Consultation on UTUC II Stockholm 2022: diagnostics, prognostication, and follow-up-where are we today?

PURPOSE: To summarise the current knowledge regarding diagnostics, prognostication and follow-up in upper tract urothelial carcinoma (UTUC). METHODS: A scoping review combined with expert opinion was applied to provide an overview of the current research field. Based on the published literature and the experts' own experience and opinions, consensus was reached through presentations and discussions at the meeting Consultation on UTUC II in Stockholm 2022. RESULTS: The strongest prognostic factors in UTUC are tumour grade and stage. They are correlated, and grade is used for indirect staging. The diagnostic examinations should include multiphase computed tomography urography (CTU) with corticomedullary phase, and urethrocystoscopy with cytology. If there is no clear diagnosis for clinical decision-making, ureterorenoscopy (URS) with focal cytology and biopsies should be performed. Both WHO classification systems (1973/1999 and 2004/2016) should be used. Novel biomarker tests are not yet widespread nor recommended for the detection of UTUC. Long-term, regular follow-up, including URS in patients who have had organ-sparing treatment, is important to check for tumour recurrences, intravesical recurrences, metastases and progression of the tumour. CONCLUSION: Proper diagnostics with correct grading of UTUC are necessary for appropriate treatment decisions. The diagnostics should include CTU with corticomedullary phase, urine or bladder cytology, URS with focal barbotage cytology, and biopsies when needed for proper diagnosis and risk stratification. Regular, long-term follow-ups are fundamental, due to the high rate of recurrence and risk of progression.

A balance between putting on the researcher's hat and being a fellow human being: a researcher perspective on informal carer involvement in health and social care research.

BACKGROUND: Public involvement in health and social care research is increasingly prioritized by policy-makers and research funders. Often, the impact of the involvement is described in terms of how it has contributed to the research outcomes and how it has affected the involved members of the public. There is a dearth of studies reporting from the perspective of researchers themselves of having involved members of the public in their research. Nevertheless, there is a general expectation for researchers to accept and embrace public involvement in research. This study aims to explore researchers' views of involving informal carers in health and social care research. METHODS: Eleven individual in-depth interviews with researchers in the fields of social work, caring science, health science and medical science constituted the dataset of this qualitative study, inspired by discourse psychology. RESULTS: The qualitative data analysis resulted in two interpretative repertoires describing researchers' views of involving informal carers in research, "Philosophy of Science" and "Personal relationships and growth". Both repertoires need to be recognized; however, as of today, the Philosophy of Science repertoire is more acknowledged, while the second repertoire describing empathy, relationships and emotions may be viewed as the researcher being "unprofessional". Further, the findings highlighted the dual perspective of being a researcher and a carer as creating opportunities for growth on the part of the researcher, on both a professional and a personal level. CONCLUSIONS: Researchers and their research work would benefit from acknowledging, discussing and reporting both interpretative repertoires in their publications, as well as recognizing the benefit of dialectal positions, for example, having a dual perspective as both a researcher and an informal carer.

S-phase - an independent prognostic marker in upper tract urothelial carcinoma.

OBJECTIVES: To evaluate S-phase fraction as a predictor of invasiveness and cancer-specific survival in upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: One hundred and fifteen patients having undergone radical nephroureterectomy were analysed with histology in radical nephroureterectomy specimens as reference test and S-phase fraction as index test. Ploidy and S-phase were determined using flow cytometry. Differences in S-phase fraction were calculated between stages, grades (WHO 1999 and 2004 classifications), ploidy and patients that died of UTUC and those who did not. Five- and 10-year-cancer-specific survivals were calculated. Areas under the ROC curve (AUCs) of S-phase fraction in relation to tumour stage and to death from UTUC were measured. Multiple Cox regression was performed. RESULTS: Independent prognostic markers of death from UTUC were S-phase fraction and stage. Correlation between S-phase fraction and risk of dying from UTUC was strong, with a 17% greater risk of death from UTUC with every 1% increase in S-phase fraction, hazard ratio = 1.17, 95% CI = 1.10-1.25, p < 0.001, Spearman's rho ρ = 0.65. AUCs for S-phase fraction as predictors of stage and death from UTUC were 0.8 (95% CI = 0.705-0.894) and 0.77 (95% CI = 0.67-0.87), respectively. Cancer-specific survival was statistically significantly different between stages, ploidy and WHO 1999 grades, but not between WHO 2004 grades. This was also reflected in S-phase fraction, which differed in LG-G1 compared with LG-G2 and in HG-G2 compared with HG-G3. CONCLUSION: S-phase fraction was a good test for predicting both invasiveness and cancer-specific survival. Using both WHO 1999 and 2004 classifications, rather than one system alone, had a higher predictive value of cancer-specific survival.

Genomic profile - a possible diagnostic and prognostic marker in upper tract urothelial carcinoma.

OBJECTIVES: To investigate gene alterations as diagnostic and prognostic markers in upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: Patients with UTUC who underwent nephroureterectomy between 2005 and 2012 were followed until November 2020. DNA was extracted from paraffin-embedded tumour tissue. Next-generation sequencing using a 388-gene panel was performed. First a blinded analysis using principal component analysis and hierarchical clustering was used to search for patterns of mutations. Then a comparative analysis using analysis of variance (ANOVA) was used to search for mutations enriched in groups of various grades, stages, and survival. In addition, careful manual annotation was used to identify pathogenic mutations over-represented in tumours of high grade/stage and/or poor survival. RESULTS: A total of 39 patients were included. All tumour stages and grades were represented in the cohort. The median follow-up was 10.6 years. In all, 11 patients died from UTUC during the follow-up. Tumour mutational burden showed a statistically significant correlation with stage, grade, and stage + grade. Grade 1, Grade 2, and Grade 3 tumours had different mutational patterns. Patients who died from UTUC had pathogenic mutations in specific genes e.g. tumour protein p53 (TP53) and HRas proto-oncogene, GTPase (HRAS). Patients with Ta Grade 1 tumours with a known pathogenic fibroblast growth factor receptor 3 (FGFR3) mutation did not die from UTUC. CONCLUSION: The genetic analysis was highly concordant with histopathological features and added prognostic information in some cases. Thus, results from genomic profiling may contribute to the choice of treatment and follow-up regimens in the future.

What motivates informal carers to be actively involved in research, and what obstacles to involvement do they perceive?

BACKGROUND: Due to demographic changes and a strained public sector operating in many countries globally, informal care is increasing. Currently, at least 1.3 million adults in Sweden regularly provide help, support and/or care to a family member/significant other. With no sign of an imminent decrease in their caring activities, it is important that informal carers are considered as a key stakeholder group within research that affects them, e.g., the co-design of carer and/or dyadic support interventions. The objective of this descriptive, quantitative study was to investigate informal carers' perceived motivations and obstacles to become involved in research. METHODS: A cross-sectional survey design was adopted, using first-wave data from a panel study. The data, collected in Sweden between September 2019 and March 2020, included survey responses from 147 informal carers who were either aged 60+ years themselves or were caring for someone who was aged 60+ years. RESULTS: Our main results showed that informal carers are, in general, interested in research. Slightly fewer were interested in becoming actively involved themselves, but older age was the only characteristic significantly associated with less interest of being actively involved. Two latent motivational dimensions emerged from the factor analysis: 'family motivation' and 'the greater good motivation'. These, according to our results, almost equally valued dimensions, described the differing reasons for informal carers to become involved in research. The most common perceived obstacle was lack of time and it was reported by more women than men. CONCLUSION: Our study contributes with new knowledge of informal carers' perceived motivations and obstacles regarding carer involvement in research. Paying attention to the differing motivational dimensions held by informal carers could help researchers create conditions for more inclusive and systematic participation of informal carers within research. Thereby, increasing the opportunities for research that is deemed to be of higher societal impact. IRRID (International Registered Report Identifier): RR2-10.2196/17759.

Around 1.3 million adults in Sweden give help, support and care to an ill, aged or disabled family member, neighbour or friend. As informal carers contribute a lot to our societies, it is important to recognise them and, where possible, to involve them in research that affects them, together with patients and professionals. The rationale for our study is the current lack of studies on carers' views of being involved in research. 147 carers aged 60+, or who were caring for a person 60+ answered a survey that asked about carers' motivations for and obstacles to being actively involved in research. By actively involved, we mean that participation was more than filling in a questionnaire or one single interview. We found that carers are, in general, interested in research. Slightly fewer were interested in becoming actively involved themselves. Older age was the only characteristic associated with less interest of being actively involved. A statistical test showed two motivational categories; 'family motivation' and 'the greater good motivation'. These almost equally valued categories described the different reasons for carers to become involved in research. The most common obstacle was lack of time and more women than men reported this. This study adds new knowledge about carer involvement in research. The results of our study could help researchers to create a more supportive climate for actively involving carers in research. For example, by finding more flexible and creative ways to recruit carers and carry out research with them.

Predicting invasiveness and disease-specific survival in upper tract urothelial carcinoma: identifying relevant clinical tumour characteristics.

PURPOSE: The aim of this prospective study was to identify the tumour characteristics that are associated with invasiveness and those that are relevant for disease-specific survival (DSS) in upper tract urothelial carcinoma, UTUC. METHODS: From a prospective consecutive cohort of patients with suspicion of UTUC, those who were diagnosed with UTUC using URS prior to rNU between 2005 and 2012 were included. Tumour characteristics were analysed for prediction of invasiveness and association with DSS. Stages were categorised as superficial (pTa-1 and CIS only) or invasive (≥  pT2). Tumours were graded according to WHO 1999 classification. DSS was analysed regarding possible association with stage, grade, size, multifocality, location, ploidy and rate of proliferation. Associations were tested using Fisher's exact test, Pearson Chi-square or Cox's regression. Kaplan-Meier survival curves were constructed. RESULTS: Forty-five consecutive patients were included, and 43 of them were included in the final analyses because their rNU specimens were available for reassessment. The only tumour characteristics that were significantly associated with stage were tumour grade (P < 0.001), DNA ploidy (P = 0.045) and rate of proliferation (P = 0.004). No association with stage was noted for size, multifocality or location. Grade, stage and rate of proliferation were associated with DSS. CONCLUSIONS: Grade, DNA ploidy and S-phase fraction were the only tumour characteristics associated with stage in our study. However, DNA ploidy was not associated with DSS. The prognostic factors that we identified were tumour grade, stage, and S-phase fraction.

Diagnostic accuracy of upper tract urothelial carcinoma: how samples are collected matters.

OBJECTIVES: The aims of this study were to determine the accuracy and reliability of cytology, histopathology and ploidy of specimens obtained at ureterorenoscopy, to evaluate the importance of how samples are collected and to determine whether cytology is an alternative to histology of biopsies. METHODS: This prospective study investigated the accuracy of grading of endoscopically taken cytology and histopathology samples from 45 consecutive patients by comparing these with subsequent nephroureterectomy specimens. Histopathology grading was done according to WHO 1999 and 2004 classifications. Ploidy was determined using photospectrometry. RESULTS: Forty-five patients were included. Both cytology and histopathology identified almost all cancers (91% and 94%, respectively) in collected samples. In cytology as well as in histopathology, agreement in grade between barbotage and nephroureterectomy specimens was statistically significant for both 1999 and 2004 WHO classifications. All cancers in the endoscopic biopsies were identified as pathological, although the grading was not correct in all cases. A statistically significant correlation was found between grade and ploidy in grade 1 and grade 3 nephroureterectomy specimens. CONCLUSIONS: Specimens collected at ureterorenoscopy (biopsies for histology, barbotages for cytology and analysis of ploidy) proved to be relevant and useful. Barbotage cytology identified 91% of all cancers, a high rate compared to techniques used in other studies, and was also sensitive in detecting low-grade tumours. Barbotage cytology and biopsy histology were equally efficient in detecting cancer. The authors recommend that both barbotage and biopsy be performed in addition to complete ureterorenoscopy. Moreover, if there is no visible lesion, cytology is the only reliable option.

Diagnostic accuracy of computed tomography urography and visual assessment during ureterorenoscopy in upper tract urothelial carcinoma.

OBJECTIVE: To investigate diagnostic accuracy of multiphase computed tomography urography (MCTU) and visual assessment at ureterorenoscopy (URS) for detection of upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: Consecutive patients referred to our tertiary care centre were included in a prospective study covering the period 2005 to 2012. The patients underwent initial imaging and URS with focal samples taken. Cytopathological results served as reference standard. RESULTS: We investigated 174 renal units (RUs; renal pelvis and adjacent ureter) in 148 patients. UTUC was found in 104 RUs. MCTU had an accuracy of 0.74, sensitivity of 0.89, specificity of 0.51, positive predictive value of 0.73, and negative predictive value of 0.75; corresponding values for URS were 0.84, 0.84, 0.85, 0.89, and 0.78, respectively. MCTU had significantly higher sensitivity and accuracy compared with other imaging techniques (P<0.05). Compared with MCTU, URS had similar sensitivity but significantly greater specificity and accuracy. CONCLUSION: Both MCTU and URS are important tools in the diagnostic evaluation of UTUC although neither of those techniques achieves 100% accuracy. MCTU should be chosen as the radiographical method if there are no contraindications and URS should always be combined with focal cytology and biopsies of suspicious lesions. To enhance diagnostic precision both MCTU and URS with focal samples should be included in the diagnostic procedure. The present results add impact to current diagnostic guidelines.