Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach

Abstract

High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ( \({\bar{\text{X}}}\) = 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.

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Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach

Abstract

High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ( \({\bar{\text{X}}}\) = 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.

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Global analysis of H3K27me3 as an epigenetic marker in prostate cancer progression

Abstract

Background

H3K27me3 histone marks shape the inhibition of gene transcription. In prostate cancer, the deregulation of H3K27me3 marks might play a role in prostate tumor progression.

Methods

We investigated genome-wide H3K27me3 histone methylation profile using chromatin immunoprecipitation (ChIP) and 2X400K promoter microarrays to identify differentially-enriched regions in biopsy samples from prostate cancer patients. H3K27me3 marks were assessed in 34 prostate tumors: 11 with Gleason score > 7 (GS > 7), 10 with Gleason score ≤ 7 (GS ≤ 7), and 13 morphologically normal prostate samples.

Results

Here, H3K27me3 profiling identified an average of 386 enriched-genes on promoter regions in healthy control group versus 545 genes in GS ≤ 7 and 748 genes in GS > 7 group. We then ran a factorial discriminant analysis (FDA) and compared the enriched genes in prostate-tumor biopsies and normal biopsies using ANOVA to identify significantly differentially-enriched genes. The analysis identified ALG5, EXOSC8, CBX1, GRID2, GRIN3B, ING3, MYO1D, NPHP3-AS1, MSH6, FBXO11, SND1, SPATS2, TENM4 and TRA2A genes. These genes are possibly associated with prostate cancer. Notably, the H3K27me3 histone mark emerged as a novel regulatory mechanism in poor-prognosis prostate cancer.

Conclusions

Our findings point to epigenetic mark H3K27me3 as an important event in prostate carcinogenesis and progression. The results reported here provide new molecular insights into the pathogenesis of prostate cancer.

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Systemic therapy in younger and elderly patients with advanced biliary cancer: sub-analysis of ABC-02 and twelve other prospective trials

Abstract

Background

Outcomes in younger (<40 years) and elderly (≥70 years) patients with advanced biliary cancer (ABC) receiving palliative chemotherapy are unclear. This study assessed outcomes in those receiving monotherapy or combination therapy in thirteen prospective systemic-therapy trials.

Methods

Multivariable analysis explored the impact of therapy on progression-free (PFS) and overall survival (OS) in two separate age cohort groups: <70 years and ≥70 years, and <40 years and ≥40 years.

Results

Overall, 1163 patients were recruited (Jan 1997-Dec 2013). Median age of entire cohort: 63 years (range 23–85); 36 (3%) were <40, 260 (22%); ≥70. Combination therapy was platinum-based in nine studies. Among patients <40 and ≥70 years, 23 (64%) and 182 (70%) received combination therapy, respectively. Median follow-up was 42 months (95%-CI 37–51). Median PFS for patients <40 and ≥40 years was 3.5 and 5.9 months (P = 0.12), and OS was 10.8 and 9.7 months, respectively (P = 0.55). Median PFS for those <70 and ≥70 years was 6.0 and 5.0 months (P = 0.53), and OS was 10.2 and 8.8 months, respectively (P = 0.08). For the entire cohort, PFS and OS were significantly better in those receiving combination therapy: Hazard Ratio [HR]-0.66, 95%-CI 0.58–0.76, P < 0.0001 and HR-0.72, 95%-CI 0.63–0.82, P < 0.0001, respectively; and in patients ≥70 years: HR-0.54 (95%-CI 0.38–0.77, P = 0.001) and HR-0.60 (95%-CI 0.43–0.85, P = 0.004), respectively. There was no evidence of interaction between age and treatment for PFS (P = 0.58, P = 0.66) or OS (P = 0.18, P = 0.75).

Conclusions

In ABC, younger patients are rare, and survival in elderly patients in receipt of systemic therapy for advanced disease, whether monotherapy or combination therapy, is similar to that of non-elderly patients, therefore age alone should not influence decisions regarding treatment.

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Infections and cancer: the “fifty shades of immunity” hypothesis

Abstract

Background

Since the beginning of the twentieth century, infection has emerged as a fundamental aspect of cancer causation with a growing number of pathogens recognized as oncogenic. Meanwhile, oncolytic viruses have also attracted considerable interest as possible agents of tumor destruction.

Discussion

Lost in the dichotomy between oncogenic and oncolytic agents, the indirect influence of infectious organisms on carcinogenesis has been largely unexplored. We describe the various ways – from functional aspects to evolutionary considerations such as modernity mismatches – by which infectious organisms could interfere with oncogenic processes through immunity. Finally, we discuss how acknowledging these interactions might impact public health approaches and suggest new guidelines for therapeutic and preventive strategies both at individual and population levels.

Summary

Infectious organisms, that are not oncogenic neither oncolytic, may play a significant role in carcinogenesis, suggesting the need to increase our knowledge about immune interactions between infections and cancer.

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Hypermethylation of CDKN2A exon 2 in tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

Abstract

Background

Breast carcinogenesis is a multistep process involving genetic and epigenetic changes. Tumor tissues are frequently characterized by gene-specific hypermethylation and global DNA hypomethylation. Aberrant DNA methylation levels have, however, not only been found in tumors, but also in tumor-surrounding tissue appearing histologically normal. This phenomenon is called field cancerization. Knowledge of the existence of a cancer field and its spread are of clinical relevance. If the tissue showing pre-neoplastic lesions is not removed by surgery, it may develop into invasive carcinoma.

Methods

We investigated the prevalence of gene-specific and global DNA methylation changes in tumor-adjacent and tumor-distant tissues in comparison to tumor tissues from the same breast cancer patients (n = 18) and normal breast tissues from healthy women (n = 4). Methylation-sensitive high resolution melting (MS-HRM) analysis was applied to determine methylation levels in the promoters of APC, BRCA1, CDKN2A (p16), ESR1, HER2/neu and PTEN, in CDKN2A exon 2 and in LINE-1, as indicator for the global DNA methylation extent. The methylation status of the ESR2 promoter was determined by pyrosequencing.

Results

Tumor-adjacent and tumor-distant tissues frequently showed pre-neoplastic gene-specific and global DNA methylation changes. The APC promoter (p = 0.003) and exon 2 of CDKN2A (p < 0.001) were significantly higher methylated in tumors than in normal breast tissues from healthy women. For both regions, significant differences were also found between tumor and tumor-adjacent tissues (p = 0.001 and p < 0.001, respectively) and tumor and tumor-distant tissues (p = 0.001 and p < 0.001, respectively) from breast cancer patients. In addition, tumor-adjacent (p = 0.002) and tumor-distant tissues (p = 0.005) showed significantly higher methylation levels of CDKN2A exon 2 than normal breast tissues serving as control. Significant correlations were found between the proliferative activity and the methylation status of CDKN2A exon 2 in tumor (r = −0.485, p = 0.041) and tumor-distant tissues (r = −0.498, p = 0.036).

Conclusions

From our results we can conclude that methylation changes in CDKN2A exon 2 are associated with breast carcinogenesis. Further investigations are, however, necessary to confirm that hypermethylation of CDKN2A exon 2 is associated with tumor proliferative activity.

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Weight change during chemotherapy in breast cancer patients: a meta-analysis

Abstract

Background

Weight gain during chemotherapy in women with breast cancer is commonly reported.

However, there are important differences between studies that examined weight change during chemotherapy; e.g. type of chemotherapy, menopausal status, time between body weight measurements and sample size. The purpose of this meta-analysis was to quantify changes in body weight during chemotherapy for women with breast cancer, taking these differences into account.

Methods

We identified relevant studies using PubMed, Scopus and Embase databases. The search was limited to human studies published in English up to and including December 2015. Only studies among women with early stage breast cancer treated with chemotherapy, with reported body weight before and after chemotherapy and type of chemotherapy were included. Random-effect models were used, and heterogeneity between studies was explored through stratified analyses and meta-regression. Sensitivity analyses were done to explore whether a specific study markedly affected the results.

Results

In total 25 papers were found, including data from 2620 women. Overall, body weight increased during chemotherapy: 2.7 kg (95% CI 2.0, 7.5) with a high degree of heterogeneity (I² = 94.2%). Stratified analyses showed weight gain in all strata, but did not substantially reduce heterogeneity. Univariate meta-regression showed less weight gain in prospective studies compared to chart review studies (−2.0, 95% CI: -3.1, −0.8). Studies including cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimes showed a greater weight gain compared to those that did not (2.2, 95% CI: 1.1, 3.3); and papers published until the year 2000 showed a greater weight gain compared to those published after 2000 (1.9, 95% CI:-0.8, 3.1). In the multivariate models only studies including CMF regimes and studies published until 2000 were associated with significant weight gain of respectively 1.3 and 1.4 kg.

Conclusion

Despite the high heterogeneity, this meta-analysis shows significant weight gain during chemotherapy for women with breast cancer. Weight gain was more pronounced in papers published until 2000 and women receiving CMF as chemotherapy regime. Although weight gain after chemotherapy has decreased over the course of time, weight gain is still substantial and deserves clinical attention.

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