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BackgroundPreclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer.Methods and findingsThis prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial.ConclusionsMRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials.Trial registrationclinicaltrials.gov, identifier NCT04431674.

Abstract Preclinical studies have demonstrated focused ultrasound (FUS) stimulated microbubble (MB) rupture leads to the activation of acid sphingomyelinase-ceramide pathway in the endothelial cells. When radiotherapy (RT) is delivered concurrently with FUS-MB, apoptotic pathway leads to increased cell death resulting in potent radiosensitization. Here we report the first human trial of using magnetic resonance imaging (MRI) guided FUS-MB treatment in the treatment of breast malignancies. In the phase 1 prospective interventional study, patients with breast cancer were treated with fractionated RT (5 or 10 fractions) to the disease involving breast or chest wall. FUS-MB treatment was delivered before 1st and 5th fractions of RT (within 1 h). Eight patients with 9 tumours were treated. All 7 evaluable patients with at least 3 months follow-up treated for 8 tumours had a complete response in the treated site. The maximum acute toxicity observed was grade 2 dermatitis in 1 site, and grade 1 in 8 treated sites, at one month post RT, which recovered at 3 months. No RT-related late effect or FUS-MB related toxicity was noted. This study demonstrated safety of combined FUS-MB and RT treatment. Promising response rates suggest potential strong radiosensitization effects of the investigational modality. Trial registration: clinicaltrials.gov, identifier NCT04431674.

Summary: Background: Developing strategies to prevent breast cancer-related arm lymphoedema (BCRAL) is a critical unmet need because there are no effective interventions to eradicate it once it reaches a chronic state. Certain strategies such as prospective surveillance programs and prophylactic lymphatic reconstruction have been reported to be effective in clinical trials. However, a large variation exists in practice based on clinician preference, organizational standards, and local resources. Methods: A two-round international Delphi consensus process was performed from February 27, 2023 to May 25, 2023 to compile opinions of 55 experts involved in the care and research of breast cancer and lymphoedema on such interventions. Findings: Axillary lymph node dissection, use of post-operative radiotherapy, relative within-arm volume increase one month after surgery, greater number of lymph nodes dissected, and high body mass index were recommended as the most important risk factors to guide selection of patients for interventions to prevent BCRAL. The panel recommended that prospective surveillance programs should be implemented to screen for and reduce risks of BCRAL where feasible and resources allow. Prophylactic compression sleeves, axillary reverse mapping and prophylactic lymphatic reconstruction should be offered for patients who are at risk for developing BCRAL as options where expertise is available and resources allow. Recommendations on axillary management in clinical T1–2, node negative breast cancer patients with 1–2 positive sentinel lymph nodes were also provided by the expert panel. Routine axillary lymph node dissection should not be offered in these patients who receive breast conservation therapy. Axillary radiation instead of axillary lymph node dissection should be considered in the same group of patients undergoing mastectomy. Interpretation: An individualised approach based on patients' preferences, risk factors for BCRAL, availability of treatment options and expertise of the healthcare team is paramount to ensure patients at risk receive preventive interventions for BCRAL, regardless of where they are receiving care. Funding: This study was not supported by any funding. RJC received investigator grant support from the Australian National Health and Medical Research Council (APP1194051).

BackgroundThe acceleration of population aging calls for simple and effective interventions catered for older people. Gerontechnology, the combination of gerontology and technology, can promote quality of life in older adults. However, public health-related events incorporating information communication technology (ICT) for older people have seldom been evaluated.ObjectiveWe reported the development and evaluation of two simple and brief digital health promotion games hosted at the annual Hong Kong Gerontech and Innovation Expo cum Summit (GIES) in 2018 and 2019 to promote well-being.MethodsTwo game booths (Dinosaur Augmented Reality photo-taking in 2018, Sit-and-Stand fitness challenge in 2019) were designed by our interdisciplinary team. Four gaming technologies were employed: augmented reality, chroma key (green screen), motion detection and 3D modeling. Immediately after the game, we administered a brief questionnaire survey to assess participant satisfaction, happiness and perceived benefits, and collected qualitative data through observations and informal interviews.ResultsMajority of 1,186 and 729 game booth participants in 2018 and 2019, respectively, were female (73.4% and 64.7%) and older adults (65.5 and 65.2%). Overall satisfaction toward the game booths was high (4.64 ± 0.60 and 4.54 ± 0.68 out of 5), with females and older adults reporting higher scores. Average personal and family happiness of participants in 2018 were 8.2 and 8.0 (out of 10). 90.3 and 18.4% of participants in 2019 chose one or more personal (e.g. enhance healthy living habits 62.4%, enhance personal happiness 61.6%) and family (e.g. enhance family happiness 15.6%, improve family relationships 10.8%) benefits of the game booth, respectively. Participants showed enthusiasm toward the technologies, and pride in their physical abilities in the fitness challenge.ConclusionOur report on the development and evaluation of brief game interventions with ICT showed high satisfaction and immediate perceived benefits in community participants. Females and older adults reported higher satisfaction. Simple tools measuring happiness and perceived benefits showed positive results. Older adults were receptive and enthusiastic about the new technologies. Our findings can inform researchers and organizers of similar events. More research on simple and enjoyable ICT interventions is needed to attract older adults and promote their well-being.Trial registrationThe research protocol was registered at the National Institutes of Health (Identifier number: NCT03960372) on May 23, 2019.

Radiation dermatitis is a common adverse effect of radiotherapy (RT) in breast cancer patients. Although radiation dermatitis is reported by either the clinician or the patient, previous studies have shown disagreement between clinician-reported outcomes (CROs) and patient-reported outcomes (PROs). This review evaluated the extent of discordance between CROs and PROs for radiation dermatitis. Studies reporting both clinician and patient-reported outcomes for external beam RT were eligible. Nine studies met the inclusion criteria for the systematic review, while 8 of these studies were eligible for inclusion in a meta-analysis of acute and late skin toxicities. We found an overall agreement between CROs and PROs of acute skin colour change, fibrosis and/or retraction, and moist desquamation (p > 0.005). Reporting of late breast pain, breast edema, skin colour change, telangiectasia, fibrosis and/or retraction and induration/fibrosis alone (p > 0.005) were also in agreement between clinicians and patients. Our meta-analysis revealed a greater reporting of acute breast pain by patients (RR = 0.89, 95% CI 0.87–0.92, p

Purpose: Radiation dermatitis (RD) is a side effect that frequently arises during radiotherapy (RT) in breast cancer patients. The present study investigates possible predictive factors of RD, as well as the use of skin treatments to manage symptoms. Methods: Demographic and treatment characteristics were collected retrospectively, while skin symptoms and treatments were collected prospectively for patients who received adjuvant RT between December 2013 and November 2015. Patients were seen weekly by clinicians throughout treatment, during which a clinician-reported survey was completed on RD symptoms and skin treatments. Possible predictive factors were correlated with skin outcomes through a univariate ordinal logistic regression analysis. Results: A total of 1093 patients were included in this analysis. Predictive factors for erythema included dose fractionation (p

Purpose: Pathological metastatic fractures in lower-extremity weight bearing bones often require surgical reconstruction. Post-operative radiation is routinely recommended following surgical reconstruction. This study evaluated the clinical outcomes of patients that undergo surgical fixation of an established or an impending pathologic lower extremity fracture without post-operative radiation. Materials and methods: A retrospective chart review of patients at Sunnybrook Health Sciences Center between 2007 and 2019 was performed. Descriptive statistical analyses were performed. Results: A total of 161 surgical reconstruction procedures were identified. Among these cases, 86/161 (53.4%) received post-operative radiation, 75/161 (47%) did not receive post-operative radiation within 12 weeks of their index surgery. Of the 75 patients not receiving post-operative radiation, 40 patients had prior radiation to the surgical site and 35 patients were radiation naïve. 5 patients (6.7%) required a second operation to the index surgical site, with 4 patients (5.3%) requiring a second fixation surgery to stabilize hardware at a median of 6.0 months post-surgery. Post-surgical radiation to the surgical site (at >12 weeks) was administered to 12 patients (16.0%) at a median of 9.1 months post-surgery. Conclusions: The surgical revision rate was low despite absence of immediate post-operative radiation therapy and was similar to prior reports in patients receiving post-operative radiation.

Background: The influence of cigarette smoking on cancer risk has been well-studied. Similarly, exposure to ionizing radiation from radiotherapy (RT) can produce detrimental effects on an individual's health. In patients administered RT, there has been an observed relationship in other primary carcinomas. The purpose of this systematic review was to summarize the influence of cigarette smoking on outcomes post adjuvant RT in breast cancer patients. Methods: OVID Medline, Cochrane and Embase were searched and 1893 articles were identified. A total of 71 articles were included in the review. Study type, published year and sample size, age, systemic therapies, RT techniques and treatment side effects were collected if available. Results: The review found 198 different outcomes which fell into 7 categories and similar outcomes were recorded. 40% of skin reaction outcomes, 50% of cardiovascular outcomes, 71% of reconstruction outcomes, 29% of pulmonary function outcomes, 33% of mortality outcomes and 42% of secondary recurrence outcomes reported significant differences between smokers and non-smokers. None of the articles reported non-smokers to have a higher risk than smokers. Conclusion: Cigarette smoking can pose a higher risk of post-treatment complications that can influence an individual's quality of life, survival rate and/or recurrence risk. This review further assessed the impact of smoking on various patient outcomes and side-effects in the adjuvant breast RT setting. The information provided in this review suggest that smoking cessation programs would help educate patients to understand their risks of being a current or former smoker when undergoing RT.

Introduction: Microglandular adenosis (MGA) is a rare benign proliferative lesion lacking a myoepithelial cell layer; 27% of all reported cases have progressed to invasive carcinoma. Salivary gland-type carcinomas of the breast are also uncommon, representing 2% of all breast cancers. This wide spectrum of neoplasms tends to be triple negative and generally has an excellent prognosis. Given the rarity of salivary gland-type carcinomas of the breast arising from MGA, there are few reports of these cases in literature. As such, there is uncertainty regarding their diagnosis and treatment strategies. Presentation of case: We report the rare case of a 66-year-old woman who presented with a triple negative, invasive carcinoma with salivary gland-type features, arising from MGA. The patient underwent mastectomy with sentinel lymph node biopsy, followed by Taxotere and Cyclophosphamide (TC) chemotherapy and 50 Gy in 25 fractions of radiation to her chest wall. We reviewed the available literature on salivary gland-type breast carcinomas arising from MGA. Discussion: Despite the generally unfavourable characteristics associated with carcinoma arising in microglandular adenosis (MGACA), most patients with MGACA have favourable outcomes. Conclusions: The findings of the present case and reviewed cases are consistent with the literature on MGA, atypical MGA (AMGA), and MGACA. Future study of this rare entity is warranted to establish a consensus surrounding its clinical significance and treatment methods.

Background and purpose: Antiemetic guidelines suggest daily prophylaxis with a serotonin3 receptor antagonist (5-HT3RA) as an option for patients receiving long-course neoadjuvant radiation therapy and concurrent 5-fluorouracil-based chemotherapy for rectal cancer, despite the risks that 5-HT3RA-induced constipation may pose. We explored the incidence of patient-reported vomiting, retching, nausea and antiemetic intake among patients in this setting to determine if these risks are justified. Materials and methods: We carried out a single-centre non-randomised prospective cohort study of adult patients receiving long-course neoadjuvant radiation therapy and concurrent 5-fluorouracil-based chemotherapy for rectal adenocarcinoma. Patients recorded symptoms and medication intake daily until 7 days following treatment completion. Results: From 33 evaluable patients, we collected 1407 days of patient-reported data. Vomiting was reported by 7 patients (21%), retching by 5(15%) and nausea by 21(64%). No patients were administered prophylactic antiemetics. The median number of days with vomiting was 2, and the cumulative number of days for all affected patients was 22 (1.6% of 1407 evaluable days). There were no differences in PTV or small bowel loop V15Gy, V45Gy and V50Gy volumes between patients that did and did not vomit. Conclusions: The cumulative incidence of days with vomiting was only 1.6%. 5-HT3RA prophylaxis during long-course neoadjuvant treatment seems unnecessary. Keywords: Antiemetic, Nausea, Patient-reported outcome, Radiation therapy, Rectal cancer, Vomiting

Purpose: Whole brain radiation therapy (WBRT) remains the standard of care for patients with multiple brain metastases, but more than half of treated patients will develop intracranial progression. Because there is no clear consensus on the optimal therapeutic approach, a prognostic index would be helpful to guide treatment options at progression. We explored whether the recursive partitioning analysis (RPA) score prior to repeat WBRT is predictive of survival. Methods and materials: This multi-institutional pooled analysis included patients with 2 or more brain metastases from any solid primary tumor that was treated with 2 courses of WBRT. Information on demographics, disease characteristics, and intervals between courses was collected. RPA class was abstracted or retrospectively assigned, and descriptive statistics calculated. Median survival (MS) was determined using the Kaplan-Meier method and compared using log rank tests. Univariate and multivariate analyses were performed via Cox regression analysis. Results: For 205 patients, the median age was 55 years (range, 25-83 years), 68% were female, 40.5% had non-small cell lung cancer, and 31.2% had small cell lung cancer. Prior to the second WBRT, 4.9% of patients were RPA class 1, 36.6% were RPA2, and 58.5% were RPA3, with an MS of 7.5 months (95% confidence interval [CI], 4.7-10.3), 5.2 months (95% CI, 3.7-6.7 months), and 2.9 months (95% CI, 2.2-2.9 months), respectively (P = .001). On univariate and multivariate analyses, a Karnofsky Performance Status of

Introduction: In bone metastases, the disruption of normal bone processes results in increased resorption and formation rates, which can often be quantitatively measured by biomarkers in the urine and blood. The purpose of this review is to summarize relevant studies of urinary markers used as a diagnostic and/or prognostic tool, as well as its potential and advances in directing therapy. Methods: A literature search was conducted using Ovid MEDLINE (1950 to July 2014), EMBASE (1950 to 2014 week 30) and Cochrane Central Register of Controlled Trials (3rd Quarter 2014) to identify studies that detailed the use of urinary markers in the cancer setting, specifically involving markers for bone metastases. Search terms included “urinary markers”, “cancer”, and “bone metastases”. Results: A total of 35 articles, with 24 original studies, were identified. In general, urinary markers can be used to detect early signs of bone metastases prior to skeletal imaging, but still must be used in conjunction with imaging to avoid false positive results. The use of urinary markers, such as N-telopeptide, as a prognostic tool remains controversial, but can provide information on the relative risk of skeletal related events (SREs), disease progression, as well as death. Finally, while urinary markers have shown to be potentially useful in confirming the efficacy of bone metastases treatments, exploring the appropriate dosages for treatment, and directing therapy, it is still unclear to what extent urinary markers should be reduced by. Conclusion: The potential use of urinary markers in the management of bone metastases is promising as it can allow for earlier and more convenient detection of bone metastases in comparison to other techniques. However, additional studies involving prospective clinical trials are suggested to further examine the potential of urinary markers in developing appropriate treatment strategies and endpoints, especially in developing a clearer protocol on the extent urinary markers should be reduced by to correlate with achievement of clinical benefit.

Objective: To investigate the quality of life (QOL) following palliative radiotherapy for painful bone metastases. Methods: A literature search was conducted in OvidSP Medline (1946–Jan Week 4 2014), Embase (1947–Week 5 2014), and the Cochrane Central Register of Controlled Trials (Dec 2013) databases. The search was limited to English. Subject headings and keywords included ‘palliative radiation’, ‘cancer palliative therapy’, ‘bone metastases’, ‘quality of life’, and ‘pain’. All studies (prospective or retrospective) reporting change in QOL before and after palliative radiotherapy for painful bone metastases were included. Results: Eighteen articles were selected from a total of 1730. The most commonly used tool to evaluate QOL was the Brief Pain Inventory. Seventeen studies collected data prospectively. An improvement in symptoms and functional interference scores following radiotherapy was observed in all studies. The difference in changes in QOL between responders and non responders was inconsistently reported. Conclusion: QOL improves in patients who respond to palliative radiotherapy for painful bone metastases.

The most recent systematic review of randomized trials in patients with bone metastases has shown equal efficacy of single fraction (SF) and multiple fraction (MF) palliative radiation therapy in pain relief. It is important to determine the patient population to which the evidence applies. This study aims to examine the eligibility criteria of the studies included in the systematic review to define characteristics of “uncomplicated” bone metastases. Inclusion and exclusion criteria of 21 studies included in the systematic review were compared. Common eligibility criteria were documented in hopes of defining the specific features of a common patient population representative of those in the studies. More than half of the studies included patients with cytological or histological evidence of malignancy. Patients with impending and/or existing pathological fracture, spinal cord compression or cauda equina compression were excluded in most studies. Most studies also excluded patients receiving retreatment to the same site. “Uncomplicated” bone metastases can be defined as: presence of painful bone metastases unassociated with impending or existing pathologic fracture or existing spinal cord or cauda equina compression. Therefore, MF and SF have equal efficacy in patients with such bone metastases.

Purpose: Radiation therapy is the standard treatment for symptomatic bone metastases. Several randomized control trials and meta-analyses have concluded a similar efficacy in pain relief when comparing single versus multiple fraction regimes. However, there continues to be reluctance to conform to published guidelines that recommend a single treatment for the palliation of painful bone metastases. The purpose of this literature review is to summarize international patterns of practice, and to determine if guidelines recommending single fraction treatment have been implemented in clinical care. Methods: A literature search was conducted in Ovid Medline, Embase, and Cochrane Central. Search words included, ‘bone metastases’, ‘radiation therapy’, ‘radiotherapy’, ‘patterns of practice’, and ‘dose fractionation’. Both prospective and retrospective studies that investigated the prescription of radiotherapy to bone metastases using actual patient databases were included. Articles were excluded if they investigated hypothetical scenarios. Results: Six hundred and thirteen results were generated from the literature search. Twenty-six articles met the inclusion criteria. Of these, 11 were Canadian, 8 were European, 6 were American, and 1 was Australian. The use of single fraction radiotherapy (SFRT) ranged from 3% to 75%, but was generally lower in American studies. Choice of fractionation depended on a variety of factors, including patient age, prognosis, site of irradiation, and physician experience. Conclusion: Despite the publication of robust randomized control trials, meta-analyses, and clinical practice guidelines recommending the use of a single treatment to palliate uncomplicated bone metastasis, SFRT is internationally underutilized.

Purpose: Pain flare is a temporary increase in pain and is a potential side effect of radiotherapy treatment. However, its incidence has been reported only in recent studies, and with great variability. A few studies have reported on the use of dexamethasone as a prophylactic agent in the prevention of pain flare. The objective of this study is to present a review of the available literature regarding the incidence of pain flare and use of dexamethasone as a preventative measure. Methods: A literature search was conducted in PubMed using subject keywords including: “radiation therapy”, “stereotactic radiation therapy”, “bone metastases”, “pain flare”, and “dexamethasone”. The search was limited to English only but not restricted to any time period. Additionally, a search was also conducted in the American Society for Therapeutic Radiology and Oncology (ASTRO) 2014 book of published abstracts. Inclusion criteria were primary studies published with full text and/or abstracts only. Letters to the editor were excluded. Results: A total of 11 studies were selected, two of which were abstracts published by ASTRO in 2014. Seven articles investigated pain flare and/or dexamethasone use for conventional external beam radiation therapy (EBRT) while the remaining four investigated stereotactic body radiation therapy (SBRT). Pain flare incidence ranged from 2 to 44% for EBRT and 10 to 68% in SBRT. The use of dexamethasone also showed to be effective in both the prophylaxis and treatment of pain flare. Conclusions: Pain flare has been established as an acute toxicity of both EBRT and SBRT, although its incidence is widely variable due to differences in data collection. The use of dexamethasone in the prophylaxis of pain flare is efficacious. Future studies are required in order to both optimize the reporting of pain and the dexamethasone regimens in the prevention of pain flare.

A nipple shield is a breastfeeding aid with a nipple-shaped shield that is positioned over the nipple and areola prior to nursing. Nipple shields are usually recommended to mothers with flat nipples or in cases in which there is a failure of the baby to effectively latch onto the breast within the first two days postpartum. The use of nipple shields is a controversial topic in the field of lactation. Its use has been an issue in the clinical literature since some older studies discovered reduced breast milk transfer when using nipple shields, while more recent studies reported successful breastfeeding outcomes. The purpose of this review was to examine the evidence and outcomes with nipple shield use. Methods: A literature search was conducted in Ovid MEDLINE, OLDMEDLINE, EMBASE Classic, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL. The primary endpoint was any breastfeeding outcome following nipple shield use. Secondary endpoints included the reasons for nipple shield use and the average/median length of use. For the analysis, we examined the effect of nipple shield use on physiological responses, premature infants, mothers’ experiences, and health professionals’ experiences. Results: The literature search yielded 261 articles, 14 of which were included in this review. Of these 14 articles, three reported on physiological responses, two reported on premature infants, eight reported on mothers’ experiences, and one reported on health professionals’ experiences. Conclusion: Through examining the use of nipple shields, further insight is provided on the advantages and disadvantages of this practice, thus allowing clinicians and researchers to address improvements on areas that will benefit mothers and infants the most.

Sukirtha Tharmalingam, Edward Chow, Kristin Harris, Amanda Hird, Emily SinclairRapid Response Radiotherapy Program, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, CanadaAbstract: Quality of life (QOL) has become an important consideration in the care of patients with bone metastases as prevalence, incidence and patient survival are on the rise. As a result, more interventional studies now measure patient’s QOL as a meaningful endpoint. However, well-developed bone metastases specific quality of life instruments are lacking. A literature review was conducted to better understand the nature of QOL instruments used in bone metastases trials. A total of 47 articles evaluating QOL in patients with bone metastases were identified. Twenty-five different instruments were used to evaluate QOL with study-designed questionnaires and the EORTC QLQ-C30 being most commonly employed. Many studies used more than one scale or instrument to measure QOL. This makes it difficult to compare QOL in bone metastases patients across studies and come to any formal conclusions. Therefore, this review demonstrates the need to develop a bone module that can be used across countries in future clinical trials.Keywords: bone metastases, quality of life, QOL instrument, review

Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.