Traumatic distress symptoms in early breast cancer I: Acute response to diagnosis

In this study, the concept of ‘acute traumatic stress response’ was applied to breast cancer diagnosis. A total of 106 patients were studied before surgery, by means of a psychiatric interview and questionnaires (Impact of Event Scale, General Health Questionnaire and Clinical Global Impression Scale). The traumatic stress response was related to age, marital status, occurrence of breast cancer in first-degree relatives, previous physical and psychological health parameters, social support and life events during the last year. Of the patients, 44% reported a high level of intrusive symptoms (mean score 17.2) and 29% of avoidance symptoms (mean score 15.0). Younger age and being married were positively correlated with intrusive symptomology while patients with a first-degree relative with breast cancer had less intrusive distress. Previous physical and psychiatric health parameters showed no association to acute traumatic stress symptoms except for those who had experienced ‘a serious illness/accident/hospitalisation last year’ who had some more avoidant symptomology. Multiple regression showed a statistically significant effect for age only on intrusive symptoms when other factors were controlled for in this analysis.     

Traumatic distress symptoms in early breast cancer. II: Outcome six weeks post surgery

One hundred and six consecutive patients with a confirmed diagnosis of breast cancer were studied before and after surgery with a clinical psychiatric interview and questionnaires (Impact of Event Scale, General Health Questionnaire and Clinical Global Impression scale). The traumatic stress response after six weeks was related to sociodemographic factors, premorbid health problems, negative life events and clinical-oncological parameters. Symptoms of traumatic distress were significantly reduced post-surgery compared to acutely, and most so among patients with no premorbid health problems and negative life events according to pre-surgery interview and self-report data. Eighteen percent of the patients reported a high level (>19) of intrusive symptoms and 14%, avoidance symptoms. Patients with premorbid impairment in work, family and social functioning and patients who during the last year had experienced the death of a close relative or a serious illness other than cancer showed the greatest distress. Previous consultations for nervous problems, age, marital status, stage of disease, type of surgery (breast-conserving versus mastectomy) and adjuvant cytostatic treatment did not influence the traumaticstress response six weeks after surgery. The level of acute posttraumatic stress response to breast cancer surgery seems best predicted by premorbid variables.     

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study

Treatment of glioblastoma (GBM) remains a challenging task, with limited treatment options, none offering a cure. Immune therapy has proven effective across different cancers with remarkable response rates. Tumor mutational burden (TMB) is a marker of response, but technical and methodological differences in TMB estimates have made a proper assessment and comparison challenging. Here, we analyzed a prospective collection of paired samples from 35 patients with newly diagnosed GBM, all of whom were wild‐type (WT) for isocitrate dehydrogenase, before and after treatment with radiotherapy and temozolomide. Seven patients (20%) had O6‐methylguanine‐DNA methyltransferase‐methylated tumors. Six patients (17%) had two relapse surgeries, and tissue from all three surgeries was collected. We found that accurate evaluation of TMB was confounded by high variability in the cancer cell fraction of relapse samples. To ameliorate this, we developed a model to adjust for tumor purity based on the relative density distribution of variant allele frequencies in each primary–relapse pair. Additionally, we examined the mutation spectra of shared and private mutations. After tumor purity adjustment, we found TMB comparison reliable in tumors with tumor purity between 15% and 40%, resulting in 27/35 patients (77.1%). TMB remained unchanged from 0.65 mutations per megabase (Mb) to 0.67/Mb before and after treatment, respectively. Examination of the mutation spectra revealed a dominance of C > T transitions at CpG sites in both shared and relapse‐private mutations, consistent with cytosine deamination and the clock‐like mutational signature 1. We present and apply a cellularity correction approach that enables more accurate assessment of TMB in paired tumor samples. We did not find a significant increase in TMB after correcting for cancer cell fraction. Our study raises significant concerns when determining TMB. Although a small sample size, corrected TMB can have a clinical significance when stratifying patients to experimental treatment, for example, immune checkpoint therapy.     

Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme

Nintedanib (BIBF 1120) is a small, orally available, triple angiokinase inhibitor in phase III development (various indications) that targets VEGFR 1–3, FGFR 1–3, and PDGFR-α/β. This open-label, uncontrolled, phase II study assessed the efficacy and safety of nintedanib in patients with recurrent glioblastoma multiforme (GBM) who had previously failed radiotherapy plus temozolomide as first-line therapy (STUPP), or the same regimen with subsequent bevacizumab-based therapy as second-line treatment (BEV). Patients with a performance status of 0–1, histologically proven GBM, and measurable disease (by RANO) were enrolled. Nintedanib was given orally at a dose of 200 mg twice daily (bid), with magnetic resonance imaging undertaken every 8 weeks. The primary endpoint was objective response rate. The study was stopped prematurely following a preplanned futility analysis after inclusion of 13 patients in the STUPP arm and 12 in the BEV arm. Best response was stable disease (SD) in three patients (12 %); all other patients progressed within the first four 28-day cycles. One patient in the BEV arm has had SD for 17+ months. Median progression-free survival was 1 month and median overall survival was 6 months. Nintedanib had an acceptable safety profile, with no CTCAE grade 3–4 adverse events. Common adverse events were CTCAE grade 1–2 fatigue, loss of appetite, diarrhea, and nausea. Single-agent nintedanib (200 mg bid) demonstrated limited, but clinically non-relevant antitumor activity in patients with recurrent GBM who had failed 1–2 prior lines of therapy.