Mirels' score for upper limb metastatic lesions: do we need a different cutoff for recommending prophylactic fixation?

Hypothesis: The aim of this study was to investigate the reproducibility, reliability, and accuracy of Mirels' score in upper limb bony metastatic disease and validate its use in predicting pathologic fractures. Methods: Forty-five patients with upper limb bony metastases met the inclusion criteria (62% male 28/45). The mean age was 69 years (SD 9.5), and the most common primaries were lung (29%, 13/45), followed by prostate and hematological (each 20%, 9/45). The most commonly affected bone was the humerus (76%, 35/45), followed by the ulna (6.5%, 3/45). Mirels' score was calculated in 32 patients; with plain radiographs at index presentation scored using Mirels' system by 6 raters. The radiological aspects (lesion size and appearance) were scored twice by each rater (2 weeks apart). Intraobserver and interobserver reliability were calculated using Fleiss' kappa test. Bland-Altman plots compared the variances of both individual components and the total Mirels' score. Results: The overall fracture rate of upper limb metastatic lesions was 76% (35/46) with a mean follow-up of 3.6 years (range 11 months-6.8 years). Where time from diagnosis to fracture was known (n = 20), fractures occurred at a median 19 days (interquartile range 60-10), and 80% (16/20) occurred within 3 months of diagnosis.Mirels' score of ≥9 did not accurately predict lesions that fractured (fracture rate 11%, 5/46, for Mirels' ≥ 9 vs. 65%, 30/46, for Mirels' ≤ 8, P < .001). Sensitivity was 14%, and specificity was 73%. When Mirels' cutoff was lowered to ≥7, patients were more likely to fracture than not (48%, 22/46, vs. 28%, 13/46, P = .045); sensitivity rose to 63%, but specificity fell to 55%.Kappa values for interobserver variability were κ = 0.358 (fair, 95% confidence interval [CI] 0.288-0.429) for lesion size, κ = 0.107 (poor, 95% CI 0.02-0.193) for radiological appearance, and κ = 0.274 (fair, 95% CI 0.229-0.318) for total Mirels' score. Values for intraobserver variability were κ = 0.716 (good, 95% CI 0.432-0.999) for lesion size, κ = 0.427 (moderate, 95% CI 0.195-0.768) for radiological appearance, and κ = 0.580 (moderate, 95% CI 0.395-0.765) for total Mirels' score. Conclusions: This study demonstrates moderate to substantial agreement between and within raters using Mirels' score on upper limb radiographs. However, Mirels' score had a poor sensitivity and specificity in predicting upper extremity fractures. Until a more valid scoring system has been developed, based on our study, we recommend a Mirels' threshold of ≥7/12 for considering prophylactic fixation of impending upper limb pathologic fractures. This contrasts with the current ≥9/12 cutoff, which is recommended for lower limb pathologic fractures.

Ninjaflex vs Superflab: A comparison of dosimetric properties, conformity to the skin surface, Planning Target Volume coverage and positional reproducibility for external beam radiotherapy.

BACKGROUND AND PURPOSE: When planning and delivering radiotherapy, ideally bolus should be in direct contact with the skin surface. Varying air gaps between the skin surface and bolus material can result in discrepancies between the intended and delivered dose. This study assessed a three-dimensional (3D) printed flexible bolus to determine whether it could improve conformity to the skin surface, reduce air gaps, and improve planning target volume coverage, compared to a commercial bolus material, Superflab. MATERIALS AND METHODS: An anthropomorphic head phantom was CT scanned to generate photon and electron treatment plans using virtual bolus. Two 3D printing companies used the material Ninjaflex to print bolus for the head phantom, which we designated Ninjaflex1 and Ninjaflex2. The phantom was scanned a further 15 more times with the different bolus materials in situ allowing plan comparison of the virtual to physical bolus in terms of planning target volume coverage, dose at the prescription point, skin dose, and air gap volumes. RESULTS: Superflab produced a larger volume and a greater number of air gaps compared to both Ninjaflex1 and Ninjaflex2, with the largest air gap volume of 12.02 cm3 . Our study revealed that Ninjaflex1 produced the least variation from the virtual bolus clinical goal values for all modalities, while Superflab displayed the largest variances in conformity, positional accuracy, and clinical goal values. For PTV coverage Superflab produced significant percentage differences for the VMAT and Electron3 plans when compared to the virtual bolus plans. Superflab also generated a significant difference in prescription point dose for the 3D conformal plan. CONCLUSION: Compared to Superflab, both Ninjaflex materials improved conformity and reduced the variance between the virtual and physical bolus clinical goal values. Results illustrate that custom-made Ninjaflex bolus could be useful clinically and may improve the accuracy of the delivered dose.

Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data.

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Environmental and social benefits of the targeted intraoperative radiotherapy for breast cancer: data from UK TARGIT-A trial centres and two UK NHS hospitals offering TARGIT IORT.

OBJECTIVE: To quantify the journeys and CO2 emissions if women with breast cancer are treated with risk-adapted single-dose targeted intraoperative radiotherapy (TARGIT) rather than several weeks' course of external beam whole breast radiotherapy (EBRT) treatment. SETTING: (1) TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy, (2) 2 additional UK centres offering TARGIT. PARTICIPANTS: 485 UK patients (249 TARGIT, 236 EBRT) in the prepathology stratum of TARGIT-A trial (where randomisation occurred before lumpectomy and TARGIT was delivered simultaneously with lumpectomy) for whom geographical data were available and 22 patients treated with TARGIT after completion of the TARGIT-A trial in 2 additional UK breast centres. OUTCOME MEASURES: The shortest total journey distance, time and CO2 emissions from home to hospital to receive all the fractions of radiotherapy. METHODS: Distances, time and CO2 emissions were calculated using Google Maps and assuming a fuel efficiency of 40 mpg. The groups were compared using the Student t test with unequal variance and the non-parametric Wilcoxon rank-sum (Mann-Whitney) test. RESULTS: TARGIT patients travelled significantly fewer miles: TARGIT 21 681, mean 87.1 (SE 19.1) versus EBRT 92 591, mean 392.3 (SE 30.2); had lower CO2 emissions 24.7 kg (SE 5.4) vs 111 kg (SE 8.6) and spent less time travelling: 3 h (SE 0.53) vs 14 h (SE 0.76), all p<0.0001. Patients treated with TARGIT in 2 hospitals in semirural locations were spared much longer journeys (753 miles, 30 h, 215 kg CO2 per patient). CONCLUSIONS: The use of TARGIT intraoperative radiotherapy for eligible patients with breast cancer significantly reduces their journeys for treatment and has environmental benefits. If widely available, 5 million miles (8 000 000 km) of travel, 170 000 woman-hours and 1200 tonnes of CO2 (a forest of 100 hectares) will be saved annually in the UK. TRIAL REGISTRATION NUMBER: ISRCTN34086741; Post-results.

Goserelin, as an ovarian protector during (neo)adjuvant breast cancer chemotherapy, prevents long term altered bone turnover.

BACKGROUND: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients "OPTION" trial (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of primary ovarian insufficiency (POI) at 12 months in women randomised to 6-8 cycles of (neo)adjuvant chemotherapy (CT) +/- goserelin (G). Here we report the results of a secondary endpoint analysis of the effects of CT+/-G on markers of bone turnover. METHODS: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers were evaluated for the overall population, according to age stratification at randomisation (≤40 vs >40 years) and with exploratory analysis according to POI rates at 12 months. RESULTS: In the overall population, there was a significant increase in NTX at 6 months compared to baseline in patients treated with CT+G (40.81 vs 57.82 p=0.0074) with normalisation of levels thereafter. BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving CT+G, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36 months (CT+G 5.845 vs CT 8.5 p=0.0006). These changes were predominantly seen in women >40 years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a longer duration than women who maintained menses. CONCLUSION: Addition of G to CT increases bone turnover during treatment with normalisation after cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to negate longstanding altered bone turnover associated with POI.

Towards predicting the response of a solid tumour to chemotherapy and radiotherapy treatments: clinical insights from a computational model.

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules.

Topoisomerase IIα levels and G2 radiosensitivity in T-lymphocytes of women presenting with breast cancer.

Previous studies from our laboratory have identified a link between intracellular topoisomerase IIα (topo IIα) levels and chromosomal radiosensitivity, as measured by the frequencies of chromatid breaks in the so-called G2-assay. Lower topo IIα levels were associated with reduced chromosomal radiosensitivity in cultured human cells. These findings supported a model, in which it is proposed that such chromatid breaks are the result of radiation-induced errors made by topoisomerase IIα during decatenation of chromatids. Studies from our and other laboratories, using the G2-assay, have shown that phytohaemagglutinin (PHA)-stimulated peripheral blood T-lymphocytes from 40% of female breast cancer cases show elevated chromatid break frequencies when exposed to a small standard dose of ionizing radiation, i.e. elevated above the 90th percentile of a group of female control samples. In the present study we have used a modified G2-assay to test whether elevated frequency of chromatid breaks in breast cancer cases is linked with elevated intracellular topo IIα level in PHA-stimulated T-lymphocytes, and also whether there is a general correlation between chromosomal radiosensitivity and topo IIα level. Our results confirm previous studies that 40% of breast cancer cases show elevated radiosensitivity as compared with controls. Also, the mean chromatid break frequency in breast cancer cases was significantly higher than in controls (P = 0.0001). We found that the mean topo IIα level in the cohort of breast cancer cases studied was significantly raised, as compared with controls (P = 0.0016), which could indicate a genetic propensity towards a raised intracellular production of topo IIα in these individuals. There was no direct correlation between chromosomal radiosensitivity and topo IIα level for individual samples either in the breast cancer cohort or in controls. However, a comparison between control and breast cancer samples shows a higher mean topo IIα level in breast cancer samples that correlates with the elevated mean chromatid break frequency seen in these patient samples. We found no meaningful correlations between either chromatid break frequency or topo IIα level and either tumour grade or hormone status. We conclude that elevated intracellular topo IIα level is likely to be a significant factor in determining the chromosomal response of stimulated T-lymphocytes from certain breast cancer cases.

CA 19-9 and survival in advanced and unresectable pancreatic adenocarcinoma and cholangiocarcinoma.

BACKGROUND: The CA 19-9 tumour marker is increasingly used to monitor response to therapy in patients with pancreatic adenocarcinoma. Serum CA 19-9 levels have also been shown to correlate with survival. However, their role in cholangiocarcinoma is less clear. AIM OF STUDY: To assess the utility of CA 19-9 levels in the management of patients with advanced pancreatic adenocarcinoma or cholangiocarcinoma in routine clinical practice is the aim of the study. METHODS: A retrospective analysis of CA 19-9 values and survival was performed in 26 patients with pancreatic adenocarcinoma receiving gemcitabine and in 18 patients with cholangiocarcinoma. RESULTS: Patients with advanced pancreatic adenocarcinoma receiving gemcitabine who experienced a decrease of > or = 20% in CA 19-9 concentration had a median survival of 13.9+ months (range 4.2-23.5) compared to 7.6+ months (range 4.0-14.7) in those without such a change (p = 0.0109). In patients with advanced cholangiocarcinoma, the median survival was longest in those with a baseline CA 19-9 level of less than 1,000 U/ml; 11.8 months (range 1.0-41.4) vs 6.2 months (range 3.1-9.4; p = 0.0075). CONCLUSIONS: The CA 19-9 concentration has a valuable role in predicting outcome in patients with pancreatic adenocarcinoma and cholangiocarcinoma. It is helpful in guiding therapy and should be used accordingly in oncology practice.

Diclofenac antagonizes peroxisome proliferator-activated receptor-gamma signaling.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor-gamma (PPARgamma), activation of which decreases cancer cell proliferation. NSAIDs have been shown to activate this receptor, but only at high concentrations. Here, we have examined binding of diclofenac to PPARgamma using a cis-parinaric acid displacement assay and studied the effect of diclofenac effect on PPARgamma trans-activation in a COS-1 cell reporter assay. Unexpectedly, diclofenac bound PPARgamma at therapeutic concentrations (K(i) = 700 nM) but induced only 2-fold activation of PPARgamma at a concentration of 25 microM and antagonized PPARgamma trans-activation by rosiglitazone. This antagonism was overcome with increasing rosiglitazone concentrations, indicating that diclofenac is a partial agonist. No effect of diclofenac was seen without exogenous receptor, confirming that it was working through a PPARgamma-specific mechanism. This is the first description of an NSAID that can antagonize PPARgamma. In addition, this is the first time that an NSAID has been shown to bind this receptor at clinically meaningful concentrations. The physiological relevance of these findings was tested using adipocyte differentiation and cancer cell proliferation assays. Diclofenac decreased PPARgamma-mediated adipose cell differentiation by 60% and inhibited the action of rosiglitazone on the prostate cancer cell line, DU-145, allowing a 3-fold increase in proliferation. This work shows that standard doses of diclofenac may have pharmacodynamic interactions with rosiglitazone and this has therapeutic implications, both in the management of type 2 diabetes and during cancer treatment.