Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Practical Approach to Reporting Based on the International System for Serous Fluid Cytopathology.

The International System for Serous Fluid Cytopathology (TIS) is intended for reporting cytological specimens from serous cavities: pleural, abdominal and pericardial cavities. TIS is being adopted into practice in cytology laboratories worldwide. In this system, there are six diagnostic categories: non-diagnostic, negative for malignancy, atypia of undetermined significance, suspicious for malignancy, malignant-primary and malignant-secondary. Malignant-primary category almost always implies malignant mesothelioma and malignant-secondary usually refers to metastasis from carcinoma but also to involvement of serous cavity by haematolymphoid and other malignancies. When evaluating effusion cytological specimen adequacy, the factors that must be considered are sample volume, cellular content and cellular preservation. In the diagnostic analysis and interpretation, it is helpful to consider systematically all basic cytomorphological components in a sample. The basic components are architecture, cell populations, cell size, cytoplasm, nuclei and background elements. One important requirement for a successful evaluation of an effusion cytological specimen is sufficient clinical and radiological information in a referral. Clinical information may guide ancillary testing. In the present review, we provide a practical and educational approach to reporting serous effusion cytology based on the TIS.

Review of the impact of the International System for Serous Fluid Cytopathology.

The International System for Reporting Serous Fluid Cytology (TIS) has been proposed by an expert working team composed of the International Academy of Cytology and the American Society of Cytopathology, following an international survey. Since its introduction, the TIS has gained worldwide acceptance, and this review aims to assess its global impact. A literature search revealed 25 studies which have presented data on the impact of the TIS. Most of them provide data, including risk of malignancy (ROM) for each diagnostic category, separately for pleural, peritoneal and pericardial effusions, while a few do not separate them. A few studies focus on specific diagnoses like mesothelioma on specific types of fluids or more specific issues like the optimal fluid volume for cytology or interobserver variability. A synopsis of the data from the literature search is presented in four tables. The ROM assessment is discussed, as well as interobserver variability and the use of ancillary diagnostic immunochemistry. In conclusion, our review of the published data suggests that the TIS is a valid classification scheme that has been widely accepted by pathologists globally, is highly reproducible and makes a valuable contribution to clinical therapeutic management.

Updates in head and neck cytopathology: Insights from European Congress of Pathology Short Course.

Cytological specimens play a pivotal role in head and neck nodule/mass work up and diagnoses. The specimens´ importance has grown with the onset of personalized medicine and the routine use of molecular markers in the diagnostic work up. The Updates in Head and Neck Cytopathology Short Course ran during the 35th European Congress of Pathology held in Dublin, Ireland, in 2023 and brought together experts in cytopathology, pathology, and related fields to share their expertise and experience in the field of head and neck cytopathology and its future directions. Topics such as a one-stop clinic, the Milan System for Reporting Salivary Gland Cytopathology, next generation sequencing, and human papilloma virus detection in the head and neck area were covered during the short course. These topics are briefly summarized in the present review.

Resident training in interventional pathology: Ultrasound-guided fine-needle aspiration and rapid on site evaluation-5 years of teaching experience in a single university hospital.

INTRODUCTION: Despite the established role of the interventional pathologist, their diagnostic performance is difficult to establish. At least in Spain training of pathology residents in ultrasound-guided interventional procedures for specimen collection is limited or absent in most institutions. We present our teaching experience in the instruction of ultrasound-guided fine-needle aspiration (FNA) to pathology residents in a tertiary-level hospital. MATERIALS AND METHODS: The training of pathology residents who rotated through the interventional unit of the pathology department and the application of ultrasound-guided FNA and rapid on-site evaluation (U-ROSE) was documented over 5 years. The training period was broken down into learning phases and included the number of ultrasound-guided FNA performed, anatomical location, and their diagnostic performance, among other aspects. RESULTS: Nineteen (19) pathology residents were trained in U-ROSE, and performed a total of 4003 procedures, with a mean of 211 per resident. In 53% of cases only one pass was required for an adequated sample. The specimen was diagnostic in more than 97% of cases. The most frequently sampled anatomical sites were the thyroid gland (n = 2347), followed by lymph node (n = 667), soft tissues (n = 663) and salivary glands (n = 322). CONCLUSION: The results support the training programme followed by pathology residents in learning U-ROSE, which is essential to lay the foundations for the future interventional pathologist.

The international system for reporting serous fluid cytopathology: The initial project survey.

OBJECTIVE: An international panel in the field of body fluid cytology, supported by the International Academy of Cytology and the American Society of Cytopathology, conducted a survey to identify opinions and explore existing practice patterns regarding body fluid cytopathology. METHODS: The study group, formed during the 2018 European Congress of Cytology in Madrid, generated a survey of 54 questions related to the practice and taxonomy of body fluid cytology. The survey was available online from 28 August 2018 until 10 December 2018. Participants were invited through the websites and listserves of the professional societies. RESULTS: The survey collected 593 international participant responses. Questions pertained to practice patterns and diagnostic language. Information was collected regarding credentials, work setting, work volume (4-10,000 samples) and years in practice (0-60 years). The responses revealed variations in diagnostic practice and sample management. Direct smears and ThinPrep® preparations are the most popular methods, followed by Cytospin® and SurePath®. Most (70%) respondents perform ancillary studies on their material, with over 50% preferring a cell block preparation. Approximately 32% indicated that they are capable of performing genetic studies on the samples. Nearly 78% of participants would accept a two-stage cytology report, with a preliminary assessment followed by a final diagnosis that accounts for ancillary studies to generate a more precise cytological interpretation. Approximately one-third (36%) never report adequacy on body fluid samples. Most (78%) report a general category result (negative, atypical, suspicious, or positive) and 22% provide a detailed surgical pathology type report. Most (73.6%) participants believe that both Papanicolaou stains and a modified Giemsa stain (eg Diff Quik) should be standard preparations for all serous fluid cytology. CONCLUSIONS: The results of the survey demonstrated strong support for the development of a unified system for reporting body fluid cytopathology among respondents.

Targeted and systematic cognitive freehand-guided transperineal biopsy: is there still a role for systematic biopsy?

OBJECTIVES: To assess whether targeted cognitive freehand-assisted transperineal biopsies using a PrecisionpointTM device still require additional systematic biopsies to avoid missing clinically significant prostate cancer, and to investigate the benefit of a quadrant-only biopsy approach to analyse whether a quadrant or extended target of the quadrant containing the target only would have been equivalent to systematic biopsy. PATIENTS AND METHODS: Patients underwent combined systematic mapping and targeted transperineal prostate biopsies at a single institution. Biopsies were performed using the Precisionpoint device (Perineologic, Cumberland, MD, USA) under either local anaesthetic (58%, 163/282), i.v. sedation (12%, 34/282) or general anaesthetic (30%, 85/282). A mean (range) of 24 (5-42) systematic and 4.2 (1-11) target cores were obtained. Magnetic resonance imaging (MRI) scans were reported using the Likert scale. Clinically significant cancer was defined as Gleason 7 or above. Histopathological results were correlated with the presence of an MRI abnormality within a spatial quadrant and the other adjoining or non-adjoining (opposite) quadrants. Histological concordance with radical prostatectomy specimens was analysed. RESULTS: A total of 282 patients were included in this study. Their mean (range) age was 66.8 (36-80) years, median (range) prostate-specific antigen level 7.4 (0.91-116) ng/mL and mean prostate volume 45.8 (13-150) mL. In this cohort, 82% of cases (230/282) were primary biopsies and 18% (52/282) were patients on surveillance. In all, 69% of biopsies (195/282) were identified to have clinically significant disease (Gleason ≥3 + 4). Any cancer (Gleason ≥3 + 3) was found in 84% (237/282) of patients. Of patients with clinically significant disease, the target biopsies alone picked up 88% (171/195), with systematic biopsy picking up the additional 12% (24/195) that the target biopsies missed. This altered with Likert score; 73% of Likert score 3 disease was detected by target biopsy, 92% of Likert score 4 and 100% of Likert score 5. Target biopsies with additional same-quadrant-only systematic cores picked up 75% (18/24) of significant cancer that was missed on target only, found in the same quadrant as the target. CONCLUSION: Systematic biopsy is still an important tool when evaluating all patients referred for prostate biopsy, but the need is decreased with increasing suspicion on MRI. Patients with very high suspicion of prostate cancer (Likert score 5) may not require systematic cores, unless representative surrounding biopsies are required for other specific treatments (e.g. focal therapy, or operative planning). More prospective studies are needed to evaluate this in full.

The impact of non-urothelial variant histology on oncological outcomes following radical cystectomy.

OBJECTIVES: To determine if the presence of non-urothelial variant histology (NUVH) is associated with a poorer prognosis following radical cystectomy (RC) compared to pure urothelial carcinoma (PUC). PATIENTS AND METHODS: A prospectively maintained database of all patients undergoing RC at a high-volume regional tertiary bladder cancer service between January 2010 and January 2017 was retrospectively analysed looking for patients with NUVH. Multivariate Cox proportional hazards regression analysis was used to determine disease recurrence, overall survival and bladder cancer-specific survival, as well as lymph node positivity. Association of tumour stage was determined using chi-squared analysis. RESULTS: In total, 430 patients underwent RC of which 73 (17%) had NUVH and 357 (83%) had PUC. The median (range) follow-up was 45.0 (8.5-100.2) months. The presence of NUVH was associated with both increased overall (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.21-2.85) and bladder cancer-specific mortality (HR 1.81, 95% CI 1.91-3.01), as well as disease recurrence (HR 1.71, 95% CI 1.06-2.75) in multivariate analysis. Squamous cell variant was also associated with increased overall mortality (HR 1.91, 95% CI 1.16-3.13), cancer-specific mortality (HR 2.03, 95% CI 1.21-3.42) and disease recurrence (HR 2.08, 95% CI 1.23-3.52), although this was not seen in other variant subtypes. Lymph node positivity was not associated with NUVH in multivariate analysis (HR 1.28, 95% CI 0.59-2.75), but NUVH was associated with advanced tumour stage on chi-squared analysis (P < 0.001). CONCLUSION: Our results showed a risk of shorter survival in NUVH compared to PUC. This suggests NUVH as an independent predictor of worse outcomes. As a result, patients with NUVH should be counselled preoperatively that overall and disease-specific outcomes are worse postoperatively and about the possible need for adjuvant treatment.

Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer.

BACKGROUND: Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. METHODS: METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London. DISCUSSION: This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. TRIAL REGISTRATION: EudraCT number 2014-005193-11 . Registered on September 09, 2015.

Significance of User Participation in a Hospital Information System Success: Insights From a Case Study.

User participation in the development of a system is universally prescribed as an effective strategy to ensure the success of the resultant system. However, the existing literature on the merits of user participation only provides equivocal evidence. Various analyses of this literature point out that this equivocal evidence may be due to inconsistent operational measures of the user participation and system success constructs. Planned organizational change and participative decision making, the underlying paradigms of user participation construct, suggest that the development of some information systems may require blending of users' system-related functional expertise and developers' technical expertise to ensure system success. These paradigms also maintain that in case of well-defined, structured information systems user participation should enhance the likelihood of system success through better user understanding of the need for the system and system content and objectives, user trust, and a sense of system ownership. This research also described a case study involving the development and implementation of a medical records system for a neonatal intensive care unit in a large hospital in Texas. The case study provides evidence that in systems that require incorporation of user functional expertise user participation will enhance the likelihood of system success.

Terminology and nomenclature schemes for reporting thyroid cytopathology: An overview.

The clinical management of thyroid nodules begins with a cytologic diagnosis. Current multidisciplinary approaches to thyroid nodule management rely on clear and concise diagnoses that can be reliably and reproducibly interpreted across institutions. Ultimately, this clinical necessity has led to multidisciplinary bodies throughout the world to develop standardized reporting formats which have themselves evolved over time. Herein we review the three major international nomenclatures for reporting thyroid cytopathology, including, the British Thyroid Association and Royal College of Pathologists (Thy), the Italian Consensus (TIR) and the Bethesda System for Reporting Thyroid Cytopathology. Alignment of these three diagnostic terminologies and the emergence of a single internationally agreed upon one has the potential to lead to more succinct, evidence-driven clinical management algorithms.

The Impact of Patient-to-Patient Interaction in Health Facility Waiting Rooms on Their Perception of Health Professionals.

Patients have to wait in waiting rooms prior to seeing the physician. But there are few studies that demonstrate what they are actually doing in the waiting room. This exploratory study was designed to investigate the types of discussions that patients in the waiting room typically engage in with other patients and how the conversations affected their opinion on general reputation of the clinic, injections/blocks as treatment procedures, waiting time, time spent with the caregiver, overall patient satisfaction, and the pain medication usage policy. The study demonstrates that patient interaction in the waiting room has a positive effect on patient opinion of the pain clinic and the caregivers.

Indications, results and safety profile of transperineal sector biopsies (TPSB) of the prostate: a single centre experience of 634 cases.

OBJECTIVE: To describe a protocol for transperineal sector biopsies (TPSB) of the prostate and present the clinical experience of this technique in a UK population. PATIENTS AND METHODS: A retrospective review of a single-centre experience of TPSB approach was undertaken that preferentially, but not exclusively, targeted the peripheral zone of the prostate with 24-38 cores using a 'sector plan'. Procedures were carried out under general anaesthetic in most patients. Between January 2007 and August 2011, 634 consecutive patients underwent TPSB for the following indications: prior negative transrectal biopsy (TRB; 174 men); primary biopsy in men at risk of sepsis (153); further evaluation after low-risk disease diagnosed based on a 12-core TRB (307). RESULTS: Prostate cancer was found in 36% of men after a negative TRB; 17% of these had disease solely in anterior sectors. As a primary diagnostic strategy, prostate cancer was diagnosed in 54% of men (median PSA level was 7.4 ng/mL). Of men with Gleason 3+3 disease on TRB, 29% were upgraded and went on to have radical treatment. Postoperative urinary retention occurred in 11 (1.7%) men, two secondary to clots. Per-urethral bleeding requiring hospital stay occurred in two men. There were no cases of urosepsis. CONCLUSIONS: TPSB of the prostate has a role in defining disease previously missed or under-diagnosed by TRB. The procedure has low morbidity.

Rehabilitation centers: marketing analysis and future challenges.

A rehabilitation center is another form of health care organization that specializes in providing care for particular conditions of patients. Patients admitted in rehab centers range from being accident victims to those suffering with a specific illness. These organizations are becoming extremely valuable in providing patient care services. However, they have not marketed themselves as aggressively as other health care organizations. This article provides an insight regarding rehab centers and examines marketing issues using a SWOT (strengths, weaknesses, opportunities, and threats) analysis. It further provides some future prospects and challenges for marketers of these organizations.

Pitfalls in Urinary Tract Cytopathology.

BACKGROUND: Urine cytopathology is a cost-effective method to diagnose and follow patients with high-grade urothelial carcinoma (UC). However, some benign, reactive, and metaplastic changes may mimic UC and pose a diagnostic challenge for cytopathologists. SUMMARY: Our comprehensive review focuses on summarizing common pitfalls encountered in urine cytopathology, based on the 2nd edition of The Paris System (TPS) for reporting urinary tract cytopathology and other recent published literature. These pitfalls include urothelial tissue fragments, degenerative changes, treatment effects, viral cytopathic changes, iatrogenic and metaplastic changes. Our aim was to provide a clear understanding of these mimics in order to avoid diagnostic errors. KEY MESSAGE: It is crucial for cytopathologists to recognize benign, reactive, or metaplastic lesions that sometimes resemble UC. An awareness of these cytological changes is essential to make an accurate diagnosis.

Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer.

OBJECTIVE: To determine if photodynamic 'blue-light'-assisted resection leads to lower recurrence rates in newly presenting non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We conducted a prospective randomized trial of hexylaminolevulinate (HAL) photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs standard white-light-assisted TURBT plus single-shot intravesical mitomycin C. A total of 249 patients with newly presenting suspected NMIBC enrolled at Guy's Hospital between March 2005 and April 2010. Patients with a history of bladder cancer were excluded. The surgery was performed by specialist bladder cancer surgical teams. Of the eligible patients, 90% agreed to be randomized. RESULTS: Of the 249 patients, 209 (84%) had cancer and in 185 patients (89%) the cancer was diagnosed as NMIBC. There were no adverse events related to HAL in any of the patients randomized to the intravesical HAL-PDD arm. Single-shot intravesical mitomycin C was administered to 61/97 patients (63%) in the HAL-PDD arm compared with 68/88 patients (77%) in the white-light arm (P = 0.04) Intravesical HAL was an effective diagnostic tool for occult carcinoma in situ (CIS). Secondary CIS was identified in 25/97 patients (26%) in the HAL-PDD arm compared with 12/88 patients (14%) in the white-light arm ((P = 0.04) There was no significant difference in recurrence between the two arms at 3 or 12 months: in the HAL-PDD and the white-light arms recurrence was found in 17/86 and 14/82 patients (20 vs 17%), respectively ((P = 0.7) at 3 months, and in 10/63 and 15/67 patients (16 vs 22%), respectively ((P = 0.4) at 12 months. CONCLUSIONS: Despite HAL-PDD offering a more accurate diagnostic assessment of a bladder tumour, in this trial we did not show that this led to lower recurrence rates of newly presenting NMIBC compared with the best current standard of care.