Effects of ozone therapy on anxiety and depression in patients with refractory symptoms of severe diseases: a pilot study.

Background: Patients with refractory symptoms of severe diseases frequently experience anxiety, depression, and an altered health-related quality of life (HRQOL). Some publications have described the beneficial effect of ozone therapy on several symptoms of this kind of patient. The aim of this study was to preliminarily evaluate, in patients treated because of refractory symptoms of cancer treatment and advanced nononcologic diseases, if ozone therapy has an additional impact on self-reported anxiety and depression. Methods: Before and after ozone treatment, we assessed (i) anxiety and depression according to the Hospital Anxiety and Depression Scale (HADS); (ii) the HRQOL (according to the EQ-5D-5L questionnaire), which includes a dimension on anxiety and depression and a visual analog scale (VAS) measuring self-perceived general health. Results: Before ozone therapy, 56% of patients were on anxiolytic and/or antidepressant treatment. Before and after ozone therapy, the anxiety and depression HADS subscales (i) significantly correlated with the anxiety/depression dimension of the EQ-5D-5L questionnaire and (ii) inversely correlated with the health status as measured by the VAS. After ozone therapy, we found a significant improvement in anxiety and depression measured by both the (i) HADS subscales and (ii) EQ-5D-5L questionnaire. Conclusion: The addition of ozone therapy for patients with refractory symptoms of cancer treatment and advanced chronic nononcologic diseases can decrease anxiety and depression severity levels. Additional, more focused studies are ongoing to provide the needed explanatory information for this finding.

Pain in High-Dose-Rate Brachytherapy for Cervical Cancer: A Retrospective Cohort Study.

High-dose-rate brachytherapy (HDR) is part of the main treatment for locally advanced uterine cervical cancer. Our aim was to evaluate the incidence and intensity of pain and patients' satisfaction during HDR. Risk factors for suffering pain were also analyzed. A retrospective study was carried out by extracting data from patients who had received HDR treatment for five years. Postoperative analgesia had been administered using pre-established analgesic protocols for 48 h. Pain assessment was collected according to a protocol by the acute pain unit. Analgesic assessment was compared according to analgesic protocol administered, number of needles implanted, and type of anesthesia performed during the procedure. From 172 patients treated, data from 247 treatments were analyzed. Pain was considered moderate in 18.2% of the patients, and 43.3% of the patients required at least one analgesic rescue. Patients receiving major opioids reported worse pain control. No differences were found regarding the analgesic management according to the intraprocedural anesthesia used or the patients' characteristics. The number of inserted needles did not influence the postoperative analgesic assessment. Continuous intravenous infusion of tramadol and metamizole made peri-procedural pain during HDR mild in most cases. Many patients still suffered from moderate pain.

Effects of Ozone Treatment on Health-Related Quality of Life and Toxicity Induced by Radiotherapy and Chemotherapy in Symptomatic Cancer Survivors.

(1) Background: The continuous improvement in cancer treatment has led to improvement in patients' survival and a subsequent increase in the number of cancer survivors living with adverse side effects of cancer treatments, sometimes with a high and adverse impact on their health-related quality of life (HRQOL). Side effects of cancer treatments are frequently associated with chronic status of oxidative stress, inflammation, and/or ischemia. The potential for ozone treatment to modulate those processes and improve some of those adverse effects has previously been described. The aim of this study was to evaluate the effect of ozone treatment on the HRQOL and grade of toxicity in symptomatic cancer survivors. (2) Methods: Before and after ozone treatment, we assessed (i) the HRQOL (according to the EQ-5D-5L questionnaire) and (ii) the grade of toxicity (according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute of EEUU (CTCAE v.5.0)) in 26 cancer survivors with chronic side effects of radiotherapy and chemotherapy. (3) Results: There was a significant (p < 0.001) improvement in the EQ-5D-5L index as per the self-reported outcome evaluation of patients' health status. All the dimensions of the EQ-5D-5L questionnaire (mobility, self-care, activities, pain/discomfort, and anxiety/depression) and the self-evaluation of the health status using the visual analog scale were significantly improved (p < 0.05). The grade of toxicity was also significantly decreased (p < 0.001). (4) Conclusions: In cancer survivors with chronic side effects of cancer treatment, ozone treatment can improve the grade of toxicity and the HRQOL. These results merit additional research. Further studies are ongoing.

Long-term improvement by ozone treatment in chronic pain secondary to chemotherapy-induced peripheral neuropathy: A preliminary report.

Background: Pain secondary to chemotherapy-induced peripheral neuropathy (CIPN) can limit the administration of chemotherapy, cancer-treatment outcomes, and the quality of life of patients. Oxidative stress and inflammation are some of the key mechanisms involved in CIPN. Successful treatments for CIPN are limited. This report shows our preliminary experience using ozone treatment as a modulator of oxidative stress in chronic pain secondary to CIPN. Methods: Ozone treatment, by rectal insufflation, was administered in seven patients suffering from pain secondary to grade II or III CIPN. Pain was assessed by the visual analog scale (VAS). Results: All patients, except one, showed clinically relevant pain improvement. Median pain score according to the VAS was 7 (range: 5-8) before ozone treatment, 4 (range: 2-6) at the end of ozone treatment (p = 0.004), 5.5 (range: 1.8-6.3) 3 months after the end of ozone treatment (p = 0.008), and 6 (range: 2.6-6.6) 6 months after the end of ozone treatment (p = 0.008). The toxicity grade, according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0), improved in half of the patients. Conclusion: This report shows that most patients obtained clinically relevant and long-lasting improvement in chronic pain secondary to CIPN after treatment with ozone. These observed effects merit further research and support our ongoing randomized clinical trial (NCT04299893).

Ozone Therapy in Refractory Pelvic Pain Syndromes Secondary to Cancer Treatment: A New Approach Warranting Exploration.

Background: Chronic pain secondary to treatment in cancer survivors without tumor evidence is not unusual. Its management often requires specific approaches that are different from those applied for cancer patients with advanced disease and short life expectancy. Some studies have described clinical benefit with ozone therapy (O3T) in the management of pain and side effects secondary to cancer treatment. Objective: We present our preliminary experience with O3T in the management of refractory pelvic pain syndromes secondary to cancer treatment. Design: Case series. Subjects and Methods: Six cancer patients (without tumor evidence) who had been treated previously with radiotherapy, chemotherapy, or endoscopic procedures and were suffering persistent or severe pelvic pain (median 14 months) received O3T using ozone-oxygen gas mixture insufflation as a complementary therapy in addition to their scheduled conventional treatment. Results: All cases, except one, showed clinically relevant pain improvement. Visual analog scale score with the standard treatment was 7.8 ± 2.1 before O3T, 4.3 ± 3.4 (p = 0.049) after one month, 3.3 ± 3.7 (p = 0.024) after two months, and 2.8 ± 3.8 (p = 0.020) after three months of O3T. The median value of "pain symptom" according to the U.S. National Cancer Institute Common Terminology Criteria for Adverse Events v. 5.0 showed a decrease from 3 (range: 2-3) to 1 (range: 0-3) (p = 0.046). Conclusions: Following unsuccessful conventional treatments, O3T provided significant benefit in our patients with refractory pelvic pain secondary to cancer treatment. These results merit further evaluation in blinded, randomized clinical trials.

Prospective intra/inter-observer evaluation of pre-brachytherapy cervical cancer tumor width measured in TRUS and MR imaging.

BACKGROUND: Ultrasound (US) imaging has been proved as an excellent diagnostic tool in gynecology and, due to its wide availability and limited cost, is under intense investigation as base for dose adaptation in cervical cancer brachytherapy. Purpose of this work is to test inter/intra-observer uncertainties between magnetic resonance (MR) and trans-rectal ultrasound (TRUS) imaging in defining maximum tumor width before first brachytherapy (BT) application in a prospective cohort of cervical cancer patients undergoing image-guided adaptive brachytherapy (IGABT). METHODS: One hundred ten consecutive cervical cancer patients treated between 2013 and 2016 were included. Before the first BT implant patients underwent MR and TRUS scan with no applicator in place. Images were independently analyzed by three examiners, blinded to the other's results. With clinical information at hand, maximum tumor width was measured on preBT TRUS and MR. Quantitative agreement analysis was undertaken. Intra-class correlation coefficient (ICC), Passing-Bablok and Bland Altman plots were used to evaluate the intra/inter-observers measurement agreement. RESULTS: Average difference between tumor width measured on MR (HRCTVMR) and TRUS (HRCTVTRUS) was 1.3 ± 3.2 mm (p <  0.001); 1.1 ± 4.6 mm (p = 0.01) and 0.7 ± 3 mm (p = 0.01). The error was less than 3 mm in 79, 82 and 80% of the measurements for the three observers, respectively. Intra-observer ICC was 0.96 (CI95% 0.94-0.97), 0.93 (CI95% 0.9-0.95) and 0.96 (CI95% 0.95-0.98) respectively. Inter-observer ICC for HRCTVMR width measures was 0.92 (CI95% 0.89-0.94) with no difference among FIGO stages. Inter-observer ICC for HRCTVTRUS was 0.86 (CI95% 0.81-0.9). For FIGO stage I and II tumors, ICC HRCTVTRUS values were comparable to respective HRCTVMR ICC values. For larger tumors HRCTVTRUS inter-observer ICC values were lower than respective HRCTVMR although remaining acceptable. CONCLUSIONS: Our results suggest that TRUS is equivalent to MR in assessing preBT tumor maximum width in cervical cancer FIGO stage I/II. In more advanced stages TRUS seems to be slightly inferior to MR although maintaining a good agreement to gold standard imaging.

Management of endometrial cancer in patients aged 80 years and older: Identifying patients who may benefit from a curative treatment.

OBJECTIVE: The goal of this study was to evaluate the demographic characteristics, pathology, treatment, prognostic factors and survival rates in elderly patients with endometrial cancer, and to compare their results with those of younger ones, in order to define the specific characteristics of this malignancy in this population. STUDY DESIGN: Retrospective analysis of all endometrial cancer patients managed at the University Hospital of the Canary Islands (Spain) between 1990 and 2016. Survival curves were calculated by using the Kaplan-Meier method and compared with the log-rank test. Logistic regression analysis was used to assess the independent effect of different variables on cancer-specific survival. Statistical significance was considered for p < 0.05. RESULTS: The study included 1799 endometrial cancer patients; 170 of them (9.4%) were 80 years old or older. Elderly patients received less surgery (68.2% vs. 92.4%), lymphadenectomy (10.3% vs. 26.2%) and adjuvant treatment (37.1% vs. 51.2%) than younger ones, and presented higher probability of receiving palliative treatment (27.6% vs. 4%). Endometrioid tumors were more frequently diagnosed in younger patients (78.8% vs. 62.9%), while type 2-endometrial cancer was more frequently diagnosed in elderly ones (37.1% vs. 21.2%). Cancer-specific survival in older patients was significantly poorer than in younger ones, with a mean of 61.4 months (95%CI 51.7-71.1) versus 226 months (95%CI 218.9-233.1), respectively. In a multivariate analysis: age, FIGO stage, histology, tumor differentiation and adjuvant treatment were independently associated with survival. CONCLUSION: Although endometrial cancer is more aggressive in older patients, they are less likely to receive optimal treatment, which negatively affects their survival. Specific guidelines for the management of this population, including a comprehensive geriatric assessment, should be developed to improve their prognosis.

Locally advanced cervix cancer: a study of 156 cases from a single institution / Cáncer de cérvix localmente avanzado: un estudio de 156 casos en un único hospital

Objective: The objective of our study was to identify prognostic factors, management strategies, and outcomes for locally advanced cervical cancer in our hospital. Material and methods: We performed a retrospective study of 156 patients with locally advanced cervical cancer (FIGO IB2-IVA). All patients underwent staging of the para-aortic lymph nodes by computed tomography. A total of 93 patients with para-aortic lymph nodes with no signs of malignancy in the imaging tests underwent pretherapy surgical staging up to the level of the left renal vein. All patients were treated with chemoradiation. Results: The study included a total of 156 patients. The average age was 54.04 years (range 28-97 years). Squamous cell carcinoma was the most frequent histological type (82.1%). Most patients had FIGO stage IIB disease (43.6%). Histopathology revealed metastatic disease in the para-aortic lymph nodes in 19.3% of patients. The status of the para-aortic lymph nodes was the only factor that was independently associated with an increased risk of mortality (OR 33 [95% CI, 8-135.89], p<0.0001). Conclusions: Patients with an advanced tumor stage at the time of diagnosis and those with pathological para-aortic lymph nodes are at greater risk of developing distant metastases and of more frequent disease-related mortality. In this group of high-risk patients, a more marked therapeutic effort must be made in order to improve survival

Objetivo: El objetivo del estudio fue identificar los factores pronósticos, las estrategias de manejo y los resultados de los cánceres cervicales localmente avanzados tratados en nuestro hospital. Material y métodos: Estudio retrospectivo de 156 pacientes con cánceres cervicales localmente avanzados (FIGO IB2-IVA). A todas las pacientes se les realizó estadiaje de los ganglios linfáticos paraaórticos mediante Tomografía Axial Computarizada. 93 pacientes con ganglios linfáticos paraaórticos sin signos de malignidad en las pruebas de imagen fueron sometidas a estadiaje quirúrgico preterapéutico hasta el nivel de la vena renal izquierda. Todas las pacientes fueron tratadas con quimio-radioterapia. Resultados: El estudio incluyo un total de 156 pacientes. La edad media fue de 54,04 años (rango 28-97 años). El carcinoma de células escamosas fue el tipo histológico más frecuente (82,1%). La mayoría de las paciente tenían un estadio FIGO IIB (43,6%). El estudio anatomopatológico reveló enfermedad metastásica en ganglios paraórticos en un 19,3% de la pacientes. El estado de los ganglios para-aórticos fue el único factor que se asoció de manera independiente con el incremento del riesgo de mortalidad [OR 33 (IC 95% 8-135,89; p<0,0001]. Conclusiones: Las pacientes con un estadio tumoral avanzado en el momento del diagnóstico y aquellas con ganglios paraórticos patológicos tienen mayor riesgo de desarrollar metástasis a distancia y mayores tasas de mortalidad causadas por la enfermedad. En este grupo de pacientes de alto riesgo se debe realizar un esfuerzo terapéutico superior con el fin de mejorar la supervivencia de esta enfermedad

Should the Presence of Metastatic Para-Aortic Lymph Nodes in Locally Advanced Cervical Cancer Lead to More Aggressive Treatment Strategies?

STUDY OBJECTIVE: To evaluate risk factors in patients with locally advanced cervical cancer (LACC) undergoing pretherapeutic laparoscopic para-aortic lymphadenectomy (LPL) as well as the progression-free and overall survival rates specifically in the subgroup of patients with metastatic para-aortic lymph nodes (PLNs). DESIGN: Retrospective study conducted on demographic data, pathologic and surgical findings, complications, and disease status recorded for LACC patients undergoing LPL during the period 2009 to 2015. SETTING: Department of Gynecologic Oncology of the Complejo Hospitalario Universitario Insular-Materno Infantil, Canary Islands, Spain (Canadian Task Force Classification II-3). PATIENTS: Women with LACC undergoing pretherapeutic LPL. All patients were treated with definitive chemoradiotherapy after surgery, and those with metastatic PLN received extended lumboaortic radiation therapy. INTERVENTIONS: Survival analysis was performed with the Kaplan-Meier method. Statistical significance was considered for p <.05. MEASUREMENTS AND MAIN RESULTS: The study included 139 patients. The median age was 48 years (range, 28-73). The most frequent histologic type was squamous cell carcinoma (77%), and the most frequent 2009 FIGO stage was IIB (48.2%). LPL identified metastatic PLN in 18.7% of patients (n = 26). The mean overall survival for the whole population, after 23 months of follow-up, was 68.2 months (95% CI, 63-73.4). For patients without para-aortic metastases, the mean survival time was 76.9 months (95% CI, 70.3-80.4), whereas for patients with positive PLNs the median survival time was 21 months (95% CI, 6.1-35.9; p <.0001). A logistic regression analysis revealed that the presence of metastatic PLNs and tumor size (>5 cm) were both independent risk factors for poor survival (OR, 117.5; 95% CI, 11.6-990.2; p <.0001, and OR, 21.5; 95% CI, 2-230.3; p = .01, respectively). CONCLUSION: LACC patients with metastatic PLNs had a poor prognosis and low survival rate. We postulate that this finding could be accounted for by the presence of hidden systemic disease and high recurrence rate after therapy. Efforts should be made to improve available therapeutic strategies for this particular subgroup of patients.

Value of Magnetic Resonance Imaging Without or With Applicator in Place for Target Definition in Cervix Cancer Brachytherapy.

PURPOSE: To define, in the setting of cervical cancer, to what extent information from additional pretreatment magnetic resonance imaging (MRI) without the brachytherapy applicator improves conformity of CT-based high-risk clinical target volume (CTVHR) contours, compared with the MRI for various tumor stages (International Federation of Gynecology and Obstetrics [FIGO] stages I-IVA). METHODS AND MATERIALS: The CTVHR was contoured in 39 patients with cervical cancer (FIGO stages I-IVA) (1) on CT images based on clinical information (CTVHR-CTClinical) alone; and (2) using an additional MRI before brachytherapy, without the applicator (CTVHR-CTpre-BT MRI). The CT contours were compared with reference contours on MRI with the applicator in place (CTVHR-MRIref). Width, height, thickness, volumes, and topography were analyzed. RESULTS: The CT-MRIref differences hardly varied in stage I tumors (n=8). In limited-volume stage IIB and IIIB tumors (n=19), CTVHR-CTpre-BT MRI-MRIref volume differences (2.6 cm(3) [IIB], 7.3 cm(3) [IIIB]) were superior to CTVHR-CTClinical-MRIref (11.8 cm(3) [IIB], 22.9 cm(3) [IIIB]), owing to significant improvement of height and width (P<.05). In advanced disease (n=12), improved agreement with MR volume, width, and height was achieved for CTVHR-CTpre-BT MRI. In 5 of 12 cases, MRIref contours were partly missed on CT. CONCLUSIONS: Pre-BT MRI helps to define CTVHR before BT implantation appropriately, if only CT images with the applicator in place are available for BT planning. Significant improvement is achievable in limited-volume stage IIB and IIIB tumors. In more advanced disease (extensive IIB to IVA), improvement of conformity is possible but may be associated with geographic misses. Limited impact on precision of CTVHR-CT is expected in stage IB tumors.

Quality assurance in MR image guided adaptive brachytherapy for cervical cancer: Final results of the EMBRACE study dummy run.

PURPOSE: Upfront quality assurance (QA) is considered essential when starting a multicenter clinical trial in radiotherapy. Despite the long experience gained for external beam radiotherapy (EBRT) trials, there are only limited audit QA methods for brachytherapy (BT) and none include the specific aspects of image guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS: EMBRACE is a prospective multicenter trial aiming to assess the impact of (MRI)-based IGABT in locally advanced cervical cancer. An EMBRACE dummy run was designed to identify sources and magnitude of uncertainties and errors considered important for the evaluation of clinical, and dosimetric parameters and their relation to outcome. Contouring, treatment planning and dose reporting was evaluated and scored with a categorical scale of 1-10. Active feedback to centers was provided to improve protocol compliance and reporting. A second dummy run was required in case of major deviations (score <7) for any item. RESULTS: Overall 27/30 centers passed the dummy run. 16 centers had to repeat the dummy run in order to clarify major inconsistencies to the protocol. The most pronounced variations were related to contouring for both EBRT and BT. Centers with experience in IGABT (>30 cases) had better performance as compared to centers with limited experience. CONCLUSION: The comprehensive dummy run designed for the EMBRACE trial has been a feasible tool for QA in IGABT of cervix cancer. It should be considered for future IGABT trials and could serve as the basis for continuous quality checks for brachytherapy centers.

High-risk clinical target volume delineation in CT-guided cervical cancer brachytherapy: impact of information from FIGO stage with or without systematic inclusion of 3D documentation of clinical gynecological examination.

PURPOSE: The aim of the study was to improve computed tomography (CT)-based high-risk clinical target volume (HR CTV) delineation protocols for cervix cancer patients, in settings without any access to magnetic resonance imaging (MRI) at the time of brachytherapy. Therefore the value of a systematic integration of comprehensive three-dimensional (3D) documentation of repetitive gynecological examination for CT-based HR CTV delineation protocols, in addition to information from FIGO staging, was investigated. In addition to a comparison between reference MRI contours and two different CT-based contouring methods (using complementary information from FIGO staging with or without additional 3D clinical drawings), the use of standardized uterine heights was also investigated. MATERIAL AND METHODS: Thirty-five cervix cancer patients with CT- and MR-images and 3D clinical drawings at time of diagnosis and brachytherapy were included. HR CTV(stage) was based on CT information and FIGO stage. HR CTV(stage + 3Dclin) was contoured on CT using FIGO stage and 3D clinical drawing. Standardized HR CTV heights were: 1/1, 2/3 and 1/2 of uterine height. MRI-based HR CTV was delineated independently. Resulting widths, thicknesses, heights, and volumes of HR CTV(stage), HR CTV(stage + 3Dclin) and MRI-based HR CTV contours were compared. RESULTS: The overall normalized volume ratios (mean ± SD of CT/MRI(ref) volume) of HR CTV(stage) and HR stage + 3Dclin were 2.6 (± 0.6) and 2.1 (± 0.4) for 1/1 and 2.3 (± 0.5) and 1.8 (± 0.4), for 2/3, and 1.9 (± 0.5) and 1.5 (± 0.3), for 1/2 of uterine height. The mean normalized widths were 1.5 ± 0.2 and 1.2 ± 0.2 for HR CTV(stage) and HR CTV(stage + 3Dclin), respectively (p < 0.05). The mean normalized heights for HR CTV(stage) and HR CTV(stage + 3Dclin) were both 1.7 ± 0.4 for 1/1 (p < 0.05.), 1.3 ± 0.3 for 2/3 (p < 0.05) and 1.1 ± 0.3 for 1/2 of uterine height. CONCLUSION: CT-based HR CTV contouring based on FIGO stage alone leads to large overestimation of width and volume. Target delineation accuracy can systematically improve through incorporation of additional information from comprehensive 3D documentation of repetitive gynecological examination in the contouring protocol, and thus help to improve the accuracy of dose optimization in settings with limited access to imaging facilities at the time of brachytherapy. If CT information is only available, minimum 2/3 of uterine height may be a good surrogate for the height of HR CTV.

Uncertainty analysis for 3D image-based cervix cancer brachytherapy by repetitive MR imaging: assessment of DVH-variations between two HDR fractions within one applicator insertion and their clinical relevance.

PURPOSE: To investigate dosimetric uncertainties of MRI-based cervix cancer brachytherapy, when applying two HDR fractions for each applicator insertion and their clinical relevance. METHODS: 21 patients with 84 MRI-examinations and fractions were investigated. After insertion of the MRI compatible tandem-ring applicator, an MRI-set was recorded and the treatment plan optimised for the first fraction. Prior to the second fraction 16-20 h later a second MRI-set was recorded, and the dose distribution from the plan of the previous day superimposed and analysed. The same procedure was repeated for fractions 3 and 4. Dose from EBRT and brachytherapy was normalised to 2 Gy-fractionation (EQD2), added up to a total dose, and compared to a calculated total dose if only 1 MRI-examination per insertion is available. RESULTS: The total D(90) for High risk (HR) CTV was 1.2±2.7 Gy(αß10) (1±3%) (mean±1SD) lower by individual MRI-evaluation of each fraction compared to 1 MRI per insertion. The D(2cm(3)) increased by 0.7±4.7 Gy(αß3) (1±6%) for bladder, 1.1±2.4 Gy(αß3) (2±4%) for rectum and decreased by 0.8±3.4 Gy(αß3) (1±5%) for sigmoid. For HR CTV the individual approach did not identify any case with a decrease of D(90) >5 Gy(αß10). For the bladder 3 cases, for the rectum no case and for the sigmoid 1 case was identified with an increase of D(2cm(3)) >5 Gy(αß3). For the bladder all dose variations of more than 5 Gy(αß3) could have been avoided by ensuring a constant bladder filling. Individual MRI-evaluation did not determine any case where dose constraints were not fulfilled. CONCLUSIONS: For the treatment schedule as applied in this study, geometric differences between applicator, target and OAR result in overall dosimetric changes, which seem to be of minor relevance in regard to clinical dose volume constraints applied at present.

Single line source with and without vaginal loading and the impact on target coverage and organ at risk doses for cervix cancer Stages IB, II, and IIIB: treatment planning simulation in patients treated with MRI-guided adaptive brachytherapy in a multicentre study (EMBRACE).

PURPOSE: Three-dimensional evaluation and comparison of target and organs at risk (OARs) doses from two traditional standard source loading patterns in the frame of MRI-guided cervical cancer brachytherapy for various clinical scenarios based on patient data collected in a multicenter trial setting. METHODS AND MATERIALS: Two nonoptimized three-dimensional MRI-based treatment plans, Plan 1 (tandem and vaginal loading) and Plan 2 (tandem loading only), were generated for 134 patients from seven centers participating in the EMBRACE study. Both plans were normalized to point A (Pt. A). Target and OAR doses were evaluated in terms of minimum dose to 90% of the high-risk clinical target volume (HRCTV D90) grouped by tumor stage and minimum dose to the most exposed 2cm³ of the OARs volume. RESULTS: An HRCTV D90 ≥ Pt. A was achieved in 82% and 44% of the patients with Plans 1 and 2, respectively. Median HRCTV D90 with Plans 1 and 2 was 120% and 90% of Pt. A dose, respectively. Both plans had optimal dose coverage in 88% of Stage IB tumors; however, the tandem-only plan resulted in about 50% of dose reduction to the vagina and rectum. For Stages IIB and IIIB, Plan 1 had on average 35% better target coverage but with significant doses to OARs. CONCLUSIONS: Standard tandem loading alone results in good target coverage in most Stage IB tumors without violating OAR dose constraints. For Stage IIB tumors, standard vaginal loading improves the therapeutic window, however needs optimization to fulfill the dose prescription for target and OAR. In Stage IIIB, even optimized vaginal loading often does not fulfill the needs for dose prescription. The significant dose variation across various clinical scenarios for both target and OARs indicates the need for image-guided brachytherapy for optimal dose adaptation both for limited and advanced diseases.

Adaptive image guided brachytherapy for cervical cancer: a combined MRI-/CT-planning technique with MRI only at first fraction.

PURPOSE: To investigate and test the feasibility of adaptive 3D image based BT planning for cervix cancer patients in settings with limited access to MRI, using a combination of MRI for the first BT fraction and planning of subsequent fractions on CT. MATERIAL AND METHODS: For 20 patients treated with EBRT and HDR BT with tandem/ring applicators two sets of treatment plans were compared. Scenario one is based on the "gold standard" with individual MRI-based treatment plans (applicator reconstruction, target contouring and dose optimization) for two BT applications with two fractions each. Scenario two is based on one initial MRI acquisition with an applicator in place for the planning of the two fractions of the first BT application and reuse of the target contour delineated on MRI for subsequent planning of the second application on CT. Transfer of the target from MRI of the first application to the CT of the second one was accomplished by use of an automatic applicator-based image registration procedure. Individual dose optimization of the second BT application was based on the transferred MRI target volume and OAR structures delineated on CT. DVH parameters were calculated for transferred target structures (virtual dose from MRI/CT plan) and CT-based OAR. The quality of the MRI/CT combination method was investigated by evaluating the CT-based dose distributions on MRI-based target and OAR contours of the same application (real dose from MRI/CT plan). RESULTS: The mean difference between the MRI based target volumes (HR CTVMRI2) and the structures transferred from MRI to CT (HR CTVCT2) was -1.7±6.6 cm(3) (-2.9±20.4%) with a median of -0.7 cm(3). The mean difference between the virtual and the real total D90, based on the MRI/CT combination technique was -1.5±4.3 Gy EQD2. This indicates a small systematic underestimation of the real D90. CONCLUSIONS: A combination of MRI for first fraction and subsequent CT based planning is feasible and easy when automatic applicator-based image registration and target transfer are technically available. The results show striking similarity to fully MRI-based planning in cases of small tumours and intracavitary applications, both in terms of HR CTV coverage and respecting of OAR dose limits. For larger tumours and complex applications, as well as situations with unfavourable OAR topography, especially for the sigmoid, MRI based adaptive BT planning remains the superior method.

Histone deacetylase inhibitors in the treatment of hematological malignancies and solid tumors.

The human genome is epigenetically organized through a series of modifications to the histone proteins that interact with the DNA. In cancer, many of the proteins that regulate these modifications can be altered in both function and expression. One example of this is the family of histone deacetylases (HDACs), which as their name implies remove acetyl groups from the histone proteins, allowing for more condensed nucleosomal structure. HDACs have increased expression in cancer and are also believed to promote carcinogenesis through the acetylation and interaction with key transcriptional regulators. Given this, small molecule histone deacetylases inhibitors have been identified and developed, which not only inhibit HDACs, but can also lead to growth arrest, differentiation, and/or apoptosis in tumors both in vitro and in vivo. Here, we will discuss some of the recent developments in clinical trials utilizing HDACs inhibitors for the treatment of both hematological malignancies as well as solid tumors.

R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair.

BACKGROUND: CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor R-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms. RESULTS: We found that R-Roscovitine alone was unable to alter cyclin A1 transcriptional levels, however it was able to reduce protein expression through a proteosome-dependent mechanism. When combined with DNA damaging agents, R-Roscovitine was able to prevent the DNA damage-induced upregulation of cyclin A1 on a transcriptional and post-transcriptional level. This, moreover resulted in a significant decrease in non-homologous end-joining (NHEJ) paired with an increase in DNA DSBs and overall DNA damage over time. Furthermore, microarray analysis demonstrated that R-Roscovitine affected DNA repair mechanisms in a more global fashion. CONCLUSIONS: Our data reveal a new mechanism of action for R-Roscovitine on DNA repair through the inhibition of the molecular switch between cyclin A family members under genotoxic conditions resulting in reduced NHEJ capability.

Male breast cancer.

Male breast cancer (MaleBC) is a rare disease, accounting for <1% of all male tumors. During the last few years, there has been an increase in the incidence of this disease, along with the increase in female breast cancer (FBC). Little is known about the etiology of MaleBC: hormonal, environmental and genetic factors have been reported to be involved in its pathogenesis. Major risk factors include clinical disorders carrying hormonal imbalances, radiation exposure and, in particular, a positive family history (FH) for BC, the latter suggestive of genetic susceptibility. Rare mutations in high-penetrance genes (BRCA1 and BRCA2) confer a high risk of BC development; low-penetrance gene mutations (i.e. CHEK-2) are more common but involve a lower risk increase. About 90% of all male breast tumors have proved to be invasive ductal carcinomas, expressing high levels of hormone receptors with evident therapeutic returns. The most common clinical sign of BC onset in men is a painless palpable retroareolar lump, which should be evaluated by means of mammography, ultrasonography and core biopsy or fine needle aspiration (FNA). To date, there are no published data from prospective randomized trials supporting a specific therapeutic approach in MaleBC. Tumor size together with the number of axillary nodes involved are the main prognostic factors and should guide the treatment choice. Locoregional approaches include surgery and radiotherapy (RT), depending upon the initial clinical presentation. When systemic treatment (adjuvant, neoadjuvant and metastatic) is delivered, the choice between hormonal and or chemotherapy (CT) should depend upon the clinical and biological features, according to the FBC management guidelines. However great caution is required because of high rates of age-related comorbidities.