Carlotta Becherini

A PPAR gamma agonist protects against oral mucositis induced by irradiation in a murine model

BACKGROUND Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis. MATERIAL AND METHODS Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy. RESULTS Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12-15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfα, Il-6 and Il-1β gene expression. Rosiglitazone controlled the increase of TGF-β and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation. CONCLUSION Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer.

SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab

Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient’s approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.

Radiotherapy in the age of cancer immunology: Current concepts and future developments

Major advances in the knowledge of cancer biology and its interactions with tumor immune environment led to the emergence, in the last five years of new immunotherapy-based treatment strategies in cancer patients. At the same time, improvement in radiation technique and progress in radiobiology allowed in the last decade to expand the applications of radiotherapy in a growing number of settings. At present, there are strong theoretical basis to propose immune-enhanced radiation therapy that may represent in the future a new paradigm of treatment, combining the intrinsic power of radiotherapy to elicit a specific, systemic, tumor-directed immune response with modern highly conformal and precise dose delivery, in order to maximize response at the major site of disease and obtain durable disease control. The aim of this review is to describe the principal mechanisms of immune modulation of response to radiation and investigational strategies to harness the potential of radiation-inducible immune response: radiation therapy is expected to be not just a local treatment but the cornerstone of a multimodal strategy that might achieve long-lasting tumor remission at the primary site and systemic efficacy metastatic lesions.

Core needle biopsy for the assessment of unilateral male breast lesions

The importance of preoperative histological diagnosis in the assessment of breast lesions in women is widely established, but in men with breast lesions histological diagnosis is obtained in a limited number of cases. The aim of this study was to report our single-center experience in a large series of 131 CNB performed for suspicious male breast lesions. Our data confirmed that CNB is an effective method in distinguishing between benign and neoplastic lesions in the male breast, thus validating the few published data. CNB should be a routine part of the unilateral male breast swelling diagnostic assessment, being precious tool for the clinicians for surgery planning or avoidance.

Safety of concurrent adjuvant radiotherapy and chemotherapy for locally advanced soft tissue sarcoma

Introduction: This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). Methods: A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Results: Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2–21.1 years). Local DFS–recurrence-free survival, distant DFS–relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28–72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81–12.58, p = .002 and HR 4.83, CI 1.41–16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02–4.87, p = .045; HR 2.88, 95% CI 1.10–7.52, p = .031; HR 2.59, 95% CI 1.11–6.04, p = .028). Conclusions: Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Stereotactic body radiation therapy (SBRT) on renal cell carcinoma, an overview of technical aspects, biological rationale and current literature

BACKGROUND Stereotactic body radiotherapy (SBRT) is characterized by the delivery of high doses of ionizing radiation in few fractions. It is highly effective in achieving local control, and, due to the high biological effective dose administered, it seems to overcome the radioresistance of renal cell carcinoma (RCC). Thus, SBRT could constitute a treatment option for the management of localized RCC in patients who are not surgical candidates. In this paper, we report an overview about data from the current evidence about SBRT in patients affected by localized RCC. MATERIALS AND METHODS A non-systematic review was performed, including data from both retrospective and prospective studies focusing on the use of SBRT for localized RCC and its biological rationale. Furthermore, ongoing trials on this issue are reported. CONCLUSION Currently, SBRT might be considered a treatment alternative in inoperable patients affected by primary RCC. Currently, dose-escalation to 48 Gy in 3-4 fractions are effective and well tolerated. Emerging role of immune therapies in RCC patients warrant further studies to explore interactions between SBRT and immune response.

Partial breast irradiation for ductal carcinoma in situ: The Goldilocks principle?

The outcome of patients treated with breast‐conserving surgery affected by ductal carcinoma in situ (DCIS) has considerably improved thanks to better imaging, clinical‐pathologic correlation, surgical localization, and attention to margins, postoperative radiation therapy (RT) and, to a lesser extent, by adjuvant endocrine treatments. Due to the potential adverse events related to these interventions, de‐escalation attempts were undertaken for postoperative RT and, and more recently, surgical approaches without affecting survival. Even though low‐risk DCIS has been often considered as an indolent disease for which any treatment might be redundant, a significant increase in long‐term mortality in case of an invasive breast tumor recurrence (BTR) was demonstrated. RT has been the mainstay treatment for DCIS after breast conservative surgery. Updates of recently published studies confirmed the long‐term benefit of RT in terms of local recurrence, without reaching a plateau over time. Therefore, the omission of postoperative RT could represent a dangerous approach, caused by the systematic underestimation of its benefit. At a median follow‐up of 7.2 years, RTOG 9804 trial showed a BTR risk of 6.7% in the observation arm compared to 0.9% in the whole breast irradiation arm. Similar results were observed in the ECOG 5194 trial among patients meeting similar very low‐risk criteria, with the observation arm yielding a 6.1% and 14.4% risk of BTR at 6.7 and 12 years median follow‐up, respectively. Partial breast irradiation (PBI) is a safe and effective treatment able to obtain an equivalent control rate in selected low risk invasive breast cancer patients. For a long time, its effectiveness for DCIS has been debated, due to limited and conflicting published results and the intrinsic biologic nature of the disease with a persistent higher recurrence risk after breast conservation compared to its invasive counterpart. Therefore, up to now, PBI has not been considered recommended for DCIS according to both the American (ASTRO) and the European (GEC‐ESTRO) radiation oncology societies’ recommendations. However, when applying ECOG 5194 inclusion criteria to publish PBI series, a 5‐year BTR risk of far below 4% was found. Therefore, this acceptable observed rate of BTR in low‐risk DCIS treated with wide local excision alone, combined with the encouraging results following PBI for this selected group of patients, led the ASTRO PBI task force to include these patients in the suitable group (screen‐detected, low to intermediate nuclear grade, ≤2.5 cm size, with margins negative at ≥3 mm). In view of the persisting lack of knowledge about biologic features and response to treatment, a thorough discussion with the patient on the benefits and the limitations of each treatment option should be held, emphasizing all possible implications of the different approaches. Even though data from randomized trials on PBI versus whole breast irradiation including DCIS patients are largely pending, and the follow‐up time of the published results is too short to draw any definitive conclusions, we feel that PBI could present a reasonable compromise to reach the equilibrium between over‐treatment by whole breast RT and under‐treatment due to omission of RT for low‐risk DCIS patients. Since there will likely be no time for specific phase 3 trials designed for combining DCIS and PBI in this era of de‐escalation of treatments for breast cancer patients, and pending results of studies to mature, a joint initiative for a pooled analysis of available data from existing randomized trials is strongly encouraged.

Complete response in metastatic renal cell carcinoma after radiotherapy and everolimus: a clinical case and review of the literature

We report the case of a man affected by renal cell carcinoma with vertebral metastases, who presented a radiological complete response after systemic treatment with everolimus.