Background This study was designed to examine the effect of adjuvant 5-FU-based chemoradiation therapy (CRT) after distal pancreatectomy for adenocarcinoma of the distal pancreas. Methods All patients underwent curative resection for adenocarcinoma of the distal pancreas between December 1985 and June 2006. Patients who received adjuvant CRT were compared with those who underwent surgery alone. A Kaplan–Meier estimate of the survival curve was used to determine estimates of the median survival and proportion alive at 1 and 2 years; log-rank tests were used to make comparisons between groups. Results A total of 123 patients underwent distal pancreatectomy; 29 patients were excluded for distant metastases at the time of surgery (n = 12, 10%) or before adjuvant therapy (n = 11, 9%), death within 2 months of surgery (n = 2, 2%), or if CRT treatment status was unknown (n = 4, 3%). Of the remaining 94 patients, 72% received adjuvant 5-FU-based CRT and 28% underwent surgery alone. Overall median survival was 16.2 (95% confidence interval (CI), 13.1–18.9) months. The groups were similar with respect to tumor size, nodal status, and margin status. There was no significant difference in overall survival between patients treated with adjuvant CRT versus surgery alone (p = 0.23). An exploratory subgroup analysis suggested a potential survival benefit of adjuvant CRT in patients with lymph node metastases (16.7 vs. 12.1 months, p < 0.01). Conclusions Adjuvant CRT did not increase survival compared with surgery alone; however, patients with node-positive disease appear to benefit from adjuvant CRT.

The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

The auditory brainstem pathways require stimulation to mature, but do they develop in the absence of auditory input? To answer this, peaks of the electrically evoked auditory nerve (wave eN1) and brainstem response (eII, eIII, and eV) were measured in 117 children with early-onset deafness who had received cochlear implants. Data were collected at cochlear implant activation. In the absence of significant input, the interpeak latency eN1-eIII decreased over the first year of life but remained constant thereafter. Chronic cochlear implant stimulation was required to promote significant reduction in eIII-eV interpeak latency. Thus, activity-independent changes occurring in infancy are concentrated in the caudal auditory brainstem and likely involve the auditory nerve. Changes requiring input are most prevalent in rostral brainstem.

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INTRODUCTION:Medulloblastoma is the most common malignant pediatric brain tumor. Radiation(RT) is a part of standard care but causes significant neurocognitive impairment. Strategies to sensitize RT is critical to improving the quality of life and long-term survival of patients. Previous studies show that inhibition of protein-phosphatase 2A(PP2A)–a ubiquitous serine/threonine phosphatase–enhanced sensitivity to RT in multiple brain tumor xenografts. However, the mechanism behind enhanced radio-cytotoxicity is poorly understood. We hypothesize that PP2A inhibition combined with RT will increase cytoplasmic double-stranded DNA (dsDNA) and induce cGAS-cGAMP-STING signaling, promoting cellular senescence and thereby decreasing tumor growth.METHODS:D425-WT, a human group-3 medulloblastoma cell line, was used to generate a CRISPR sgPP2A knock out, D425-KO. We radiated WT and KO cells in vitro, quantified dsDNA in cytoplasmic extract using dsDNA Assay kit, and measured cGAMP levels in whole cell lysate using ELISA. Through FACS, we quantified the proportion of b-gal-expressing senescent cells. We measured protein expression of senescence markers (p21, p16, g-h2aX) by Western blot(WB). Finally, we injected D425 WT or KO cells orthotopically into cerebellum of nude NU/J mice followed by RT (10Gy) 3 days post-injection and monitored survival.RESULTS:In response to RT, D425-KO compared to WT showed significant increase in cytoplasmic dsDNA and intracellular cGAMP--a cyclic di-nucleotide STING agonist. There was also an increase in b-gal+ senescent cells and senescence markers expression in WB. In vivo, PP2AKO alone extended longevity, but PP2AKO with RT further prolonged survival compared to KO or RT alone.CONCLUSION:PP2A inhibition enhances RT induced cytosolic dsDNA damage and STING activation, promoting cellular senescence in vitro and sensitivity to RT in vivo.

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