ResearchPad - genitourinary-tract-tumors https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Analytical performance of thrombospondin-1 and cathepsin D immunoassays part of a novel CE-IVD marked test as an aid in the diagnosis of prostate cancer]]> https://www.researchpad.co/article/elastic_article_15745 The Prostate Specific Antigen (PSA) test suffers from low specificity for the diagnosis of Prostate Cancer (PCa). We originally discovered two cancer-related proteins thrombospondin-1 (THBS1) and cathepsin D (CTSD) using a mass-spectrometry-based proteomics approach. The two serum proteins were shown to improve the diagnosis of high-grade PCa. Thus, we developed quantitative ELISAs for the determination of their concentration in human serum. Here we report their analytical performance in terms of limit of detection, specificity, precision, linearity and interferences, which were determined based on CLSI guidelines. Further, we investigated the influence of pre-analytical factors on concentration measurements. For this, blood from 4–6 donors was collected in different tubes and stored at room temperature for different times prior to centrifugation at different centrifugal forces and temperatures. Stability of THBS1 and CTSD under different storage temperatures was also evaluated. Our results show that the assays are specific, linear and sensitive enough to allow measurement of clinical samples. Precision in terms of repeatability and total within-laboratory coefficient of variation (CV) are 5.5% and 8.1% for THBS1 and 4.3% and 7.2% for CTSD, respectively. Relative laboratory-to-laboratory differences were -6.3% for THBS1 and -3% for CTSD. Both THBS1 and CTSD were stable in serum samples, with 80–120% recoveries of concentrations across donors, sample preparation and storage. In conclusion, the ELISAs as part of the novel commercial in vitro diagnostic test Proclarix are suitable for the use in clinical practice. THBS1 and CTSD can be accurately measured for their intended use independent of the lot and laboratory when conditions consistent with routine practice for PSA sampling and storage are used.

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<![CDATA[SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models]]> https://www.researchpad.co/article/elastic_article_14741 Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1’s role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.

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<![CDATA[CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation]]> https://www.researchpad.co/article/elastic_article_14711 Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR-/- cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

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<![CDATA[Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity]]> https://www.researchpad.co/article/elastic_article_14708 Estrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERβ, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERβ is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ERβ and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ERβ. Transcriptomic analysis indicated relatively few changes in gene expression with ERβ overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ERβ activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ERβ. These findings suggest that ERβ-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ERβ in PCa.

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<![CDATA[Validation of risk factors for recurrence of renal cell carcinoma: Results from a large single-institution series]]> https://www.researchpad.co/article/Ne7ebe4b8-b927-4fd1-a438-3fd04efc5df6

Purpose

To validate prognostic factors and determine the impact of obesity, hypertension, smoking and diabetes mellitus (DM) on risk of recurrence after surgery in patients with localized renal cell carcinoma (RCC).

Materials and methods

We performed a retrospective cohort study among patients that underwent partial or radical nephrectomy at Weill Cornell Medicine for RCC and collected preoperative information on RCC risk factors, as well as pathological data. Cases were reviewed for radiographic evidence of RCC recurrence. A Cox proportional-hazards model was developed to determine the contribution of RCC risk factors to recurrence risk. Disease-free survival and overall survival were analyzed using the Kaplan-Meier method and log-rank test.

Results

We identified 873 patients who underwent surgery for RCC between the years 2000–2015. In total 115 patients (13.2%) experienced a disease recurrence after a median follow up of 4.9 years. In multivariate analysis, increasing pathological T-stage (HR 1.429, 95% CI 1.265–1.614) and Nuclear grade (HR 2.376, 95% CI 1.734–3.255) were independently associated with RCC recurrence. In patients with T1-2 tumors, DM was identified as an additional independent risk factor for RCC recurrence (HR 2.744, 95% CI 1.343–5.605). Patients with DM had a significantly shorter median disease-free survival (1.5 years versus 2.6 years, p = 0.004), as well as median overall survival (4.1 years, versus 5.8 years, p<0.001).

Conclusions

We validated high pathological T-stage and nuclear grade as independent risk factors for RCC recurrence following nephrectomy. DM is associated with an increased risk of recurrence among patients with early stage disease.

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<![CDATA[Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome]]> https://www.researchpad.co/article/5c8accc2d5eed0c48498ff04

Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7–27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.

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<![CDATA[Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma]]> https://www.researchpad.co/article/5c8823dbd5eed0c484639163

Background

In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC).

Methods

Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed.

Results

Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0.

Conclusions

Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

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<![CDATA[Real-time adaptive planning method for radiotherapy treatment delivery for prostate cancer patients, based on a library of plans accounting for possible anatomy configuration changes]]> https://www.researchpad.co/article/5c818e8ad5eed0c484cc24c8

Background and purpose

In prostate cancer treatment with external beam radiation therapy (EBRT), prostate motion and internal changes in tissue distribution can lead to a decrease in plan quality. In most currently used planning methods, the uncertainties due to prostate motion are compensated by irradiating a larger treatment volume. However, this could cause underdosage of the treatment volume and overdosage of the organs at risk (OARs). To reduce this problem, in this proof of principle study we developed and evaluated a novel adaptive planning method. The strategy proposed corrects the dose delivered by each beam according to the actual position of the target in order to produce a final dose distribution dosimetrically as similar as possible to the prescribed one.

Material and methods

Our adaptive planning method was tested on a phantom case and on a clinical case. For the first, a pilot study was performed on an in-silico pelvic phantom. A “library” of intensity modulated RT (IMRT) plans corresponding to possible positions of the prostate during a treatment fraction was generated at planning stage. Then a 3D random walk model was used to simulate possible displacements of the prostate during the treatment fraction. At treatment stage, at the end of each beam, based on the current position of the target, the beam from the library of plans, which could reproduce the best approximation of the prescribed dose distribution, was selected and delivered. In the clinical case, the same approach was used on two prostate cancer patients: for the first a tissue deformation was simulated in-silico and for the second a cone beam CT (CBCT) taken during the treatment was used to simulate an intra-fraction change. Then, dosimetric comparisons with the standard treatment plan and, for the second patient, also with an isocenter shift correction, were performed.

Results

For the phantom case, the plan generated using the adaptive planning method was able to meet all the dosimetric requirements and to correct for a misdosage of 13% of the dose prescription on the prostate. For the first clinical case, the standard planning method caused underdosage of the seminal vesicles, respectively by 5% and 4% of the prescribed dose, when the position changes for the target were correctly taken into account. The proposed adaptive planning method corrected any possible missed target coverage, reducing at the same time the dose on the OARs. For the second clinical case, both with the standard planning strategy and with the isocenter shift correction target coverage was significantly worsened (in particular uniformity) and some organs exceeded some toxicity objectives. While with our approach, the most uniform coverage for the target was produced and systematically the lowest toxicity values for the organs at risk were achieved.

Conclusions

In our proof of principle study, the adaptive planning method performed better than the standard planning and the isocenter shift methods for prostate EBRT. It improved the coverage of the treatment volumes and lowered the dose to the OARs. This planning method is particularly promising for hypofractionated IMRT treatments in which a higher precision and control on dose deposition are needed. Further studies will be performed to test more extensively the proposed adaptive planning method and to evaluate it at a full clinical level.

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<![CDATA[Liver metastasis and Heng risk are prognostic factors in patients with non-nephrectomized synchronous metastatic renal cell carcinoma treated with systemic therapy]]> https://www.researchpad.co/article/5c76fe33d5eed0c484e5b6ea

Objective

This study aimed to determine the prognostic factors of progression-free survival (PFS) and overall survival (OS) in non-nephrectomized patients with synchronous metastatic renal cell carcinoma (mRCC) receiving first-line vascular endothelial growth factor (VEGF)-targeted therapy or immunotherapy.

Methods

Of 70 patients, 57 (81.4%) were treated with targeted therapy, including 5 (7.1%) with previous immunotherapy and 13 (18.6%) with immunotherapy only. The medical records of patients were retrospectively reviewed and analyzed to determine factors of PFS and OS using the Cox proportional hazards model with a statistical significance p-value <0.05.

Results

The median treatment and follow-up periods were 3.9 and 30.9 months, respectively. Disease progression was reported in 90.0% of patients, with an objective response rate and clinical benefit rate of 26.1% and 76.8%, respectively. The lung (77.1%) was the most common site of metastasis. Multivariable analysis showed that poor Heng risk (hazard ratio [HR]: 2.37) and liver metastasis (HR: 2.34) were significant prognostic factors for PFS, and female sex (HR: 2.13), poor Heng risk (HR: 3.14), and liver metastasis (HR: 2.78) were significant prognostic factors for OS (p < 0.05). A subset analysis of risk factors among patients without previous history of immunotherapy also showed poor Heng risk (HR 2.92 and HR 4.24 for PFS) and liver metastasis (HR 2.87 and HR 4.81 for OS) as significant factors for both PFS and OS (p<0.05).

Conclusion

Poor Heng risk, sex, and liver metastasis were associated with survival outcomes after first-line systemic therapy in patients with non-nephrectomized synchronous mRCC.

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<![CDATA[A natural history model for planning prostate cancer testing: Calibration and validation using Swedish registry data]]> https://www.researchpad.co/article/5c6f1520d5eed0c48467ae2e

Recent prostate cancer screening trials have given conflicting results and it is unclear how to reduce prostate cancer mortality while minimising overdiagnosis and overtreatment. Prostate cancer testing is a partially observable process, and planning for testing requires either extrapolation from randomised controlled trials or, more flexibly, modelling of the cancer natural history. An existing US prostate cancer natural history model (Gulati et al, Biostatistics 2010;11:707-719) did not model for differences in survival between Gleason 6 and 7 cancers and predicted too few Gleason 7 cancers for contemporary Sweden. We re-implemented and re-calibrated the US model to Sweden. We extended the model to more finely describe the disease states, their time to biopsy-detectable cancer and prostate cancer survival. We first calibrated the model to the incidence rate ratio observed in the European Randomised Study of Screening for Prostate Cancer (ERSPC) together with age-specific cancer staging observed in the Stockholm PSA (prostate-specific antigen) and Biopsy Register; we then calibrated age-specific survival by disease states under contemporary testing and treatment using the Swedish National Prostate Cancer Register. After calibration, we were able to closely match observed prostate cancer incidence trends in Sweden. Assuming that patients detected at an earlier stage by screening receive a commensurate survival improvement, we find that the calibrated model replicates the observed mortality reduction in a simulation of ERSPC. Using the resulting model, we predicted incidence and mortality following the introduction of regular testing. Compared with a model of the current testing pattern, organised 8 yearly testing for men aged 55–69 years was predicted to reduce prostate cancer incidence by 14% and increase prostate cancer mortality by 2%. The model is open source and suitable for planning for effective prostate cancer screening into the future.

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<![CDATA[Structured reporting of prostate magnetic resonance imaging has the potential to improve interdisciplinary communication]]> https://www.researchpad.co/article/5c75abfdd5eed0c484d07f7d

Background

Effective interdisciplinary communication of imaging findings is vital for patient care, as referring physicians depend on the contained information for the decision-making and subsequent treatment. Traditional radiology reports contain non-structured free text and potentially tangled information in narrative language, which can hamper the information transfer and diminish the clarity of the report. Therefore, this study investigates whether newly developed structured reports (SRs) of prostate magnetic resonance imaging (MRI) can improve interdisciplinary communication, as compared to non-structured reports (NSRs).

Methods

50 NSRs and 50 SRs describing a single prostatic lesion were presented to four urologists with expert level experience in prostate cancer surgery or targeted MRI TRUS fusion biopsy. They were subsequently asked to plot the tumor location in a 2-dimensional prostate diagram and to answer a questionnaire focusing on information on clinically relevant key features as well as the perceived structure of the report. A validated scoring system that distinguishes between “major” and “minor” mistakes was used to evaluate the accuracy of the plotting of the tumor position in the prostate diagram.

Results

The mean total score for accuracy for SRs was significantly higher than for NSRs (28.46 [range 13.33–30.0] vs. 21.75 [range 0.0–30.0], p < 0.01). The overall rates of major mistakes (54% vs. 10%) and minor mistakes (74% vs. 22%) were significantly higher (p < 0.01) for NSRs than for SRs. The rate of radiologist re-consultations was significantly lower (p < 0.01) for SRs than for NSRs (19% vs. 85%). Furthermore, SRs were rated as significantly superior to NSRs in regard to determining the clinical tumor stage (p < 0.01), the quality of the summary (4.4 vs. 2.5; p < 0.01), and overall satisfaction with the report (4.5 vs. 2.3; p < 0.01), and as more valuable for further clinical decision-making and surgical planning (p < 0.01).

Conclusions

Structured reporting of prostate MRI has the potential to improve interdisciplinary communication. Through SRs, expert urologists were able to more accurately assess the exact location of single prostate cancer lesions, which can facilitate surgical planning. Furthermore, structured reporting of prostate MRI leads to a higher satisfaction level of the referring physician.

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<![CDATA[Histogram analysis of prostate cancer on dynamic contrast-enhanced magnetic resonance imaging: A preliminary study emphasizing on zonal difference]]> https://www.researchpad.co/article/5c6c75d9d5eed0c4843d02ed

Background

This study evaluated the performance of histogram analysis in the time course of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for differentiating cancerous tissues from benign tissues in the prostate.

Methods

We retrospectively analyzed the histograms of DCE-MRI of 30 patients. Histograms within regions of interest(ROI) in the peripheral zone (PZ) and transitional zone (TZ) were separately analyzed. The maximum difference wash-in slope (MWS) and delay phase slope (DPS) were defined for each voxel. Differences in histogram parameters, namely the mean, standard deviation (SD), the coefficient of variation (CV), kurtosis, skewness, interquartile range (IQR), percentile (P10, P25, P75, P90, and P90P10), Range, and modified full width at half-maximum (mFWHM) between cancerous and benign tissues were assessed.

Results

In the TZ, CV for ROIs of 7.5 and 10mm was the only significantly different parameter of the MWS (P = 0.034 and P = 0.004, respectively), whereas many parameters of the DPS (mean, skewness, P10, P25, P50, P75 and P90) differed significantly (P = <0.001–0.016 and area under the curve [AUC] = 0.73–0.822). In the PZ, all parameters of the MWS exhibited significant differences, except kurtosis and skewness in the ROI of 7.5mm(P = <0.001–0.017 and AUC = 0.865–0.898). SD, IQR, mFWHM, P90P10 and Range were also significant differences in the DPS (P = 0.001–0.035).

Conclusion

The histogram analysis of DCE-MRI is a potentially useful approach for differentiating prostate cancer from normal tissues. Different histogram parameters of the MWS and DPS should be applied in the TZ and PZ.

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<![CDATA[Assessment of patient information needs: A systematic review of measures]]> https://www.researchpad.co/article/5c5ca313d5eed0c48441f0cf

Background

Providing patient information is a central aspect of patient-centered care. Fulfilling personal information needs has positive effects on several health-related outcomes. Measurement instruments help to identify individual information needs in an effective way. The present study gives an overview of existing information needs measures and further evaluates the quality of their psychometric properties and their psychometric studies.

Methods

We conducted a systematic search on psychometric studies of measures that assess information needs in PubMed and Embase. Furthermore, we carried out a secondary search with reference and citation tracking of the included articles. Title, abstracts and full texts were screened by two independent reviewers for eligibility. We extracted data on content of the measures, validation samples and psychometric properties. In addition we rated the methodological quality with the COSMIN checklist and the quality of psychometric properties with the criteria of Terwee and colleagues.

Results

24 studies on 21 measures were included. Most instruments assessed information needs of patients with cancer or cardiac diseases. The majority of the instruments were in English language and from western countries. Most studies included information on internal consistency and content validity. The ratings showed mixed results with clear deficiencies in the methodological quality of most studies.

Discussion

This is the first systematic review that summarized the existing evidence on measures on patient information needs using two instruments for a systematic quality assessment. The results show a need for more psychometric studies on existing measures. In addition, reporting on psychometric studies needs to be improved to be able to evaluate the reliability of the psychometric properties. Furthermore, we were not able to identify any measures on information needs for some frequent chronic diseases. Other methods to elicit information needs (e.g. open-ended interviews, question prompt sheets) could be considered as alternatives if sound measures are missing.

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<![CDATA[Intensity-modulated radiotherapy for prostate cancer with seminal vesicle involvement (T3b): A multicentric retrospective analysis]]> https://www.researchpad.co/article/5c79b004d5eed0c4841e3c37

Objectives

No study has reported clinical results of external-beam radiotherapy specifically for T3b prostate cancer. The possibility of escalating the dose to the involved seminal vesicles (ISV) while respecting the dose constraints in the organs at risk is thus so far not clearly demonstrated. The objective of the study was to analyze the dose distribution and the clinical outcome in a large series of patients who received IMRT for T3b prostate cancer.

Materials and methods

This retrospective analysis included all patients who received IMRT and androgen deprivation therapy for T3b prostate cancer, between 2008 and 2017, in six French institutions, with available MRI images and dosimetric data.

Results

A total of 276 T3b patients were included. The median follow-up was 26 months. The median (range) prescribed doses (Gy) to the prostate and to the ISV were 77 (70–80) and 76 (46–80), respectively. The dose constraint recommendations were exceeded in less than 12% of patients for the rectum and the bladder. The 5-year risks of biochemical and clinical recurrences and cancer-specific death were 24.8%, 21.7%, and 10.3%, respectively. The 5-year risks of local, pelvic lymph node, and metastatic recurrences were 6.4%, 11.3%, and 15%, respectively. The number of involved lymph nodes (≤ 2 or ≥ 3) on MRI was the only significant prognostic factor in clinical recurrence (HR 9.86) and death (HR 2.78). Grade ≥ 2 acute and 5-year late toxicity rates were 13.2% and 12% for digestive toxicity, and 34% and 31.5% for urinary toxicity, respectively. The dose to the pelvic lymph node and the age were predictive of late digestive toxicity.

Conclusion

IMRT for T3b prostate cancer allows delivery of a curative dose in the ISV, with a moderate digestive toxicity but a higher urinary toxicity. Lymph node involvement increases the risk of recurrence and death.

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<![CDATA[Recent incidence and surgery trends for prostate cancer: Towards an attenuation of overdiagnosis and overtreatment?]]> https://www.researchpad.co/article/5c61e937d5eed0c48496f9f2

Background

Screening for prostate cancer is frequent in high-income countries, including Switzerland. Notably due to overdiagnosis and overtreatment, various organisations have recently recommended against routine screening, potentially having an impact on incidence, mortality, and surgery rates. Our aim was therefore to examine whether secular trends in the incidence and mortality of prostate cancer, and in prostatectomy rates, have recently changed in Switzerland.

Methods

We conducted a population-based trend study in Switzerland from 1998 to 2012. Cases of invasive prostate cancer, deaths from prostate cancer, and prostatectomies were analysed. We calculated changes in age-standardised prostate cancer incidence rates, stratified by tumor stage (early, advanced), prostate cancer-specific mortality, and prostatectomy rates.

Results

The age-standardised incidence rate of prostate cancer increased greatly in men aged 50–69 years (absolute mean annual change +4.6/100,000, 95% CI: +2.9 to +6.2) between 1998 and 2002, and stabilised afterwards. In men aged ≥ 70 years, the incidence decreased slightly between 1998 and 2002, and more substantially since 2003. The incidence of early tumor stages increased between 1998 and 2002 only in men aged 50–69 years, and then stabilised, while the incidence of advanced stages remained stable across both age strata. The rate of prostatectomy increased markedly until 2002, more so in the 50 to 69 age range than among men aged ≥ 70 years; it leveled off after 2002 in both age strata. Trends in surgery were driven by radical prostatectomy. Since 1998, the annual age-standardised mortality rate of prostate cancer slightly declined in men aged 50–69 years (absolute mean annual change -0.1/100,000, 95% CI: -0.2 to -0.1) and ≥ 70 years (absolute mean annual change -0.5/100,000, 95% CI: -0.7 to -0.3).

Conclusions

The increases in the incidence of early stage prostate cancer and prostatectomy observed in Switzerland among men younger than 70 years have concomitantly leveled off around 2002/2003. Given the decreasing mortality, these trends may reflect recent changes in screening and clinical workup practices, with a possible attenuation of overdiagnosis and overtreatment.

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<![CDATA[Predictive genomic markers of response to VEGF targeted therapy in metastatic renal cell carcinoma]]> https://www.researchpad.co/article/5c644872d5eed0c484c2e6fb

Background

First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection.

Methods

From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed.

Results

Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner.

Conclusion

In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.

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<![CDATA[Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate]]> https://www.researchpad.co/article/5c536a9fd5eed0c484a476f6

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

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<![CDATA[regQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors]]> https://www.researchpad.co/article/5c21518bd5eed0c4843fab22

Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with trait diversity and disease susceptibility, yet their functional properties often remain unclear. It has been hypothesized that SNPs in microRNA binding sites may disrupt gene regulation by microRNAs (miRNAs), short non-coding RNAs that bind to mRNA and downregulate the target gene. While several studies have predicted the location of SNPs in miRNA binding sites, to date there has been no comprehensive analysis of their impact on miRNA regulation. Here we investigate the functional properties of genetic variants and their effects on miRNA regulation of gene expression in cancer. Our analysis is motivated by the hypothesis that distinct alleles may cause differential binding (from miRNAs to mRNAs or from transcription factors to DNA) and change the expression of genes. We previously identified pathways—systems of genes conferring specific cell functions—that are dysregulated by miRNAs in cancer, by comparing miRNA–pathway associations between healthy and tumor tissue. We draw on these results as a starting point to assess whether SNPs on dysregulated pathways are responsible for miRNA dysregulation of individual genes in tumors. Using an integrative regression analysis that incorporates miRNA expression, mRNA expression, and SNP genotype data, we identify functional SNPs that we term “regulatory QTLs (regQTLs)”: loci whose alleles impact the regulation of genes by miRNAs. We apply the method to breast, liver, lung, and prostate cancer data from The Cancer Genome Atlas, and provide a tool to explore the findings.

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<![CDATA[GRP78 expression in tumor and perinephric adipose tissue is not an optimal risk stratification marker for clear cell renal cell carcinoma]]> https://www.researchpad.co/article/5c61b7d2d5eed0c484937fff

Objective

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, which is difficult to treat and lacks a reliable prognostic marker. A previous study showed that the endoplasmic reticulum stress marker, glucose-regulated-protein-78 (GRP78), is a potential prognostic marker for ccRCC. The present study aimed to: (1) examine whether GRP78 was upregulated in ccRCC compared with matched non-neoplastic renal tissue; and (2) investigate whether GRP78 expression in ccRCC tissue or perinephric adipose tissue has any association with ccRCC aggressiveness.

Methods

A retrospective cross-sectional study of 267 patients who underwent nephrectomy for renal tumors between June 2013 and October 2017 was conducted at Princess Alexandra Hospital, Brisbane, Australia. Software-assisted quantification of average grey value of staining intensity (staining intensity method) and proportion of positive pixels (positive pixel method) was applied to measure expression of GRP78 in archived specimens of renal tumor tissues (n = 114), adjacent non-neoplastic renal tissues (n = 68), and perinephric adipose tissues (n = 60) in participants diagnosed with ccRCC.

Results

GRP78 was not upregulated in renal tumor tissue compared with paired normal renal tissue. In tumor tissue, GRP78 expression did not show any association with ccRCC aggressiveness using either quantification method. In adipose tissue, downregulation of GRP78 demonstrated poor correlation with increased probability of metastasis, with one unit increase in average grey value of GRP78 staining weakly correlating with a 17% increase in the odds ratio of metastasis (95% confidence interval: 0.99 to 1.38, p = 0.07).

Conclusion

GRP78 is not valuable as a risk stratification marker for ccRCC.

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<![CDATA[Wagging the long tail of drivers of prostate cancer]]> https://www.researchpad.co/article/5c61b7c9d5eed0c484937fa7 ]]>