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The kinetics of γ-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis

Abstract

Background

The aim of the study was to evaluate the changes in γ-H2AX expression in peripheral blood lymphocytes (PBL) according to severity of radiation-induced mucositis.

Patients and method

Fifty patients with head and neck cancer treated with radiotherapy (RT) or chemoradiation were included in the study. Blood samples were collected before treatment to measure baseline γ-H2AX levels. Second sample was taken 45 minutes after the first RT fraction and then once a week, 45 min after irradiation. In patients treated with chemoradiation the blood sample was taken the day after chemotherapy. Mucositis was evaluated once a week and reported according to CTCAE v4 and RTOG/EORTC scales. PBL were analyzed with flow cytometry and level of H2AX phosphorylation at every time point was evaluated.

Results

In 35 patients mild to moderate (grade 1–2) mucositis was observed and 15 patients developed severe (grade 3) mucositis. No cases of grade 4 mucositis were observed. The difference in baseline levels of γ-H2AX between groups with mild and severe mucositis was statistically insignificant (p = 0.25). The statistically significant difference in γ-H2AX level was observed in week 7 of treatment (p = 0.01). No significant differences in γ-H2AX level were found neither between group treated with concomitant chemoradiation or RT alone neither between groups with and without common comorbidities. In the analysis of the kinetics of γ-H2AX during treatment, a statistically significant difference (p = 0.0088) between groups with mild and severe mucositis was observed. After fourth week of treatment levels of γ-H2AX decreased significantly in the group with severe mucositis and increased in patients with mild side effects. The observed difference was not caused by the decrease in peripheral lymphocyte count, which was similar in both groups.

Conclusions

Presented results indicate that severity of radiation-induced mucositis does not correlate directly with γ-H2AX levels measured in vivo in PBL. Prediction of mucositis grade based on γ-H2AX level is not yet possible, either before treatment or early during treatment, but preliminary results, indicating significant differences in γ-H2AX kinetics between groups, encourage further studies.

Open access
Molecular heterogeneity in breast carcinoma cells with increased invasive capacities

Abstract

Background

Metastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes.

Materials and methods

In order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach.

Results

Independently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells.

Conclusions

We can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.

Open access
Percutaneous mechanical thrombectomy in patients with high-risk pulmonary embolism and contraindications for thrombolytic therapy

Abstract

Background

High-risk pulmonary embolism is associated with a high early mortality rate. We report our experience with percutaneous mechanical thrombectomy in patients with high-risk pulmonary embolism and contraindications for thrombolytic therapy.

Patients and methods

This was a retrospective analysis of consecutive patients with high-risk pulmonary embolism and contraindications to thrombolytic therapy. They were treated with percutaneous mechanical thrombectomy which included thrombectomy and additional thrombus aspiration when needed. Clinical parameters and survival to discharge were measured.

Results

From November 2005 to September 2015 we treated 25 patients with a mean age of 62.6 ± 12.7 years, 64% were men. Mean simplified Pulmonary Embolism Severity Index was 2.9. Mean maximum lactate levels were 7.8 ± 6.6 mmol/L, vasopressors were used in 77%, and 59% needed mechanical ventilation. Mechanical treatment included thrombus fragmentation complemented with aspiration (56%) and aspiration using Aspirex®S catheter (44%). Local (5 patients; 20%) and systemic (3 patients; 12%) thrombolytics were used as a salvage therapy. We observed nonsignificant improvements in systemic blood pressure (100 ± 41 mm Hg vs 119 ± 34; p = 0.100) and heart frequency (99 ± 35 min-1 vs 87 ± 31 min-1; p = 0.326) before and after treatment, respectively. Peak systolic tricuspid pressure gradient was significantly lower after treatment (57 ± 14 mm Hg vs 31 ± 3 mm Hg; p = 0.018). Overall the procedure was technically successful in 20 patients (80%) and 17 patients (68%) survived to hospital discharge.

Conclusions

In patients with high-risk pulmonary embolism who cannot receive thrombolytic therapy, percutaneous mechanical thrombectomy is a promising alternative to reduce pulmonary artery pressure.

Open access
Safety margin assessment after microwave ablation of liver tumors: inter- and intrareader variability

Abstract

Background

The aim of the study was to evaluate the inter- and intrareader variability of the safety margin assessment after microwave ablation of liver tumors using post-procedure computed tomography (CT) images as well as to determine the sensitivity and specificity of identification remnant tumor tissue.

Patients and methods

A retrospective analysis of 58 patients who underwent microwave ablation (MWA) of primary or secondary liver malignancies (46 hepatocellular carcinoma, 9 metastases of a colorectal cancer and 3 metastases of pancreatic cancer) between September 2017 and June 2019 was conducted. Three readers estimated the minimal safety margin in millimeters using side-by-side comparison of the 1-day pre-ablation CT and 1-day post-ablation CT and judged whether ablation was complete or incomplete. One reader estimated the safety margin again after 6 weeks. Magnetic resonance imaging (MRI) after 6 weeks was the gold standard.

Results

The intraclass correlation coefficient (ICC) for estimation of the minimal safety margin of all three readers was 0.357 (95%-confidence interval 0.194–0.522). The ICC for repeated assessment (reader 1) was 0.774 (95%-confidence interval 0.645–0.860). Sensitivity and specificity of the detection of complete tumor ablation, defined as no remnant tumor tissue in 6 weeks follow-up MRI, were 93%/82%/82% and 33%/17%/83%, respectively.

Conclusions

In clinical practice, the safety margin after liver tumor ablation is often assessed using side-by-side comparison of CT images. In the study, we were able to show, that this technique has a poor reliability (ICC 0.357). From our point of view, this proves the necessity of new technical procedures for the assessment of the safety distance.

Open access
Sequential intra-arterial infusion of 90Y-resin microspheres and mitomycin C in chemo refractory liver metastatic breast cancer patients: a single centre pilot study

Abstract

Background

The aim of the study was to evaluate the safety and feasibility of intra-arterial mitomycin C (MMC) infusion after selective internal radiation therapy (SIRT) using Yttrium-90 (90Y) resin microspheres in liver metastatic breast cancer (LMBC) patients.

Patients and methods

The prospective pilot study included LMBC patients from 2012–2018. Patients first received infusion of 90Y resin microspheres, after 6–8 weeks response to treatment was assessed by MRI, 18F-FDG PET/CT and laboratory tests. After exclusion of progressive disease, MMC infusion was administrated 8 weeks later in different dose cohorts; A: 6 mg in 1 cycle, B: 12 mg in 2 cycles, C: 24 mg in 2 cycles and D: maximum of 72 mg in 6 cycles. In cohort D the response was evaluated after every 2 cycles and continued after exclusion of progressive disease. Adverse events (AE) were reported according to CTCAE version 5.0.

Results

Sixteen patients received 90Y treatment. Four patients were excluded for MMC infusion, because of extra hepatic disease progression (n = 3) and clinical and biochemical instability (n = 1). That resulted in the following number of patient per cohort; A: 2, B: 1, C: 3 and D: 6. In 4 of the 12 patients (all cohort D) the maximum dose of MMC was adjusted due biochemical toxicities (n = 2) and progressive disease (n = 2). One grade 3 AE occurred after 90Y treatment consisting of a gastrointestinal ulcer whereby prolonged hospitalization was needed.

Conclusions

Sequential treatment of intra-arterial infusion of MMC after 90Y SIRT was feasible in 75% of the patients when MMC was administrated in different escalating dose cohorts. However, caution is needed to prevent reflux after 90Y SIRT in LMBC patients.

Open access
Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab – real-world experience

Abstract

Background

Based on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question remains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials.

Patients and methods

This observational retrospective cohort study included 138 consecutive metastatic treatment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019.

Results

The estimated median overall survival (OS) was 25.1 months (95% CI, 14.6–35.6) and the median progression-free survival (PFS) was 10.7 months (95% CI, 5.9–15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3–4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment.

Conclusions

Our real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients.

Open access
Three-dimensional MRI evaluation of the effect of bladder volume on prostate translocation and distortion

Abstract

Background

The accuracy of any radiation therapy delivery is limited by target organ translocation and distortion. Bladder filling is one of the recognised factors affecting prostate translocation and distortion. The purpose of our study was to evaluate the effect of bladder volume on prostate translocation and distortion by using detailed three-dimensional prostate delineation on MRI.

Patients and methods

Fifteen healthy male volunteers were recruited in this prospective, institutional review board-approved study. Each volunteer underwent 4 different drinking preparations prior to imaging, with MR images acquired pre- and post-void. MR images were co-registered by using bony landmarks and three-dimensional contouring was performed in order to assess the degree of prostate translocation and distortion. According to changes in bladder or rectum distention, subdivisions were made into bladder and rectal groups. Studies with concomitant change in both bladder and rectal volume were excluded.

Results

Forty studies were included in the bladder volume study group and 8 in the rectal volume study group. The differences in rectal volumes yielded higher levels of translocation (p < 0.01) and distortion (p = 0.02) than differences in bladder volume. Moderate correlation of prostate translocation with bladder filling was shown (r = 0.64, p < 0.01). There was no important prostate translocation when bladder volume change was < 2-fold (p < 0.01). Moderate correlation of prostate distortion with bladder filling was shown (r = 0.61, p < 0.01).

Conclusions

Bladder volume has a minimal effect on prostate translocation and effect on prostate distortion is negligible. Prostate translocation may be minimalised if there is < 2-fold increase in the bladder volume.

Open access
Scintigraphic load of bone disease evaluated by DASciS software as a survival predictor in metastatic castration-resistant prostate cancer patients candidates to 223RaCl treatment

Abstract

Background

Aim of our study was to assess the load of bone disease at starting and during Ra-223 treatment as an overall survival (OS) predictor in metastatic castration-resistant prostate cancer (mCRPC) patients. Bone scan index (BSI) is defined as the percentage of total amount of bone metastasis on whole-body scintigraphic images. We present a specific software (DASciS) developed by an engineering team of “Sapienza” University of Rome for BSI calculation.

Patients and methods

127 mCRPC patients bone scan images were processed with DASciS software, and BSI was tested as OS predictor.

Results

546 bone scans were analyzed revealing that the extension of disease is a predictor of OS (0–3% = 28 months of median survival (MoMS]; 3%–5% = 11 MoMS, > 5% = 5 MoMS). BSI has been analyzed as a single parameter for OS, determining an 88% AUC. Moreover, the composition between the BSI and the 3-PS (3-variable prognostic score) determines a remarkable improvement of the AUC (91%), defining these two parameters as the best OS predictors.

Conclusions

This study suggests that OS is inversely correlated with the load of bone disease in mCRPC Ra-223-treated subjects. DASciS software appears a promising tool in identifying mCRPC patients that more likely take advantage from Ra-223 treatment. BSI is proposed as a predictive variable for OS and included to a multidimensional clinical evaluation permits to approach the patients’ enrollment in a rational way, allowing to enhance the treatment effectiveness together with cost optimization.

Open access
Budget Impact of Intravenous Iron Therapy with Ferric Carboxymaltose in Patients with Chronic Heart Failure and Iron Deficiency in Romania

Abstract

Background: Ferric carboxymaltose (FCM) treatment in case of iron deficient (ID) patients with chronic heart failure (CHF) has shown great promise according to the findings of recent studies in improvement of symptoms and quality of life, New York Heart Association (NYHA) classification, and exercise capacity.

Aim of the study: The purpose of the current study is to assess the budget impact of treating CHF patients with FCM in a sample of Romanian hospitals.

Material and methods: Calculations have been based on the budget impact model developed by Theidel et al. The assumptions and clinical outcomes of the current study were based on a multivariate statistical approach used in the same German study. The predicted outcomes were based on data pooled from four double-blind randomized controlled trials. The time horizon of the model was 1 year. Budget impact calculations were performed from the public payer perspective. Two scenarios have been handled: one without applying the Clawback tax and one with applying the tax to the cost of medication.

Results: The yearly budget impact of FCM vs. no iron-replacement treatment without applying the tax ranged between €678,383 and €641,588 for 1,000 patients, resulting in €37 of additional costs per patient per year. The yearly budget impact of FCM vs. no iron-replacement treatment with applying the tax ranged between €616,934 and €641,588 for 1,000 patients, resulting in €9 of cost reduction per patient per year. Key cost drivers included the cost of outpatient visits and the cost of hospitalization due to HF worsening. Sensitivity analysis for both scenarios proved the robustness of the results.

Conclusions: The FCM treatment of CHF patients has a moderate budget impact. Moreover, this budget impact/saving translates into a reduction of the rate and length of hospitalization stay and a better symptomatic profile of the patients.

Open access