Renal cell carcinoma.

The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting. The treatment of advanced disease, including landmark trials that have established immune checkpoint inhibition as a standard of care, are also reviewed. We also discuss the current controversies that exist surrounding the management of metastatic renal cell carcinoma, including the use of risk assessment models for disease stratification and treatment selection for frontline therapy. Management of non-clear cell renal cell carcinoma subtypes is also reviewed. Future directions of research, including a discussion of ongoing clinical trials and the need for reliable biomarkers to guide treatment in kidney cancer, are also highlighted.

Applications of machine and deep learning to thyroid cytology and histopathology: a review.

This review synthesises past research into how machine and deep learning can improve the cyto- and histopathology processing pipelines for thyroid cancer diagnosis. The current gold-standard preoperative technique of fine-needle aspiration cytology has high interobserver variability, often returns indeterminate samples and cannot reliably identify some pathologies; histopathology analysis addresses these issues to an extent, but it requires surgical resection of the suspicious lesions so cannot influence preoperative decisions. Motivated by these issues, as well as by the chronic shortage of trained pathologists, much research has been conducted into how artificial intelligence could improve current pipelines and reduce the pressure on clinicians. Many past studies have indicated the significant potential of automated image analysis in classifying thyroid lesions, particularly for those of papillary thyroid carcinoma, but these have generally been retrospective, so questions remain about both the practical efficacy of these automated tools and the realities of integrating them into clinical workflows. Furthermore, the nature of thyroid lesion classification is significantly more nuanced in practice than many current studies have addressed, and this, along with the heterogeneous nature of processing pipelines in different laboratories, means that no solution has proven itself robust enough for clinical adoption. There are, therefore, multiple avenues for future research: examine the practical implementation of these algorithms as pathologist decision-support systems; improve interpretability, which is necessary for developing trust with clinicians and regulators; and investigate multiclassification on diverse multicentre datasets, aiming for methods that demonstrate high performance in a process- and equipment-agnostic manner.

Glioblastoma initiation, migration, and cell types are regulated by core bHLH transcription factors ASCL1 and OLIG2.

Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex driver mutations and glioma stem cells (GSCs). The neurodevelopmental transcription factors ASCL1 and OLIG2 are co-expressed in GBMs, but their role in regulating the heterogeneity and hierarchy of GBM tumor cells is unclear. Here, we show that oncogenic driver mutations lead to dysregulation of ASCL1 and OLIG2, which function redundantly to initiate brain tumor formation in a mouse model of GBM. Subsequently, the dynamic levels and reciprocal binding of ASCL1 and OLIG2 to each other and to downstream target genes then determine the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in defining GSCs by upregulating a collection of ribosomal protein, mitochondrial, neural stem cell (NSC), and cancer metastasis genes - all essential for sustaining the high proliferation, migration, and therapeutic resistance of GSCs.

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.

Variants in the ubiquitously expressed DNA/RNA-binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). Most FUS mutation studies have focused on motor neuron degeneration; little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues, given the link between ALS-frontotemporal dementia and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. Magnetic resonance imaging brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller than heterozygous and wild-type brains and displayed significant morphological alterations, including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. These findings show that the disease aetiology of FUS variants can include both neurodevelopmental and systemic alterations.

Measuring cancer burden in prostatic needle core biopsies: simplified assessments outperform complex measurements in assessing outcome: evidence to assist pathologist efficiency and minimize datasets.

AIMS: The optimal method of measuring cancer extent in prostate cancer (PCa) biopsies is unknown. METHODS AND RESULTS: Nine hundred eighty-one men with clinically localised PCa managed conservatively were reviewed with follow up. The number of positive cores (NPC), the Maximum Cancer Length in a core (MCL), Total Cancer Length (TCL), and percentage of positive cores (%+cores) was calculated and univariate and multivariate analysis performed using prostate-specific antigen (PSA), T-stage, and Gleason score. The presence of stromal gaps (SG) was recorded. Univariate models were run where SG made a difference to the MCL. All variables showed significant association with PCa death in univariate models. In multivariate models, incorporating PSA, T-stage, and Gleason score, only %+cores was a significant predictor of outcome, with a 10% increase in %+cores resulting in a hazard ratio (HR) of 1.07 (likelihood-ratio test P > Χ2  = 0.01). There were 120 patients where SG made a difference to the MCL and a total of 20 events in this group. Including SG, on univariate analysis the median MCL was 10 mm and HR was 1.16 (P = 0.007), not including SG, the median MCL was 6 mm and HR was 1.23 (P = 6.3 × 10-4 ). Inclusion or exclusion of SG made no significant difference to TCL as a predictor of outcome. CONCLUSION: Cancer extent is a strong predictor of PCa death but only %+cores added to the multivariate model. Expressed as a fraction of NPC/total number of cores, this is the simplest method of assessment, which we favour over more complicated methods in nontargeted biopsies.

Aplicación de una ley matemática exponencial a la dinámica cardíaca en 16 horas: estudio realizado con 250 pacientes / Application of an exponential mathematical law to cardiac dynamics in 16 hours: a study of 250 patients

Resumen Introducción: Los sistemas dinámicos y la geometría fractal han sido el sustrato para el advenimiento de una ley matemática aplicada al diagnóstico de la dinámica cardíaca en 21 horas. Objetivo: Confirmar la aplicabilidad clínica de la ley matemática exponencial en 16 horas a partir de un estudio de concordancia diagnóstica frente a la norma de referencia. Materiales y método: Se realizó un estudio con 250 registros electrocardiográficos continuos y ambulatorios; 50 pertenecían a pacientes normales y 200 a pacientes con diversas enfermedades cardíacas. Se simuló la secuencia de frecuencias cardíacas y se construyeron los atractores correspondientes. Se calculó la dimensión fractal y la ocupación del atractor en el espacio generalizado de box-counting. Por último, se estableció el diagnóstico fisicomatemático en 16 y 21 horas y se efectuó la validación estadística. Resultados: Los espacios de ocupación para normalidad en la rejilla pequeña se encontraron entre 205 y 372, y entre 56 y 201 para dinámicas patológicas, lo cual permitió evidenciar la capacidad del método para diferenciar normalidad de enfermedad a través de la ocupación espacial de los atractores con base en la ley matemática en 16 horas. Se hallaron valores de sensibilidad y especificidad del 100% y un coeficiente kappa del orden de 1, luego de comparar el diagnóstico fisicomatemático frente a la norma de referencia. Conclusión: La ley matemática exponencial en 16 horas demostró su utilidad como herramienta de ayuda diagnóstica y predictiva, lo cual permitió diferenciar normalidad y estados evolutivos hacia enfermedad y agudización.

Abstract Introduction: Dynamic systems and fractal geometry have been the substrate for the rising of a mathematical law applied to the diagnosis of cardiac dynamics in 21 hours. Objective: To confirm the clinical applicability of the exponential mathematical law in 16 hours, with a study of diagnostic agreement against the Gold Standard. Materials and method: It was made a study with 250 ambulatory and continuous electrocardiographic recordings, 50 belonged to normal patients and 200 to patients with various cardiac pathologies. The sequence of heart rates was simulated, and attractors were constructed. It was calculated the fractal dimension of the attractor and its occupation in the generalized Box-Counting space. Finally, it was determined the physical-mathematical diagnostic in 16 and 21 hours, and statistical validation was performed. Results: The occupation spaces in the small grid were between 205 and 372 for normality, and between 56 and 201 for pathologic dynamics, which demonstrated the ability of the method to differentiate normal condition from sickness, through spatial occupation of attractors according to mathematical law in 16 hours. There were obtained values of sensitivity and specificity of 100% and Kappa coefficient was 1, after comparing the physic-mathematical analysis against the Gold Standard. Conclusion: The exponential mathematical law in 16 hours proved its utility as diagnostic and predictive tool support, allowing to differentiate normal, developmental stages to disease and exacerbation.

The Transcriptomic Landscape of Prostate Cancer Development and Progression: An Integrative Analysis.

Next-generation sequencing of primary tumors is now standard for transcriptomic studies, but microarray-based data still constitute the majority of available information on other clinically valuable samples, including archive material. Using prostate cancer (PC) as a model, we developed a robust analytical framework to integrate data across different technical platforms and disease subtypes to connect distinct disease stages and reveal potentially relevant genes not identifiable from single studies alone. We reconstructed the molecular profile of PC to yield the first comprehensive insight into its development, by tracking changes in mRNA levels from normal prostate to high-grade prostatic intraepithelial neoplasia, and metastatic disease. A total of nine previously unreported stage-specific candidate genes with prognostic significance were also found. Here, we integrate gene expression data from disparate sample types, disease stages and technical platforms into one coherent whole, to give a global view of the expression changes associated with the development and progression of PC from normal tissue through to metastatic disease. Summary and individual data are available online at the Prostate Integrative Expression Database (PIXdb), a user-friendly interface designed for clinicians and laboratory researchers to facilitate translational research.

Pathological predictors of metastatic disease in testicular non-seminomatous germ cell tumors: which tumor-node-metastasis staging system?

Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for cancer (AJCC). We investigated pathological predictors of metastatic disease at presentation in 219 non-seminomatous germ cell tumors with reference to both classifications. Age, tumor size, percentage of embryonal carcinoma, lymphovascular invasion, invasion of stromal rete testis, hilar soft tissue, epididymis, spermatic cord, and tunica vaginalis, as well as tumor at spermatic cord margin, were assessed and correlated with clinical stage at presentation. Of the 219 NSGCT cases, 151 (69%) were clinical stage I, 68 (31%) were clinical stage II/III. On univariate analysis, tumor size (P = 0.028), percentage of embryonal carcinoma (P = 0.004), lymphovascular invasion (P = 0.001), stromal rete testis invasion (P = 0.001), hilar soft tissue invasion (P = 0.010), epididymis invasion (P = 0.010), direct spermatic cord invasion (P = 0.001), and tumor at spermatic cord margin ((P = 0.009) were associated with higher clinical stage. On multivariate analysis, lymphovascular invasion (P = 0.003), tumor size (P = 0.005), percentage of embryonal carcinoma (P = 0.005), stromal rete testis invasion (P = 0.008) remained significant. A tumor size of 6 cm and an embryonal carcinoma percentage of 70% were the significant cut-off values. We conclude that in addition to lymphovascular invasion, stromal rete testis invasion, tumor size, and embryonal carcinoma percentage are strong predictors of metastatic disease at presentation and their inclusion should be considered in any future TNM revision. Further, our results support the changes in the AJCC TNM eighth edition as invasion of the epididymis and hilar soft tissue were both univariately significant.

Mortality in civilian trauma patients and massive blood transfusion treated with high vs low plasma: red blood cell ratio. Systematic review and meta-analysis / Mortalidad en pacientes con trauma civil y transfusion masiva tratados con una relación alta de plasma: globulos rojos versus una relacion baja. Revision sistemática y metaanálisis

Abstract Introduction: Massive bleeding in civilian trauma patients leads to dilutional coagulopathy. Transfusion with high plasma:red blood cell (RBC) ratio has been effective in reducing mortality in war trauma patients. However, in civilian trauma the evidence is controversial. Objective: To assess the impact on mortality of high vs low plasma:RBC ratio transfusion, in civilian trauma patients with massive bleeding. Methods: A systematic review and meta-analysis, including observational studies and clinical trials, was conducted. Data bases were systemically searched for relevant studies between January 2007 and June 2019. The main outcome was early (24-hours) and late (30-day) mortality. Fixed and random effects models were used. Results: Out of 1295 studies identified, 33 were selected: 2 clinical trials and 31 observational studies. The analysis of observational trials showed both decreased early mortality (odds ratio [OR] 0.67; 95% confidence interval [CI], 0.60-0.75) and late mortality (OR 0.79; 95% CI, 0.71-0.87) with the use of high plasma:RBC ratio transfusion, but there were no differences when clinical trials were evaluated (OR 0.89; 95% CI, 0.64-1.26). The exclusion of patients who died within the first 24 hours was a source of heterogeneity. The Injury Severity Score (ISS) altered the association between high plasma:RBC ratio and mortality, with a reduced protective effect when the ISS was high. Conclusion: The use of high vs low plasma: RBC ratio transfusion, in patients with massive bleeding due to civil trauma, has a protective effect on early and late mortality in observational studies. The exclusion of patients who died within the first 24 hours was a source of heterogeneity.

Resumen Introducción: El sangrado masivo en los pacientes con trauma civil propicia el desarrollo de coagulopatía dilucional. La transfusión de plasma y glóbulos rojos con una relación alta ha sido efectiva para disminuir la mortalidad en pacientes con trauma de guerra; sin embargo, su evidencia en trauma civil es controversial. Objetivo: Evaluar el efecto sobre la mortalidad de la transfusión de plasma: glóbulos rojos con relación alta (TPGR-RA) versus baja, en pacientes con sangrado masivo por trauma civil. Métodos: Se realizó una revisión sistemática y metaanálisis de estudios observacionales y experimentos clínicos publicados en el periodo de enero de 2007 a junio de 2019. El desenlace principal fue mortalidad temprana (24 horas) y tardía (30 días), utilizando el modelo de efectos fijos y aleatorios. Resultados: De 1.295 estudios identificados se incluyeron 33: dos experimentos clínicos y 31 estudios observacionales. El uso de TPGR-RA mostró una disminución de la mortalidad temprana (OR 0,67; IC 95 %, 0,60-0,75) y tardía (OR 0,79; IC 95 %, 0,71-0,87) cuando se analizaron los estudios observacionales, pero no hubo diferencias cuando se evaluaron los experimentos clínicos (OR 0,89; IC 95 %, 0,64-1,26). La exclusión de pacientes que fallecieron en las primeras 24 horas fue una fuente de heterogeneidad. La gravedad del trauma, ISS (por las iniciales en inglés de injury severity score)modificó la asociación entre la TPGR-RA y mortalidad, siendo menor el efecto protector cuando el ISS era alto. Conclusiones: El uso de TPGR-RA en pacientes con trauma civil y transfusión masiva (TM) tiene efecto protector sobre la mortalidad en los estudios observacionales. La exclusión de pacientes fallecidos en las primeras 24 horas fue causa de heterogeneidad.

Ultrasound-guided Therapeutic Injection and Cryoablation of the Medial Plantar Proper Digital Nerve (Joplin's Nerve): Sonographic Findings, Technique, and Clinical Outcomes.

RATIONALE AND OBJECTIVES: The medial plantar proper digital nerve, also called Joplin's nerve, arises from the medial plantar nerve, courses along the medial hallux metatarsophalangeal joint, and can be a source of neuropathic pain due to various etiologies, following acute injury including bunion surgery and repetitive microtrauma. We describe our clinical experience with diagnostic ultrasound assessment of Joplin's neuropathy and technique for ultrasound-guided therapeutic intervention including both injection and cryoablation over a 6-year period. MATERIALS AND METHODS: Retrospective review of all diagnostic studies performed for Joplin's neuropathy and therapeutic Joplin's nerve ultrasound-guided injections and cryoablations between 2012 and 2018 was performed. Indications for therapeutic injection and cryoablation, were recorded. Studies were assessed for sonographic abnormalities related to the nerve and perineural soft tissues. Post-treatment outcomes including immediate pain scores, clinical follow-up, and periprocedural complications were documented. RESULTS: Twenty-four ultrasound-guided procedures were performed, including 15 perineural injections and nine cryoablations. With respect to sonographic abnormalities, nerve thickening (33%) and perineural hypoechoic scar tissue (27%) were the most common findings. The mean pain severity score prior to the therapeutic injection was 6.4/10 (range 4-10) and 0.25/10 (range 0-2) following the procedure; mean follow-up was 26.2 months (range 3-63 months). All of the cryoablation patients experienced sustained pain relief with a mean length follow-up of 3.75 months (range 0.2-10 months). CONCLUSION: Therapeutic injection of Joplin's nerve is a safe and easily performed procedure under ultrasound guidance, with high rates of immediate symptom improvement. For those experiencing a relapse or recurrent symptoms, cryoablation offers an effective secondary potential treatment option.

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

BACKGROUND: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH). OBJECTIVE: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions. INTERVENTION: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria. RESULTS AND LIMITATIONS: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design. CONCLUSIONS: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required. PATIENT SUMMARY: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.

Prospective molecular and morphological assessment of testicular prepubertal-type teratomas in postpubertal men.

In 2016, the World Health Organization classification system of testicular tumors included the new entity prepubertal-type teratoma based on its morphological and molecular profile, and the realization that these tumors may occur in postpubertal men. For treatment and prognostic purposes, it is important to distinguish prepubertal-type teratoma from the usual postpubertal-type teratoma, because the former is benign unlike the latter. The distinction may be challenging. In this study, we investigated clinical, morphological, and molecular criteria for distinguishing prepubertal-type teratoma from postpubertal-type teratoma in a prospective series of pure testicular teratomas. All cases of pure teratoma in postpubertal men assessed at Barts Health NHS Trust or in consultation since the introduction of routine investigation of chromosome 12p status in 2010 were reviewed. Morphological features suggestive of prepubertal-type teratoma were observed in 14 out of 35 cases. All underwent molecular testing and none displayed 12p amplification. Mean tumor size was 16 mm (range 7-28 mm). None had associated germ cell neoplasia in situ or significant atrophy. Four incorporated a well-differentiated neuroendocrine tumor, 1-2 mm in size. Of the ten patients with follow-up information, none have recurred or metastasized. Twenty-one of the 35 cases were diagnosed as postpubertal-type teratoma, mean tumor size 40 mm (range 6-90 mm). One case underwent molecular testing: a tumor of pure skeletal muscle differentiation and possessed 12p amplification. Three cases presented with clinical metastases. Eight cases contained immature areas, ten cases had associated germ cell neoplasia in situ, and 17 cases had severe atrophy of the parenchyma. One case with neither germ cell neoplasia in situ nor atrophy showed necrosis. We conclude that both morphological and molecular features are of help in differentiating prepubertal-type teratoma from postpubertal-type teratoma. In nearly all postpubertal-type teratomas, molecular testing was unnecessary, and merely confirmed the morphological impression in the prepubertal-type teratomas. Our study confirmed the high incidence of well-differentiated neuroendocrine tumors in the prepubertal-type.

Pathological risk factors for metastatic disease at presentation in testicular seminomas with focus on the recent pT changes in AJCC TNM eighth edition.

Management of clinical stage (CS) 1 testicular seminoma is controversial. Treatment choice is based on a number of pathological risk factors. However, they have been inconsistently associated with risk of metastatic disease. The eighth edition of the American Joint Committee on Cancer Tumor-Node-Metastasis staging system has separated pT1a and pT1b tumors according to a 3-cm size cutoff and upstaged invasion of hilar soft tissue and epididymis as pT2. We investigated pathological predictors of metastatic disease at presentation in 332 testicular seminomas. Age, tumor size, invasion of vessels, hilar soft tissue, rete testis, epididymis, spermatic cord, tunica vaginalis and tumor at spermatic cord margin were assessed and correlated with CS at presentation. A total of 290 (87%) tumors were CS 1; 42 (13%) were CS 2/3. Median patient age of CS 1 was 36 years (20-81); that of CS 2/3 was 36 years (26-63). Mean tumor size of CS 1 was 38 mm (5-95 mm); that of CS 2/3 was 54 mm (8-95 mm). On univariate analysis, lymphovascular invasion (P = .044), epididymal invasion (P = .009) and tumor size (P = .0001) were associated with higher CS. On multivariate analysis, tumor size (P = .0001) and epididymis invasion (P = .023) remained significant. Optimal tumor size cutoff was 4.25 cm. We conclude that tumor size and epididymal invasion are the strongest predictors of metastatic disease at presentation. The results validate changes in American Joint Committee on Cancer Tumor-Node-Metastasis staging eighth edition but suggest a tumor size of 4 cm as better cutoff value.

Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant disease of lipid metabolism caused by defects in the genes LDLR, APOB, and PCSK9. The prevalence of heterozygous familial hypercholesterolemia (HeFH) is estimated between 1/200 and 1/250. Early detection of patients with FH allows initiation of treatment, thus reducing the risk of coronary heart disease. In this study, we performed in vitro characterization of new LDLR variants found in our patients. Genetic analysis was performed by Next Generation Sequencing using a customized panel of 198 genes in DNA samples of 516 subjects with a clinical diagnosis of probable or definitive FH. All new LDLR variants found in our patients were functionally validated in CHO-ldlA7 cells. The LDLR activity was measured by flow cytometry and LDLR expression was detected by immunofluorescence. Seven new variants at LDLR were tested: c.518 G>C;p.(Cys173Ser), c.[684 G>T;694 G>T];p.[Glu228Asp;Ala232Ser], c.926C>A;p.(Pro309His), c.1261A>G;p.(Ser421Gly), c.1594T>A;p.(Tyr532Asn), and c.2138delC;p.(Thr713Lysfs*17). We classified all variants as pathogenic except p.(Ser421Gly) and p.(Ala232Ser). The functional in vitro characterization of rare variants at the LDLR is a useful tool to classify the new variants. This approach allows us to confirm the genetic diagnosis of FH, avoiding the classification as "uncertain significant variants", and therefore, carry out cascade family screening.

Ki-67 is an independent predictor of prostate cancer death in routine needle biopsy samples: proving utility for routine assessments.

Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ12 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ12 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ12 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.

The percentage of high-grade prostatic adenocarcinoma in prostate biopsies significantly improves on Grade Groups in the prediction of prostate cancer death.

AIMS: It has been recommended that the percentage of high-grade (HG) Gleason patterns 4 and 5 should be quantified in prostate cancer. However, this has not been assessed in a cohort using prostate cancer death as an outcome, and there is debate as to whether the biopsy with the 'worst' percentage of HG disease or an 'overall' percentage of HG disease should be reported. Such data may assist in active surveillance decisions. METHODS AND RESULTS: Men with clinically localised prostate cancer diagnosed by needle biopsy from 1990 to 2003 were included. The endpoint was prostate cancer death. Clinical variables included Gleason score (GS), prostate-specific antigen level, age, clinical stage, and disease extent. Deaths were divided into those from prostate cancer and those from other causes, according to World Health Organization criteria. Nine hundred and eighty-eight biopsy cases were centrally reviewed according to criteria agreed at the Chicago International Society of Urological Pathology conference in 2014. Cores were given individual GSs and Grade Groups (GGs), and a percentage of each grade was given for each core. Both the worst percentage of HG disease seen in a biopsy series and overall percentage of HG disease were calculated. The overall percentage of HG disease was highly significant, with a hazard ratio of 4.45 for the interquartile range (95% confidence interval 3.30-6.01, P < 2.2 × 10-16 ), and was similar to the percentage of HG disease seen in the worst core. In multivariate analysis, both were highly significant. GG2 cases with ≤5% Gleason pattern 4 showed similar survival to GG1 cases. CONCLUSIONS: These data validate the use of percentage of HG disease to predict prostate cancer death. As both worst and overall percentage of HG disease are powerful predictors of outcome, either could be chosen to provide prognostic information.

Percutaneous Ultrasound-Guided Intervention for Upper Extremity Neural and Perineural Abnormalities: A Retrospective Review of 242 Cases.

OBJECTIVE: The purpose of this study was to describe clinical experience with ultrasound-guided therapeutic procedures and associated pathologic conditions involving the peripheral nerves of the upper extremity over 5 years at a large academic institution. MATERIALS AND METHODS: A retrospective database search of procedure codes was performed for all ultrasound-guided upper extremity peripheral nerve procedures between 2012 and 2017. Retrospective review of the electronic medical record for patient demographics, indications, interval follow-up pain relief, and complications was undertaken. Retrospective review of ultrasound and other correlative imaging findings was performed to assess for neural and perineural abnormalities. RESULTS: In total, 242 procedures performed on a cohort of 183 patients (53% women, 47% men; mean age, 53 years; range, 15-97 years) were reviewed. Nine patients underwent multifocal injections in a single encounter, and 39 underwent repeat injections of previously documented symptom generators. Perineural injections included ulnar (n = 109), median (n = 81), posterior interosseous-deep radial (n = 39), sensory branch of the radial (n = 7), anterior interosseous (n = 2), axillary (n = 2), suprascapular (n = 1), and digital (n = 1) nerves. Structural or dynamic abnormality seen either during the procedure or at preprocedural imaging included loss of normal morphologic features (n = 148), nerve subluxation (n = 8), ganglion cyst (n = 4), and neuroma (n = 7). Forty-four patients reported immediate pain relief after the procedure. Of the 89 patients with documented clinical follow-up, 52 reported a period of symptom relief (mean, 125 days), and six reported complete resolution of symptoms. Subsequent surgical procedures were performed on 32 patients, a combination of those who did (n = 12) and did not (n = 20) experience a period of symptom relief from the perineural injection. There were no complications with regard to the site or distribution of perineural injections. Three episodes of vasovagal reaction were reported. CONCLUSION: Ultrasound-guided percutaneous interventions for upper extremity neural abnormalities can be safely performed for a variety of indications. Real-time ultra-sound evaluation during the procedure allows assessment for neural and perineural abnormalities and tailoring of the procedure to potentially symptomatic structural abnormalities.

MRI of synovitis and joint fluid.

Synovitis and joint effusion are common manifestations of rheumatic disease and play an important role in the disease pathophysiology. Earlier detection and accurate assessment of synovial pathology, therefore, can facilitate appropriate clinical management and hence improve prognosis. Magnetic resonance imaging (MRI) allows unparalleled assessment of all joint structures and associated pathology. It has emerged as a powerful tool, which enables not only detection of synovitis and effusion, but also allows quantification, detailed characterization, and noninvasive monitoring of synovial processes. The purpose of this article is to summarize the pathophysiology of synovitis and to review the role of qualitative, semiquantitative, and quantitative MRI in the assessment of synovitis and joint fluid. We also discuss the utility of MRI as an outcome measure to assess treatment response, particularly with respect to osteoarthritis and rheumatoid arthritis. Emerging applications such as hybrid positron emission tomography / MRI and molecular imaging are also briefly discussed. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019.