Concurrent administration of Docetaxel and Stealth® liposomal doxorubicin with radiotherapy in non-small cell lung cancer : excellent tolerance using subcutaneous amifostine for cytoprotection

The substantial augmentation of the radiation sequelae during chemo–radiotherapy with novel drugs masks the real potential of such regimens. In this study we examined whether subcutaneous administration of amifostine can reduce the toxicity of a highly aggressive chemo–radiotherapy scheme with Stealth® liposomal doxorubicin (Caelyx®) and Docetaxel (Taxotere®) in non-small cell lung cancer. Twenty-five patients with stage IIIb non-small cell lung cancer were recruited in a phase I/II dose escalation trial. The starting dose of Taxotere® was 20 mg m−2 week and of Caelyx® was 15 mg m−2 every two weeks, during conventionally fractionated radiotherapy (total dose of 64 Gy). The dose of Taxotere®/Caelyx® was, thereafter, increased to 20/25 (five patients) and 30/25 mg m−2 (15 patients). Amifostine 500 mg was given subcutaneously before each radiotherapy fraction, while an i.v. amifostine dose of 1000 mg preceded the infusion of docetaxel. The ‘in-field’ radiation toxicity was low. Grade 3 esophagitis occurred in 9 out of 25 (36%) patients. Apart from a marked reduction of the lymphocyte counts, the regimen was deprived from any haematological toxicity higher than grade 1. No other systemic toxicity was noted. The CR and CR/PR rates in 15 patients treated at the highest dose level was 40% (6 out of 15) and 87% (13 out of 15) respectively. It is concluded that the subcutaneous administration of amifostine during high dose Taxotere®/Caelyx® chemo–radiotherapy is a simple and effective way to render this aggressive regimen perfectly well tolerated, by reducing the systemic and the ‘in-field’ toxicity to the levels expected from simple conventional radiotherapy. The impressive tolerance and the high CR rate obtained encourages the conduct of a relevant randomized trial to assess an eventual survival benefit in patients with non-small cell lung cancer

gamma-H2AX: A Novel Prognostic Marker in a Prognosis Prediction Model of Patients with Early Operable Non-Small Cell Lung Cancer

Cancer is a leading cause of death worldwide and the prognostic evaluation of cancer patients is of great importance in medical care. The use of artificial neural networks in prediction problems is well established in human medical literature. The aim of the current study was to assess the prognostic value of a series of clinical and molecular variables with the addition of gamma-H2AX-a new DNA damage response marker-for the prediction of prognosis in patients with early operable non-small cell lung cancer by comparing the gamma-H2AX-based artificial network prediction model with the corresponding LR one. Two prognostic models of 96 patients with 27 input variables were constructed by using the parameter-increasing method in order to compare the predictive accuracy of neural network and logistic regression models. The quality of the models was evaluated by an independent validation data set of 11 patients. Neural networks outperformed logistic regression in predicting the patient’s outcome according to the experimental results. To assess the importance of the two factors p53 and gamma-H2AX, models without these two variables were also constructed. JR and accuracy of these models were lower than those of the models using all input variables, suggesting that these biological markers are very important for optimal performance of the models. This study indicates that neural networks may represent a potentially more useful decision support tool than conventional statistical methods for predicting the outcome of patients with non-small cell lung cancer and that some molecular markers, such as gamma-H2AX, enhance their predictive ability

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli (APC) and Ras association domain family 1 isoform A (RASSF1A) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P=0.012), higher stage (P=0.014) and methylated RASSF1A status (P=0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, P<0.001) and advanced disease (37±7 vs. 15±3 months, P<0.001), compared with patients with methylated APC. Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, P<0.001) and advanced disease (28±4 vs. 16±3 months, P<0.001) than patients with methylated RASSF1A. The observed significant correlations between APC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies. © 2016, Spandidos Publications. All rights reserved

Late results of a randomized trial on the role of mild hypofractionated radiotherapy for the treatment of localized prostate cancer

Background: Prostate cancer is considered to be highly sensitive to changes in radiation therapy dose per fraction, specifically to hypofractionation. An increase in the fractionation dose could cause a higher increase to the prostate than to the normal tissues leading to better disease control with less toxicity. Here we present the results of a randomized trial comparing mild hypofractionation to conventional fractionation after a median of 3,6 years follow up. Patients and Methods: 139 patients were randomized to receive either hypofractionated radiotherapy with 2,25 Gy/fr to a total of 72 Gy (arm 1) or conventionally fractionated treatment with 2Gy/fr to a total of 74 Gy (arm 2). 72 patients were assigned to arm 1 and 67 to arm 2. Results: After a median follow up of 3,6 years, 23 patients (31,9%) from arm 1 developed grade≥ 2 acute genitourinary toxicity and 21 (31,3%) from arm 2 (p=0,79). The corresponding values from gastrointestinal were 15 (20,8%) and 12 (17,9%) (p=0,6). For late toxicity from GU, 8 patients (11,1%) developed grade≥ 2 symptoms in arm 1 and 7 (10,4%) in arm 2 (p=0,92). late GI toxicity grade≥ 2 was observed in 8 (11,1%) patients in arm 1 and 8 (11,9%) in arm 2 (p=0,88). In multivariate analysis, hormone therapy was significantly associated with late GI events, while acute toxicity from both GU and GI was a prognostic factor of late adverse reaction. Conclusion: No difference in the toxicity profile could be identified between hypofractionation and conventional fractionation. Our schedule of 2,25Gy/fr seems safe and tolerable by the patients with acceptable rates of acute and late toxicity. © The author(s)

Gender differences in obstructive sleep apnea: The value of sleep questionnaires with a separate analysis of cardiovascular patients

Background: Gender affects the clinical presentation of obstructive sleep apnea (OSA). The classic OSA symptoms, such as sleepiness, snoring, and apnea, are not so frequent in women. Objectives: To evaluate possible gender differences in questionnaires used for OSA prediction, such as the Epworth Sleepiness Scale (ESS), STOP, STOP Bang (SB), Berlin Questionnaire (BQ), Athens Insomnia Scale (AIS), and Fatigue Scale (FS). Methods: 350 males were matched with 350 women referred to a sleep clinic, according to OSA severity. All responded to the questionnaires and underwent a sleep study. Cardiovascular disease (CVD) patients were separately analyzed. Results: ESS did not differ between genders. SB was higher in males, whereas STOP, BQ, AIS, and FS were higher in females. BQ presented the highest sensitivity in both genders, whereas STOP exhibited the highest specificity in males and ESS in females. AIS and FS were more sensitive and SB more specific in females, whereas BQ was more specific in males. For severe OSA, the predictive values of SB and BQ were almost similar for both genders; however AIS and FS were higher in women. CVD patients presented higher scores, independent of gender, except for AIS, which was higher in females. Conclusion: Gender-specific evaluation of questionnaires is necessary to prevent OSA under-diagnosis. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

The role of hypofractionated radiotherapy for the definitive treatment of localized prostate cancer: Early results of a randomized trial

Background: Prostate cancer is considered to have a special biology which could affect the radiation therapy result based on the selected fractionation scheme. We present the preliminary results of a randomized trial comparing conventionally and hypofractionated radiation therapy for prostate cancer. Methods: Patients included in the study had localized prostate cancer (cT1c-T3bN0M0) and were randomly assigned to mild hypofractionated (72 Gy in 32 fractions, arm1) or conventionally fractionated (74 Gy in 37 fractions, arm2) radiation therapy treatment with Volumetric Arc Therapy technique. The treatment was delivered only to the prostate with or without the seminal vesicles according to physician’s discretion and hormone therapy was optional according to the disease stage and comorbidities. Here we present the preliminary results of acute toxicity from the gastrointestinal (GI) and genitourinary (GU) system. Results: Between 2015 and 2016, 139 patients were enrolled. 67 patients were treated with conventional fractionation and 72 were treated with hypofractionation. Grade≥ 2 toxicity from GU and GI was observed in 23 and 21 patients (31,9% vs 31,3%, p=0,79) and 15 and 12 (20,8% vs 17,9%, p=0,6) for arm1 and arm2 respectively. No statistically significant differences were observed between arms in the incidence of early toxicity. There was no correlation observed between patient characteristics and toxicity from either GU or GI. Conclusions: Hypofractionated radiotherapy appears to be equally tolerated compared to conventional fractionation in the early setting. Longer follow up is needed to assess the late toxicity profile of the patients and any potential differences between the control and experimental arm. © The author(s)