A prospective, multicenter head-to-head comparative study in patients with primary high-risk prostate cancer investigating the bone lesion detection of conventional imaging and 18F-PSMA-PET/CT.

PURPOSE: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is an emerging staging tool for patients with primary high-risk prostate cancer (PCa). Patients with primary metastatic disease are staged using PSMA-PET/CT imaging, while previously published randomized clinical trials relied on conventional imaging (i.e., bone scintigraphy (BS) results. The aim of this study was to compare the ability of bone metastatic lesion detection and changes in staging for 18F-PSMA-PET/CT versus BS in high-risk PCa patients. METHODS: 79 patients with high-risk PCa were prospectively staged using BS and subsequent 18F-PSMA-PET/CT before initial therapy. Patients who presented with a BS showing no metastases represented Group 1, and patients with a BS showing low-volume disease according to the CHAARTED criteria (<4 bone metastases, no metastases outside vertebral column or pelvis and no visceral metastases) represented Group 2. Metastatic risk group according to CHAARTED and treatment strategies based on both imaging modalities were assessed. RESULTS: A change of CHAARTED risk group was observed in 9/70 (12.8%) of patients in Group 1. In Group 2, a change of risk group was found in 66.7% of patients, due to either upstaging (4/9 patients (44.4%)) and downstaging (2/9 patients (22.2%)). Treatment changes due to use of a different imaging modality occurred in almost 20% of patients. CONCLUSION: In patients with negative for cancer results on BS, upstaging on 18F-PSMA-PET/CT occurred only infrequently. Moreover, 18F-PSMA-PET/CT resulted in both upstaging and downstaging in a substantial subset of patients with low-volume metastatic disease on BS. Treatment changes occurred in almost 20% of cases depending on imaging results.

Measuring school level attributable risk to support school-based HPV vaccination programs.

BACKGROUND: In Australia in 2017, 89% of 15-year-old females and 86% of 15-year-old males had received at least one dose of the HPV vaccine. However, considerable variation in HPV vaccination initiation (dose one) across schools remains. It is important to understand the school-level characteristics most strongly associated with low initiation and their contribution to the overall between-school variation. METHODS: A population-based ecological analysis was conducted using school-level data for 2016 on all adolescent students eligible for HPV vaccination in three Australian jurisdictions. We conducted logistic regression to determine school-level factors associated with lower HPV vaccination initiation (< 75% dose 1 uptake) and estimated the population attributable risk (PAR) and the proportion of schools with the factor (school-level prevalence). RESULTS: The factors most strongly associated with lower initiation, and their prevalence were; small schools (OR = 9.3, 95%CI = 6.1-14.1; 33% of schools), special education schools (OR = 5.6,95%CI = 3.7-8.5; 8% of schools), higher Indigenous enrolments (OR = 2.7,95% CI:1.9-3.7; 31% of schools), lower attendance rates (OR = 2.6,95%CI = 1.7-3.7; 35% of schools), remote location (OR = 2.6,95%CI = 1.6-4.3; 6% of schools,) and lower socioeconomic area (OR = 1.8,95% CI = 1.3-2.5; 33% of schools). The highest PARs were small schools (PAR = 79%, 95%CI:76-82), higher Indigenous enrolments (PAR = 38%, 95%CI: 31-44) and lower attendance rate (PAR = 37%, 95%CI: 29-46). CONCLUSION: This analysis suggests that initiatives to support schools that are smaller, with a higher proportion of Indigenous adolescents and lower attendance rates may contribute most to reducing the variation of HPV vaccination uptake observed at a school-level in these jurisdictions. Estimating population-level coverage at the school-level is useful to guide policy and prioritise resourcing to support school-based vaccination programs.

A Child with a Painful Foot: How to Get a Definitive Diagnosis.

This case report describes an 8-year-old healthy boy with a retained wooden foreign body in his 4th metatarsal bone of his right foot. He was presented several months after the initial trauma, stepping into a toothpick, had occurred. He was operated in our hospital, and the wooden toothpick was removed. The operation and recovery were both uncomplicated. History and physical examination are essential in these types of cases with a history of penetrating trauma but can be inconclusive due to the delay in presentation. Aggressive treatment on the other hand is necessary to prevent bigger problems such as the development of inflammatory problems and persisting complaints. A thorough, systematic, and complete work-up from the history to treatment is therefore necessary and will be described in this case report.

Determining the diagnostic value of PSMA-PET/CT imaging in patients with persistent high prostate specific antigen levels and negative prostate biopsies.

PURPOSE: To assess the diagnostic performance of prostate specific membranous antigen (PSMA) positron emission tomography/computed tomography (PET/CT) imaging to localize primary prostate cancer (PCa) in men with persistent elevated prostate-specific antigen (PSA) levels and previous prostate biopsies that were negative for PCa. METHODS: In this study, 34 men with persistently elevated PSA-levels, previous negative for PCa biopsies and who subsequently underwent diagnostic PSMA-PET/CT imaging were retrospectively evaluated. Men were divided into 3 groups: 1. 12 men with a previous negative mpMRI scan (PI-RADS 1-2) 2. 17 men with a positive mpMRI scan (PI-RADS 3-5), but negative MRI-targeted biopsies and 3. Four men in whom mpMRI was contraindicated. If PSMA-avid lesions were seen, patients underwent 2-4 cognitive targeted biopsies in combination with systematic biopsies. The detection rate of PSMA-PET/CT for PCa, and the accuracy of (possible) targeted biopsies were calculated. RESULTS: Included men had a median PSA-level of 22.8 ng/mL (Interquartile Range 15.6-30.0) at the time of PSMA-PET/CT. Elevated PSMA-ligand uptake in the prostate suspicious for PCa was observed in 22/34 patients (64.7%). In 18/22 patients (54.5%), PSMA-targeted prostate biopsies were performed. In 3/18 patients (16.6%), the targeted biopsies showed International Society of Urological Pathology (ISUP) score 1-2 PCa. The other men had inflammation or benign findings after histopathological examination of the biopsy cores. CONCLUSION: In this study, the clinical value of PSMA-PET/CT for patients with an elevated PSA-level, and negative for PCa biopsies was low. Only very few men were diagnosed with PCa, and no clinically significant PCa was found.

Differences in school factors associated with adolescent HPV vaccination initiation and completion coverage in three Australian states.

BACKGROUND: Schools are the primary setting for the delivery of adolescent HPV vaccination in Australia. Although this strategy has achieved generally high vaccination coverage, gaps persist for reasons that are mostly unknown. This study sought to identify school-level correlates of low vaccination course initiation and completion in New South Wales, Tasmania, and Western Australia to inform initiatives to increase uptake. METHODS: Initiation was defined as the number of first doses given in a school in 2016 divided by vaccine-eligible student enrolments. Completion was the number of third doses given in a school in 2015-2016 divided by the number of first doses. Low initiation and completion were defined as coverage ≤ 25thpercentile of all reporting schools. We investigated correlations between covariates using Spearman's rank correlation coefficients. Due to multicollinearity, we used univariable logistic regression to investigate associations between school characteristics and low coverage. RESULTS: Median initiation was 84.7% (IQR: 75.0%-90.4%) across 1,286 schools and median completion was 93.8% (IQR: 86.0%-97.3%) across 1,295 schools. There were strong correlations between a number of school characteristics, particularly higher Indigenous student enrolments and lower attendance, increasing remoteness, higher postcode socioeconomic disadvantage, and smaller school size. Characteristics most strongly associated with low initiation in univariate analyses were small school size, location in Tasmania, and schools catering for special educational needs. Low completion was most strongly associated with schools in Tasmania and Western Australia, remote location, small size, high proportion of Indigenous student enrolments, and low attendance rates. CONCLUSION: This study provides indicative evidence that characteristics of schools and school populations are associated with the likelihood of low initiation and completion of the HPV vaccination course. The findings will guide further research and help target initiatives to improve vaccination uptake in schools with profiles associated with lower coverage.

LEDs Make It Resilient: Effects on Plant Growth and Defense.

Light spectral composition influences plant growth and metabolism, and has important consequences for interactions with plant-feeding arthropods and their natural enemies. In greenhouse horticulture, light spectral composition can be precisely manipulated by light-emitting diodes (LEDs), and LEDs are already used to optimize crop production and quality. However, because light quality also modulates plant secondary metabolism and defense, it is important to understand the underlying mechanisms in the context of the growth-defense trade-off. We review the effects of the spectral composition of supplemental light currently used, or potentially used, in greenhouse horticulture on the mechanisms underlying plant growth and defense. This information is important for exploring opportunities to optimize crop performance and pest management, and thus for developing resilient crop-production systems.

Adoption of direct discharge of simple stable injuries amongst (orthopaedic) trauma surgeons.

INTRODUCTION: The importance of routine follow-up of several relatively simple stable injuries (SSIs) is questionable. Multiple studies show that direct discharge (DD) of patients with SSIs from the Emergency Department results in patient outcomes and experiences comparable to 'standard care' with outpatient follow-up. The purpose of this study was to evaluate to which extent DD of SSIs has been adopted amongst trauma and orthopedic surgeons internationally, and to assess the variation in the management of these common injuries. METHODS: An online survey was sent to members of an international trauma- and orthopaedic surgery collaboration. Participants, all trauma- or orthopaedic surgeons, were presented with eleven hypothetical cases of patients with simple stable injuries in which they were asked to outline their treatment plan regarding number of follow-up appointments and radiographs, physiotherapy and when to start functional movement. The primary outcome was the proportion of surgeons selecting direct discharge (i.e. zero scheduled appointments), per injury. Secondary outcomes included clinical agreement (>80% of respondents answering similarly) on total number of follow-up appointments (0, 1 or ≥2), radiographs (0, 1 or ≥2), routine physiotherapy referral (yes/no) and when to start functional movement (weeks). RESULTS: 138 of 667 (20.7%) surgeons completed the survey. Adoption of direct discharge ranged from 4-45% of case examples. In 10 out of 11 cases, less than 25% of surgeons selected direct discharge. Clinical agreement regarding number of appointments and when to start functional movement was not reached for any of the injuries. There was clinical agreement on number of radiographs for one injury and for four injuries regarding routine referral to a physiotherapist. DISCUSSION: Despite available evidence, DD of SSIs has not been widely adopted worldwide. Practice variation still exists even for these common injuries. This variation suggests inefficiency and consequently unnecessarily high healthcare costs. (Orthopaedic) trauma surgeons are encouraged to evaluate their current treatment protocols of SSIs.

Detection of prostate cancer with 18F-DCFPyL PET/CT compared to final histopathology of radical prostatectomy specimens: is PSMA-targeted biopsy feasible? The DeTeCT trial.

PURPOSE: In primary prostate cancer (PCa) patients, accurate staging and histologic grading are crucial to guide treatment decisions. 18F-DCFPyL (PSMA)-PET/CT has been successfully introduced for (re)staging PCa, showing high accuracy to localise PCa in lymph nodes and/or osseous structures. The diagnostic performance of 18F-DCFPyL-PET/CT in localizing primary PCa within the prostate gland was assessed, allowing for PSMA-guided targeted-prostate biopsy. METHODS: Thirty patients with intermediate-/high-risk primary PCa were prospectively enrolled between May 2018 and May 2019 and underwent 18F-DCFPyL-PET/CT prior to robot-assisted radical prostatectomy (RARP). Two experienced and blinded nuclear medicine physicians assessed tumour localisation within the prostate gland on PET/CT, using a 12-segment mapping model of the prostate. The same model was used by a uro-pathologist for the RARP specimens. Based on PET/CT imaging, a potential biopsy recommendation was given per patient, based on the size and PET-intensity of the suspected PCa localisations. The biopsy recommendation was correlated to final histopathology in the RARP specimen. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for clinically significant PCa (csPCa, Gleason score ≥ 3 + 4 = 7) were assessed. RESULTS: The segments recommended for potential targeted biopsy harboured csPCA in 28/30 patients (93%), and covered the highest Gleason score PCa segment in 26/30 patient (87%). Overall, 122 of 420 segments (29.0%) contained csPCa at final histopathological examination. Sensitivity, specificity, PPV and NPV for csPCa per segment using 18F-DCFPyL-PET/CT were 61.4%, 88.3%, 68.1% and 84.8%, respectively. CONCLUSIONS: When comparing the PCa-localisation on 18F-DCFPyL-PET/CT with the RARP specimens, an accurate per-patient detection (93%) and localisation of csPCa was found. Thus, 18F-DCFPyL-PET/CT potentially allows for accurate PSMA-targeted biopsy.

Pelvic lymph-node staging with 18F-DCFPyL PET/CT prior to extended pelvic lymph-node dissection in primary prostate cancer - the SALT trial.

PURPOSE: The detection of lymph-node metastases (N1) with conventional imaging such as magnetic resonance imaging (MRI) and computed tomography (CT) is inadequate for primarily diagnosed prostate cancer (PCa). Prostate-specific membrane antigen (PSMA) PET/CT is successfully introduced for the staging of (biochemically) recurrent PCa. Besides the frequently used 68gallium-labelled PSMA tracers, 18fluorine-labelled PSMA tracers are available. This study examined the diagnostic accuracy of 18F-DCFPyL (PSMA) PET/CT for lymph-node staging in primary PCa. METHODS: This was a prospective, multicentre cohort study. Patients with primary PCa underwent 18F-DCFPyL PET/CT prior to robot-assisted radical prostatectomy (RARP) with extended pelvic lymph-node dissection (ePLND). Patients were included between October 2017 and January 2020. A Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram risk probability of ≥ 8% of lymph-node metastases was set to perform ePLND. All images were reviewed by two experienced nuclear physicians, and were compared with post-operative histopathologic results. RESULTS: A total of 117 patients was analysed. Lymph-node metastases (N1) were histologically diagnosed in 17/117 patients (14.5%). The sensitivity, specificity, positive predictive value and negative predictive value for the 18F-DCFPyL PET/CT detection of pelvic lymph-node metastases on a patient level were 41.2% (confidence interval (CI): 19.4-66.5%), 94.0% (CI 86.9-97.5%), 53.8% (CI 26.1-79.6%) and 90.4% (CI 82.6-95.0%), respectively. CONCLUSION: 18F-DCFPyL PET/CT showed a high specificity (94.4%), yet a limited sensitivity (41.2%) for the detection of pelvic lymph-node metastases in primary PCa. This implies that current PSMA PET/CT imaging cannot replace diagnostic ePLND. Further research is necessary to define the exact place of PSMA PET/CT imaging in the primary staging of PCa.

Posterior malleolar fracture morphology determines outcome in rotational type ankle fractures.

INTRODUCTION: Rotational type ankle fractures with a concomitant fracture of the posterior malleolus are associated with a poorer clinical outcome as compared to ankle fractures without. However, clinical implications of posterior malleolar (PM) fracture morphology and pattern have yet to be established. Many studies on this subject report on fragment size, rather than fracture morphology based on computed tomography (CT). The overall purpose of the current study was to elucidate the correlation of PM fracture morphology and functional outcome, assessed with CT imaging and not with -unreliable- plain radiographs. METHODS: Between January 2010 and May 2014, 194 patients with an operatively (ORIF) treated ankle fracture, were prospectively included in the randomized clinical EF3X-trial at our Level-I trauma center. The current study retrospectively included 73 patients with rotational type ankle fractures and concomitant fractures of the posterior malleolus. According to the CT-based Haraguchi fracture morphology, all patients were divided into three groups: 20 Type I (large posterolateral-oblique), 21 Type II (transverse medial-extension) and 32 Type III (small-shell fragment). At 12 weeks, 1 year and 2 years postoperatively the Foot and Ankle Outcome Scores (FAOS) and SF-36 scores were obtained, with the FAOS domain scores at two years postoperative as primary study outcome. Statistical analysis included a multivariate regression and secondary a mixed model analysis. RESULTS: Haraguchi Type II PM ankle fractures demonstrated significantly poorer outcome scores at two years follow-up compared to Haraguchi Types I and III. Mean FAOS domain scores at two years follow-up showed to be significantly worse in Haraguchi Type II as compared to Type III, respectively: Symptoms 48.2 versus 61.7 (p = 0.03), Pain 58.5 versus 84.4 (p < 0.01), Activities of Daily Living (ADL) 64.1 versus 90.5 (p < 0.01). CONCLUSION: Posterior malleolar ankle fractures with medial extension of the fracture line (i.e. Haraguchi Type II) are associated with significantly poorer functional outcomes. The current dogma to fix PM fractures that involve at least 25-33% of the tibial plafond may be challenged, as posterior malleolar fracture pattern and morphology - rather than fragment size - seem to determine outcome.

The Pellegrini-Stieda Lesion of the Knee: An Anatomical and Radiological Review.

The Pellegrini-Stieda lesion is a calcification on the medial side of the knee. The origin of this tissue is controversial. The purpose of our study is to investigate the origin of the Pellegrini-Stieda lesion using conventional radiography as to recreate the circumstances in which Pellegrini and Stieda had to study this pathology. Six nonpaired fresh-frozen cadaveric knees were used. A surgical approach to the medial side of the knee was performed using the layered approach. The origin of the gastrocnemius muscle (GM) (n = 3) or the superficial medial collateral ligament (sMCL) (n = 3) were marked with a radio-opaque fluid. X-ray analysis was performed by measuring the distance from the proximal part of the marking to the medial tibial plateau, multilayer views, and comparison to the original X-rays by Pellegrini-Stieda. Two out of three markings in both the GM and sMCL group were matched with the correct structure. The images were digitally processed so that the osseous structures became partly transparent. After overlaying the images, we found a random distribution of the markings. The Stieda/GM group had no overlap of the markings at all. Compared with the original images from the publications by Pellegrini and Stieda, no comparable position could be found between the original lesions and the markings in our specimens. Conventional X-ray of the knee could not reproduce a distinction between the sMCL and GM as origins for the Pellegrini-Stieda lesion as suggested by Pellegrini and Stieda.

QTL mapping in diploid potato by using selfed progenies of the cross S. tuberosum × S. chacoense.

Usually, mapping studies in potato are performed with segregating populations from crosses between highly heterozygous diploid or tetraploid parents. These studies are hampered by a high level of genetic background noise due to the numerous segregating alleles, with a maximum of eight per locus. In the present study, we aimed to increase the mapping efficiency by using progenies from diploid inbred populations in which at most two alleles segregate. Selfed progenies were generated from a cross between S. tuberosum (D2; a highly heterozygous diploid) and S. chacoense (DS; a homozygous diploid clone) containing the self-incompatibility overcoming S locus inhibitor (Sli-gene). The Sli-gene enables self-pollination and the generation of selfed progenies. One F2 population was used to map several quality traits, such as tuber shape, flesh and skin color. Quantitative trait loci were identified for almost all traits under investigation. The identified loci partially coincided with known mapped loci and partially identified new loci. Nine F3 populations were used to validate the QTLs and monitor the overall increase in the homozygosity level.

Bio-soliton model that predicts non-thermal electromagnetic frequency bands, that either stabilize or destabilize living cells.

Solitons, as self-reinforcing solitary waves, interact with complex biological phenomena such as cellular self-organization. A soliton model is able to describe a spectrum of electromagnetism modalities that can be applied to understand the physical principles of biological effects in living cells, as caused by endogenous and exogenous electromagnetic fields and is compatible with quantum coherence. A bio-soliton model is proposed, that enables to predict which eigen-frequencies of non-thermal electromagnetic waves are life-sustaining and which are, in contrast, detrimental for living cells. The particular effects are exerted by a range of electromagnetic wave eigen-frequencies of one-tenth of a Hertz till Peta Hertz that show a pattern of 12 bands, and can be positioned on an acoustic reference frequency scale. The model was substantiated by a meta-analysis of 240 published articles of biological electromagnetic experiments, in which a spectrum of non-thermal electromagnetic waves were exposed to living cells and intact organisms. These data support the concept of coherent quantized electromagnetic states in living organisms and the theories of Fröhlich, Davydov and Pang. It is envisioned that a rational control of shape by soliton-waves and related to a morphogenetic field and parametric resonance provides positional information and cues to regulate organism-wide systems properties like anatomy, control of reproduction and repair.

Guesstimation of posterior malleolar fractures on lateral plain radiographs.

BACKGROUND: Accurate assessment of articular involvement of the posterior malleolar fracture fragments in ankle fractures is essential, as this is the leading argument for internal fixation. The purpose of this study is to assess diagnostic accuracy of measurements on plain lateral radiographs. METHODS: Quantification of three-dimensional computed tomography (Q-3D-CT) was used as a reference standard for true articular involvement (mm(2)) of posterior malleolar fractures. One-hundred Orthopaedic Trauma surgeons were willing to review 31 trimalleolar ankle fractures to estimate size of posterior malleolus and answer: (1) what is the involved articular surface of the posterior malleolar fracture as a percentage of the tibial plafond? and (2) would you fix the posterior malleolus? RESULTS: The average posterior malleolar fragment involved 13.5% (SD 10.8) of the tibial plafond articular surface, as quantified using Q-3D-CT. The average involvement of articular surface of the posterior malleolar fragment, as estimated by 100 observers on plain radiographs was 24.4% (SD 10.0). The factor 1.8 overestimation of articular involvement was statistically significant (p<0.001). Diagnostic accuracy of measurements on plain lateral radiographs was 22%. Interobserver agreement (ICC) was 0.61. Agreement on operative fixation, showed an ICC of 0.54 (Haraguchi type I=0.76, Haraguchi type II=0.40, Haraguchi type III=0.25). CONCLUSIONS: Diagnostic accuracy of measurements on plain lateral radiographs to assess articular involvement of posterior malleolar fractures is poor. There is a tendency to misjudge posteromedial involvement (Haraguchi type II).

High levels of soluble MICA are significantly related to increased disease-free and disease-specific survival in patients with cervical adenocarcinoma.

Downregulation of major histocompatibility complex class I chain-related molecule A (MICA) and upregulation of human leukocyte antigen G (HLA-G) on the tumor cells are important immune escape mechanisms for different epithelial tumors. In addition, upregulation of the soluble forms of the latter molecules in serum leads to peripheral T-cell and natural killer (NK)-cell tolerance. As for cervical cancer, it remains unknown whether soluble MICA (sMICA) and soluble HLA-G (sHLA-G) concentrations are related to tumor characteristics or patient survival rates. We measured sMICA and sHLA-G in pre-treatment sera of a large cohort of cervical cancer patients (n = 366) by enzyme-linked immunosorbent assay (ELISA). We detected a median sMICA of 174.73 pg/ml and a median sHLA-G of 5.35 U/ml. We did not find an association between sHLA-G levels and clinicopathological characteristics. In adenocarcinoma, low sMICA concentration was positively related to recurrent disease, a higher International Federation of Gynecology and Obstetrics (FIGO) stage and vaginal involvement (Mann-Whitney U-test; P = 0.018, P = 0.042 and P = 0.013, respectively). In the latter patient group, high sMICA levels were associated with better disease-free survival (DFS) and disease-specific survival (DSS) (P = 0.011 and P = 0.047). After adjusting for confounding factors, high sMICA proved to be an independent predictor for a better DFS and DSS [HR 0.16; 95% confidence interval (CI) 0.04-0.64; P = 0.009 and HR 0.12; 95% CI 0.03-0.50; P = 0.004]. sHLA-G did not influence survival in cervical cancer patients, regardless of histology. We conclude that cervical adenocarcinoma patients with high sMICA levels have an increased DFS and DSS. This data warrants a prospective trial to study the functional role of sMICA in cervical adenocarcinoma.

Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance.

BACKGROUND: Chondrosarcomas are malignant cartilage-forming tumors notorious for their resistance to conventional chemo- and radiotherapy. Postulated explanations describe the inaccessibility due to abundant hyaline cartilaginous matrix, presence of multidrug resistance (MDR) pumps, and expression of anti-apoptotic BCL-2 family members. MATERIALS AND METHODS: We studied the sensitivity of chondrosarcoma cell lines (SW1353, CH2879, JJ012, OUMS27) and two primary cultures for doxorubicin and cisplatin. We examined the role of extracellular matrix using three-dimensional (3D) pellet models and MDR pump activity using fluorescence-activated cell sorter analysis. The role of BCL-2 family members was investigated using the BH3 mimetic ABT-737. RESULTS: Chondrosarcoma cells showed highest resistance to cisplatin. 3D cell pellets, morphologically strongly resembling chondrosarcoma in vivo, confirmed nuclear incorporation of doxorubicin. MDR pump activity was heterogeneous among cultures. Chondrosarcoma cells responded to ABT-737 and combination with doxorubicin led to complete loss of cell viability and apoptosis with cytochrome C release. CONCLUSIONS: Despite MDR pump activity and abundance of hyaline cartilaginous matrix, doxorubicin is able to accumulate in the cell nuclei. By repairing the apoptotic machinery, we were able to sensitize chondrosarcoma cells to doxorubicin and cisplatin, indicating an important role for BCL-2 family members in chemoresistance and a promising new treatment strategy for inoperable chondrosarcoma.

Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer.

BACKGROUND: Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function. METHODS: BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model. RESULTS: Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance. CONCLUSION: BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy.