Prevention and Treatment of Bone Metastases in Breast Cancer

In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach

Prevention and Treatment of Bone Metastases in Breast Cancer

In breast cancer patients, bone is the most common site of metastases. Medical therapies are the basic therapy to prevent distant metastases and recurrence and to cure them. Radiotherapy has a primary role in pain relief, recalcification and stabilization of the bone, as well as the reduction of the risk of complications (e.g., bone fractures, spinal cord compression). Bisphosphonates, as potent inhibitors of osteoclastic-mediated bone resorption are a well-established, standard-of-care treatment option to reduce the frequency, severity and time of onset of the skeletal related events in breast cancer patients with bone metastases. Moreover bisphosphonates prevent cancer treatment-induced bone loss. Recent data shows the anti-tumor activity of bisphosphonates, in particular, in postmenopausal women and in older premenopausal women with hormone-sensitive disease treated with ovarian suppression. Pain is the most frequent symptom reported in patients with bone metastases, and its prevention and treatment must be considered at any stage of the disease. The prevention and treatment of bone metastases in breast cancer must consider an integrated multidisciplinary approach

Correction: Ripamonti, C.; Trippa, F.; Barone, G.; Maranzano, E. Prevention and Treatment of Bone Metastases in Breast Cancer. J. Clin. Med. 2013, 2, 151–175

The authors wish to make the following corrections to this paper [1]: The authors’ names: [...

An Italian survey on “palliative intent” radiotherapy

Background: The aim of this paper is to provide a comprehensive overview of the scenario on radiotherapy (RT) delivered with palliative intent in Italy. Materials and methods: A structured online questionnaire was submitted to Italian radiation oncologists in order to explore the clinical practice in different areas of palliation, namely: bone, lung, brain, liver, and emergencies suitable to RT. Results: 209 radiation oncologists took part in the study. Stereotactic body irradiation was found to be the preferred technique in lung and liver metastases, whereas 3D conformal RT was registered as the technique of choice for bone and brain metastases. The majority (98%) of participants stated to treat mainly radiotherapy emergencies with 3D conformal RT at doses ranging from 25 to 50Gy. Re-irradiation is delivered by the majority of respondents, whereas post-treatment follow-up is done only by 51.4% of them. Conclusions: This nationwide study highlights some heterogeneity among Italian radiation oncologists regarding treatment and follow-up of metastatic cancer patients

Re-irradiation of brain metastases and metastatic spinal cord compression: clinical practice suggestions

The recent improvements of therapeutic approaches in oncology have allowed a certain number of patients with advanced disease to survive much longer than in the past. So, the number of cases with brain metastases and metastatic spinal cord compression has increased, as has the possibility of developing a recurrence in areas of the central nervous system already treated with radiotherapy.Clinicians are reluctant to perform re-irradiation of the brain, because of the risk of severe side effects. The tolerance dose for the brain to a single course of radiotherapy is 50-60 Gy in 2 Gy daily fractions. New metastases appear in 22-73% of the cases after whole brain radiotherapy, but the percentage of re-irradiated patients is 3-10%. An accurate selection must be made before giving an indication to re-irradiation. Patients with Karnofsky performance status >70, age <65 years, controlled primary and no extracranial metastases are those with the best prognosis. The absence of extracranial disease was the most significant factor in conditioning survival, and maximum tumor diameter was the only variable associated with an increased risk of unacceptable acute and/or chronic neurotoxicity. Re-treatment of brain metastases can be done with whole brain radiotherapy, stereotactic radiosurgery or fractionated stereotactic radiotherapy. Most patients had no relevant radiation-induced toxicity after a second course of whole brain radiotherapy or stereotactic radiosurgery. There are few data on fractionated stereotactic radiotherapy in the re-irradiation of brain metastases.In general, the incidence of an "in-field" recurrence of spinal metastasis varies from 2.5-11% of cases and can occur 2-40 months after the first radiotherapy cycle. Radiation-induced myelopathy can occur months or years (6 months-7 years) after radiotherapy, and the pathogenesis remains obscure. Higher radiotherapy doses, larger doses per fraction, and previous exposure to radiation could be associated with a higher probability of developing radiation-induced myelopathy. Experimental data indicate that also the total dose of the first and second radiotherapy, interval to re-treatment length of the irradiated spinal cord, and age of the treated animals influence the risk of radiation-induced myelopathy. An alpha/beta ratio of 1.9-3 Gy could be generally the reference value for fractionated radiotherapy. However, when fraction sizes are up to 5 Gy, the linear-quadratic equation become a less valid model. The early diagnosis of relapse is crucial in conditioning response to re-treatment

Apical Medium Flow Influences the Morphology and Physiology of Human Proximal Tubular Cells in a Microphysiological System

There is a lack of physiologically relevant in vitro human kidney models for disease modelling and detecting drug-induced effects given the limited choice of cells and difficulty implementing quasi-physiological culture conditions. We investigated the influence of fluid shear stress on primary human renal proximal tubule epithelial cells (RPTECs) cultured in the micro-physiological Vitrofluid device. This system houses cells seeded on semipermeable membranes and can be connected to a regulable pump that enables controlled, unidirectional flow. After 7 days in culture, RPTECs maintained physiological characteristics such as barrier integrity, protein uptake ability, and expression of specific transporters (e.g., aquaporin-1). Exposure to constant apical side flow did not cause cytotoxicity, cell detachment, or intracellular reactive oxygen species accumulation. However, unidirectional flow profoundly affected cell morphology and led to primary cilia lengthening and alignment in the flow direction. The dynamic conditions also reduced cell proliferation, altered plasma membrane leakiness, increased cytokine secretion, and repressed histone deacetylase 6 and kidney injury molecule 1 expression. Cells under flow also remained susceptible to colistin-induced toxicity. Collectively, the results suggest that dynamic culture conditions in the Vitrofluid system promote a more differentiated phenotype in primary human RPTECs and represent an improved in vitro kidney model

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

International audienceCandida albicans is an important human pathogen and a major concern in intensive care units around the world. C. albicans infections are associated with a high mortality despite the use of antifungal treatments. One of the causes of therapeutic failures is the acquisition of antifungal resistance by mutations in the C. albicans genome. Fluconazole (FLC) is one of the most widely used antifungal and mechanisms of FLC resistance occurring by mutations have been extensively investigated. However, some clinical isolates are known to be able to survive at high FLC concentrations without acquiring resistance mutations, a phenotype known as tolerance. Mechanisms behind FLC tolerance are not well studied, mainly due to the lack of a proper way to identify and quantify tolerance in clinical isolates. We proposed here culture conditions to investigate FLC tolerance as well as an easy and efficient method to identity and quantify tolerance to FLC. The screening of C. albicans strain collections revealed that FLC tolerance is pH- and strain-dependent, suggesting the involvement of multiple mechanisms. Here, we addressed the identification of FLC tolerance mediators in C. albicans by an overexpression strategy focusing on 572 C. albicans genes. This strategy led to the identification of two transcription factors, CRZ1 and GZF3. CRZ1 is a C2H2-type transcription factor that is part of the calcineurin-dependent pathway in C. albicans, while GZF3 is a GATA-type transcription factor of unknown function in C. albicans. Overexpression of each gene resulted in an increase of FLC tolerance, however, only the deletion of CRZ1 in clinical FLC-tolerant strains consistently decreased their FLC tolerance. Transcription profiling of clinical isolates with variable levels of FLC tolerance confirmed a calcineurin-dependent signature in these isolates when exposed to FLC

Hypofractionated radiotherapy for complicated bone metastases in patients with poor performance status: a phase II international trial

Purpose: To evaluate the efficacy and safety of hypofractionated radiotherapy (16 Gy in 2 fractions, 1 week apart) in patients with complicated bone metastases and poor performance status.Methods: A prospective single-arm phase II clinical trial was conducted from July 2014 to May 2016. The primary endpoint was pain response as defined in the International Consensus on Palliative Radiotherapy Endpoints. Secondary endpoints included quality of life as measured by quality of life questionnaire (QLQ) PAL-15 and QLQ-BM22 European Organisation for Research and Treatment of Cancer guidelines, pain flare, adverse events, re-irradiation, and skeletal complications.Results: Fifty patients were enrolled. There were 23 men with a median age of 58 years (range 26-86). Of the 50 patients, 38 had an extraosseous soft tissue component, 18 needed postsurgical radiation, 3 had neuropathic pain, and 3 had an impending fracture in a weight-bearing bone. At 2 months, 33 patients were alive (66%). Four (12.5%) had a complete response and 12 (37.5%) had a partial response. A statistically significant improvement was seen in the functional interference (p = 0.01) and psychosocial aspects (p = 0.03) of the BM22. No patient had spinal cord compression. One patient required surgery for pathologic fracture, and another re-irradiation.Conclusions: Hypofractionated radiotherapy (16 Gy in 2 fractions of 8 Gy 1 week apart) achieved satisfactory pain relief and safety results in patients with complicated bone metastases and poor performance status