Robert Siemens

Increasing Detection and Increasing Incidence in Thyroid Cancer

BackgroundIt has been proposed that the increasing incidence of thyroid cancer is due to increasing detection.MethodsUsing administrative data, we compare by year from 1993 to 2006, the rates of diagnostic imaging tests of the neck (computed axial tomography—CT, magnetic resonance imaging—MRI, and non-obstetrical ultrasound—US) to the incidence of thyroid cancer for the population of the Province of Ontario Canada.ResultsWomen and men have different rates of tests, and those rates reflect the rates of new diagnoses of thyroid cancer.ConclusionsThe rising incidence of thyroid disease in women is associated with increasing numbers of diagnostic imaging tests.

Growth kinetics of small renal masses: A prospective analysis from the Renal Cell Carcinoma Consortium of Canada

INTRODUCTION Most small renal masses (SRMs) are diagnosed incidentally and have a low malignant potential. As more elderly patients and infirm patients are diagnosed with SRMs, there is an increased interest in active surveillance (AS) with delayed intervention. Patient and tumour characteristics relating to aggressive disease have not been well-studied. The objective was to determine predictors of growth of SRMs treated with AS. METHODS A multicentre prospective phase 2 clinical trial was conducted on 207 SRMs in 169 patients in 8 institutions in Canada from 2004 to 2009; in these patients treatment was delayed until disease progression. Patient and tumour characteristics were evaluated to determine predictors of growth of SRMs by measuring rates of change in growth (on imaging) over time. All patients underwent AS for presumed renal cell carcinoma (RCC) based on diagnostic imaging. We used the following factors to develop a predictive model of tumour growth with binary recursive partitioning analysis: patient characteristics (age, symptoms at diagnosis) and tumour characteristics (consistency [solid vs. cystic] and maximum diameter at diagnosis. RESULTS With a median follow-up of 603 days, 169 patients (with 207 SRMs) were followed prospectively. Age, symptoms at diagnosis, tumour consistency and maximum diameter of the renal mass were not predictors of growth. This cohort was limited by lack of availability of patient and tumour characteristics, such as sex, degree of endophytic component and tumour location. CONCLUSION Slow growth rates and the low malignant potential of SRMs have led to AS as a treatment option in the elderly and infirm population. In a large prospective cohort, we have shown that age, symptoms, tumour consistency and maximum diameter of the mass at diagnosis are not predictors of growth of T1a lesions. More knowledge on predictors of growth of SRMs is needed.

ACTIVE SURVEILLANCE OF SMALL RENAL MASSES: A PROSPECTIVE MULTI-CENTER CANADIAN URO-ONCOLOGY GROUP TRIAL

(39.7%), cardiovascular disease, diabetes mellitus, and CRI remained among the top five causes of death. CONCLUSIONS: Comorbid conditions associated with the metabolic syndrome are important causes of mortality in patients with T1b RCC. In fact, patients over 65 are as likely to die from cardiovascular disease as RCC, and even for patients younger than 65 with a 4-7 cm renal mass, cardiovascular disease, diabetes mellitus and CRI remained among the most common causes of death. These data, together with the evolving link between CRI and the metabolic syndrome, provide further support for the continued application of NSS for T1b tumors.

Separation of benign and malignant glands in prostatic adenocarcinoma.

This paper presents an analysis of the high resolution histopathology images of the prostate with a focus on the evolution of morphological gland features in prostatic adenocarcinoma. Here we propose a novel technique of labeling individual glands as malignant or benign. In the first step, the gland and nuclei objects of the images are automatically segmented. Individual gland units are segmented out by consolidating their lumina with the surrounding layers of epithelium and nuclei. The nuclei objects are segmented by using a marker controlled watershed algorithm. Two new features, Number of Nuclei Layer (N(NL)) and Ratio of Epithelial layer area to Lumen area (R(EL)) have been extracted from the segmented units. The main advantage of this approach is that it can detect individual malignant gland units, irrespective of neighboring histology and/or the spatial extent of the cancer. The proposed algorithm has been tested on 40 histopathology scenes taken from 10 high resolution whole mount images and achieved a sensitivity of 0.83 and specificity of 0.81 in a leave-75%-out cross-validation.

Automated detection of prostate cancer using wavelet transform features of ultrasound RF time series

The aim of this research was to investigate the performance of wavelet transform based features of ultrasound radiofrequency (RF) time series for automated detection of prostate cancer tumors in transrectal ultrasound images. Sequential frames of RF echo signals from 35 extracted prostate specimens were recorded in parallel planes, while the ultrasound probe and the tissue were fixed in position in each imaging plane. The sequence of RF echo signal samples corresponding to a particular spot in tissue imaging plane constitutes one RF time series. Each region of interest (ROI) of ultrasound image was represented by three groups of features of its time series, namely, wavelet, spectral and fractal features. Wavelet transform approximation and detail sequences of each ROI were averaged and used as wavelet features. The average value of the normalized spectrum in four quarters of the frequency range along with the intercept and slope of a regression line fitted to the values of the spectrum versus normalized frequency plot formed six spectral features. Fractal dimension (FD) of the RF time series were computed based on the Higuchis approach. A support vector machine (SVM) classifier was used to classify the ROIs. The results indicate that combining wavelet coefficient based features with previously proposed spectral and fractal features of RF time series data would increase the area under ROC curve from 93.1% to 95.0%, respectively. Furthermore, the accuracy, sensitivity, and specificity increases to 91.7%, 86.6%, and 94.7%, from 85.7%, 85.2%, and 86.1%, respectively, using only spectral and fractal features.

Quality indicators in the management of bladder cancer: A modified Delphi study

BACKGROUND Survival in patients with bladder cancer has only moderately improved over the past 2 decades. A potential reason for this is nonadherence to clinical guidelines and best practice, leading to wide variations in care. Common quality indicators (QIs) are needed to quantify adherence to best practice and provide data for benchmarking and quality improvement. OBJECTIVE To produce an evidence- and consensus-based list of QIs for the management of bladder cancer. METHODS A modified Delphi method was used to develop the indicator list. Candidate indicators were extracted from the literature and rated by a 27-member Canadian expert panel in several rounds until consensus was reached on the final list of indicators. In rounds with numeric ratings, a frequency analysis was performed. RESULTS A total of 86 indicators were rated, 52 extracted from the literature and 34 suggested by the panel. After iterative rounds of ratings and discussion, a final list of 60 QIs spanning several disciplines and phases of the cancer care continuum was developed. CONCLUSIONS This is the first study to comprehensively produce common QIs representing structure, process, and outcome measures in bladder cancer management. Though developed in Canada, these indicators can be used in other countries with slight modifications to track performance and improve care.

Canadian Consensus Conference: The FDA decision on the use of 5ARIs

In late 2010, the U.S. Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) recommended against prostate cancer chemoprevention labelling for the 5-alpha reductase inhibitors (5ARIs). The ODAC met on December 1, 2010 to hear presentations from GlaxoSmithKline (GSK) and Dr. Ian Thompson (Merck) regarding dutasteride and finasteride.1 GSK was seeking a prostate cancer risk reduction label. Merck was not seeking a risk-reduction label, but rather a change in their product monograph. The FDA presented new, unpublished analyses of the data from the Prostate Cancer Prevention Trial (PCPT) and the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, as well as risk-benefit analyses unadjusted for detection-bias.2–4 The FDA asked the voting panel to consider whether the “real world” risk-benefit ratio was favourable for: Finasteride in men >55 years old with a normal digital rectal examination (DRE) and prostate-specific antigen (PSA) <3 ng/mL Dutasteride in men with an elevated PSA and a negative biopsy In discussing the real world risks and benefits of these drugs, panel members expressed concern that some men would take the drug without adequate follow-up. ODAC voted against recommending dutasteride for the prostate cancer risk reduction indication because, in the view of the ODAC members, the risk for an increase in high-grade tumours outweighed the benefits of prostate cancer risk reduction, given the potential for widespread use of this agent in the United States. The ODAC recommended against prostate cancer chemoprevention labelling for 5ARIs (Table 1). Table 1. Results of the ODAC vote chemoprevention On June 9, 2011, the FDA notified health care professionals that the Warnings and Precautions section of the labels for 5ARIs was revised to include new safety information about the increased risk of high-grade prostate cancer. This risk appears to be low, but health care professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5ARIs in the approved indication for benign prostatic hyperplasia (BPH). To review the FDA’s decision from a Canadian perspective, the Canadian Urological Association (CUA), with direction from Dr. Laurence Klotz, assembled a team of experts and a meeting was convened on November 20, 2011 in Toronto, Ontario. The objectives of the meeting were as follows: To review the FDA’s decision regarding the use of 5ARIs in prostate cancer prevention, specifically with respect to the increase in high-grade cancer. To develop a Canadian consensus statement based on expert opinion and review of the evidence, on the use of 5ARIs in prostate cancer prevention and BPH.3–9 The deliverables proposed by the consensus panel chair and the CUA Office of Education are as follows: (a) To prepare a Canadian statement on the use of 5ARIs in prostate cancer prevention, which reflects a broad consensus of academic and community practitioners, and primary care physicians with an interest in prostate cancer; (b) To publish this statement as a peer-reviewed article in CUAJ; and (c) To produce a patient brochure, which reflects this Canadian consensus. Meeting participants were provided with all pertinent data, a description outlining the meeting objectives, expected outcomes and presentations and three position statements for voting (Appendices 1–4). After an introduction and review of the positions by Dr. Laurence Klotz, participants were asked to vote on the three positions prior to the initiation of discussion. After the initial vote, 7 presentations were made to the group: A summary of the ODAC hearing and the FDA position: Laurence Klotz and David Penson Personal take on the ODAC hearing as a participant: Howard Parnes Pathology issues/Gleason scoring system: Linda Sugar The CCO position on risk reduction of prostate cancer: Neil Fleshner The modelling of cytoreduction and PSA effects: Eric Klein The link between the FDA decision and the United States Preventive Services Task Force (USPSTF) screening decision: Laurence Klotz Implications for use of 5ARIs in surveillance: Tony Finelli Key findings 1. Preliminary vote Attendees were given a ballot containing three positions (Appendix 1–4) and were asked to vote secretly. Position 1: The FDA Position (3 votes) Position 2: The “Pro” Position (3 votes) Position 3: The Middle Ground (6 votes) Expert Presentations a) David Penson: A summary of the ODAC hearing Dr. Penson reviewed the ODAC decision and the data that were presented. His recommended use of 5ARIs moving forward is: Continue to use 5ARIs for BPH with the following proviso: – Explain possible increased risk of high-grade prostate cancer to patients and DOCUMENT in chart – Closely monitor PSA kinetics after starting therapy – Unclear if you need to send a letter to your patients currently on 5ARIs Only consider 5ARI use for chemoprevention for men at increased risk of prostate cancer who are motivated to pursue chemoprevention – Explain to patient that it is off-label use and highlight the possible risks of treatment and DOCUMENT in chart – Closely monitor PSA after starting therapy and contact patient if he misses follow-up PSA mean scores or appointments to reschedule b) Howard Parnes: A personal take on the ODAC hearing as a participant Dr. Parnes also provided a summary of the decision-making process by the ODAC panel. Of note: - ODAC met on 12/1/2010 to hear presentations by GSK and Merck regarding dutasteride and finasteride, respectively. GSK was seeking a risk-reduction label Merck was not seeking a risk-reduction label - Merck stated that the post-hoc analyses addressing the observed increase in high-grade prostate cancer “did not rise to the level of a label.” - ODAC took the position that mortality reduction is the goal of chemoprevention - Burden of prostate cancer was not considered by ODAC - No weight was given to the possible role of detection-bias - The addition of the “real world” setting did not leave much choice for the panel to vote in favour of dutas-teride as widespread use has significant public health implications. The crux of the controversy is whether the observed increase in high-grade cancer in the two trials was an artifact caused by several unavoidable biases associated with the use of 5ARIs, or represents a true increased risk. If the latter, it is unclear what the mechanism for the increase in high grade cancer is.

Prognostic pathological factors in radical cystectomy after neoadjuvant chemotherapy

We undertook a systematic evaluation of the prognostic value of numerous histological factors in 165 radical cystectomies (RCs) of patients with invasive urothelial carcinoma (UC) who underwent surgery after neoadjuvant chemotherapy (NAC).

Abstract 2690: Evaluation of the hemostatic status in patients with prostate cancer using thromboelastography and tissue factor- microparticles

Coagulopathy is reported as the second most common cause of death from cancers, particularly prostate cancer. DVT and pulmonary embolism are two major thrombotic complications in prostate cancer and the risk is even higher with chemotherapy and hormonal therapy. Thromboelastography (TEG) is a global hemeostatic test that detects and specifies the type of coagulopathy encountered through a vesicoelastic trace that reflects the kinetics of the clot from the initial fibrin thread till and fibrinolysis. We performed a hemostatic study in 27 patients (age range 59-88 years) diagnosed with prostate cancer at various stages (metastatic and non-metastatic) as compared to a control group (n=9) matching the same age range and with -ve pathology for prostate cancer. The study included whole blood TEG and flow cytometry analysis of microprticles (MPs) in plasma using Annexin V- FITC and anti-tissue factor - PE. Analysis of the data revealed hypercoagulable state in all patients except two who were maintained on coumadin as prophylaxis for previous DVT. Hypercoagulability was indicated by shorter R time, increased alpha angle, MA and clot index. The mean values for TEG parameters in the patients were: R: 6.01 vs 9.8 minutes in the control group, alpha angle: 68.3 vs 53.1 degrees in controls, MA: 69.3 vs 57.9 mm in controls, and CI: 3.32 vs 0.7 in controls. Paired student t test showed significant differences as regards R time (P=0.009), MA (p=0.053) and CI (P=0.051). Microparticle assay revealed significant elevation in the number of microparticles carrying tissue factor in the patient group compared to the control group (p=0.05). The mean plasma TF-MPs in patient group was 5,142 MPs/uL compared to 2,914 MPs/ uL in the control group suggesting a link between elevated tissue factor and hypercoagulability observed in these patients. To our knowledge, this is the first report for the use of TEG in patients with prostate cancer. TEG is a relatively simple test that uses a small volume of blood and can be a useful tool for evaluation of patients’ thrombotic potential and may help identification of those who may require anticoagulant prophylaxis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2690. doi:1538-7445.AM2012-2690

Prostate Cancer Probability Maps Based on Ultrasound RF Time Series and SVM Classifiers

We describe a very efficient method based on ultrasound RF time series analysis and support vector machine classification for generating probabilistic prostate cancer colormaps to augment the biopsy process. To form the RF time series, we continuously record ultrasound RF echoes backscattered from tissue while the imaging probe and the tissue are stationary in position. In an in-vitro study involving 30 prostate specimens, we show that the features extracted from RF time series are significantly more accurate and sensitive compared to two other established categories of ultrasound-based tissue typing methods. The method results in an area under ROC curve of 0.95 in 10-fold cross-validation.