen in itself. Dr. Leroy Lowe recruited 12 groups of experts—not specifically cancer biologists (one for each Hallmark, one for microenviroment as a whole, one for cross validation). Each group was asked to identify one or more common chemical(s) of commerce that induced their specific Hallmark. The requirements for the chemicals were that they were considered “safe” and affected the Hallmark specifically (thus excluding global mutagens) either: 1. in a dose range measured in humans; 2. at a dose lower than usually tested; 3. at a dose lower than the LOEL for carcinogenesis; or 4. at animal blood or tissue levels similar to humans. The Project identified one or more chemicals that activated each Hallmark, including 89 chemicals (it is likely more exist that were not identified) not currently classified as carcinogens that can affect Hallmarks. Fifty of these 89 chemicals (59%) had low-dose effects. The Project thus confirmed the possibility that a mixture of “noncarcinogens” could induce all 10 Hallmarks, i.e., be a virtual carcinogen. This finding leads to follow-up questions such as, How do chemical mixtures interact when they have dissimilar structures as well as similar ones? (Corollary: Xenoestrogens are a target of convenience, but there are other chemicals.) We are unlikely to find clarity without mechanistic data on how chemicals work together, so we should avoid a rush to oversimplify and to create answers just to have an answer. What happens after a chemical exposure ends? If a mixture induces “cancer,” will it be sustained if chemicals are removed? How do known carcinogens, e.g., diethylstilbestrol, cause cancer years later? And why does cancer sometimes persist when the inciting mutation is inactivated? Might cells become addicted to being malignant? Testing the mixtures hypothesis in a meaningful way requires resources at least somewhat similar to the magnitude of funds spent on deciphering genetic carcinogenesis and developing target therapies. With over 300 million persons at risk in the US alone, even a small chance of inducing cancer creates a significant risk. Citation Format: William H. Goodson III. The Halifax Project: Can a chemical mixture be a virtual carcinogen? [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA16.

Apocrine breast carcinoma as an extremely rare breast cancer subtype – histopathological characteristics

Apocrine carcinoma (AC) is a distinctive and rare type of malignancy, counted for 0.3–4% of all breast cancer cases. It does not have a particular clinical or radiological features, although it is characterized by the apocrine morphology, estrogen receptor-negative and androgen receptor-positive profile. In the present study, among 1122 patients with breast cancer only 5 of them were diagnosed with apocrine carcinoma (0.4%). All patients were above 50 years old (51–63, mean: 57). Tumor size varied from 1.4 cm to 3.8 cm with a mean size of 2.4 cm, while mean size of all 1122 studied cases counted for 1.9 cm. Two tumors were classified as high-grade (G3), 2 as G2, and 1 as G1. Four tumors out of 5 did not affect lymph nodes (pN0 stage), whereas 1 was classified as pN2 with 9/19 regional lymph nodes affected. This observation was consistent with the whole studied group, in which pN0 stage made up the largest percentage. Presented results suggest that AC is less frequent in premenopausal patients. AC tends to present as invasive malignancy without nodal involvement and is usually characterized by relatively less aggressive biological behavior compared to other histological types of breast cancer. Due to the fact that AC is definitely a rare type of breast cancer, modern medicine has still limited treatment options to offer. Further research needs to be conducted in order to develop target therapies for this carcinoma.

Effects of U0126 and MK2206 on cell growth and re-growth of endometriotic stromal cells grown on substrates of varying stiffness

Endometriosis is a common gynecological disorder responsible for infertility and pelvic pain. A complete cure for patients with endometriosis awaits new targets and strategies. Here we show that U0126 (a MEK inhibitor) and MK2206 (an AKT inhibitor) synergistically inhibit cell growth of deep endometriotic stromal cells (DES) grown on polyacrylamide gel substrates (PGS) of varying stiffness (2 or 30 kilopascal [kPa]) or plastic in vitro. No significant differences in cell proliferation were observed among DES, endometrial stromal cells of patients with endometriosis (EES) from the proliferative phase (P), EES-S (secretory phase) and EES-M (menstrual phase) compared to cells grown on a substrate of the same stiffness at both higher (U0126 [30 μM] and MK2206 [9 μM]) and lower (U0126 [15 μM] and MK2206 [4.5 μM]) combined doses. However, cell re-growth of DES after drug discontinuation was higher than that of EES-P and EES-S when cells were grown on rigid substrates at both combined doses. Combination U0126 and MK2206 treatment is more effective than each drug alone in cell growth inhibition of DES. However, further studies are required to investigate the mechanisms underlying high cell survival and proliferation after drug discontinuation for developing target therapies that prevent recurrence.

Clinicopathological Significance of the Proliferation Markers Ki67, RacGAP1, and Topoisomerase 2 Alpha in Breast Cancer.

Objectives The aims of this study are to evaluate expressions of Ki67, RacGAP1 (MgcRacGAP) and topoisomerase 2 alpha (TOP2a), the markers related with cell proliferation that have been proposed to affect the prognosis in the literature and correlate the results with clinicopathological parameters of breast cancer patients. Methods Ki67, RacGAP1, and TOP2a antibodies were applied immunohistochemically to the tissue micrarray blocks of 457 female breast cancer patients. The results were correlated with clinical, prognostic, histopathological features, and other immunohistochemical findings (estrogen receptor [ER], progesterone receptor [PR], HER2, cytokeratin [CK]5/6, CK14, epidermal growth factor receptor [EGFR] and vimentin), statistically. Results Ki67 expression demonstrated direct correlation with TOP2a expression, mitotic count, tumor grade, geographic necrosis, basal-like phenotype. RacGAP1 expression was directly correlated with TOP2a expression, nipple invasion, and number of metastatic lymph nodes, and it was inversely correlated with PR expression. TOP2a expression was directly correlated with vimentin and Ki67 expressions, mitotic count, tumor grade, and geographic necrosis, and nipple invasion, and negatively correlated with ER and PR expressions. Higher TOP2a and Ki67 expressions were correlated with shorter overall survival. Higher TOP2a expression and RacGAP1 positivity were directly correlated with shorter disease-free survival. Conclusion This study showed that the overexpressions of Ki67, RacGAP1, and TOP2a affect the prognosis adversely, thus to develop target therapies against RacGAP1 and TOP2a as well as using Ki67 as a part of routine pathology practice might be beneficial in breast cancer therapy and prediction of prognosis.

KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies.

Mutation of oncogene KRAS is common in non-small cell lung cancer (NSCLC), however, its clinical significance is still controversial. Independent studies evaluating its prognostic and predictive value usually drew inconsistent conclusions. Hence, We performed a meta-analysis with 41 relative publications, retrieved from multi-databases, to reconcile these controversial results and to give an overall impression of KRAS mutation in NSCLC. According to our findings, KRAS mutation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in early stage resected NSCLC (hazard ratio or HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively), and with inferior outcomes of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment and chemotherapy (relative risk or RR=0.21 and 0.66 for objective response rate or ORR, 95% CI 0.12-0.39 and 0.54-0.81 respectively; HR=1.46 and 1.30 for progression-free survival or PFS, 95%CI 1.23-1.74 and 1.14-1.50 respectively) in advanced NSCLC. When EGFR mutant patients were excluded, KRAS mutation was still significantly associated with worse OS and PFS of EGFR-TKIs (HR=1.40 and 1.35, 95 % CI 1.21-1.61 and 1.11-1.64). Although KRAS mutant patients presented worse DFS and PFS of chemotherapy (HR=1.33 and 1.11, 95% CI 0.97-1.84 and 0.95-1.30), and lower response rate to EGFR-TKIs or chemotherapy (RR=0.55 and 0.88, 95 % CI 0.27-1.11 and 0.76-1.02), statistical differences were not met. In conclusion, KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC. There's a need for developing target therapies for KRAS mutant lung cancer and other tumors.

Therapeutic drug monitoring: A patient management tool for precision medicine.

The precision medicine initiative is designed to better understand the causes of disease, to develop target therapies, and to identify patients that would benefit from treatment. Prescribing the right dose, which is not always the same to all patients, is needed for a successful outcome. The purpose of this commentary is to discuss the role of dose individualization based on therapeutic drug monitoring as a clinical patient management tool in the application of precision medicine.

The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH)

Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis-like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation.

A qualitative study of resilience and posttraumatic stress disorder in United States ICU nurses

Intensive care unit (ICU) nurses are at increased risk of developing psychological problems including posttraumatic stress disorder (PTSD). However, there are resilient individuals who thrive and remain employed as ICU nurses for many years. The purpose of this study was to identify mechanisms employed by highly resilient ICU nurses to develop preventative therapies to obviate the development of PTSD in ICU nurses. Qualitative study using semi-structured telephone interviews with randomly selected ICU nurses in the USA. Purposive sampling was used to identify ICU nurses who were highly resilient, based on the Connor-Davidson Resilience Scale and those with a diagnosis of PTSD, based on the posttraumatic diagnostic scale. New interviews were conducted until we reached thematic saturation. Thirteen highly resilient nurses and fourteen nurses with PTSD were interviewed (n=27). A constructivist epistemological framework was used for data analysis. Differences were identified in four major domains: worldview, social network, cognitive flexibility, and self-care/balance. Highly resilient nurses identified spirituality, a supportive social network, optimism, and having a resilient role model as characteristics used to cope with stress in their work environment. ICU nurses with a diagnosis of PTSD possessed several unhealthy characteristics including a poor social network, lack of identification with a role model, disruptive thoughts, regret, and lost optimism. Highly resilient ICU nurses utilize positive coping skills and psychological characteristics that allow them to continue working in the stressful ICU environment. These characteristics and skills may be used to develop target therapies to prevent PTSD in ICU nurses.