Investigating the effect of polymerase inhibitors on cellular proliferation: Computational studies, cytotoxicity, CDK1 inhibitory potential, and LC-MS/MS cancer cell entrapment assays.

Directly acting antivirals (DAAs) are a breakthrough in the treatment of HCV. There are controversial reports on their tendency to induce hepatocellular carcinoma (HCC) in HCV patients. Numerous reports have concluded that the HCC is attributed to patient-related factors while others are inclined to attribute this as a DAA side-effect. This study aims to investigate the effect of polymerase inhibitor DAAs, especially daclatasivir (DLT) on cellular proliferation as compared to ribavirin (RBV). The interaction of DAAs with variable cell-cycle proteins was studied in silico. The binding affinities to multiple cellular targets were investigated and the molecular dynamics were assessed. The in vitro effect of the selected candidate DLT on cancer cell proliferation was determined and the CDK1 inhibitory potential in was evaluated. Finally, the cellular entrapment of the selected candidates was assessed by an in-house developed and validated LC-MS/MS method. The results indicated that polymerase inhibitor antiviral agents, especially DLT, may exert an anti-proliferative potential against variable cancer cell lines. The results showed that the effect may be achieved via potential interaction with the multiple cellular targets, including the CDK1, resulting in halting of the cellular proliferation. DLT exhibited a remarkable cell permeability in the liver cancer cell line which permits adequate interaction with the cellular targets. In conclusion, the results reveal that the polymerase inhibitor (DLT) may have an anti-proliferative potential against liver cancer cells. These results may pose DLT as a therapeutic choice for patients suffering from HCV and are liable to HCC development.

The prognostic value of bone marrow retention index and bone marrow-to-liver ratio of baseline 18F-FDG PET/CT in diffuse large B-cell lymphoma.

OBJECTIVE: To determine prognostic value of bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) measured on baseline dual-phase 18F-FDG PET/CT in a series of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated homogeneously with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. PATIENTS AND METHODS: This prospective study enrolled 135 patients with newly diagnosed DLBCL. All patients underwent dual-phase 18F-FDG PET/CT. The following PET parameters were calculated for both tumor and bone marrow: maximum standardized uptake value (SUVmax) at both time points (SUVmax early and SUVmax delayed), SUVmax increment (SUVinc), RI, and BLR. Patients were treated with R-CHOP regimen and response at end of treatment was assessed. RESULTS: The final analysis included 98 patients with complete remission. At a median follow-up of 22 months, 57 patients showed no relapse, 74 survived, and 24 died. The 2-year relapse-free survival (RFS) values for patients with higher and lower RI-bm were 20% and 65.1%, respectively (p < 0.001), and for patients with higher and lower BLR were 30.2% and 69.6%, respectively (p < 0.001). The 2-year overall survival (OS) values for patients with higher and lower RI-bm were 60% and 76.3%, respectively (p = 0.023), and for patients with higher and lower BLR were 57.3% and 78.6%, respectively (p = 0.035). Univariate analysis revealed that RI-bm and BLR were independent significant prognostic factors for both RFS and OS (hazard ratio [HR] = 4.02, p < 0.001, and HR = 3.23, p < 0.001, respectively) and (HR = 2.83, p = 0.030 and HR = 2.38, p = 0.041, respectively). CONCLUSION: Baseline RI-bm and BLR were strong independent prognostic factors in DLBCL patients. CLINICAL RELEVANCE STATEMENT: Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) could represent suitable and noninvasive positron emission tomography/computed tomography (PET/CT) parameters for predicting pretreatment risk in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. KEY POINTS: • Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) are powerful prognostic variables in diffuse large B-cell lymphoma (DLBCL) patients. • High BLR and RI-bm are significantly associated with poor overall survival (OS) and relapse-free survival (RFS). • RI-bm and BLR represent suitable and noninvasive risk indicators in DLBCL patients.

The utility of technetium-99m pertechnetate thyroid scintigraphy assessing thyroid/salivary ratio as an alternative to thyroid uptake percentage in evaluation of thyroid function, with establishing normal reference values of both parameters: single Egyptian center study.

BACKGROUND/OBJECTIVE: Management of thyroid disorders depends on accurate clinical assessment, appropriate investigations and radionuclide imaging, which plays an established important role either qualitatively or quantitatively. The aim of this study was to assess the utility of the thyroid/salivary ratio (TSR) as an alternative to technetium-99m (Tc99m) pertechnetate thyroid uptake (TcU) percentage in the evaluation of thyroid function and in the same time to establish reference range for the thyroid uptake of Tc99m-pertechnetate and TSR among Egyptian populations. PATIENTS AND METHODS: This retrospective study enrolled 270 patients, out of which 250 with different thyroid disorders and 20 without thyroid diseases, as a control group who all underwent full clinical examination, thyroid function tests and Tc99m pertechnetate thyroid scintigraphy. The TcU percentage and TSR were calculated and then correlated to the thyroid hormonal profile. RESULTS: The normal reference ranges of TcU and TSR were 0.75-3.5% and 1.25-4.8%, respectively. The sensitivity and specificity of TSR to diagnose hyperthyroidism were slightly lower compared with TcU (84.5 and 92.3% vs. 86.2 and 98.3%, respectively) at TSR cutoff value of more than 4.8 and TcU cutoff value of more than 3.5. Meanwhile, they had comparable sensitivity and specificity to diagnose hypothyroidism (86.0 and 93.3% vs. 86.5 and 94.5%) at cutoff values <0.75 and <1.25, respectively. CONCLUSION: The current study established a reference range for TcU and TSR in our institution. TSR is comparable to TcU in the evaluation of thyroid function among hyper-and hypothyroid patients and TSR can be used in doubtful cases of mal-thyroid function for confirmation of the diagnosis.

Comparative Study between 18F FDG-PET/CT and Whole Body MRI DWIBS in Assessment of Recurrent Breast Cancer (Prospective, Comparative, Cross-sectional Study Design).

AIM: This study aims to assess the diagnostic performance of 18F-fluorodeoxyglucose-positron emission tomography/computerized tomography (18FDG-PET/CT) compared to whole body (WB) magnetic resonance diffusion-weighted imaging (DWI) with background body signal suppression (MR/DWIBS) in lesions detection in patients with recurrent breast cancer. MATERIALS AND METHODS: Twenty-three female patients with suspected breast cancer recurrence by clinical, laboratory, or conventional imaging underwent both 18FDG-PET/CT and WB MR/DWIBS. WB 18FDG-PET/CT was performed using the standard technique. WB MR/DWIBS acquired sequences were WB DWI with short tau inversion recovery (STIR), coronal T1, and coronal STIR. Both 18FDG-PET/CT and WB-magnetic resonance imaging/DWIBS were independently interpreted using visual qualitative and quantitative analysis. Pathological findings and combined clinical/radiological follow-up data were used as a reference standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were calculated for both techniques. RESULTS: PET/CT demonstrated higher specificity and sensitivity indices than MR/DWIBS in the detection of the nodal and distant lesions, while the latter displayed higher sensitivity in the detection of local breast lesions. The overall sensitivity, specificity, NPV, PPV, and accuracy of PET/CT were 84.8%, 86.3%, 90.4%, 78.7%, and 85.4% versus 82.1%, 78.0%, 85.2%, 74.0%, and 80.5% for MR/DWIBS. A high degree of agreement existed between PET/CT and MR-DWIBS. CONCLUSION: 18FDG-PET/CT is more sensitive and has superiority in the assessment of nodal and distant lesions than DWIBS that has a potential superior role in the assessment of local breast lesions. DWIBS has a promising and helpful complementary tool for 18FDG-PET/CT in the evaluation of patients with proven malignancies.