Our results implied that there were noticeable differences between different oral RV doses used for cisplatin ototoxicity. Especially in higher doses, RV was observed to enhance cisplatin ototoxicity.
As increased NLR, MLR, and PLR predicted poor clinical outcome in MM patients with autologous transplantation in this study, they may serve as cost-effective and rapidly available prognostic biomarkers for these patients.
1 (HEI-OC1) cell line. Cells were treated with CDDP, KRG, and their combination for 24 h. Cell viability, apoptosis, and the expression of 84 apoptosis-related genes were analyzed. In the second part of the study, 30 Wistar albino rats were divided into five groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were obtained. In groups I, II, and III, only saline, KRG, and CDDP, respectively, were given. In group IV, 500 mg/kg KRG and in group V, 150 mg/kg of KRG were administered for 10 days. In groups III, IV, and V, 16 mg/kg CDDP injections were administered on day 11. On day 14, final DPOAEs and ABR measurements were completed. The rats were then sacrificed, and their inner ear structures were evaluated by transmission electron microscopy. RESULTS:In the first part of the study, pretreatment with 1 mg/mL KRG protected cells from CDDP ototoxicity. This protection was mainly due to a decline in apoptotic gene expression and an increase in antiapoptotic gene expression. In the in vivo part of the study, we found that both KRG doses had otoprotective effects. This protection was more prominent at the lower dose, especially on the spiral ganglion and the brainstem.CONCLUSION: KRG was shown to be an otoprotective agent against CDDP-induced ototoxicity both in vivo and in vitro.
As in all living cells, cancer cells are evaluating is very important in the frames of tumor development and treatment. As in all evolutionary process, the environment of living cells has an important role. Tumor cells have an environment is called tumor microenvironment, affects the therapeutic response and clinical results. Tumor microenvironments involve various cell types, extracellular matrix substances that are in the niche of cancer cells. The microenvironment is not only important in tumorigenesis but it is effective on therapeutic efficacy. In this review, we carried out the interaction between non-small cell lung cancer and its microenvironment to point out the significance of the tumor environment.
Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing, we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8+ T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8+ T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8+ T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.
Introduction: Voiding symptoms, storage symptoms and post-voiding symptoms together constitute lower urinary tract symptoms (LUTS). Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The most common finding is lymphadenomegaly. Although infrequent, extranodal sites of involvement such as prostate can be detected. Mantle cell lymphoma (MCL) is a subtype of B cell non-Hodgkin lymphomas. Extranodal involvement findings such as prostate may be observed. In this case report, we will present a case in which we performed an open suprapubic prostatectomy (Freyer’s) and had CLL as a result of pathology, and a case whose pathology was MCL after transurethral resection of the prostate. Case 1: A 60-year-old male patient with LUTS for 6 years. Open suprapubic prostatectomy (Freyer’s) was performed on the patient. The pathology result of the prostatectomy material was compatible with CLL involvement. Case 2: A 62-year-old male patient with LUTS for 4 years. Transurethral resection of the prostate (TUR-P) was performed on the patient. The pathology result of the prostate was compatible with MCL involvement. Discussion and Conclusion: There are limited number of cases have been reported about CLL pathology after prostatectomy due to benign prostatic obstruction (BPO). There is no study indicating how often CLL pathology is seen after open prostatectomy or TUR-P due to BPO. In patients with CLL pathology after RRP, open prostatectomy, TUR-P, the need for additional surgery, the difference in prognosis or the difference between the treatment have not been shown in the studies. It should be kept in mind that patients with leukocytosis, lymphocytosis, cytopenias, and LUTS in their clinical presentation and who have not yet been diagnosed with CLL and other hematological malignancies such as mantle cell lymphoma may also have prostate gland involvement and can be diagnosed incidentally by any prostatic intervention.
Background: Follicular lymphoma is the second most frequent non-Hodgkin lymphoma (NHL) accounting for 20-25% of NHL cases in western countries. Although it has an indolent character, progressive disease or relapse occurs within first two years following therapy initiation in ~20% of FL cases. Several somatic mutations were identified in genes of epigenetic regulation or other biological processes by sequencing of FL tumors. Current diagnostic and prognostic evaluations include invasive methodologies that may be less effective and more risky for the FL patients. Therefore, there is urgent need for development of non-invasive methods to improve diagnosis as well as risk stratification. Accumulating evidence has shown that circulating cell-free DNA (cfDNA) includes tumor-derived mutations in several cancer types; however, this possibility has not been comprehensively investigated in FL patients. Here we evaluated the potential diagnostic and prognostic value of cfDNA in FL cases by addressing the proportion by which cfDNA samples contains cancer-associated and prognosis-related mutations. Methods: Twenty FL cases with available clinic data were included in this study. Thirteen of these cases were symptomatic who were later treated with R-chemo whereas rest of the cases were asymptomatic who were in watchful-waiting. Plasma cfDNA, granulocyte DNA, and FFPE tumor tissue DNA samples were obtained from treatment-naive FL cases. A custom gene panel including exons and exon-intron boundaries of 110 FL-associated genes was constructed based on previously published studies for ultra-deep targeted sequencing. Paired-end sequencing of the captured regions were performed using a HiSeq system in Novogene, which generated 150 bp NGS reads. Targeted genomic regions were covered with > 1500X average effective sequencing depth for identification of somatic variants with low variant allele fractions (VAF). Variants present in cfDNA and tumor tissue DNA but not in patient-matched granulocyte DNA were identified with the GATK pipeline including the MuTect2 variant caller. Somatic variants associated with hematopoietic and lymphoid tissues in the COSMIC database were chosen for further analyses. The final high-confident list of variants was determined by visual investigation and through additional filtering of each variant using Integrative Genomics Viewer. Selected variants were cross-validated with Sanger sequencing. Survival analyses were performed with Survival and Survminer R packages. Results: Ultra-deep targeted sequencing revealed 91 somatic variants (71 missense, 12 nonsense, 4 indel, 4 splice site) in 31 genes included in the panel. Consistent with previous reports, the most frequently mutated genes were CREBBP (40%), BCL2 (30%), STAT6 (25%), EZH2 (20%), and CARD11 (20%). In symptomatic cases, 41.5% of the variants was present in both cfDNA and tumor tissue DNA, whereas 52.3% and 6.2% of them was present only in tumor tissue DNA or in cfDNA samples, respectively. In asymptomatic cases, 11.5% of the detected variants was present in both cfDNA and tumor tissue DNA, while 84.6% and 3.8% of them were in only tumor tissue DNA or cfDNA samples. Mutations previously reported to be associated with FL pathogenesis (e.g. KMT2D R2417*) were in the list of common variants observed in both cfDNA and tumor tissue DNA. We observed high Ki67 staining, elevated LDH levels, presence of BCL2 or CCND3 mutations to be significantly associated with progression-free survival (Figure 1A, B). Importantly, survival analysis by stratifying patients based on BCL2 mutations present only in cfDNA also predicted poor prognosis (Figure 1C). One of the FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in the cfDNA but not in tumor tissue DNA sample. Finally, we cross-validated the selected somatic variants with VAF >20% using Sanger sequencing, which showed 100% consistency with NGS results. Conclusions: Tumor tissue-derived mutations can be detected in most FL patients albeit to a lesser extent than those in DLBCL. Plasma cfDNA genotyping may be useful for improving diagnosis and prognosis especially in symptomatic FL patients. Given that some somatic mutations associated with disease progression are detected only in plasma cfDNA samples, cfDNA genotyping may be useful for choosing appropriate therapy for high-risk FL patients. Disclosures No relevant conflicts of interest to declare.
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