Citations

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas, with 40% associated with neurofibromatosis type 1 (NF1). Surgical excision is the main treatment for localized disease; however, local recurrence (LR) remains high. Radiotherapy (RTx) is increasingly used to enhance local control in STS, but its use remains controversial due to the potential for increased major wound complications and an increased risk of secondary malignancies in NF1 patients. This study investigated the use and impact of RTx on local control in MPNSTs, particularly in the NF1 setting. Methods Surgically treated primary MPNSTs from 1988 to 2019 in the MONACO multicenter cohort were included. Differences in demographics, treatment, and RTx use between NF1 and non-NF1 cases were examined. Factors influencing RTx administration and LR were assessed via multivariable analyses. Results Among 499 patients (33.1% NF1), 143 (28.7%) experienced LRs. Radiotherapy was administered to 56.3% of patients (57.0% in the NF1 group), with 27.3% receiving neoadjuvant and 72.7% adjuvant RTx. RTx was administered significantly more often to high-grade and extremity tumors. While RTx did not affect overall survival, it reduced LR risk in sporadic cases (hazard ratio [HR] 0.530; 95% confidence interval [CI], 0.354–0.793) but not in the NF1 subgroup (HR 1.00; 95% CI, 0.545–1.85). In NF1 patients, a microscopically positive margin (R1) was the only risk factor for LR development (HR 2.1; 95% CI, 1.19–3.79). Conclusions RTx is frequently used in the treatment of MPNSTs, regardless of NF1 status. While it may affect the LR rate in sporadic cases, its impact on NF1 patients is less clear.

Abstract Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

Abstract Background Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/− concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization. Results Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

Abstract Purpose: In a previous retrospective study, we have shown that 75% of gastric MALT lymphomas that did not respond to H. pylori eradication could be identified by detection of t(11;18)(q21;q21). The present study examined the value of t(1;14)(p22;q32) in prediction of the response of gastric MALT lymphomas to H. pylori eradication. Patients and Methods: A total of 111 patients with H. pylori-positive gastric MALT lymphoma, who were treated by H. pylori eradication, were screened for BCL10 involved chromosome translocation by BCL10 immunohistochemistry, followed by interphase FISH and real-time quantitative reverse transcription PCR (qRT-PCR). The clinical presentation of 11 cases of MALT lymphoma including 6 from the stomach with known BCL10 involved chromosome translocation was reviewed. Results: Of the 111 cases of gastric MALT lymphoma treated by H. pylori eradication, 75 including 35 from the complete regression group and 40 from the non-responsive group, had adequate specimens for BCL10 immunohistochemistry. Two cases showed strong BCL10 nuclear staining in virtually all tumor cells, similar to that seen in those with t(1;14)(p22;q32). Both were from the H. pylori eradication non-responsive group. Although interphase FISH failed to show evidence of BCL10 gene break or amplification, one case showed an IGH break. This case also showed a high level of BCL10 mRNA expression, compatible to that seen in MALT lymphoma with t(1;14)(p22;q32). 9 of the 11 cases with known BCL10 involved translocation were at stage IIE or above, with three showing agressive clinical presentations. Conclusion: Gastric MALT lymphomas with strong BCL10 nuclear expression or t(1;14)(p22;q32) are mostly likely resistant to H. pylori eradication.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 . This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 . Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.