Background: MicroRNA (MiR) influences the growth of cancer by regulation of mRNA for 50–60% of all genes. We present as per our knowledge the first global analysis of microRNA expression in anal ...cancer patients and their prognostic impact. Methods: Twenty-nine patients with T1-4 N0-3 M0 anal cancer treated with curative intent from September 2003 to April 2011 were included in the study. RNA was extracted from fresh frozen tissue and sequenced using NGS. Differentially expressed microRNAs were identified using the R-package DEseq2 and the endpoints were time to progression (TTP) and cancer specific survival (CSS). Results: Five microRNAs were significantly associated with 5-year progression free survival (PFS): Low expression of two microRNAs was associated with higher PFS, miR-1246 (100% vs. 55.6%, p = 0.008), and miR-135b-5p (92.9% vs. 59.3%, p = 0.041). On the other hand, high expressions of three microRNAs were associated with higher PFS, miR-148a-3p (93.3% vs. 53.6%, p = 0.025), miR-99a-5p (92.9% vs. 57.1%, p = 0.016), and let-7c-3p (92.9% vs. 57.1%, p = 0.016). Corresponding findings were documented for CSS. Interpretation: Our study identified five microRNAs as prognostic markers in anal cancer. MiR-1246 and microRNA-135b-5p were oncoMiRs (miRs with oncogene effects), while miR-148a-3p, miR- 99a-5p, and let-7c-3p acted as tumour suppressors in anal cancer patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Long-term toxicity after cancer treatment has gained increasing clinical attention. We evaluated pulmonary function in long-term survivors of testicular cancer (TC).
The pulmonary function of 1,049 ...TC survivors treated during 1980 to 1994 at three university hospitals in Norway was assessed by spirometry and a questionnaire (1998 to 2002). The patients were categorized into five treatment groups, as follows: surgery only (n = 202); radiotherapy only (n = 449); chemotherapy (cisplatin < or = 850 mg; n = 306); chemotherapy (cisplatin > 850 mg higher-dose group; n = 62); and chemotherapy and pulmonary surgery (cis/pulmsurg; n = 30). Spirometry variables included forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). Actual values and percentages of predicted normal values (FVC%pred and FEV1%pred, respectively) are reported. Restrictive lung disease was defined as FEV1/FVC > or = 70% and FVC%pred less than 80%.
Median observation time was 11.2 years (range, 5 to 21 years). Compared with the surgery group, the higher-dose or cis/pulmsurg groups had considerably lower age-adjusted FVC (higher-dose: beta = -.37; P = .001; cis/pulmsurg: beta = -.58; P < .001), FEV1 (higher-dose: beta = -.24; P = .014; cis/pulmsurg: beta = -.55; P < .001), FVC%pred (higher-dose: beta = -8.3; cis/pulmsurg: beta = -10.5; bothP < .001), and FEV1%pred (higher-dose: beta = -6.8; P = .003; cis/pulmsurg: beta = -12.4; P < .001). Adjustment for total testosterone, body mass index, smoking, and physical activity did not change these associations. Eight percent of all patients had restrictive lung disease, and the highest prevalence was in the higher-dose group (17.7%) and the cis/pulmsurg (16.7%) group. Compared with patients who underwent surgery only, these groups had odds ratio for restrictive disease of 3.1 (95% CI, 1.3 to 7.3) and 2.5 (95% CI, 0.8 to 7.6), respectively.
Large doses of cisplatin-based chemotherapy and combined chemotherapy/pulmonary surgery are significantly associated with decreased pulmonary function several years after TC treatment.
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Background: To report 10 year results after image guided intensity-modulated radiotherapy (IMRT) with hypofractionated simultaneous integrated boost (SIB) in high-risk prostate ...cancer. Methods: Between 2007 and 2009, 97 patients with an estimated risk of lymph node metastases above 15% (Roach equation) were prospectively included in a phase II study. Patients were treated with 2-2.7 Gy to the prostate, vesicula seminalis and elective pelvic field in 25 fractions over 5 weeks with androgen deprivation therapy for 2 years. Toxicity was scored according to RTOG criteria and biochemical free survival (BFS) using the Phoenix definition. Patients were divided into three groups; very high-risk patients (VHR) according to NCCN 2015 criteria (n=50), high-risk patients (HR) (n=32), and patients with N+ disease and/or pretreatment s-PSA ≥100 (n=15). Differences were examined using Kaplan Meier estimates with log rank test. Results: Ten year BFS in the entire cohort was 63%. Metastasis-free survival (MFS) was 77% and prostate-cancer-specific-survival (PCSS) 88%. Overall survival (OS) was 69% and local failure rate was 11%. VHR vs. HR subgroups had significant different BFS; 58% vs 84% (p=0.01) respectively. MFS and PCSS in the VHR group compared to the HR group was 78% vs 91% (p=0.108) and 86% vs 97% (p=0.157) respectively. Patients with N+ and/or PSA>100 had worse outcome compared to the HR/VHR groups, but not all had treatment failure. BFS was 33% vs 68% (p=0.001), MFS 47% vs 83% (p=0.000) and PCSS 73 % vs 90% (p=0.04), respectively. Patients who reached a PSA nadir value below 0.1 (n=80) had significant better outcomes, with PCSS 93% vs 65% (p= 0.001) and BFS 74% vs 12% (p=0.000), respectively. Acute gr 2 GI and GU toxicity was observed in 27% and 40%, gr 3 GI and GU toxicity in 1% and 3%. Late gr 2 GI and GU toxicity at 3 years appeared in 3% and 4% with no gr 3 toxicity. Conclusions: High-risk prostate cancer patients treated with IMRT with SIB obtained favorable outcomes with few serious side effects. There were significant better results in the HR versus the VHR group, both better than the N+/PSA≥100 group.
To evaluate treatment results, elucidate whether national guidelines were followed, and identify areas demanding further treatment optimization.
Between July 2000 and June 2007, 328 patients were ...treated with curatively intended chemoradiotherapy (CRT) for nonmetastatic squamous cell carcinoma of the anal region, according to national treatment guidelines based on tumor stage.
Complete response after CRT was obtained in 87% of patients, rising to 93% after salvage surgery. Chemotherapy, elective irradiation of the groin and salvage surgery were performed to a lesser extent in elderly patients, mainly because of frailty and comorbidity. Recurrence occurred in 24% of the patients, resulting in a 3- and 5-year recurrence-free survival (RFS) of 79% and 74%, respectively. Locoregional recurrences dominated, most commonly in the primary tumor site. Recurrence was treated with curative intent in 45% of the cases. The 3- and 5-year overall survival were 79% and 66%, and cancer-specific survival (CSS) were 84% and 75%, respectively. The risk of adverse outcome increased significantly with more locally advanced tumors and for male gender in multivariable analyses for RFS and CSS.
The treatment results are in accordance with similar cohorts. The primary treatment control rate was high, but there was a significant risk of locoregional recurrence in advanced tumors. The loyalty to national guidelines was broad, although individual adjustments occurred. However, caution to avoid toxicity must not lead to inadequate treatment. Male gender seems to have inferior outcome.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The prevalence of long-term survivors after treatment for testicular cancer (TC) is increasing, and most studies display normal or only slightly reduced quality of life (QOL) in TC survivors (TCSs). ...Impaired QOL is claimed to be associated with treatment modality and its side effects, although most studies in this field can be criticized for various methodologic shortcomings. We wanted to examine variation in long-term QOL in TCSs in relation to TC treatment modality, side effects, and TC-related stress in a large population.
QOL, side effects, and TC-related stress were self-rated by a questionnaire at a mean of 11 years of follow-up in 1,409 TCSs treated from 1980 to 1994. Norm data was obtained from 2,678 males who were representative of the general population. QOL was measured with the Short Form-36 (SF-36), and TC-related stress was measured with the Impact of Event Scale.
There were no clinically relevant differences in QOL between TCSs and age-adjusted norm data, although there was a slightly lowered SF-36 Physical Component Summary Score in TCSs. Variation of QOL in TCSs was related to self-reported side effects and TC-related stress but not to TC treatment modality. A significant association was found between side effects and TC-related stress.
TCSs do not suffer long term from reduced QOL, and only minor differences in QOL were found between different treatment modalities. TCSs who report more side effects or TC-related stress have increased risk for reduced QOL, but these associations are not explained by TC treatment modalities. Further QOL research in this area should explore vulnerability factors for side effects and TC-related stress.
From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict ...guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response.
Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for α-fetoprotein (AFP) of ≤ 7 days and/or for β-human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2.
Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients.
With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.
The prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients with non-small-cell lung cancer (NSCLC) is unclear. The present study investigated the effect ...of tumor cell expression of FGF-2 on the outcome of 60 patients irradiated for Stage II-III NSCLC.
The effect of FGF-2 expression and 13 additional factors on locoregional control (LRC), metastasis-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These additional factors included age, gender, Karnofsky performance status, histologic type, histologic grade, T and N category, American Joint Committee on Cancer stage, surgery, chemotherapy, pack-years, smoking during radiotherapy, and hemoglobin during radiotherapy. Locoregional failure was identified by endoscopy or computed tomography. Univariate analyses were performed with the Kaplan-Meier method and the Wilcoxon test and multivariate analyses with the Cox proportional hazard model.
On univariate analysis, improved LRC was associated with surgery (p = .017), greater hemoglobin levels (p = .036), and FGF-2 negativity (p <.001). On multivariate analysis of LRC, surgery (relative risk RR, 2.44; p = .037), and FGF-2 expression (RR, 5.06; p <.001) maintained significance. On univariate analysis, improved MFS was associated with squamous cell carcinoma (p = .020), greater hemoglobin levels (p = .007), and FGF-2 negativity (p = .001). On multivariate analysis of MFS, the hemoglobin levels (RR, 2.65; p = .019) and FGF-2 expression (RR, 3.05; p = .004) were significant. On univariate analysis, improved OS was associated with a lower N category (p = .048), greater hemoglobin levels (p <.001), and FGF-2 negativity (p <.001). On multivariate analysis of OS, greater hemoglobin levels (RR, 4.62; p = .002) and FGF-2 expression (RR, 3.25; p = .002) maintained significance.
Tumor cell expression of FGF-2 appeared to be an independent negative predictor of LRC, MFS, and OS.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
During radiation therapy for pediatric brain tumors, the brainstem is a critical organ at risk, possibly with different radio-sensitivity across its substructures. In proton therapy, treatment ...planning is currently performed using a constant relative biological effectiveness (RBE) of 1.1 (RBE1.1), whereas preclinical studies point toward spatial variability of this factor. To shed light on this biological uncertainty, we investigated the spatial agreement between isodose maps produced by different RBE models, with emphasis on (smaller) substructures of the brainstem.
Proton plans were recalculated using Monte Carlo simulations in 3 anonymized pediatric patients with brain tumors (a craniopharyngioma, a low-grade glioma, and a posterior fossa ependymoma) to obtain dose and linear energy transfer distributions. Doses and volume metrics for the brainstem and its substructures were calculated using a constant RBE1.1, 4 phenomenological RBE models with varying (α/β)x parameters, and with a simpler linear energy transfer-dependent model. The spatial agreement between the dose distributions of constant RBE1.1 versus the variable RBE models was compared using the Dice similarity coefficient.
The spatial agreement between the variable RBE dose distributions and RBE1.1 decreased with increasing isodose levels in all patient cases. The patient with ependymoma showed the greatest variation in dose and dose volumes, where V50Gy(RBE) in the brainstem increased from 32% (RBE1.1) to 35% to 49% depending on the applied model, corresponding to a spatial agreement (Dice similarity coefficient) between 0.79 and 0.95. The remaining patients showed similar trends, however, with lower absolute values due to lower brainstem doses.
All phenomenological RBE models fully enclosed the isodose volumes of the constant RBE1.1, and the volumes based on variable RBE spatially agreed. The spatial agreement was dependent on the isodose level, where higher isodose levels showed larger expansions and less agreement between the variable RBE models and RBE1.1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is no consensus on how to treat high-risk prostate cancer, and long-term results from hypofractionated radiation therapy are lacking. We report 10-year results after image guided, intensity ...modulated radiation therapy with hypofractionated simultaneous integrated boost and elective pelvic field.
Between 2007 and 2009, 97 consecutive patients with high-risk prostate cancer were included, treated with 2.7 to 2.0 Gy × 25 Gy to the prostate, seminal vesicles, and elective pelvic field. Toxicity was scored according to Radiation Therapy Oncology Group criteria and biochemical disease-free survival (BFS) defined by the Phoenix definition. Patients were subsequently divided into 3 groups: high risk (HR; n = 32), very high risk (VHR; n = 50), and N+/s–prostate-specific antigen (PSA) ≥100 (n = 15). Differences in outcomes were examined using Kaplan-Meier analyses.
BFS in the patients at HR and VHR was 64%, metastasis-free survival 80%, prostate cancer-specific survival 90%, and overall survival (OS) 72%. VHR versus HR subgroups demonstrated significantly different BFS, 54% versus 79% (P = .01). Metastasis-free survival and prostate cancer-specific survival in the VHR group versus HR group were 76% versus 87% (P = .108) and 74% versus 100% (P = .157). Patients reaching nadir PSA <0.1 (n = 80) had significantly better outcomes than the rest (n = 17), with BFS 70% versus 7% (P < .001). Acute grade 2 gastrointestinal tract (GI) and genitourinary tract (GU) toxicity occurred in 27% and 40%, grade 3 GI and GU toxicity in 1% and 3%. Late GI and GU grade 2 toxicity occurred in 1% and 8%.
High-risk prostate cancer patients obtained favorable 10-year outcomes with low toxicity. There were significantly better results in the HR versus the VHR group, both better than the N+/PSA ≥100 group. A nadir PSA value < 0.1 predicted good prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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