Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response.

In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters. Most of the molecular dysregulation occurring in sporadic colorectal carcinogenesis is documented in colitis-associated adenocarcinoma too, but marked differences have been established in both their timing and prevalence. Unlike sporadic cancers, TP53 alterations occur early in IBD-related carcinogenesis, while APC dysregulation emerges mainly in the most advanced stages of the oncogenic cascade. From the therapeutic standpoint, colitis-associated cancers are associated with a lower prevalence of KRAS mutations than the sporadic variant. Epigenetic changes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, are significantly involved in colitis-associated cancer development and progression. The focus now is on identifying diagnostic and prognostic biomarkers, with a view to ultimately designing patient-tailored therapies.

Objective: To investigate the TNFAIP3/A20 abnormalities and its association with Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (CHL). Methods: Formalin-fixed, paraffinembedded tissue blocks of 54 CHL patients were collected and subjected to the construction of tissue microarray (TMA) for further analyses. EBV status was evaluated by in situ hybridization (ISH) for EBER1/2 and immunohistochemistry (IHC) with anti-LMP-1 antibody. Fluorescence in situ hybridization (FISH) and IHC were performed to determine the copy number alterations of TNFAIP3 and A20 protein expression respectively. Results: The concordance rate of IHC for LMP-1 and ISH for EBER1/2 was100%, and 25.9% (14/54) cases were identified with EBV infection. Immunohistochemistry analysis demonstrated 27.8% (15/54) cases with A20 expression deficiency. Of the 54 cases tested for A20 expression, 49 cases were simultaneously analyzed by FISH, which showed 10 (20.4% ) cases harboring TNFAIP3 deletion. However, discrepancy was observed between the results of A20 by IHC and TNFAIP3 deletion by FISH. Only 1 case with TNFAIP3 deletion demonstrated complete loss of A20 immunoreactivity. In addition, comparison of the frequency of either A20 expression loss or TNFAIP3 deletion between EBV-positive and-negative cases did not reveal any significance (P>0.05). Conclusion: TNFAIP3 deletion could be observed in both EBV-positive and - negative CHL cases. A20 expression by IHC could not confirm TNFAIP3 deletion by FISH, which might be related to the technical issues.

Objective: To explore the clinical features of lymphoplasmacytic diseases with MyD88 L265P mutation. Methods: To analyze the distribution of MYD88 L265P mutation in patients with lymphoplasmacytic diseases by using of ARMS PCR-CE. Results: There were 25(30.9%) MyD88 L265P mutated patients in 81 patients. The mutation was frequently observed in 14 patients with WM (77.8%, 14/18), 2 patients with lymphoplasmacytic lymphoma (66.7%, 2/3), 1 acute lymphocytic leukemia patient (50.0%, 1/2), 3 multiple myeloma patients (30.0%, 3/10), 1 patient with monoclonal gammopathy of undetermined significance (25%, 1/4), 3 patients with chronic lymphocytic leukemia (13.0%, 3/23) and 1 lymphoma patient (4.8%, 1/21). 20 (80%, 20/25) patients were identified with IgM subtype. Compared with wild-type group of 56 cases, mutated patients were older (median age: 67 years vs 55 years, P< 0.001), with lower WBC count (median count: 5.23 × 109/L vs 10.80 × 109/L, P=0.001), lower HGB level (median count: 85 g/L vs 119 g/L, P<0.001). Conclusion: MyD88 L265P mutation was mainly observed in patients with IgM subtype lymphoplasmacytic diseases, and Waldenstrom' s macroglobulinemia was the most common disease. Compared with the wild-type group, patients with MyD88 L265P mutation were older and had lower WBC count, lower level of HGB. However, further studies were needed to test the prognostic value of MyD88 L265P mutation.

Objective: To explore the efficacy and safety of Sorafenib as monotherapy to FLT3 positive acute myeloid leukemia (AML). Methods: From April 2014 to December 2015, fourteen AML patients with FLT3 positive, 7 males and 7 females with a median age of 42 (range: 14-81) years old, were enrolled in this study. Of the 14 cases, 4 were de novo cases, 9 refractory cases and 1 relapsed case, including 78.6% patients with severe complications and 57.1% patients with KPS score less than 60 [the median KPS score was 45 (20-70) ]. The administration of Sorafenib was 400 mg twice daily and Sorafenib was continued if tolerated. The treatment response was evaluated by MICM and the data were analyzed by paired samples t test before and after Sorafenib treatment. Results: The peripheral blood WBC count [4.2 (0.9-11.8) ×109/L vs 39.6 (2.3-209.5) ×109/L, P<0.001 ], the percentage of peripheral blast cell [0.07 (0-0.54) vs 0.53 (0-0.94), P<0.001] and the percentage of bone marrow blast cell [0.266 (0.020-0.880) vs 0.604 (0.180-0.900), P=0.003] were significantly decreased after Sorafenib monotherapy compared with before. The overall response rate was 57.1% (8/14), including 5 cases (35.7%) with complete remission (CR). Of 4 de novo cases, 2 achieved CR, 1 with PR, 1 with NR; 3 of 10 refractory and relapsed patients achieved CR and 2 cases achieved PR, 5 cases NR. The median duration of achieving molecular remission (FLT3-ITD negative) after Sorafenib was 46(33-72) days, and the median progression free survival (PFS) was 53 (28-175) days. Conclusion: Sorafenib shows activity in FLT3-ITD mutation positive AML patients. Sorafenib monotherapy could be used as a treatment option for elderly patients or patients with severe complications, and refractory and relapsed patients with not suitable for intensive chemotherapy.

Erythrocytosis, or increased red blood cell mass, may be primary as in the case of polycythemia vera (PV), or secondary due to a variety of causes related to erythropoietin (EPO) secretion and hypoxia. Chronic pulmonary disease and certain EPO-secreting tumors should be addressed and excluded early during the course of evaluation for a patient presenting with increased red blood cell mass. Inclusion of the JAK2 V617F gene mutation in the recent World Health Organization criteria for the diagnosis of PV allows for facilitated diagnosis and guides therapy. EPO levels can be helpful in diagnosis and guiding therapy, but in the case of cystic renal diseases, EPO levels are often not elevated, creating diagnostic uncertainty. This report describes a case of symptoms directly attributable to erythrocytosis in the setting of negative JAK2 mutation and normal EPO levels. The subsequent discovery of a large cystic renal kidney and PV were the leading diagnostic considerations.

Recent technological advances in DNA sequencing have enabled a remarkably detailed understanding of the molecular changes that define gynecologic and other cancers. Several groups have carried out large-scale genomic analyses of ovarian, uterine, and most recently, cervical cancer. These analyses have led to new insights into the molecular changes characterizing these cancers, which provide insight into clinical outcomes. These molecular characterizations have similarly led to new genomic-based classification schemas, which may better stratify clinical outcomes, help prognosticate and guide treatments. Discovery of characteristic mutations may also provide potential new targets for molecularly targeted chemotherapies, as has been already described with poly-ADP ribose polymerase inhibitors and ovarian cancer. The purpose of this article is to provide an overview of the defining molecular abnormalities and markers in gynecologic cancer, to discuss the clinical implications, and to provide a comprehensive view of the current state of genomic knowledge in gynecologic cancer.

Arsenic is a well-known toxic element and carcinogenic agent. The aim of this study was to investigate p63, E-cadherin, and β-catenin proteins in urothelial carcinoma (UC) in both arsenic contaminated areas [so-called blackfoot disease (BFD) area] and non-BFD areas. The expressions of p63, E-cadherin, and β-catenin proteins in 20 UC cases of blackfoot disease and 22 UC cases in non-BFD areas were detected using immunohistochemical methods. The results revealed a high p63 expression in 20 (47.6%) UC cases and high E-cadherin expression in six (14.3%) UC cases. Expressions of p63 and E-cadherin showed no significant correlations with clinicopathologic parameters. However, all 20 BFD cases and 12 of 22 (54.5%) non-BFD cases showed aberrant β-catenin expression. Ten out of 22 (45.5%) non-BFD cases also had normal membranous immunoreactivity. The β-catenin staining pattern significantly differed between cases in endemic and nonendemic areas of BFD (p=0.001). Tumor sites also significantly correlated with β-catenin expression (p=0.044). In addition, membranous localization of β-catenin was lower in UC from BFD-endemic areas compared with those from non-BFD endemic areas. In conclusion, it is suggested that relocalization of β-catenin from membrane to cytoplasm may be involved in the tumorigenesis of UC from BFD-endemic areas.

Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors.

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

MicroRNAs (miRNAs) are endogenous short non-coding RNAs found to play key roles in the pathogenesis of leukemia. Apart from being traditionally identified as modulators of oncogenes, the potential roles of miRNAs seems to be growing with novel and recent findings among different subtypes of hematological malignancies. Leukemia is one of the earliest malignancies to be linked to abnormal expression of miRNAs. However, a clear understanding of the involvement of miRNAs in intricate mechanisms of leukemogenesis is still a necessity. This review summarizes the multiple roles of miRNAs in the pathogenesis of leukemia and highlights major research findings contributing to these aspects.

The outcome prediction of patients can greatly help to personalize cancer treatment. A large amount of quantitative features (clinical exams, imaging, …) are potentially useful to assess the patient outcome. The challenge is to choose the most predictive subset of features. In this paper, we propose a new feature selection strategy called GARF (genetic algorithm based on random forest) extracted from positron emission tomography (PET) images and clinical data. The most relevant features, predictive of the therapeutic response or which are prognoses of the patient survival 3 years after the end of treatment, were selected using GARF on a cohort of 65 patients with a local advanced oesophageal cancer eligible for chemo-radiation therapy. The most relevant predictive results were obtained with a subset of 9 features leading to a random forest misclassification rate of 18±4% and an areas under the of receiver operating characteristic (ROC) curves (AUC) of 0.823±0.032. The most relevant prognostic results were obtained with 8 features leading to an error rate of 20±7% and an AUC of 0.750±0.108. Both predictive and prognostic results show better performances using GARF than using 4 other studied methods.

Although useful prognostic and predictive insights can be gained from patient and tumour characteristics in early-stage breast cancer, it is not always straightforward to predict the likely risk of recurrence for each individual patient following breast surgery. One of the most difficult challenges faced by clinicians is identifying patients who may benefit most from adjuvant chemotherapy, and distinguishing these cases from those where endocrine therapy may be sufficient for cure. Genomic tests such as the Oncotype DX® Breast Recurrence Score® Assay have been developed to provide a robust and clinically validated assessment of a patient's individual tumour signature. The Oncotype DX Assay is included in treatment guidelines for estimating both the risk of distant recurrence and predicting adjuvant chemotherapy benefit for early-stage breast cancer patients with human epidermal growth factor receptor 2-negative, oestrogen-receptor positive, and axillary lymph node negative or positive (1-3 positive nodes) disease. In this article, we review unmet needs for prognostication and prediction in early-stage breast cancer, and consider how the information provided by the Recurrence Score is complementary to that gained from the assessment of more traditional clinicopathologic criteria. Routine use of the assay in clinical practice, limitations and possible future directions are also discussed.

Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.

The epithelial-mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as single cells. Tumor cells reactivate EMT to acquire molecular alterations that enable the partial loss of epithelial features and partial gain of a mesenchymal phenotype. Our understanding of the contribution of EMT to tumor invasion, migration, and metastatic outgrowth has evolved over the past decade. In this review, we provide a summary of both historic and recent studies on the role of EMT in the metastatic cascade from various experimental systems, including cancer cell lines, genetic mouse tumor models, and clinical human breast cancer tissues.

Multiple myeloma (MM) is a plasma-cell malignancy derived from an early precursor of the B-cell lineage characterised by bone-marrow infiltration, lytic bone lesions, and the presence of a monoclonal protein in serum and/or urine. Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B-cell development and function that is required during immune response for lymphocyte activation and the generation of immunoglobulin-secreting plasma cells. Immunomodulatory drugs, derivatives of thalidomide, are commonly used in therapy against MM. They are known to target a protein called cereblon (CRBN); however, the exact mechanism remains unknown. The present study aimed to assess the association of two (rs12203592 and rs872071) polymorphisms within the IRF4 gene and two (rs711613 and rs1045433) in the CRBN gene with MM susceptibility, progression, and response to treatment. For this purpose, 144 MM patients and 126 healthy individuals were genotyped for the IRF4 and CRBN alleles. The presence of the IRF4 (rs872071) G allele was more frequently detected in patients than healthy individuals (OR 1.78; P = 0.034), and this relationship was especially pronounced in women (OR 2.83; P = 0.012). The CRBN (rs711613) A allele-carriers were better responders to the treatment (P = 0.012), in particular to thalidomide including therapy (P = 0.023). These results underline the prognostic significance of the IRF4 and CRBN polymorphisms in patients with MM.

An effective cytotoxic immune response to neoplastic cells requires efficient presentation of antigenic peptides to T lymphocytes by HLA class I (HLA-I) molecules. The HLA-I-bound peptide repertoire depends on antigen-processing machinery molecules. Aminopeptidase residing in endoplasmic reticulum 1 (ERAP1) trims peptides to the optimal length for HLA-I binding. Single nucleotide polymorphisms (SNPs) in the ERAP1 gene result in changes in aminopeptidase activity and specificity. This may affect susceptibility to cancer. However, non-small cell lung carcinoma (NSCLC) has not been studied in this respect. We compared genotype and haplotype frequencies of four coding, nonsynonymous ERAP1 SNPs, rs26653G > C, rs26618T > C, rs30187C > T, and rs27044C > G, in NSCLC occurring in two genetically distant populations, Chinese and Poles. We found associations of all four SNPs with NSCLC in Chinese but not in Poles. The differences in ERAP1-NSCLC associations might be explained by highly significant differences in SNP genotype frequencies between Chinese and Poles (except for rs26618). In accordance with this, the most frequent ERAP1 haplotypes were distributed differently in cases versus controls in Chinese, but not in Poles. Our findings add to the differences between Orientals and Caucasians in genetics of disease susceptibility.

B-cell chronic lymphocytic leukemia (B-CLL) presents with progressive accumulation of monoclonal B cells in the peripheral blood, bone marrow and lymphoid organs. B-CLL is characterized by heterogeneous clinical outcome. The expression of Toll-like receptors (TLRs) and their association with other prognostic factors in B-CLL patients remain unclear. The aim of our study was to evaluate the expression of TLR2, TLR4 and TLR9 genes and their significance as biological markers in patients with B-CLL. Sixty patients with newly diagnosed B-CLL were evaluated. The healthy control group included 20 age-matched individuals. Using quantitative reverse transcriptase PCR, the mRNA expression of genes TLR2, TLR4 and TLR9 was measured. TLR4 gene expression was lower in B-CLL patients as compared to the control group and TLR2 gene expression was higher in B-CLL patients than in healthy individuals. TLR9 gene expression was higher in the control group than in patients with B-CLL. TLR4 mRNA expression was lower in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II). TLR2 gene expression was higher in patients with advanced-stage CLL (Rai stages III and IV) than in patients with early stage disease (Rai stages 0-II; p < 0.05). Our results suggest that TLRs could become potential biological markers for the clinical outcome in patients with B-CLL.

Many studies have described the role of killer immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) class I ligands in the immune protection against melanoma, but the effect of these markers on intra-individual variations in tumor development and progression has remained less clear. We performed KIR, HLA, and KIR/ligand analysis in 283 patients with malignant melanoma in order to evaluate their integrated influence on disease stage and progression. The patients were grouped according to AJCC staging, histological type of the primary tumor, progression, and survival rate. Analysis of HLA class I alleles revealed positive association of HLA-C*14 (Pc = 0.026, OR = 5.99) and negative association of HLA-C*02 (Pc = 0.026, OR = 0.43) with the disease. Decreased frequency of KIR2DS5 was observed in patients with rapid progression, as compared to those with slow progression. KIR BB genotype was prevalent in patients with metastasis (p = 0.004, OR = 0.025). KIR AA genotype was nearly twice as frequent in rapidly progressive cases, but without statistical relevance (p = 0.055, OR = 2.6). Significantly increased frequency of KIR2DL2 in the presence of C1 ligand (strong inhibition) was found in patients with AJCC III and IV, as compared to individuals with AJCC I stage (p = 0.045, OR = 1.93). In summary, our data imply that KIR/ligand gene content in patients could modulate the disease course towards unfavorable tumor behavior.