Cancer Science & Therapy

Objective: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by no efficient hematopoiesis and frequent progression to acute myeloid leukemia (AML). Even in low risk MDS, clonal hematopoiesis already dominates at diagnosis, and clones found in secondary AML originate from the MDS stage of disease, highlighting the need to specifically target the MDS-initiating clone. Glasdegib is a potent and selective hedgehog pathway inhibitor that acts by binding Smoothened (SMO) and blocking signal transduction. Glasdegib demonstrated preliminary antitumor activity in a phase I trial, when given as monotherapy in patients with several hematopoietic malignancies. In the present study, we investigated the molecular mechanisms by which glasdegib regulate the self-renewal of MDS-derived iPS cells (iPSCs) in vivo.

Methods: We generated iPSCs from bone marrow mononuclear cells of an MDS patient with chromosome 5 deletion and complex karyotypic abnormalities. We examined the activity of glasdegib against MDS-derived iPSCs transferred NOD/SCID mice in vivo and in vitro. We performed the serial in vivo transplantation to assess the effects of hedgehog inhibition on long term self-renewal. NOD/SCID mice were injected with MDS-iPSCs then treated with glasdegib.

Results: We observed that glasdegib significantly reduced the self-renewal of NOD/SCID re-populating cells from MDS-derived iPSC during serial transplantation in vivo. Further, NOD/SCID mice were injected with MDS-iPSCs, and then treated with glasdegib on day 21 for 7 days. These treatments reduced the population of CD34+CD38-cells. To investigate the entire the apoptosis-induction pathways by hedgehog inhibition, MSD-L cells were incubated with 5-azacytidine and glasdegib for 72 hrs. Glasdegib enhanced the expression of cleaved PARP, cleaved caspase-3, p21 and reduced expression of c-Myc.

Conclusion: Our pre-clinical results indicate that glasdegib have potential as an important option for controlling the drug-resistant MDS-initiating cells. It is expected that the glasdegib may become extremely useful therapeutic interventions in a number of hematological neoplasms, including MDS, where the persistence of cancer stem cells.

Background: Between primary and progressive muscle-invasive bladder cancer, in the current literature, data regarding the prognostic difference and survival between this two entities are controversial. Objectives: To assess differences in survival between the primary and progressive MIBC and to determine main prognostic factors in muscle-invasive bladder tumors (MIBT).

Material and methods: All patients who were underwent radical cystectomy for MIBC in our institution between 1990 and 2014 were retrospectively evaluated using an institutional database. A total of 308 patients had met inclusion criteria, 218 (70,77%) (Group 1) with primary MIBC and 90 (29.22%) (Group 2) with progressive MIBC. The main variables studied were: age, sex, initial tumor stage of TURs in group 2, pathologic stage (T/N), type of urinary diversion and extent of LND. Survival rate was investigated with Kaplan-Meier method and a multivariate analysis using the Cox regression analysis was performed to evaluate potential prognostic factors.

Results: In Group 2, the median time of progression to invasive cancer was 32 months. 2, 3 and 5-year cancer specific survival rate after surgery was 77%, 63% and 51% in Group 1 and 59%, 49% and 32% in group 2, respectively (p < 0.05). Analyzing pN stage, overall 2,3 and 5-year survival rate were 75%, 62%, and 53% in group 1 and 61%, 49%, and 37% in group 2 respectively for pN0 (P <0.05). On multivariate analysis, lympho-vascular invasion and pT stage of the primary tumor remained significant independent prognostic factors for cancer-specific survival.

Conclusions: Our study has shown that Progressive MIBC have a worse prognosis than Primary MIBC. Lympho-vascular invasion and Positive nodes in RC specimens seems to be an independent factor that decreases survival in patients with MIBC.

In recent years, with the improvement of cancer survival through more effective treatment, the emphasis has been in trying to minimize the side-effects caused by chemo- and radiotherapy, to ensure that patients have the best quality of life throughout their cancer journey. The tumor suppressor p53 is widely implicated in a broad range of cancers, and here we summarize its role and the possibilities of its manipulation to improve side effects during active treatment through survivorship.

Thrombosis can be a clinical symptom of hidden cancer, as evidenced by numerous studies. Inherited and acquired thrombophilia are well-known risk factors for venous thromboembolism. The incidence of thrombotic events in cancer patients is increased compared to normal population. Data on inherited thrombophilia and cancer is limited. In most cases, a key role in the pathogenesis of thrombosis of rare localization is played by hereditary thrombophilia. Clinically, venous thromboembolism and cancer are almost always closely interrelated, and often thrombosis can be the only clinical symptom of latent cancer. Here in this case report, we present a case of thrombosis of rare localization in a cancer patient with combined form of thrombophilia.

Background: According to the literature, vitamin D (Vit D) deficiency is a risk factor for breast cancer developing with lack of information on its direct prognostic effects in breast cancer.

Patients and methods: A total of 168 women with proven breast cancer diagnosed in Zagazig university hospitals- Egypt were enrolled in this study. Serum level of 25 (OH) Vit D was measured in stored blood just after diagnosis. Vit D levels were classified into three groups: deficient: <10 ng/ml; insufficient: 10 ng/ml to 30 ng/ml; and sufficient: >30 ng/ml. Clinical-pathological data and disease outcome were accessed to examine prognostic effect of vitamin D in breast cancer.

Results: Median age was 51.5 (26-77) years, Metastasis was present in 13.1% of the cases. The median serum level of 25(OH) Vit D was 20 (5-98) ng/ml; it was deficient in 36.9% of patients, insufficient in 32.1% of patients, and sufficient in 31% of patients. Serum level of 25 (OH) VitD levels decreased significantly with increasing body mass index (BMI) (P=0.00), also the relations of 25 (OH) Vit D level with the number of positive lymph nodes, tumor size, tumor stage and KI 67 level were statistically significant (p= 0.01, p=0.011, p=0.002, p= 0.001 respectively). The level of 25 (OH) vitamin D was significantly low in metastatic patients (p=0.01). For those non -metastatic BC patients; there was no statistically significant difference in mean Disease-Free Survival (DFS) times across the 3 categories of serum Vitamin D (p=0.13), also for metastatic patients, serum vit D level didn’t affect the median PFS (p=0.98). The mean OS of the 3 different categories of serum vit D (sufficient, insufficient and deficient) were 45.8 months, 39.7 months and 39 months respectively (p=0.047). Univariate analysis, showed that OS was significantly affected by age, BMI, grade, stage, molecular type and vit D levels (p=0.014, p=0.002, p=0.002, p<0.0001, and p=0.047 respectively), but in Multivariate analysis: age, BMI, stage, and vit D levels were the only independent factors significantly affect the OS (p=0.01, 0.001, p<0.0001 and p=0.022, respectively).

Conclusion: There may be an association between serum 25 (OH) Vit D level and breast cancer prognosis.

Based on early results from a single phase III trial, Brentuximab Vedotin (BV), a drug-conjugated anti-CD30 monoclonal antibody, is changing the treatment strategy, especially for relapsed/refractory cutaneous anaplastic large cell lymphomas (cALCL) patients with limited therapeutic options. However, despite high response rates registered in this setting, follow-up data about duration of response and long-term toxicity profile are still lacking. Here, we report a case of refractory, advanced stage cALCL in a 78-year old patient with poor prognosis, which showed a dramatic, long-lasting response even to reduced doses of BV as salvage treatment.

Cyanobacteria from exotic niches represent a rich resource of a wide array of unique bioactive compounds that are largely under explored, and proving to be potent source of anticancer drugs. A filamentous non-heterocystous isolate was identified by light microscopy and molecular methods using 23S rDNA as a marker was found to belong to Plectonema genus of Cyanobacteria. Organic extract of different cyanobacterial isolates was screened for their cytotoxicity against hepatocellular carcinoma cell line (HepG2). Extracts of (Cyanothece sp.) and (Plectonema terebrans) were found to have the most cytotoxic effect as they caused cell growth inhibition with IC50 value of 13.3% and 8.3% respectively. The cell viability, cell cycle analysis and caspase3 activity were measured. The cell viability of (Cyanothece sp.) and (Plectonema terebrans) showed high reduced (66.7% 57.4% respectively) compared with untreated cells (6.6%). Cell cycle analysis results showed significant arrest in G0/G1 and G2/M phases in the cells treated with Cyanothece sp recorded (52.8%, 0.33%) respectively, low percentage in 2n phase recorded (46.4%), while cells treated with Plectonema terebrans showed (G0/G1 recorded 63.3% and G2/M recorded 0.3 and 2n recorded 35.6%) compared to control which showed relative accumulation of cells in G0/G1 and G2/M recorded (7.38% and 0.13%) respectively and aggressive accumulation of cells in 2n phase recorded (91.8%). Also, Caspase-3 activity increased in the cells treated with Cyanothece sp with highest activity at concentration 13.3% recorded 0.397 ± SD 0.02 and Plectonema terebrans with highest activity at concentration 4% recorded 0.402 ± SD 0.002 and with significant (p<0.05) compared to untreated cells (0.157 ± SD 0.05 nM/mL). These results indicated that two extracts of Cyanobacteria have a promising agent against hepatocellular carcinoma.

Using the circular nature of the 16k base-pairs human mtDNA genome, we are looking for hypothetical proportions between the C+A and T+G bases. Remarkable proportions are thus discovered, the length of which may be much greater than the length of the genome. We then analyze the impact of evolution on these “numerical resonances” by comparing the referenced mtDNAs of Sapiens, Neanderthal and Denisova. Then, by analyzing 250 characteristic mutations associated with various pathologies, we establish a very strong formal causal correlation between these numerical meta structures and these referenced mutations. To summarize, we should think then research on the following situation: (a) Inputs: 250 cases of mtDNA mutations1 associated with various human diseases. (b) An operator: The exhaustive search for mtDNA genome “Fibonacci resonances” associated with these mutations. (c) A “binary” output: a common behavior of the mtDNA genome resulting from these 250 mutations disorders.