Genomic characterization of IDH-mutant astrocytoma progression to grade 4 in the treatment setting.

As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.

Impact of Timing of Surgery and Adjuvant Treatment on Survival of Adult IDH-wild-type Glioblastoma: A Single-center Study of 392 Patients.

BACKGROUND: The purpose of our study was to analyze the impact of time interval from referral to surgery and from surgery to adjuvant treatment on survival of adult isocitrate dehydrogenase-wild-type (IDH-wt) glioblastomas. METHODS: Data on 392 IDH-wt glioblastomas diagnosed at the Tampere University Hospital in 2004-2016 were obtained from the electronic patient record system. Piecewise Cox regression was used to calculate hazard ratios for different time intervals between referral and surgery, as well as between surgery and adjuvant treatments. RESULTS: The median survival time from primary surgery was 9.5 months (interquartile range: 3.8-16.0). Survival among patients with an interval exceeding 4 weeks from referral to surgery was no worse compared to <2 weeks (hazard ratio: 0.78, 95% confidence interval: 0.54-1.14). We found indications of poorer outcome when the interval from surgery to radiotherapy exceeded 30 days (hazard ratio: 1.42, 95% confidence interval: 0.91-2.21 for 31-44 days; and 1.59, 0.94-2.67 for over 45 days). CONCLUSIONS: Interval from referral to surgery in the range of 4-10 weeks was not associated with decreased survivals in IDH-wt glioblastomas. In contrast, delay exceeding 30 days from surgery to adjuvant treatment may decrease long-term survival.

Importance of deformable image registration and biological dose summation in planning of radiotherapy retreatments.

The purpose of this study is to evaluate the effect of nonrigid and fractionation-corrected dose summation on total doses in radiotherapy and to demonstrate the benefits of such dose summation on clinical decision-making for planning of retreatments. Dose summation of organs at risk (OARs) was investigated for 3 clinical cases with need of retreatment to the same site: head and neck, brain, and mediastinum. Three different summation methods over old and new radiotherapy treatment plans are presented and compared: (1) rigid raw sum with rigid registration of the planning images and direct dose summing; (2) deformable raw sum with deformable image registration and direct dose summing; and (3) deformable biological sum with deformable registration and takes into account the dose per fraction in biological manner in certain critical organs. In 2 cases, a user-defined dose downscaling is applied to take into account the time between the treatments and the healing from the radiation-induced effects. Of the 3 summation methods presented, the deformable biological sum was considered to offer the most biologically plausible account of the treatment. There were remarkable differences between near-maximum doses (D0.1cc) and dose-volume histogram (DVH) curves for OARs between different summation methods. The differences between deformable raw sum and rigid raw sum D0.1cc doses are in the range from -8 Gy to 2 Gy. Similarly, the deviation was from -14 Gy to 5 Gy for the deformable biological sum compared with the rigid raw sum. These differences come from incorrect summation of doses in the rigid raw sum case, and from the dose per fraction effect in biological summation. We conclude that computing the 3-dimensional deformable biological summation could be a valuable tool for treating patients with complex retreatments. It has the potential to assist the oncologist in refining plans for maximally curative doses while respecting appropriate tissue tolerances.

[Diagnosis and prognosis of gliomas--current prospects of molecular diagnostics]. / Glioomien diagnoosi ja ennuste--molekyylidiagnostiikan mahdollisuudet.

Gliomas are tumors of the support cells of the brain and the most common of the primary brain tumors. Treatment of diffuse gliomas is based on surgical excision of the tumor and on radiotherapy and chemotherapy. The diagnosis is made in histopathological examination of the tumor, which today can be complemented with examinations involving molecular diagnostics. The most important new methods predicting the prognosis of glioma patients include demonstrations of the IDH mutation and the 1p/19q co-deletion. Profiling of gliomas may in the future allow tailoring of therapy in a patient-specific manner.

Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial.

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with moderate-to-high-risk early breast cancer typically contain a taxane, an anthracycline, and cyclophosphamide. We aimed to investigate whether integration of capecitabine into such a regimen enhances outcome. METHODS: In this open-label trial, we randomly assigned (centrally by computer; stratified by node status, HER2 status, and centre) 1500 women with axillary node-positive or high-risk node-negative breast cancer to either three cycles of capecitabine and docetaxel followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (capecitabine group, n=753), or to three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (control group, n=747). The primary endpoint was recurrence-free survival. A planned interim analysis was done after 3 years' median follow-up. Efficacy analyses were by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT00114816. FINDINGS: Two patients in each group were excluded from efficacy analyses because of withdrawal of consent or distant metastases. After a median follow-up of 35 months (IQR 25.5-43.6), recurrence-free survival at 3 years was better with the capecitabine regimen than with control (93%vs 89%; hazard ratio 0.66, 95% CI 0.47-0.94; p=0.020). The capecitabine regimen was associated with more cases of grade 3 or 4 diarrhoea (46/740 [6%] vs 25/741 [3%]) and hand-foot syndrome (83/741 [11%] vs 2/741 [<1%]) and the control regimen with more occurrences of grade 3 or 4 neutropenia (368/375 [98%] vs 325/378 [86%]) and febrile neutropenia (65/741 [9%] vs 33/742 [4%]). More patients discontinued planned treatment in the capecitabine group than in the control group (178/744 [24%] vs 23/741 [3%]). Four patients in the capecitabine group and two in the control group died from potentially treatment-related causes. INTERPRETATION: The capecitabine-containing chemotherapy regimen reduced breast cancer recurrence compared with a control schedule of standard agents. Capecitabine administration was frequently discontinued because of adverse effects. FUNDING: Roche, Sanofi-Aventis, AstraZeneca, Cancer Society of Finland.

Radiological pulmonary findings after breast cancer irradiation: A prospective study.

The aim of this study was to evaluate radiation-induced pulmonary abnormalities of breast cancer patients. Altogether 202 consecutive patients receiving postoperative radiotherapy entered the study. Plain chest radiographs taken at entry and 3, 6 and 12 months after radiotherapy were evaluated according to modified Arriagada classification. In addition, pulmonary symptoms were recorded. Supplementary high-resolution computed tomography (HRCT) was employed in a subgroup of patients (n?=?15). Plain radiographs were interpreted by a radiologist, and uncertain findings were re-evaluated by a radiologist together with a radiation oncologist. Grade 2 pneumonitis was the most common abnormality. The proportion of patients yielding a grade 2 finding was 22.5%, 28.1%, and 16.0% at three, six, and twelve months, respectively. There were 2 normal findings in HRCTscans, and 8 in plain radiographs of the same patients. Radiological lung abnormalities are common after radiotherapy, but they are usually reversible, and their significance for the patient's well-being is minor. No correlation between symptoms and lung or pleural reactions was seen.