Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Survival prediction of glioblastoma patients—are we there yet? A systematic review of prognostic modeling for glioblastoma and its clinical potential

Glioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual patient despite the increasing number of prognostic models. The aim of this study is to systematically review the literature on prognostic modeling in glioblastoma patients. A systematic literature search was performed to identify all relevant studies that developed a prognostic model for predicting overall survival in glioblastoma patients following the PRISMA guidelines. Participants, type of input, algorithm type, validation, and testing procedures were reviewed per prognostic model. Among 595 citations, 27 studies were included for qualitative review. The included studies developed and evaluated a total of 59 models, of which only seven were externally validated in a different patient cohort. The predictive performance among these studies varied widely according to the AUC (0.58–0.98), accuracy (0.69–0.98), and C-index (0.66–0.70). Three studies deployed their model as an online prediction tool, all of which were based on a statistical algorithm. The increasing performance of survival prediction models will aid personalized clinical decision-making in glioblastoma patients. The scientific realm is gravitating towards the use of machine learning models developed on high-dimensional data, often with promising results. However, none of these models has been implemented into clinical care. To facilitate the clinical implementation of high-performing survival prediction models, future efforts should focus on harmonizing data acquisition methods, improving model interpretability, and externally validating these models in multicentered, prospective fashion.

     

Breast milk feeding rates of mothers of multiples compared to mothers of singletons.

OBJECTIVE: Over 3% of infants born annually in the United States are from a multiple gestation pregnancy, yet there is little data published about the feeding practices of their mothers. The objectives of this study were to determine and compare the rates of breast milk feeding of mothers of multiples and mothers of singletons. METHODS: Stratified random sampling (n = 686) on the basis of plurality of pregnancy and gestational age at delivery was performed on a 1999 birth certificate database in the greater Cincinnati area. We collected information about infant feeding during the first 6 months of life using a retrospective, self-administered questionnaire and phone interview from mothers of term singletons (TS), preterm singletons (PS), term multiples (TM), and preterm multiples (PM). Data were analyzed using chi-square and logistic or multiple regression. RESULTS: We obtained feeding information from 346 mothers (n = 81 TS, 80 PS, 90 TM, and 95 PM). By 3 days postpartum, PM provided breast milk less often than all other groups: TS = 69%, PS = 66%, TM = 73%, PM = 57% (P =.035). Among mothers who initiated breast milk feeding, the geometric mean duration of at least some breast milk feeding was significantly shorter for PM than for all other groups: TS = 23 weeks, PS = 19 weeks, TM = 24 weeks, and PM = 12 weeks (P =.002). CONCLUSIONS: Further evaluation of the potential causes for the lower breast milk feeding rates among PM is needed to develop effective intervention strategies and increase the number of preterm multiple gestation infants receiving breast milk.     

High precision conformal radiotherapy employing conservative margins in childhood benign and low-grade brain tumours.

BACKGROUND AND PURPOSE: To report local control and follow up outcome data of high precision conformal radiotherapy in childhood brain tumours. MATERIALS AND METHODS: Between December 1999 and December 2002, 26 children (17 boys and 9 girls, median age 11.5 years) with incompletely excised or recurrent benign and low-grade brain tumours [13 craniopharyngiomas, 11 low-grade gliomas (LGG) and 2 others] were treated with three-dimensional (3D) conformal radiotherapy (CRT) (12 patients) and stereotactic conformal radiotherapy (SCRT) (14 patients). Gross tumour volume (GTV) included neuro-imaging based visible tumour and/or resected tumour bed. Clinical target volume (CTV) consisted of GTV+ 5 mm margin and planning target volume (PTV) consisted of additional 5 mm margin for CRT and 2 mm for SCRT. Treatment was delivered with 3-9 conformal fixed fields to a median dose of 54 Gy/30 fractions. RESULTS: The actuarial 2 and 3 year disease free and overall survival was 96 and 100%, respectively (median follow up: 25 months, range 12-47 months). Radiological follow up available in 25 patients revealed complete response in 1, partial regression in 10, stable disease in 13 and progression in 1 patient (within the CTV). One patient with craniopharyngioma on a routine imaging revealed a mild asymptomatic cyst enlargement, which resolved with conservative management. A patient with chiasmatic glioma developed cystic degeneration and hydrocephalus 9 months after SCRT requiring cyst drainage and placement of a ventriculoperitoneal shunt. CONCLUSION: High-precision conformal techniques delivering irradiation to a computer generated target volume employing 7-10 mm 3D margins beyond the visible tumour and/or resected tumour bed appear to be safe in children with incompletely resected or recurrent benign and low-grade brain tumours, based on these data.     

Anticancer activity of Sargassum wightii Greville on Dalton’s ascitic lymphoma简

AIM： Sargassum wightii Greville is a marine brown alga belonging to the Sargassaceae family which has about 200 species. The ethanolic extract of the whole dry plant powder contained numerous phytoconstituents, including flavonoids. The study was fo- cused on the anticancer activity ofSargassum wightii in mice. METHOD： The ethanolic extract ofSargassum wightii （EESW） at two dose levels was used to examine the anticancer activity in mice using DAL cell lines to induce cancer. The body weight, viable and non-viable tumor cell count, mean survival time, increase in life span, and hematological parameters were observed for anticancer activity of EESW. RESULTS： The intraperitoneal inoculation of DAL cells in mice significantly increased cancer cell count. The decrease in the cancer cell number observed in the EESW-treated group cancer animals indicates that the test drug has a significant inhibitory ef- fect on the tumor cell proliferation. Treatment with EESW also showed a significant decrease in tumor weight, and hence increased the lifespan of DAL-treated mice. In addition, EESW administration significantly restored the hematological parameters in DAL-treated mice. CONCLUSION： The present study results suggest that administration of extract offers enhanced antioxidant potential. Therefore it can be concluded from this study that EESW possesses anticancer activity.     

Methylmalonic acidemia mimicking diabetic ketoacidosis and septic shock in infants

Methylmalonic acidemia (MMA) is most common inherited type of organic acidemia. It has diverse presentation in older infants without any initial apparent symptoms. MMA sometimes present with sudden metabolic decompensation, which may mimics common emergencies like septic shock and diabetic ketoacidosis (DKA) without early recognition can be fatal. In born error of metabolism especially organic acidemia should be suspected in any infant presented with severe high anion gap metabolic acidosis. We report two cases of MMA in infants presented acutely mimicking DKA and septic shock.     

Travel Distance and Home Dialysis Rates in the United States

♦ Introduction: Rural residence is associated with increased peritoneal dialysis (PD) utilization. The influence of travel distance on rates of home dialysis utilization has not been examined in the United States. The purpose of this study was to determine whether travel distances to the closest home and in-center hemodialysis (IHD) facilities are a barrier to home dialysis.♦ Methods: This was a retrospective cohort study of patients aged ≥ 18 years initiating dialysis between 2005 and 2011. Unadjusted PD and home hemodialysis (HHD) rates were compared by travel distances to both the closest home dialysis and closest IHD facilities. Adjusted PD and HHD utilization rates were examined using multivariable logistic regression models.♦ Results: There were 98,608 patients in the adjusted analyses. 55.5% of the dialysis facilities offered home dialysis. IHD, PD and HHD patients traveled median distances of 5.4, 3.5 and 6.6 miles respectively to their initial dialysis facilities. Unadjusted analyses showed an increase in PD rates and decrease in HHD rates with increased travel distances. Adjusted odds of PD and HHD were 1.6 and 1.2 respectively for a ten mile increase in distance to the closest home dialysis facility, while for distances to the closest IHD facility the odds ratios for both PD and HHD were 0.7 (all p < 0.01).♦ Conclusions: In metropolitan areas, PD and HHD generally increased with increased travel distance to the closest home dialysis facility and decreased with greater distance to an IHD facility. Examination of travel distances to PD and HHD facilities separately may provide further insight on specific barriers to these modalities which can serve as targets for future studies examining expansion of home dialysis utilization.