Combined Cabazitaxel and Carboplatin Treatment of Metastatic Castration Resistant Prostate Cancer Patients, With Innate or Acquired Resistance to Cabazitaxel Monotherapy.

BACKGROUND: There is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. METHODS: In this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. RESULTS: Forty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. CONCLUSIONS: In this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.

Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis From the Population-Based Phase II SABR-5 Trial.

PURPOSE: The recently developed European Society for Radiotherapy and Oncology (ESTRO)/European Organization for Research and Treatment of Cancer (EORTC) oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. METHODS AND MATERIALS: The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia (BC), Canada, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced OMD) underwent SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2, and life expectancy ≥6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modeling. RESULTS: Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). The most frequent OMD group was de novo OMD (69%), followed by repeat (16%) and induced (13%). OMD groups differed significantly in PFS (P < .001) but not OS (P = .069). The OMD classification was an independent predictor of both PFS (P = .005) and OS (P = .002). Of the 5 classification factors, only chronicity (synchronous, hazard ratio, 0.52; P = .027) and oligoprogression (hazard ratio, 2.05; P = .004) were independently prognostic for OS. CONCLUSIONS: In this large prospective cohort, the ESTRO/EORTC classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this trial population, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease of use; however, further data on underrepresented OMD groups and histologies will be required.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases.

BACKGROUND: Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties. METHODS: Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. RESULTS: A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. CONCLUSIONS: Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention.

Exposure-response analyses of abiraterone and its metabolites in real-world patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective observational trial demonstrated a relationship between abiraterone trough concentrations (Cmin) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort. PATIENTS AND METHODS: mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated Cmin values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed. RESULTS: Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone Cmin ≤ 8.4 ng/mL). In multivariable analysis, Cmin ≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A Cmin did not show a relationship with treatment efficacy. CONCLUSION: Our study shows that mCRPC patients with an abiraterone Cmin ≥ 8.4 ng/mL have a better prognosis compared with patients with low Cmin. Monitoring Cmin of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.

Androgen receptor moonlighting in the prostate cancer microenvironment.

Androgen receptor (AR) signaling is vital for the normal development of the prostate and is critically involved in prostate cancer (PCa). AR is not only found in epithelial prostate cells but is also expressed in various cells in the PCa-associated stroma, which constitute the tumor microenvironment (TME). In the TME, AR is expressed in fibroblasts, macrophages, lymphocytes and neutrophils. AR expression in the TME was shown to be decreased in higher-grade and metastatic PCa, suggesting that stromal AR plays a protective role against PCa progression. With that, the functionality of AR in stromal cells appears to deviate from the receptor's classical function as described in PCa cells. However, the biological action of AR in these cells and its effect on cancer progression remains to be fully understood. Here, we systematically review the pathological, genomic and biological literature on AR actions in various subsets of prostate stromal cells and aim to better understand the consequences of AR signaling in the TME in relation to PCa development and progression.

Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis.

Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners. Interestingly, three major subgroups of genomic subcomplexes were identified, where selective gain of function for AR genomic action in tumorigenesis was found, dictated by FOXA1 and HOXB13. In summary, by combining proteomic and genomic approaches we reveal subclasses of AR transcriptional complexes, differentiating normal AR behavior from the oncogenic state. In this process, the expression of AR interactors has key roles by reprogramming the AR cistrome and interactome in a genomic location-specific manner.

The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer.

INTRODUCTION: The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. PATIENTS AND METHODS: Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel. RESULTS: From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase. CONCLUSION: Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

Comparison between MRI and CT in prediction of peritoneal carcinomatosis index (PCI) in patients undergoing cytoreductive surgery in relation to the experience of the radiologist.

BACKGROUND: To compare CT and MRI for peritoneal carcinomatosis index (PCI) assessment and to compare assessments made by the radiologist based on their experiences. METHOD AND MATERIALS: MRI and CT of abdomen and pelvis were performed on 39 prospectively followed by surgery directly. Two blinded radiologists with different experience levels evaluated PCI separately on different occasions on 19 cases initially and later on the remaining 20. The agreement between the radiologists' assessment and surgical findings in total and per site were recorded. RESULTS: Total PCI: The experienced radiologist was able to assess total tumor burden correctly on both CT and MRI (kappa = 1.0). For the inexperienced radiologist the assessment was better on CT (kappa = 0.73) compared to MRI (kappa = 0.58). Different sites: The experienced radiologist showed high agreement with kappa = 0.77 for MRI and 0.80 for CT. Corresponding figures were 0.39 and 0.60 for the inexperienced radiologist. For the second phase the agreement levels increased for the inexperienced radiologist increased to 0.80 and 0.70, respectively. CONCLUSION: CT and MRI are equal when read by experienced radiologist. CT shows better results when read by an inexperienced radiologist compared to MRI, however the results of the latter can easily be improved.

Risk factors for tibial stress injuries: a case-control study.

OBJECTIVE: To identify physical and behavioral characteristics related to the incidence of tibial stress injuries (TSIs). DESIGN: Case-control study. No clinical care was conducted. SETTING: Research laboratories in the San Francisco (the United States) and Gold Coast (Australia) areas. PARTICIPANTS: Forty-eight patients (21 men and 27 women) with acute TSI, and 36 (16 men and 20 women) age-matched, sex-matched, height-matched, weight-matched, and activity-matched controls with no history of TSI. INDEPENDENT VARIABLES: Height, weight, body mass index, bone, lean and fat mass, lower limb alignment anomalies, foot type, orthotics, calcium, recent weight change, menstrual history, oral contraceptive use, medications, smoking, alcohol, sleep, training type, and intensity. Differences in continuous variables were tested using 1-way analysis of variance. Categorical variable comparisons were performed with Fisher exact test. MAIN OUTCOME MEASURE: Tibial stress injury. RESULTS: Tibial stress injury cases had 2.7% more fat (P < 0.001) and 2.6% less muscle (P < 0.001) as well as lower trochanteric bone mineral content (BMC) (P < 0.001), lumbar spine (LS) area (P < 0.001), femoral neck BMC (P < 0.001), length (P < 0.05), area (P < 0.001), cortical width (P < 0.01), cross-sectional moment of inertia (P < 0.001), and index of bending strength (P < 0.001) than controls. Controls had lower LS BMC (P < 0.01), length (P < 0.001), and broadband ultrasound attenuation (P < 0.001). The use of orthotic insoles was more prevalent in TSI cases than controls (25% vs 5.6%, respectively; P < 0.02), as were foot anomalies (56.3% vs 27.8%, respectively; P = 0.01). CONCLUSIONS: Tibial stress injury cases had lower lean and higher fat mass, a tendency for smaller bones, and for foot anomalies compared with uninjured matched controls. bone mineral density was normal for both groups. CLINICAL RELEVANCE: Enhancing lean mass and limiting gains in fat may provide some protection against TSI. Individuals with small skeletal frames are advised to increase training loads particularly gradually and to reduce training intensity at the first sign of pain in the shins.

The MutSß complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair.

Loss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSß (MSH2-MSH3) complex in late-onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3(-/-) mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared with p53 single mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3(-/-) mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double-strand break repair (DSBR). Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy-number variation and a moderate microsatellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late-onset tumors due to its roles in DNA DSBR as well as in DNA MMR. Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well.

Response to induction chemotherapy and surgery in non-organ confined bladder cancer: a single institution experience.

AIM: To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery. METHODS: All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC). RESULTS: In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001). CONCLUSIONS: Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy.

Can acute abdominal CT prioritize patients with suspected diverticulitis for a subsequent clean colonic examination?

AIM: The aim of this study was to investigate whether patients with diverticulitis can be prioritized with higher urgency for a subsequent full colonic examination based upon the emergency abdominal CT scan performed at the time of presentation. METHOD: All patients with a diagnosis of diverticulitis, hospitalized during 2006 and having a CT scan on admission and a subsequent 'clean colon' examination, were reviewed. The CT scan was reviewed by two independent and blinded senior radiologists (Radiologist A and Radiologist B) for signs inconsistent with diverticulitis and suggestive of malignancy. The patients were classified on the CT scan results into group 1 (normal findings, nontumour pathology or benign polyps < 1 cm) or group 2 (benign polyps ≥ 1 cm and cancer). RESULTS: Ninety-three patients (83 in group 1 and 10 in group 2) were reviewed. Radiologist A suggested high-priority colonic examination in 18% and 50% of patients in groups 1 and 2, respectively, and Radiologist B in 63% and 90% of patients, respectively. There was a statistically significant interobserver difference, and also lower accuracy of Radiologist B compared with Radiologist A in predicting a subsequent 'clean colon' examination. CONCLUSION: Use of an emergency acute CT scan at the time of diagnosis of diverticulitis to predict a clean colon examination for neoplasia is not reliable because there is a considerable degree of interobserver difference between radiologists.

Ultrasonography findings and tumour quantification in patients with pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a disease with various clinical presentations and the diagnostic value of ultrasonography (US) is under investigated. The purpose of this study was to identify the most common US finding in PMP and to investigate US sensitivity, specificity, positive and negative predictive value in quantifying tumour burden in different abdomino-pelvic regions in PMP patients. Between February 2006 and December 2008, 54 patients were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) due to PMP. The results from preoperative US examination with and without intravenously administrated contrast (SonoVue) were compared to surgical findings. The mean US peritoneal cancer index (PCI) was 6 (range 0-25) and the surgical PCI was 18 (range 3-27) p<0.0001. The histo-pathological subtypes did not influence the US findings. Ascites, bowel loops adhesions and omental cake were mostly visualised correctly by US. The sensitivity of US in quantification of tumour nodules was 91.5% (range 74-100%) and specificity was 33.8% (range 18-55%). The positive predictive value of US examination in PMP was 22% (range 11-44%) and the negative predictive value was 93% (range 77-100%). US can detect the most common PMP findings (ascites and omental cake). The sensitivity of US to quantify PMP tumour burden in different abdominio-pelvic region was relatively high, however, this imaging tool had low specificity.

Poster - Thur Eve - 30: Comparison of treatment planning and delivery performance of VMAT versus IMRT.

The purpose of this study was to determine whether VMAT (Varian RapidArc ™) treatment planning and delivery performance is in compliance with accepted quality assurance tolerances developed for sliding window IMRT. We present an analysis of data for over 1300 patients treated with VMAT and IMRT over a period of three years. Data was acquired on 6 dosimetrically matched linacs for sites including head and neck, brain, gynaecological, and a variety of other cancer cases treated with 6 MV. We have demonstrated that it is possible to dosimetrically match multiple Varian iX linacs with the millennium series MLC using a sliding gap and intercept test. QA is performed by Monte Carlo simulation and ion chamber measurement comparisons with Varian Eclipse TPS as well as linac log file analysis of MLC positions, gantry angles and monitor units on each patient. Point dose and 3D gamma analysis indicate that agreement between Eclipse and measurement or Monte Carlo calculation is site specific, with the dosimetric leaf gap parameter in Eclipse optimized for the most frequently treated site Point dose agreement within 2% and gamma pass rate of > 95% (3%/ 3 mm) is achievable for all sites for both IMRT and VMAT. Linac log file analysis indicates that planned MLC positions are achieved within 2 mm >99.7% of the time for both sliding window IMRT and VMAT. Planned gantry angles are achieved within 0.6 mm 99.8% of the time and planned MU's within 0.1 mm are achieved 99.8% of the time for VMAT.

Staging of uterine cervical cancer with MRI: guidelines of the European Society of Urogenital Radiology.

OBJECTIVE: To design clear guidelines for the staging and follow-up of patients with uterine cervical cancer, and to provide the radiologist with a framework for use in multidisciplinary conferences. METHODS: Guidelines for uterine cervical cancer staging and follow-up were defined by the female imaging subcommittee of the ESUR (European Society of Urogenital Radiology) based on the expert consensus of imaging protocols of 11 leading institutions and a critical review of the literature. RESULTS: The results indicated that high field Magnetic Resonance Imaging (MRI) should include at least two T2-weighted sequences in sagittal, axial oblique or coronal oblique orientation (short and long axis of the uterine cervix) of the pelvic content. Axial T1-weighted sequence is useful to detect suspicious pelvic and abdominal lymph nodes, and images from symphysis to the left renal vein are required. The intravenous administration of Gadolinium-chelates is optional but is often required for small lesions (<2 cm) and for follow-up after treatment. Diffusion-weighted sequences are optional but are recommended to help evaluate lymph nodes and to detect a residual lesion after chemoradiotherapy. CONCLUSIONS: Expert consensus and literature review lead to an optimized MRI protocol to stage uterine cervical cancer. MRI is the imaging modality of choice for preoperative staging and follow-up in patients with uterine cervical cancer.

Polybrominated diphenyl ethers and arylhydrocarbon receptor agonists: Different toxicity and target gene expression.

Polybrominated diphenyl ethers (PBDEs) accumulate in the environment and in humans. PBDEs are developmental neurotoxicants, disturb the endocrine system and induce tumors in rodents. However, underlying mechanisms of PBDE toxicity are still insufficiently understood. Some reports demonstrated activation but also inhibition of the aryl hydrocarbon receptor (AhR) by PBDEs based on expression of its target gene cyp1A1. In the present study, we used different PBDE congeners (BDE47, 99, 153 and 209) and analyzed their effects on AhR signaling in various cell lines and zebrafish embryos. Furthermore, we performed microarray experiments in rat hepatoma cells to compare changes in gene expression induced by either BDE47 or the AhR agonist 2,3,7,8-tetrabromo-dibenzofuran (TBDF). PBDEs did not activate but rather inhibited AhR signaling and specifically induced malformations in zebrafish embryos, which differ from those provoked by AhR agonists. Furthermore, BDE47 and TBDF differentially regulated global gene expression in hepatoma cells. Hence, PBDEs and AhR agonists trigger different toxicity and target gene expression. Several novel target genes of BDE47 and TBDF were identified and verified by RT-PCR. TBDF induced expression of the transcriptional regulators Sim2 and RevErbbeta whereas BDE47 specifically deregulated expression of two subunits of the cytochrome c oxidase complex, cox6a2 and cox4i2, which might be linked to its toxicity.