V-raf Murine Sarcoma Viral Oncogene Research Articles

Development and validation of a nomogram for predicting metachronous peritoneal metastasis in colorectal cancer: A retrospective study.

Peritoneal metastasis (PM) after primary surgery for colorectal cancer (CRC) has the worst prognosis. Prediction and early detection of metachronous PM (m-PM) have an important role in improving postoperative prognosis of CRC. However, commonly used imaging methods have limited sensitivity to detect PM early. We aimed to establish a nomogram model to evaluate the individual probability of m-PM to facilitate early interventions for high-risk patients. To establish and validate a nomogram model for predicting the occurrence of m-PM in CRC within 3 years after surgery. We used the clinical data of 878 patients at the Second Hospital of Jilin University, between January 1, 2014 and January 31, 2019. The patients were randomly divided into training and validation cohorts at a ratio of 2:1. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the variables with nonzero coefficients to predict the risk of m-PM. Multivariate logistic regression was used to verify the selected variables and to develop the predictive nomogram model. Harrell's concordance index, receiver operating characteristic curve, Brier score, and decision curve analysis (DCA) were used to evaluate discrimination, distinctiveness, validity, and clinical utility of this nomogram model. The model was verified internally using bootstrapping method and verified externally using validation cohort. LASSO regression analysis identified six potential risk factors with nonzero coefficients. Multivariate logistic regression confirmed the risk factors to be independent. Based on the results of two regression analyses, a nomogram model was established. The nomogram included six predictors: Tumor site, histological type, pathological T stage, carbohydrate antigen 125, v-raf murine sarcoma viral oncogene homolog B mutation and microsatellite instability status. The model achieved good predictive accuracy on both the training and validation datasets. The C-index, area under the curve, and Brier scores were 0.796, 0.796 [95% confidence interval (CI) 0.735-0.856], and 0.081 for the training cohort and 0.782, 0.782 (95%CI 0.690-0.874), and 0.089 for the validation cohort, respectively. DCA showed that when the threshold probability was between 0.01 and 0.90, using this model to predict m-PM achieved a net clinical benefit. We have established and validated a nomogram model to predict m-PM in patients undergoing curative surgery, which shows good discrimination and high accuracy.

Liquid Biopsy Detecting Circulating Tumor Cells in Patients with Non-Small Cell Lung Cancer: Preliminary Results of a Pilot Study.

Lung cancer is still the leading cause of cancer-related death worldwide. Interest is growing towards early detection and advances in liquid biopsy to isolate circulating tumor cells (CTCs). This pilot study aimed to detect epithelial CTCs in the peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients. We used Smart BioSurface® (SBS) slide, a nanoparticle-coated slide able to immobilize viable nucleated cellular fraction without pre-selection and preserve cell integrity. Forty patients undergoing lung resection for NSCLC were included; they were divided into two groups according to CTC value, with a cut-off of three CTCs/mL. All patients were positive for CTCs. The mean CTC value was 4.7(± 5.8 S.D.) per ml/blood. In one patient, next generation sequencing (NGS) analysis of CTCs revealed v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation, which has also been identified in tissue biopsy. CTCs count affected neither overall survival (OS, p = 0.74) nor progression-free survival (p = 0.829). Multivariable analysis confirmed age (p = 0.020) and pNodal-stage (p = 0.028) as negative predictors of OS. Preliminary results of this pilot study suggest the capability of this method in detecting CTCs in all early-stage NSCLC patients. NGS on single cell, identified as CTC by immunofluorescence staining, is a powerful tool for investigating the molecular landscape of cancer, with the aim of personalized therapies.

Recent Developments and Challenges in Molecular-Targeted Therapy of Non-Small-Cell Lung Cancer

Treatment of lung cancer with conventional therapies, which include radiation, surgery, and chemotherapy results in multiple undesirable adverse or side effects. The major clinical challenge in developing new drug therapies for lung cancer is resistance, which involves mutations and disturbance in various signaling pathways. Molecular abnormalities related to epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B1 (B-RAF) Kirsten rat sarcoma virus (KRAS) mutations, translocation of the anaplastic lymphoma kinase (ALK) gene, mesenchymal-epithelial transition factor (MET) amplification have been studied to overcome the resistance and to develop new therapies for non-small cell lung cancer (NSCLC). But, inevitable development of resistance presents limits the clinical benefits of various new drugs. Here, we review current progress in the development of molecularly targeted therapies, concerning six clinical biomarkers: EGFR, ALK, MET, ROS-1, KRAS, and B-RAF for NSCLC treatment.

Association of Clinicopathological Profile and Immunohistochemical Expression of KRAS and BRAF in Colorectal Carcinoma: A Cross-sectional Study

Introduction: Colorectal Carcinoma (CRC) is a multi-step process that occurs due to the accumulation of several genetic alterations. The most important alterations are related to the rat sarcoma viral oncogene homolog (RAS) and Rapidly Accelerated Fibrosarcoma (RAF), which have been implicated as key intermediates in the RAS-mediated signalling cascade. However, the levels of Kristen Rat Sarcoma Virus (KRAS) and v-raf Murine Sarcoma Viral Oncogene Homolog (BRAF) protein expression and their prognostic evaluation in CRC patients remain unknown. Aim: To investigate the immunohistochemical expression of KRAS and BRAF proteins in CRC. Materials and Methods: The present institutional-based cross-sectional observational study was conducted in a tertiary care centre in West Bengal, specifically in the Department of Pathology in collaboration with the Department of Surgery at Murshidabad Medical College and Hospital, Berhampore, West Bengal, India. A total of 26 CRC cases were enrolled in the present study, received over a period of one and a half years from January 2021 to June 2022. The parameters studied included demographic and clinical information of the patients, histopathological findings, pathological grade and stage of carcinoma, and immunohistochemical findings for KRAS and BRAF. For statistical analysis, data were entered into Microsoft (MS) Excel. Descriptive measures such as mean±Standard Deviation (SD), range, and percentage were used. The Chi-square test was used to determine the significance of the study. Results: A total of biopsy-proven CRC specimens were studied, consisting of 17 male patients (65.38%) with a male-to-female ratio of 1.9:1. The most common age group involved was 51-60 years (38%). Conventional adenocarcinoma accounted for the majority of cases (85%), with mucinous carcinoma comprising the remaining 15%. Among the 26 cases, 15 (58%) showed KRAS positivity, which was significantly associated with tumour grade and stage. Most of the cases were BRAF-negative. Out of the 21 cases where either KRAS or BRAF or both were positive, 20 cases showed high T stage (T3 and T4) and/or metastatic lesions (p-value 0.001). All four cases that were negative for both BRAF and KRAS belonged to the low T stage. Conclusion: A significant correlation was observed between the expression of KRAS and high-grade, high pathological Tumour, Node, Metastasis (TNM) T stage (T3 and T4) CRC. Therefore, KRAS Immunohistochemistry (IHC) biomarkers should be included in the standard diagnostic protocol for colorectal cancer, as they help identify KRAS-positive CRC cases that are resistant to targeted immunotherapy.

Oncogenic BRAFV600E induces microglial proliferation through extracellular signal-regulated kinase and neuronal death through c-Jun N-terminal kinase.

Activating V600E in v-Raf murine sarcoma viral oncogene homolog B (BRAF) is a common driver mutation in cancers of multiple tissue origins, including melanoma and glioma. BRAFV600E has also been implicated in neurodegeneration. The present study aims to characterize BRAFV600E during cell death and proliferation of three major cell types of the central nervous system: neurons, astrocytes, and microglia. Multiple primary cultures (primary cortical mixed culture) and cell lines of glial cells (BV2) and neurons (SH-SY5Y) were employed. BRAFV600E and BRAFWT expression was mediated by lentivirus or retrovirus. Blockage of downstream effectors (extracellular signal-regulated kinase 1/2 and JNK1/2) were achieved by siRNA. In astrocytes and microglia, BRAFV600E induces cell proliferation, and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase, but not c-Jun N-terminal kinase. Conditioned medium from BRAFV600E-expressing microglia induced neuronal death. In neuronal cells, BRAFV600E directly induces neuronal death, through c-Jun N-terminal kinase but not extracellular signal-regulated kinase. We further show that BRAF-related genes are enriched in pathways in patients with Parkinson's disease. Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity. It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.

Optimizing Patient Pathways in Advanced Biliary Tract Cancers: Recent Advances and a French Perspective.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors that are rare in Western countries and have a poor prognosis. Three subgroups are defined by their anatomical location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma) and exhibit distinct clinical, molecular, and epidemiologic characteristics. Most patients are diagnosed at an advanced disease stage and are not eligible for curative-intent resection. In addition to first- and second-line chemotherapies (CisGem and FOLFOX, respectively), biologic therapies are now available that target specific genomic alterations identified in BTC. To date, targets include alterations in the genes for isocitrate dehydrogenase (IDH) 1, fibroblast growth factor receptor (FGFR) 2, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2 or ERRB2), and neurotrophic tyrosine receptor kinase (NTRK), and for those leading to DNA mismatch repair deficiency. Therapies targeting these genomic alterations have demonstrated clinical benefit for patients with BTC. Despite these therapeutic advancements, genomic diagnostic modalities are not widely used in France, owing to a lack of clinician awareness, local availability of routine genomic testing, and difficulties in obtaining health insurance reimbursement. The addition of durvalumab, a monoclonal antibody targeting the immune checkpoint programmed cell death ligand-1, to CisGem in the first-line treatment of advanced BTC has shown an overall survival benefit in the TOPAZ-1 trial. Given the high mortality rates associated with BTC and the life-prolonging therapeutic options now available, it is hoped that the data presented here will support updates to the clinical management of BTC in France.

Phenotypic and Genotypic Appraisal of Pulmonary Mucinous Adenocarcinoma: A Retrospective Study

Introduction: Lung cancer is the second most common cancer diagnosed in the world. According to GLOBOCAN 2020, it is approximately 11.4% of all malignancies and accounts for one in five cancer deaths worldwide. Several driver gene mutations are known in lung adenocarcinoma including Epidermal Growth Factor Receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog(KRAS), v-raf murine sarcoma viral oncogene homolog B1(BRAF), Human epidermal growth factor receptor2 (HER 2), anaplastic lymphoma kinase (ALK), Ros Protooncogene 1, Receptor Tyrosine Kinase (ROS1) and rearranged during transfection (RET). Among these, KRAS mutation has been classically defined as bearing a negative prognostic factor. They are described to have unfavourable survival rates as compared with KRAS wild- type tumours. However, its real significance remains controversial due to heterogeneity amongst studies. Aim: The aim of this study was to assess the histomorphology, immunophenotype, EGFR and KRAS mutation profile in invasive mucinous and mixed mucinous/non mucinous type lung carcinoma. Materials and Methods: This retrospective study was done at a tertiary cancer centre in the state of Kerala, South India to identify the frequency of EGFR and KRAS mutations in invasive mucinous or mixed mucinous/non mucinous type lung carcinoma diagnosed during the period June 2017 to March 2019. Immunohistochemical assays for CK7, CK20, TTF-1, Napsin-A, CDX-2 and p63 were done on all cases. EGFR mutation analysis for exons 18, 19, 20, 21 were done using ARMS PCR and KRAS mutation analysis for codons 12, 13, 61, 146 by Sanger sequencer. Descriptive statistics was used wherever applicable. Results: Out of a total of 290 patients of pulmonary adenocarcinoma during the two year study period, twelve cases (4.1%) were diagnosed as invasive mucinous or mixed mucinous/non mucinous types based on histomorphology and immunophenotype, on both lung tissue biopsies as well as material from metastatic sites. Of the twelve, nine (75%) were pure mucinous and three (25%) were mixed mucinous and non mucinous. All the twelve cases were subjected to molecular testing for both EGFR and KRAS. Three cases (25%) showed KRAS mutations in codon 12. EGFR mutation (TKI resistant T790M mutation) was found only in a single case which had a histology of mixed mucinous and non mucinous carcinoma and a coexistent mutation in KRAS (c12 G>C) gene. Conclusions: Our study corroborates the described fact that pulmonary mucinous carcinoma differ from the conventional adenocarcinoma in terms of its histology, immunoprofile and molecular profile. KRAS mutation appears to be the main pathogenetic factor in this variant. In the current day practice, there is no demonstrable effective therapy for KRAS mutant lung adenocarcinoma and more trials are needed to identify newer mutations that can modify treatment outcomes.

Expressions of GLUT-1, PK-M2 and HIF-1α and Mutation Status of BRAF in Odontogenic Keratocysts.

To investigate the expressions and clinicopathological features of glucose transporter 1 (GLUT-1), pyruvate kinase M2 (PK-M2) and hypoxia-inducible factor 1α (HIF-1α) in odontogenic keratocysts (OKCs), and to investigate the mutation status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF). Following a retrospective review of the clinicopathological data of 28 OKC cases, the expressions of GLUT-1, PK-M2 and HIF-1α in these tissue samples were detected through immunohistochemistry. The BRAF mutation statuses of all cases were examined using polymerase chain reaction amplification and direct sequencing. The expression levels of HIF-1α varied in 96.4% of OKC tissues, and there were higher positive rates of PKM2 (100%) and GLUT-1 (100%) in these tissues. None of the 28 OKC samples carried the BRAF mutation. The positive expressions of GLUT-1, PK-M2 and HIF-1α indicate that patients with OKCs undergo anaerobic glycolysis to a certain extent, but these processes appear to be irrelevant to clinicopathological features and to the BRAF mutation.

Role of RAS signaling in ovarian cancer.

The RAS family of proteins is among the most frequently mutated genes in human malignancies. In ovarian cancer (OC), the most lethal gynecological malignancy, RAS, especially KRAS mutational status at codons 12, 13, and 61, ranges from 6-65% spanning different histo-types. Normally RAS regulates several signaling pathways involved in a myriad of cellular signaling cascades mediating numerous cellular processes like cell proliferation, differentiation, invasion, and death. Aberrant activation of RAS leads to uncontrolled induction of several downstream signaling pathways such as RAF-1/MAPK (mitogen-activated protein kinase), PI3K phosphoinositide-3 kinase (PI3K)/AKT, RalGEFs, Rac/Rho, BRAF (v-Raf murine sarcoma viral oncogene homolog B), MEK1 (mitogen-activated protein kinase kinase 1), ERK (extracellular signal-regulated kinase), PKB (protein kinase B) and PKC (protein kinase C) involved in cell proliferation as well as maintenance pathways thereby driving tumorigenesis and cancer cell propagation. KRAS mutation is also known to be a biomarker for poor outcome and chemoresistance in OC. As a malignancy with several histotypes showing varying histopathological characteristics, we focus on reviewing recent literature showcasing the involvement of oncogenic RAS in mediating carcinogenesis and chemoresistance in OC and its subtypes.

A preclinical model of cutaneous melanoma based on reconstructed human epidermis

Malignant melanoma is among the tumor entities with the highest increase of incidence worldwide. To elucidate melanoma progression and develop new effective therapies, rodent models are commonly used. While these do not adequately reflect human physiology, two-dimensional cell cultures lack crucial elements of the tumor microenvironment. To address this shortcoming, we have developed a melanoma skin equivalent based on an open-source epidermal model. Melanoma cell lines with different driver mutations were incorporated into these models forming distinguishable tumor aggregates within a stratified epidermis. Although barrier properties of the skin equivalents were not affected by incorporation of melanoma cells, their presence resulted in a higher metabolic activity indicated by an increased glucose consumption. Furthermore, we re-isolated single cells from the models to characterize the proliferation state within the respective model. The applicability of our model for tumor therapeutics was demonstrated by treatment with a commonly used v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor vemurafenib. This selective BRAF inhibitor successfully reduced tumor growth in the models harboring BRAF-mutated melanoma cells. Hence, our model is a promising tool to investigate melanoma development and as a preclinical model for drug discovery.

BRAF gene mutation and papillary thyroid carcinoma

Nowadays, Thyroid carcinoma (TC) is the most common malignant tumor of endocrine system, accounting for about 1% of the malignant tumors in the whole body, ranking first in the head and neck malignant tumors. Papillary thyroid carcinoma (PTC) is a malignant tumor originated from thyroid follicular epithelial cells, which is the most common pathological type in TC. V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a molecular biological marker for the diagnosis and prognosis of PTC and a target gene for the treatment of PTC. Its gene mutation is a hot point in the TC research field. The most common gene mutation is BRAF V600E mutation and it is a molecular marker in PTC. With the deep-going of its research, contradictions and controversies about the relationship between BRAF V600E and PTC gradually emerge. Many molecular targeted drugs targeting BRAF gene are also being continuously researched and some achievements have been made. This review mainly expounds the relationship between BRAF V600E and clinicopathological features, analyzes and expounds the controversial parts currently as well as show the research status of molecular targeted drugs.

Knockdown of 15-bp Deletion-Type v-raf Murine Sarcoma Viral Oncogene Homolog B1 mRNA in Pancreatic Ductal Adenocarcinoma Cells Repressed Cell Growth In Vitro and Tumor Volume In Vivo.

Simple SummaryThe v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene containing a 15-base pair (bp) deletion at L485-P490 is the cause of several cancers. We generated siRNA to specifically knock down BRAF mRNA containing the 15-bp deletion. This siRNA suppressed the expression of BRAF, harboring the deletion without affecting wild-type BRAF expression in BxPC-3 pancreatic ductal adenocarcinoma cells in vitro and in vivo. Cell growth and phosphorylation of downstream extracellular-signal-regulated kinase proteins were also repressed. An off-target effect is the most common side effect of siRNA therapy. In this study, we reveal that siRNA with a 2′-O-methyl chemical modification in the seed region of the siRNA guide strand reduced seed-dependent off-target effects.Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second-most common cause of death within the next 10 years. Due to the limited efficacy of available therapies, the survival rate of PDAC patients is very low. Oncogenic BRAF mutations are one of the major causes of PDAC, specifically the missense V600E and L485–P490 15-bp deletion mutations. Drugs targeting the V600E mutation have already been approved by the United States Food and Drug Administration. However, a drug targeting the deletion mutation at L485–P490 of the BRAF gene has not been developed to date. The BxPC-3 cell line is a PDAC-derived cell line harboring wild-type KRAS and L485–P490 deleted BRAF genes. These cells are heterozygous for BRAF, harboring both wild-type BRAF and BRAF with the 15-bp deletion. In this study, siRNA was designed for the targeted knockdown of 15-bp deletion-type BRAF mRNA. This siRNA repressed the phosphorylation of extracellular-signal-regulated kinase proteins downstream of BRAF and suppressed cell growth in vitro and in vivo. Furthermore, siRNAs with 2′-O-methyl modifications at positions 2–5 reduce the seed-dependent off-target effects, as confirmed by reporter and microarray analyses. Thus, such siRNA is a promising candidate therapy for 15-bp deletion-type BRAF-induced tumorigenesis.

MLH1, BRAF and p53 - searching for significant markers to predict evolution towards adenocarcinoma in colonic sessile serrated lesions.

Background and Aim: Colonic serrated lesions are premalignant lesions, using an alternative malignization pathway, including multiple genetic and epigenetic alterations, as: mismatch repair deficiency due to MutL homolog 1 (MLH1) promoter methylation, tumor protein p53 (TP53) mutations, activating mutations of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Kirsten rat sarcoma viral oncogene homolog (KRAS). Our study aims to evaluate MLH1, BRAF and p53 immunohistochemical (IHC) status in sessile serrated lesions (SSLs), with and without dysplasia. Materials and Methods: This is a retrospective case-control study including 20 SSLs with dysplasia and 20 SSLs without dysplasia (matching sex and age). IHC expression of MLH1, BRAF and p53 was evaluated as the percent of nuclear loss of MLH1, cytoplasmic positivity of BRAF and nuclear positivity of p53. Data concerning age, sex, localization of the lesion, dysplasia and IHC results were statistically processed using Microsoft Excel. Results: We had very polymorphous patterns of IHC expression for BRAF, MLH1 and p53, especially in the dysplastic group. Thus, two patients were BRAF+/MLH1-/p53+, three were BRAF+/MLH1-/p53-, one was BRAF+/MLH1+/p53- and six were BRAF+/MLH1+/p53+. Dysplastic lesions without BRAF mutation exhibited the following phenotype: one case BRAF-/MLH1-/p53+, four BRAF-/MLH1-/p53- and three BRAF-/MLH1+/p53+. In the control group (SSLs without dysplasia), there was a more homogenous distribution of cases: eight cases BRAF+/MLH1+/p53-, seven BRAF-/MLH1+/p53-, one BRAF-/MLH1-/p53+, two BRAF-/MLH1-/p53- and two BRAF-/MLH1+/p53+. Conclusions: There are more routes on the serrated pathway, with different mutations and time of acquisition of each genetic or epigenetic lesion with the same morphological result. These lesions should be stratified according to their risk to poor outcome and their need to further surveillance.

Risk factors for metachronous peritoneal carcinomatosis after radical resection for patients with nonmetastatic pT3-4 colon cancer.

Patients with nonmetastatic pT3-4 colon cancers are prone to develop metachronous peritoneal carcinomatosis (mPC). Risk factors for mPC and the influence of mutant kirsten rat sarcoma viral oncogene (KRAS)/neuroblastoma rat sarcoma (NRAS)/v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and DNA mismatch repair (MMR) status on mPC remain to be described in these patients. All enrolled patients were identified from the prospectively collected colorectal cancer database of a tertiary referral hospital between 2013 and 2018. Multivariate analysis was used to identify risk factors associated with mPC. Of the 1689 patients with nonmetastatic pT3-4 colon carcinoma, 8.4% (142/1689) progressed to mPC. Endoscopic obstruction (HR = 3.044, p < 0.001), elevated CA125 (HR = 1.795, p = 0.009), pT (T4a vs. T3, HR = 2.745, p < 0.001; T4b vs. T3, HR = 3.167, p = 0.001), pN (N1 vs. N0, HR = 2.592, p < 0.001; N2 vs. N0, HR = 4.049, p < 0.001), less than 12 lymph nodes harvested (HR = 2.588, p < 0.001), mucinous or signet ring cell carcinoma (HR = 1.648, p = 0.038), perineural invasion (HR = 1.984, p < 0.001), and adjuvant chemotherapy (HR = 1.522, p = 0.039) were strongly related to mPC but that mutant KRAS/NRAS/BRAF and MMR status was not associated with mPC. This study identified the high-risk factors for mPC in patients with nonmetastatic pT3-4 colon carcinoma, and these factors should be considered in selective preventive therapy and close follow-up for patients subsequently deemed to have high risk for mPC.

Melanoma mortality rate trend in an era of effective treatments: A retrospective study, 1975-2019.

e21555 Background: Skin cancer is the most common cancer in the US. Among all skin cancer cases, melanoma represents only about 1%, but it causes most of the deaths due to skin cancer. Unfortunately, the incidence of melanoma has increased over the last three decades. In the past decade, new and effective therapies for melanoma have emerged, with FDA-approval of multiple checkpoint inhibitors (such as PD-1 inhibitors and CTLA4 inhibitors), and multiple tyrosine kinase inhibitors (TKIs) targeting v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutated melanoma. The aim of this study is to review mortality trends in melanoma since the FDA-approval of these agents. Methods: Long term age adjusted cutaneous Melanoma Mortality Rate (MMR) trends in the United States were reviewed and evaluated using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program from 1975 to 2019. The Annual Percent Change (APC) with 95% confidence interval (CI) and p-value has been used to report long term trends. APC has been calculated using Joinpoint regression. Results: The MMR was found to be increased during 1975-1988 (APC 1.65%; p &lt; 0.01). No statistically significant change in MMR was seen during 1988-2013 (APC 0.01%; p = 0.85). MMR was significantly decreased during 2013-2017 (APC -6.24%, p &lt; 0.01). No statistically significant decrease has been seen during 2017-2019 (APC -1.56%, p = 0.53); however, there is a downward trend. Conclusions: This SEER database retrospective review of MMR provides the insight into change in long term mortality trends for melanoma in the United States. During 1975-2019, the MMR first increased, then stabilized and then decreased. After introduction of checkpoint inhibitors in 2011 and TKIs in 2013, significant reduction in melanoma mortality rate (MMR) was seen during 2013-2017 in the United States, even in the setting of increasing melanoma incidence. This likely reflects a benefit from the availability of effective therapies in the last decade. These treatment options are now also approved for use in the adjuvant setting, primarily after 2017. It will be interesting to see if a further significant reduction in MMR will be seen. It may also be worthwhile to study real-world population trends in other cancers where similar treatments have been found to be effective in recent years.[Table: see text]

Application of nanomedicine in the thetreatment of melenoma

Melanoma is the most forceful sort of skin malignant growth and has exceptionally high paces of mortality. A beginning phase melanoma can be carefully eliminated, with an endurance pace of close to 100%. Notwithstanding, metastasized melanoma is challenging to fix. The 5-year endurance rates for patients with metastasized melanoma are still beneath 20%. Metastasized melanoma is presently treated by chemotherapy, designated treatment, immunotherapy and radiotherapy. The result of the majority of the ongoing treatments is not even close to hopeful. Despite the fact that melanoma patients with a transformation include the oncogene v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) have an at first higher positive reaction rate to designated treatment, the greater part create obtained drug obstruction following a half year of the treatment. To increment treatment adequacy, early finding, more powerful pharmacological specialists, and more successful conveyance frameworks are critically required. Nanotechnology has been broadly read up for melanoma treatment and analysis,to diminish drug obstruction, increment helpful viability, and lessen secondary effects. Include this audit, we sum up the new advancement on the improvement of different nanoparticles for melanoma treatment and finding.

Survival in adult patients with BRAFV600 mutation-positive advanced melanoma: a noninterventional ambispective study of patients with cobimetinib combined with vemurafenib during the French early access program: MELANIS study.

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Genomic Landscape of Actionable Mutations in Primary and Metastatic Tissues of Colon Adenocarcinoma.

AimTo assess the actionable genomic landscape of colon adenocarcinoma in the primary and metastatic tumor tissues.MethodsThe data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) were used in this study. Colon adenocarcinoma patients with primary and metastatic tissue samples (distant organ and lymph node) were selected. Patients with samples from a local recurrence, not otherwise specified tumor samples, and data not collected for sampling localization were excluded.ResultsA total of 3286 and 1727 patients were included in the primary and metastatic tissue sample groups, respectively. There was no difference between the groups in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation rates. The rates of v-Raf murine sarcoma viral oncogene homolog B (BRAF) and mismatch repair (MMR) gene mutations were higher in the primary tumor tissues than in the metastatic tumor tissues. There was also no difference between the groups in other actionable gene alterations (e.g. ERBB2 amplification and neurotrophic receptor tyrosine kinase (NTRK) 1 and NTRK3 fusions). In contrast to all cohorts, in Asian and black patients, there was no difference in actionable genomic landscape between the primary and metastatic tumor tissues.ConclusionThis study had the largest number of colon cancer patients that evaluated the actionable genomic alterations in primary and metastatic tumor tissues. BRAF and MMR gene alterations were more frequent in the primary tumor tissues than the metastatic tumor tissues.

BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective.

V-Raf murine sarcoma viral oncogene homolog B (BRAF) kinase, which was encoded by BRAF gene, plays critical roles in cell signaling, growth, and survival. Mutations in BRAF gene will lead to cancer development and progression. In non-small cell lung cancer (NSCLC), BRAF mutations commonly occur in never-smokers, women, and aggressive histological types and accounts for 1%–2% of adenocarcinoma. Traditional chemotherapy presents limited efficacy in BRAF-mutated NSCLC patients. However, the advent of targeted therapy and immune checkpoint inhibitors (ICIs) have greatly altered the treatment pattern of NSCLC. However, ICI monotherapy presents limited activity in BRAF-mutated patients. Hence, the current standard treatment of choice for advanced NSCLC with BRAF mutations are BRAF-targeted therapy. However, intrinsic or extrinsic mechanisms of resistance to BRAF-directed tyrosine kinase inhibitors (TKIs) can emerge in patients. Hence, there are still some problems facing us regarding BRAF-mutated NSCLC. In this review, we summarized the BRAF mutation types, the diagnostic challenges that BRAF mutations present, the strategies to treatment for BRAF-mutated NSCLC, and resistance mechanisms of BRAF-targeted therapy.

Study on endocrine disruption effect of paclobutrazol and uniconazole on the thyroid of male and female rats based on lipidomics

The present study investigated the effects of paclobutrazol and uniconazole on thyroid endocrine system in rats. Lipidomic analysis was performed to obtain the biomarkers of thyroid endocrine disruption induced by paclobutrazol and uniconazole. Network pharmacology was further used to discover potential targets of biomarkers related to drugs and diseases. After paclobutrazol and uniconazole administration, seven and four common biomarkers related to thyroid endocrine disruption for female and male rats were obtained, respectively. Paclobutrazol and uniconazole significantly increased the biomarker levels of PG (12:0/15:0), PS (14:0/16:0), PA (20:1/15:0) and PG (13:0/17:0) in both sexes of rats. Exposure to paclobutrazol additionally caused a significant decrease of PG (22:6/20:2), PE (24:1/18:1) and PE (24:0/18:0) in female rats, while an increase in male rats. Changes of the common biomarkers for paclobutrazol and uniconazole revealed similar endocrine disruption effect, which was higher in the females. Network pharmacology and KEGG pathway analysis indicated that the thyroid endocrine disrupting effects of paclobutrazol and uniconazole may be related to V-akt murine thymoma viral oncogene homolog (Akts), mitogen-activated protein kinase (MAPKs), epidermal growth factor receptor (EGFR), Insulin-like growth factor (IGF-1), IGF-IR and V-Raf murine sarcoma viral oncogene homolog B1 (BRAF). The results demonstrated that paclobutrazol and uniconazole could cause thyroid endocrine disorders in male and female rats, which were sex-specific, thus highlighting the importance of safe and effective application of these plant growth regulators.