Tacrolimus as Single-Agent Immunotherapy and Minimal Manifestation Status in Nonthymoma Myasthenia Gravis

Background. Tacrolimus is a second-line immunosuppressant in myasthenia gravis (MG) therapy, which is mainly used in combination with corticosteroids to reduce steroid dose and maintain the effect of immunotherapy. However, few studies have focused on the effect of tacrolimus as single-agent immunotherapy on achieving minimal manifestation status (MMS). Thus, this study is aimed at exploring the efficacy and influencing factors of tacrolimus as single-agent immunotherapy in MG. Methods. Clinical data of 75 nonthymoma MG patients treated with tacrolimus single-agent as initial immunotherapy were retrospectively analyzed. The therapeutic effect was evaluated by Myasthenia Gravis Foundation of America postintervention status. Clinical factors affecting the achievement of MMS and treatment reactivity of different MG subtypes were determined by Cox regression analysis. Results. Tacrolimus was generally safe, with only two patients (2.7%) switching medications due to side effects. 32% of patients had improved symptoms after 1 month of treatment. 69.2% of patients achieved MMS or better after one year. The age < 39 years old, QMG score < 11 points, and AChR − Ab titer < 8.07 nmol / L were indicative of a favorable response, which was independent of gender, course of the disease. As for MG subtypes, ocular and seronegative MG showed better treatment sensitivity. Conclusions. Tacrolimus as single-agent immunotherapy takes effect quickly and can effectively enable nonthymoma MG patients to achieve MMS. Tacrolimus can be used alone for the initial immunotherapy of MG patients, especially for young, mild, and low antibody titer patients.

Immunological configuration of ovarian carcinoma: features and impact on disease outcome

Epithelial ovarian carcinoma (EOC) is a relatively rare malignancy but is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. At odds with other neoplasms, EOC is virtually insensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Here, we comparatively summarize the humoral and cellular features of primary and metastatic EOC, comparatively analyze their impact on disease outcome, and propose measures to alter them in support of treatment sensitivity and superior patient survival.

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

Machine learning predicts treatment sensitivity in multiple myeloma based on molecular and clinical information coupled with drug response

Providing treatment sensitivity stratification at the time of cancer diagnosis allows better allocation of patients to alternative treatment options. Despite many clinical and biological risk markers having been associated with variable survival in cancer, assessing the interplay of these markers through Machine Learning (ML) algorithms still remains to be fully explored. Here, we present a Multi Learning Training approach (MuLT) combining supervised, unsupervised and self-supervised learning algorithms, to examine the predictive value of heterogeneous treatment outcomes for Multiple Myeloma (MM). We show that gene expression values improve the treatment sensitivity prediction and recapitulates genetic abnormalities detected by Fluorescence in situ hybridization (FISH) testing. MuLT performance was assessed by cross-validation experiments, in which it predicted treatment sensitivity with 68.70% of AUC. Finally, simulations showed numerical evidences that in average 17.07% of patients could get better response to a different treatment at the first line.

CircMEMO1 modulates the promoter methylation and expression of TCF21 to regulate hepatocellular carcinoma progression and sorafenib treatment sensitivity

Background Cirrhosis is a recognized risk factor for developing hepatocellular carcinoma (HCC). Few studies have reported the expression profile of circRNAs in HCC samples compared to paratumour dysplastic nodule (DN) samples. Methods The Arraystar Human circRNA Array combined with laser capture microdissection (LCM) was used to analyse the expression profile of circRNAs in HCC samples compared to paratumour DN samples. Then, both in vitro and in vivo HCC models were used to determine the role and mechanism of key circRNA in HCC progression and treatment sensitivity. Results We found that circMEMO1 was significantly downregulated in HCC samples and that the level of circMEMO1 was closely related to the OS and disease-free survival (DFS) of HCC patients. Mechanistic analysis revealed that circMEMO1 can modulate the promoter methylation and gene expression of TCF21 to regulate HCC progression by acting as a sponge for miR-106b-5p, which targets the TET family of genes and increases the 5hmC level. More importantly, circMEMO1 can increase the sensitivity of HCC cells to sorafenib treatment. Conclusion Our study determined that circMEMO1 can promote the demethylation and expression of TCF21 and can be considered a crucial epigenetic modifier in HCC progression.

Cost minimization analysis of two chemotherapy regimens in the treatment of colorectal cancer in a public reimbursement hospital in Brazil

Objective: To conduct a pharmacoeconomic evaluation between XELOX and mFOLFOX6 in the adjuvant and metastatic treatment of colorectal cancer from the perspective of a public reimbursement hospital. Methods: The cost minimization analysis was conducted for patients who started treatment in 2013 and 2014. The micro-costing technique was used to verify expenditures on drugs, materials, laboratory and imaging tests, ambulatory and daily hospitalization, human and administrative resources and determine the individual cost of each alternative, per patient. To evaluate the robustness of the economic analysis, multivariate sensitivity analysis was performed in six different scenarios. Results: There was an average cost for XELOX of U$ 4,637.14 in adjuvant and U$ 3,831.48 for palliative treatment, and a cost for mFOLFOX6 of U$ 5,474.89 in adjuvant and U$ 4,432.95 in palliative treatment. Sensitivity analysis maintained the dominance of XELOX. Material and drug costs accounted for about 85% of the total cost of XELOX; for mFOLFOX6 this cost was around 36%. On the other hand, the cost of hospitalization and placement of a catheter occured exclusively for mFOLFOX6, which also presented a higher cost with human resources. Conclusion: From the perspective of the hospital, XELOX proved to be the least costly alternative on the treatment of colorectal cancer.

Detection and pathogenic potential of Clostridium difficile in commercial meat and meat products in Brazil

The aims of this study were to evaluate the occurrence of Clostridium difficile in commercial raw meat and meat products commercialized in Brazil, and to determine the pathogenic potential and antimicrobial susceptibility of the isolates. After selective enrichment, the isolation of C. difficile involved plating with and without an alcohol shock treatment onto C. difficile moxalactam agar (CDMNA). The toxigenic profile was determined through PCR for detection of tcdA, tcdB, cdtA and cdtB genes and an enzyme-linked immunosorbent assay for toxin A/B. C. difficile was isolated from 8.9% (17 out of 192) of analyzed samples. Plating without alcohol treatment (sensitivity of 88.23%) was more efficient than with alcohol treatment (sensitivity of 29.41%) in C. difficile isolation. The profile A + B+CDT- was observed in 35.0% (28/80) of the isolates. The A/B toxin was tested in 44 isolates and 15.9% of them were positive. Resistance to clindamycin, ceftizoxime tetracycline, metronidazole, vancomycin, and ceftriaxone were observed among isolates. Multi-drug resistance was detected in 36.4% (8/22) of the isolates evaluated.