క్యాన్సర్ సైన్స్ & థెరపీ

Metadichol ® a novel nano emulsion of lipid alcohols is an Inverse agonist of Vitamin D Receptor (VDR). In this communication, we show that Metadichol is an inverse agonist of the nuclear receptor AHR (Aryl Hydrocarbon receptor) and also an inhibitor of NRF2 (NF-E2-related factor-2) and is a transcription factor that is ubiquitously expressed at low levels in all human organs and regulates a primary cellular defense mechanism, tight regulation to maintain cellular homeostasis. AHR is highly expressed in a broad panel of tumors, AHR is induced by 2,3,7,8-tetrachloride-benzo-p-dioxin (TCDD) Metadichol® with inverse agonist against AHR could be potentially useful in the treatment of such diseases. Strong in vivo evidence suggests that TCDD can stimulate cross-talk between AHR and Nrf2. The constitutive up regulation of Nrf2 signaling appears to drive the cellular proliferation and resistance to chemotherapy in various cancers. Therefore, pharmacological inhibition of Nrf2 by Metadichol ® holds promise as a therapeutic strategy in chemo resistant forms of cancer.

Objective: Glioblastoma multiforme is the most aggressive form of primary brain tumors, characterized by a high molecular heterogeneity hinder its treatment. Glioblastoma multiforme cells synthesize steroids through the enzyme aromatase and express estrogen receptors. Anastrozole, a specific aromatase inhibitor, plays an important role in endocrine therapy for breast cancer treatment. However, it is unknown whether this inhibitor is useful for treating glioblastoma multiforme. The aim of this work was evaluated the anastrozole effects in the viability and proliferation of malignant cells C6 in vitro as well as apoptosis, cell division, aromatase and estrogen receptor alpha expression in a GBM model in vivo. Methods: C6 cells viability under anastrozole treatment (25, 50, 75 μg/ml) was measured by MTT method and their proliferation was determinate by immunohitofluorescence. In the tumor tissue, the proliferation was evaluated using ki-67 antibody by immunohistofluorescence. ER alpha, aromatase, caspase 8 and 9 protein expression was analyzed using western-blotting. Furthermore, GPR-30, SOX2, CD133 and GFAP were evaluated by immunohistofluorescence. Results: Anastrozole produced a reduction in the viability and proliferation of the C6 cells in culture when was used at 50 μg/ml. It reduces the number of Ki67 immunofluorescent cells in approximately 50%. The aromatase expression decreased in 95%. The estrogen receptor alpha expression increased by a 20% approximately. Caspase 8 expression increased in the treated tumor tissue, although it was undetectable in the not treated group. Caspase 9 increased in approximately 95% in the treated group. All data expressed in these experimental quantifications have a statistically significant difference (p<0.05). G protein coupled receptor-30 was observed in the tumor specimens exhibiting an expression reduction in the anastrozole treated group. Conclusion: The present study demonstrates that anastrozole reduces viability and proliferation in vitro, induces apoptosis and reduces proliferation and aromatase expression in the glioblastoma Xenograft mouse model.

Background: Sleep disruption is a common problem for patients with cancer. Several recent studies have reported an incidence of 30% to 50% in this group, compared to 15% in the general population, but it has received little attention from the oncology community compared with other symptoms accompanying cancer. Patients and methods: It is a cross-sectional study where we included a total of 284 patients with cancer during treatment. All patients were offered brief sleep questionnaires, judgment criteria were based on the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), and the Epworth Sleepiness Scale (ESS) to assess respectively sleep quality, insomnia, and sleepiness. We analyzed data by calculation of Cronbach’s alpha coefficient for the reliability of measurements, and by simple and multiple logistic regressions. Results: Internal consistency measurement of the ISI, ESC, PSQI subscales questionnaires found a Cronbach’s alpha coefficient of 0.895, 0.618 and 0.669, respectively. 52% of patients have no clinically significant insomnia, 12.5% have Subthreshold insomnia, 25% have clinical insomnia (moderate severity) and 10.5% have severe clinical insomnia. Patients with urologic, head and neck, and gastro-intestinal cancer had higher scores than patients with breast and gynecologic cancer. As for patients receiving surgery and chemotherapy, the ISI average score was respectively 14.3 ± 4.4 and 13.8 ± 4.9. it was statistically different (p<0.001) in post-hoc correction from the average scores of patients receiving radiotherapy (13.2 ± 3.8). In multivariate analysis, the strongest associated factors with insomnia were lowest SES (OR=3.849 [1,684-5,159]), head and neck cancer (OR=3.129 (1,985-5,129)), urologic cancer (OR=2.919 [1,985-5,295]), Surgery (OR=3.201 [1,993-8,157]), and Chemotherapy (OR=3.154 [2,869-7,818]). Regarding daytime sleepiness, 49.6% of patients were in normal range in healthy adults 32% have moderate sleepiness and 18.4% have severe sleepiness. Multivariate analysis of age, sex, marital status, SES, cancer type, and treatment type show that older patients more than 60 years, single patients, surgery and chemotherapy were the independent associated factors with somnolence and this was statistically significant. While married status was a protector factor. 28.2% of patients tested did not have impaired quality of sleep, 39.1% had moderate sleep quality, while 32.7% reported severe impaired sleep quality. According to the in PSQI score, independent factors associated with poor quality of sleep found in multivariate analysis were primarily younger patients (OR>8.8, p=0.001), followed by urologic cancer (OR>4, p=0.001), head and neck cancer (OR=1.979, p=0.006), and lowest level of SES (OR=4.119, p=0.001), regarding type of treatment there is no significant difference between different treatment. 74% of patients with sleep disturbances report that their sleep disorders decrease quality of life, 41% report fatigue, 53% experienced mental capacity degradation and 39% of patients report that affect Interpersonal relationship, and their humor in 42%. Conclusion: Patients with head and neck cancer and urological cancer, patients receiving chemotherapy and surgery should be investigated especially among younger ones, in order to detect those at risk of sleep disruption and offer them appropriate support.

Introduction: Chronic myeloid leukemia abbreviated as CML is a type of myeloproliferative disease characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. It is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes and their precursor is found.

Case presentation: We report the case of 58-year-old Asian lady experiencing generalized body weakness, pallor, left upper abdominal pain and sudden weight loss of 5 kg within three weeks and a high blood pressure of 190/110. She has initially diagnosed splenomegaly and a mild heart attack. Various laboratory tests including complete blood count were conducted and the test results revealed a myeloproliferative disorder. The oncologist suggested bone marrow aspiration that led to a diagnosis of chronic myeloid leukemia. The disease was thought treated at an early stage but the case became complicated by previous untreated pathological conditions.

Conclusion: Not all cases of CML are complicated in such a critical manner. Our report emphasizes on the fact of the need of good clinical evaluation by a qualified therapist and use of appropriate investigative studies is mandatory in order to secure patient from such a critical health condition.

The dogma that apoptosis and autophagy are the sole forms of Programmed Cell Death (PCD) is no longer accepted, due to the recent discovery of programmed necrosis, a non-apoptotic, non-autophagic form of PCD. Necroptosis, parthanatos, pyroptosis, and ferroptosis are all forms of programmed necrosis, as these types of cell death dismantle the cell in an ordered fashion that is distinctly different from apoptosis or autophagy. Several key cellular mediators and events in these types of PCD have been discovered. Here, we discuss the basic characteristics, molecular pathways, and possible implications of these lesser-known types of PCD in cancer treatment modalities such as chemotherapy and radiotherapy. Because resistance to apoptosis is often responsible for cancer treatment failures, novel therapeutic strategies that can activate alternative cell death programs have great appeal. Understanding the underlying mechanisms of these types of PCD may facilitate the development of diverse therapeutic strategies, particularly against apoptosis-resistant cancers.

Background: Tumor elimination and the success of cancer immunotherapy depend on the proper expression of HLA class I complex (HLA-I) required for the presentation of tumor-associated peptides to cytotoxic T-lymphocytes. Tumors escape immune attack by losing HLA-I expression, often due to irreversible genetic/chromosomal alterations, including mutations in beta2-microglobulin (B2M) or lack of HLA-A2 allele due to a haplotype loss. The introduction of these genes and re-expression of the missing HLA-I specificity on the tumor cell surface is an attractive strategy to induce tumor rejection by T-lymphocytes.

Methods: Using genomic HLA-I typing and gene sequencing we determined HLA-I phenotypes and alterations in different human tumor cell lines previously characterized in our laboratory. We used adeno- and adeno-associated viruses to reconstitute/up-regulate HLA-A2 or/and B2M expression in these cells in vitro. Using flow cytometry and immunocytochemistry we evaluated levels and patterns of HLA-I expression in these cells.

Methods: Using genomic HLA-I typing and gene sequencing we determined HLA-I phenotypes and alterations in different human tumor cell lines previously characterized in our laboratory. We used adeno- and adeno-associated viruses to reconstitute/up-regulate HLA-A2 or/and B2M expression in these cells in vitro. Using flow cytometry and immunocytochemistry we evaluated levels and patterns of HLA-I expression in these cells.

Conclusion: Using gene therapy, it is possible to recover normal B2M and HLA-A2 gene expression caused by structural “hard” alteration and to induce co-expression of both genes in cells naturally lacking HLA-A2 allele. In addition, we demonstrated that transfected tumor cells ae able to express seven HLA-I alleles. The recovery of the missing HLA-I molecules frequently observed in tumor cells using adeno and adeno-associated viruses can be a useful strategy to circumvent cancer immune escape and increase tumor rejection.

Immunologic abnormalities including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) have been described in patients with non-Hodgkin lymphoma. In some cases, anti-red cell or platelet antibodies are produced by lymphoma cells. However, cases of the occurrence of autoimmune diseases without recurrence of lymphomas have been also reported. The relationship between autoimmune diseases with post-bone marrow transplantation and Hodgkin disease may be attributed to immune dysfunctions, particularly those involving T cells. This autoimmune phenomenon may be related to imbalances in helper/suppressor T-cell populations. Imbalances in helper and suppressor T-cell populations have been reported after R-CHOP chemotherapy, and the recovery of serum IgG and CD4+ counts was observed more than 2 years after R-CHOP therapy in patients with B-cell lymphoma. In this report, we present a case of an 87-year-old man who was treated with rituximab-containing chemotherapy and maintained complete remission. However, the immunophenotyping of peripheral blood and bone mallow mononuclear cells revealed a reversed CD4/CD8 ratio. Two years later, he developed ITP. He was treated with intravenous immunoglobulin and eltrobopag, and thrombocytopenia improved. Five years later, he developed pneumonia and sudden Coombs-positive hemolytic anemia caused by autoantibodies against D antigen and thrombocytopenia without the recurrence of lymphoma. He was treated with prednisolone and a pulse dose of methylprednisolone; however, his response to therapy was poor and he subsequently died. We herein report a case who have been showed reversed imbalances in the helper/suppressor T cell populations over 2 years after R-CHOP therapy, developed AIHA and ITP without recurrence of lymphoma. The long-term monitoring of T-cell counts after rituximab containing chemotherapies is important, and careful attention to infection signs.

Purpose: To delve into the prospective of inflammatory-related indicators as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), derived neutrophil to lymphocyte ratio (dNLR), and lymphocyte to monocyte ratio (LMR) in forecasting the clinical outcome for gastric cancer managed with triple modality induction.

Methods: Participants were given two cycles of docetaxel, fluorouracil and cisplatin (TPF), succeeded by radiation (45 Gy) alongside concurrent fluorouracil plus taxotere, then finally surgical resection. The designated baseline prognosticators were linked with clinical-pathological factors. Their contribution to outcome were assessed using Log rank and Cox regression.

Results: The study’s analysis revolved around 80 eligible participants. The triple modality induction ensued 22.5% complete response (PCR) alongside 47.5% and 42.5% 3-years estimated overall (OS) and disease-free survival (DFS), respectively. The receiver operator curves (ROC) cutoffs for baseline biomarker were registered at 2.4 (NLR), 1.7(dNLR), 5.1 (LMR) and 130 (PLR). Augmented prognosticators, stage III, R1 resection and >10 % residual tumor were substantially linked to worsened OS and DFS. Interestingly, the augmented dNLR and NLR were self-directed forecasters for deteriorating OS hazard ratio (HR) 2.04 (95% CI= 2.41-8.24), 6.63 (95% CI, 1.61-10.32) and DSF with (HR) 1.84 (95% CI= 3.27-7.36), 4.63 (95% CI= 3.61-12.12), respectively. None of the participants succumbed secondary to treatment toxicities although grade 4 side effects were attained by 20% of cases.

Conclusion: The triple modality induction in resectable gastric cancer is feasible with promising outcomes. The baseline inflammatory prognosticators attained a notable statistical link to many clinical/pathological variables. Moreover, NLR and dNLR behaved as autonomous indicators of clinical consequences for patients with gastric cancer managed with triple preoperative modality.