Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA).

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Predictors of infection after 754 cranioplasty operations and the value of intraoperative cultures for cryopreserved bone flaps.

OBJECTIVE The authors' aim was to report the largest study on predictors of infection after cranioplasty and to assess the predictive value of intraoperative bone flap cultures before cryopreservation. METHODS They retrospectively examined all cranioplasties performed between March 2004 and November 2014. Throughout this study period, the standard protocol during initial craniectomy was to obtain a culture swab of the extracted autologous bone flap (ABF)-prior to its placement in cytostorage-to screen for microbial contamination. Two consecutive protocols were employed for the use and interpretation of the intraoperative swab culture results: A) From March 2004 through June 2013, any culture-positive ABF (+ABF) was discarded and a custom synthetic prosthesis was implanted at the time of cranioplasty. B) From July 2013 through November 2014, any ABF with a skin flora organism was not discarded. Instead, cryopreservation was maintained and the +ABF was reimplanted after a 10-minute soak in bacitracin irrigation as well as a 3-minute soak in betadine. RESULTS Over the 10.75-year period, 754 cranioplasty procedures were performed. The median time from craniectomy to cranioplasty was 123 days. Median follow-up after cranioplasty was 237 days for protocol A and 225 days for protocol B. The overall infection rate after cranioplasty was 6.6% (50 cases) occurring at a median postoperative Day 31. Staphylococcus spp. were involved as the causative organisms in 60% of cases. Culture swabs taken at the time of initial craniectomy were available for 640 ABFs as 114 ABFs were not salvageable. One hundred twenty-six (20%) were culture positive. Eighty-nine +ABFs occurred during protocol A and were discarded in favor of a synthetic prosthesis at the time of cranioplasty, whereas 37 +ABFs occurred under protocol B and were reimplanted at the time of cranioplasty. Cranioplasty material did not affect the postcranioplasty infection rate. There was no significant difference in the infection rate among sterile ABFs (7%), +ABFs (8%), and synthetic prostheses (5.5%; p = 0.425). All 3 +ABF infections under protocol B were caused by organisms that differed from those in the original intraoperative bone culture from the initial craniectomy. A cranioplasty procedure ≤ 14 days after initial craniectomy was the only significant predictor of postcranioplasty infection (p = 0.007, HR 3.62). CONCLUSIONS Cranioplasty procedures should be performed at least 14 days after initial craniectomy to minimize infection risk. Obtaining intraoperative bone cultures at the time of craniectomy in the absence of clinical infection should be discontinued as the culture results were not a useful predictor of postcranioplasty infection and led to the unnecessary use of synthetic prostheses and increased health care costs.

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP.

In the acute promyelocytic leukemia cell line, NB4, activation of the CD44 receptor triggers apoptosis. This pathway does not operate in the retinoid-maturation-resistant NB4-LR1 subclone. In this work, we show that the CD44 gene is silenced in these cells. The molecular defect involves DNA methylation of cytosine phosphate guanine (CpG) island and underacetylation of histone H3 at CD44 promoter. The methylating inhibitor 5-aza-CdR and cyclic AMP (cAMP) reverse the CD44 gene silencing. Contrary to 5-aza-CdR, cAMP does not induce DNA demethylation or histone modification at the CD44 promoter, whereas an H3pS10/AcK14 dual modification is observed on a global level. cAMP also induces the expression of c-Jun transcription factor and its recruitment at the CD44 promoter. Chromatin immunoprecipitation assays further show the association of brahma (Brm), a subunit of SWI/SNF chromatin-remodelling complex involved in the crosstalk between transcription and RNA polymerase II (RNA Pol II) processing, as well as the binding of phosphorylated RNA Pol II to the proximal promoter region of CD44. Finally, our study reveals that cAMP re-establishes the CD44-mediated cell death signalling. We propose that one of the actions of cAMP in restoring normal cell phenotype of leukaemia cells may consist in a broad trans-reactivation of silenced genes, despite marked hypermethylation of their promoters, as illustrated here with CD44 re-expression.