Obesity-Associated Colorectal Cancer.

Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.

Glioblastoma in the Elderly: Review of Molecular and Therapeutic Aspects.

Glioblastoma (GBM) is the most aggressive primary brain tumour. As GBM incidence is associated with age, elderly people represent a consistent subgroup of patients. Elderly people with GBM show dismal prognosis (about 6 months) and limited response to treatments. Age is a negative prognostic factor, which correlates with clinical frailty, poorer tolerability to surgery or adjuvant radio-chemotherapy, and higher occurrence of comorbidities and/or secondary complications. The aim of this paper is to review the clinical and molecular characteristics, current therapeutic options, and prognostic factors of elderly patients with GBM.

Regulation of Immunity in Clear Cell Renal Carcinoma: Role of PD-1, PD-L1, and PD-L2.

Regulation of immunity is a unique oncogenic mechanism that differs in different cancers. VHL deficient clear cell renal cell carcinomas (ccRCC) trigger the immune response resulting in cancer progression. This study aimed to investigate PD-1, PD-L1, and PD-L2 expression in ccRCC primary cancers and metastatic tissues associated with the p-VHL content, transcriptional, and growth factors expression. METHODS: A total of 62 patients with RCC were enrolled in the study. Investigation of mRNA level was performed by PCR in real-time. Western blotting analysis was used for detecting the p-VHL protein content in tissues. RESULTS: The PD-L2 prevalence in metastatic cancers is crucial in tumor progression. The VHL expression and p-VHL content determined the aggressive cancer behavior and elevated in disseminated tumors. The cancer dissemination was accompanied by an increase in both mRNA and VHL content. CONCLUSION: We present a new instrument targeting pathologies with p-VHL/HIF altered function that impact the PD-L2 expression through the change in transcriptional, growth factors, and AKT/mTOR modulation.

The Association of the BRAF-V600E Mutation with the Expression of the Molecular Markers in the Primary Tumor and Metastatic Tissue in Papillary Thyroid Cancer.

OBJECTIVE: The aim of this study was investigation the AKT / mTOR signaling pathway components, transcriptional and growth factors, as well as steroid hormone receptors and nuclear factors Brn-3α and TRIM16 expression in the tissue of the primary thyroid tumor and metastases, depending on the BRAF- V600E status. MATERIAL AND METHODS: The study was enrolled 20 patients with PTCs, who underwent surgical treatment. They were divided into negative BRAF-V600E status (12 people), positive BRAF-V600E status (8 patients). Mutation status was assessed in paired metastatic tissue samples. The molecular marker expression was determined by real-time PCR. The Real-time-PCR-BRAF-V600E reagent kit evaluated the BRAF-V600E mutation. RESULTS: A decrease in the PDK kinase, PTEN, VHL mRNA level in primary cancers was noted, compared with metastases' tissue. An increase in AKT, GSK-3ß, mTOR, 70s 6 kinase was revealed in cancers with point mutation compared with the primary tumor without a mutation. Positive mutation status was accompanied by an increase in NF-κB p65, NF-κBp50, VEGF HIF-2 VHL level compared to the primary tumor with negative BRAF-V600E status. In the metastases with the BRAF-V600E point mutation, a decrease in the PDK kinase, HIF-1; VHL; TRIM16, and ERα expression was observed, compared to lymph node metastases (LNMs) without the mutation. The concordance in the BRAF-V600E tumor status and LNMs was observed only in 50% of patients. If the BRAF gene status did not match PTCs and LNMs, an increase in the mTOR, NFkBp65, VHL, and ERα mRNA levels was found in the PTCs. In LNMs, there was an increase in the c-RAF PTEN NFkBp65 VHL expression compared to non-concordant ones. CONCLUSION: The heterogeneity in the primary tissue's expression profile and metastases was noted. The BRAF-V600E mutation can affect the molecular characteristics both in the primary cancers and metastases. The discrepancy between the mutant status and the molecular factors expression variability in the primary tumor and LNMs determines its progression.

Investigating Molecular Signatures Underlying Trapeziometacarpal Osteoarthritis Through the Evaluation of Systemic Cytokine Expression.

Purpose: Non-operative management of trapeziometacarpal osteoarthritis (TMOA) demonstrates only short-term symptomatic alleviation, and no approved disease modifying drugs exist to treat this condition. A key issue in these patients is that radiographic disease severity can be discordant with patient reported pain, illustrating the need to identify molecular mediators of disease. This study characterizes the biochemical profile of TMOA patients to elucidate molecular mechanisms driving TMOA progression. Methods: Plasma from patients with symptomatic TMOA undergoing surgical (n=39) or non-surgical management (n=44) with 1-year post-surgical follow-up were compared using a targeted panel of 27 cytokines. Radiographic (Eaton-Littler), anthropometric, longitudinal pain (VAS, TASD, quick DASH) and functional (key pinch, grip strength) data were used to evaluate relationships between structure, pain, and systemic cytokine expression. Principal Component Analysis was used to identify clusters of patients. Results: Patients undergoing surgery had greater BMI as well as higher baseline quick DASH, TASD scores. Systemically, these patients could only be distinguished by differing levels of Interleukin-7 (IL-7), with an adjusted odds ratio of 0.22 for surgery for those with increased levels of this cytokine. Interestingly, PCA analysis of all patients (regardless of surgical status) identified a subset of patients with an "inflammatory" phenotype, as defined by a unique molecular signature consisting of thirteen cytokines. Conclusion: Overall, this study demonstrated that circulating cytokines are capable of distinguishing TMOA disease severity, and identified IL-7 as a target capable of differentiating disease severity with higher levels associated with a decreased likelihood of TMOA needing surgical intervention. It also identified a cluster of patients who segregate based on a molecular signature of select cytokines.

Clinical and molecular factors for selection of nivolumab or irinotecan as third-line treatment for advanced gastric cancer.

BACKGROUND: The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial. METHODS: This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS). RESULTS: A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 versus 2.0 months) and OS (median 12.9 versus 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 versus 1.8 months) and a trend of longer OS (median 3.9 versus 6.1 months) in patients with ⩾2 of these factors. CONCLUSIONS: Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.

Perampanel in brain tumor-related epilepsy: Observational pilot study.

OBJECTIVE: Possible loss of efficacy and potential interactions between antiepileptic drugs (AEDs) and chemotherapy could complicate the management of patients with brain tumor-related epilepsy (BTRE) that may expose patients to an increased risk of adverse events. Perampanel (PER) is a highly selective, noncompetitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor antagonist. This study evaluates the effectiveness, QoL, cognition, and mood of PER in add-on therapy in BTRE patients. MATERIAL AND METHODS: Observational pilot study on the effectiveness of PER as add-on therapy in BTRE patients with uncontrolled seizures with a 6-month follow-up. RESULTS: We recruited 26 BTRE patients. During the follow-up, 16 underwent chemotherapy and 11 radiotherapy; 11 had disease progression. Five patients dropped out. Mean daily PER dosage was 6.6 mg in the 21 patients who completed the follow-up and 6.4 mg in the ITT population. The mean number of seizures/month decreased from 10.8 ± 15.03 at baseline to 1.7 ± 4.34 in the 21 patients who reached the final follow-up. Responder rate was 88.4%: Eight patients were seizure-free, 15 had ≥50% seizure reduction, and 3 remained stable. Four patients (15.4%) reported AEs: 2 required PER dose reduction, and 2 dropped out. Neuropsychological, mood, and QoL questionnaires were not statistically different compared to baseline. There were no significant differences in seizure control in patients with/without IDH1 mutation and with/without MGMT methylation. CONCLUSIONS: Perampanel proved to be effective on seizure control in BRTE patients and to be well tolerated without negative effects on cognition and QoL. Perampanel could be a valid therapeutic option in BTRE.

Mobilizing serum factors and immune cells through exercise to counteract age-related changes in cancer risk.

An increasing body of evidence suggests that age-related immune changes and chronic inflammation contribute to cancer development. Recognizing that exercise has protective effects against cancer, promotes immune function, and beneficially modulates inflammation with ageing, this review outlines the current evidence indicating an emerging role for exercise immunology in preventing and treating cancer in older adults. A specific focus is on data suggesting that muscle- derived cytokines (myokines) mediate anti-cancer effects through promoting immunosurveillance against tumourigenesis or inhibiting cancer cell viability. Previous studies suggested that the exercise-induced release of myokines and other endocrine factors into the blood increases the capacity of blood serum to inhibit cancer cell growth in vitro. However, little is known about whether this effect is influenced by ageing. Prostate cancer is the second most common cancer in men. We therefore examined the effects of serum collected before and after exercise from healthy young and older men on the metabolic activity of androgen-responsive LNCaP and androgen-unresponsive PC3 prostate cancer cells. Exercise-conditioned serum collected from the young group did not alter cell metabolic activity, whereas post-exercise serum (compared with pre-exercise serum) from the older men inhibited the metabolic activity of LNCaP cancer cells. Serum levels of candidate cancer-inhibitory myokines oncostatin M and osteonectin increased in both age groups following exercise. Serum testosterone increased only in the younger men postexercise, potentially attenuating inhibitory effects of myokines on the LNCaP cell viability. The data from our study and the evidence in this review suggest that mobilizing serum factors and immune cells may be a key mechanism of how exercise counteracts cancer in the older population.

Perampanel in patients with brain tumor-related epilepsy in real-life clinical practice: a retrospective analysis.

INTRODUCTION: Epilepsy occurs in 35-70% of patients with gliomas; glutamate plays a central role via AMPA-receptor activation, which is involved both in seizure activity and tumor growth. We conducted a retrospective study on brain tumor-related epilepsy patients (BTRE) treated with perampanel in add-on (PER) for 12 months, to evaluate efficacy and tollerability, according to real-life clinical practice. MATERIALS AND METHODS: Medical records of eleven patients (9 males, mean age 54 years) with glioma and epilepsy treated with PER in add-on, for inadequate seizure control or adverse events (AEs) from previous antiepileptic drugs (AEDs) therapy, were reviewed. Data collected included: tumor history, molecular factors, systemic therapy, type and number of seizures and concomitant AEDs, and AEs. RESULTS: After 12 months of PER therapy, five patients were seizure-free, 4 had a seizure reduction ≥50% and the seizure frequency was unchanged in 2 patients. Responder rate was 81.8%. Two patients reported AEs; PER dose was reduced only in the one case. The final median dose of PER was 7.3 mg/day. We didn't find statistically significant differences in the comparison between mean values pre, mean values post and the average of decreasing number of seizures related to: histology, presence/absence of chemotherapy, radiotherapy, progression disease, KPS, IDH1, MGMT. DISCUSSION: Despite the limitations due to small number of patients in a retrospective study, the high rate of responder and seizure-free patients suggest that PER could be a therapeutic option in BTRE. Prospective controlled studies are needed to confirm our data.

Factors affecting survival outcomes of patients with non-metastatic Ewing's sarcoma family tumors in the spine: a retrospective analysis of 63 patients in a single center.

Little information has been published in the literature regarding survival outcomes of patients with Ewing's sarcoma family tumors (ESFTs) of the spine. The purpose of this study is to explore factors that may affect the prognosis of patients with non-metastatic spinal ESFTs. A retrospective analysis of survival outcomes was performed in patients with non-metastatic spinal ESFTs. Univariate and multivariate analyses were employed to identify prognostic factors for recurrence and survival. Recurrence-free survival (RFS) and overall survival (OS) were defined as the date of surgery to the date of local relapse and death. Kaplan-Meier methods were applied to estimate RFS and OS. Log-rank test was used to analyze single factors for RFS and OS. Factors with p values ≤0.1 were subjected to multivariate analysis. A total of 63 patients with non-metastatic spinal ESFTs were included in this study. The mean follow-up period was 35.1 months (range 1-155). Postoperative recurrence was detected in 25 patients, and distant metastasis and death occurred in 22 and 36 patients respectively. The result of multivariate analysis suggested that age older than 25 years and neoadjuvant chemotherapy were favorable independent prognostic factors for RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis were favorable independent prognostic factors for OS. Age older than 25 years and neoadjuvant chemotherapy are favorable prognostic factors for both RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis are closely associated with favorable survival.

Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases.

Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors.

Expression of molecular factors correlated with metastasis in small cell lung cancer and their significance.

Distant metastasis continues to be a fatal threat to quality of life in patients with small cell lung caner (SCLC). The purpose of this work is to analyze the expressions of chemokine receptor four (CXCR4), matrix metalloproteinase-9 (MMP-9), transforming growth factor-b1 (TGF-ß1), N-cadherin and vascular endothelial growth factor (VEGF) in small cell lung caner (SCLC), and to explore their correlations with the prognosis and metastasis. Sixty-five consecutive patients with stage I-III SCLC who received operation in our hospital from Jan 2003 to Oct 2009 were retrospectively analyzed. The expression of CXCR4 was found significantly correlated with bone metastasis (P = 0.004), and were marginally correlated with brain metastasis (P = 0.068) and lymph node metastasis (P = 0.085). The expression of MMP-9 was significantly associated with pathological staging (P = 0.048). Univariate analysis suggested surgical approach, clinical stage, lymph node metastasis were significantly associated with OS and PFS (P < 0.05), high expression of CXCR4 was significantly correlated with worse OS (P = 0.004) and PFS (P = 0.005). Multivariate analysis suggested surgical approach, TGF-ß1, CXCR4 and lymph node metastasis were independent prognostic factor for PFS. In conclusion, High expression of CXCR4, MMP-9, TGF-ß1 and VEGF were found in SCLC. High expression of MMP-9 was significantly associated with pathological staging, and high expression of CXCR4 was correlated with bone metastasis and also might correlate with brain metastasis. CXCR4 were independent prognostic factor for survival in SCLC and expanded samples should be further explored in the future.

Molecular alterations in clinical stage III cutaneous melanoma: Correlation with clinicopathological features and patient outcome.

The aim of the present study was to evaluate the frequency and type of oncogenic v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in cutaneous melanoma with clinically detected nodal metastases (stage IIIB and C) in relation to clinicopathological features and outcome. The clinicopathological data of 250 patients following therapeutic lymphadenectomy (LND) between 1995 and 2010, as well as BRAF/NRAS mutational status in corresponding nodal metastases, were analyzed. The median follow-up time was 53 months. BRAF mutations were detected in 154 (62%) cases (141 p.V600E, nine p.V600K and four others) and mutually exclusive NRAS mutations were detected in 42 (17%) cases. The presence of a BRAF mutation was found to correlate with patients of a younger age. The five-year overall survival (OS) rate was 33 and 43% for LND and primary tumor excision, respectively, and the five-year disease-free survival (DFS) rate for LND was 25%. No correlation was identified between BRAF/NRAS mutational status and RFS or OS (calculated from the date of the LND and primary tumor excision); for BRAF- and NRAS-mutated melanoma, the prognosis was the same for patients with wild-type (WT) melanoma. The important factors which had a negative impact on OS and DFS were as follows: Male gender, >1 metastatic lymph node and extracapsular extension of nodal metastases. The interval between the diagnosis of the initial melanoma to regional nodal metastasis (median, 10 months) was not significantly different between BRAF-mutant and -WT patients. Our largest comprehensive molecular analysis of clinical stage III melanoma revealed that BRAF and NRAS mutational status is not a prognostic marker in stage III melanoma patients with macroscopic nodal involvement, but may have implications for potential adjuvant therapy.

Surgical margins in head and neck cancer: a contemporary review.

Adequate resection margins are critical to the treatment decisions and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). However, there are numerous controversies regarding reporting and interpretation of the status of resection margins. Fundamental issues relating to the basic definition of margin adequacy, uniform reporting standards for margins, optimal method of specimen dissection, and the role of intraoperative frozen section evaluation, all require further clarification and standardization. Future horizons for margin surveillance offer the possible use of novel methods such as "molecular margins" and contact microscopic endoscopy, However, the limitations of these approaches need to be understood. The goal of this review was to evaluate these issues to define a more rational, standardized approach for achieving resection margin adequacy for patients with HNSCC undergoing curative resection.