Renal mass biopsy - a practical and clinicopathologically relevant approach to diagnosis.

Advancements in imaging modalities have increased the frequency of renal mass discovery. Imaging has typically been considered sufficient to guide management for a large proportion of these tumours, but renal mass biopsies (RMBs) have an increasing role in determining malignancy and can be a valuable tool for preventing unnecessary surgery in patients with benign tumours. A structured approach should be used to help to navigate the expanding repertoire of renal tumours, many of which are molecularly defined. In terms of tumour subtyping, the pathologist's strategy should focus on stratifying patients into clinically different prognostic groups according to our current knowledge of tumour behaviour, including benign, low-grade or indolent, intermediate malignant or highly aggressive. Crucial pathological features and morphological mimicry of tumours can alter the tumour's prognostic group. Thus, pathologists and urologists can use RMB to select patients with tumours at a reduced risk of progression, which can be safely managed with active surveillance within a tailored imaging schedule, versus tumours for which ablation or surgical intervention is indicated. RMB is also crucial in the oncological setting to distinguish between different high-grade tumours and guide tailored management strategies.

Transcriptome profiling of lumpfish (Cyclopterus lumpus) head kidney to Renibacterium salmoninarum at early and chronic infection stages.

Renibacterium salmoninarum causes Bacterial Kidney Disease (BKD) in several fish species. Atlantic lumpfish, a cleaner fish, is susceptible to R. salmoninarum. To profile the transcriptome response of lumpfish to R. salmoninarum at early and chronic infection stages, fish were intraperitoneally injected with either a high dose of R. salmoninarum (1 × 109 cells dose-1) or PBS (control). Head kidney tissue samples were collected at 28- and 98-days post-infection (dpi) for RNA sequencing. Transcriptomic profiling identified 1971 and 139 differentially expressed genes (DEGs) in infected compared with control samples at 28 and 98 dpi, respectively. At 28 dpi, R. salmoninarum-induced genes (n = 434) mainly involved in innate and adaptive immune response-related pathways, whereas R. salmoninarum-suppressed genes (n = 1537) were largely connected to amino acid metabolism and cellular processes. Cell-mediated immunity-related genes showed dysregulation at 98 dpi. Several immune-signalling pathways were dysregulated in response to R. salmoninarum, including apoptosis, alternative complement, JAK-STAT signalling, and MHC-I dependent pathways. In summary, R. salmoninarum causes immune suppression at early infection, whereas lumpfish induce a cell-mediated immune response at chronic infection. This study provides a complete depiction of diverse immune mechanisms dysregulated by R. salmoninarum in lumpfish and opens new avenues to develop immune prophylactic tools to prevent BKD.

Epitheloid Angiomyolipomas of the Kidney: Rare Renal Tumors Associated With Poor Prognoses.

OBJECTIVE: To demonstrate the clinical spectrum and challenges associated with clinical management of epitheloid angiomyolipomas (eAML). METHODS: We retrospectively reviewed the surgical database of a high-volume tertiary kidney cancer center from 2015 to 2020 to identify cases with a final histological diagnosis of eAML. Descriptive analysis of all cases was conducted. RESULTS: Five surgical cases of eAMLs were identified. Two of which have had no tumor recurrence since surgery, and three patients passed away due to disease progression. CONCLUSION: eAML are rare renal tumors which the World Health Organisation (5th Edition, 2022) and International Classification of Diseases for Oncology classify as having unspecified, borderline, or uncertain behavior. Here, we report that can also demonstrate aggressive behavior with fatal consequences. Post-operative follow-up should be recommended for all, with shorter intervals for patients with poor prognostic factors.

Case Report: Disease progression of renal cell carcinoma containing a novel putative pathogenic KAT6A::NRG1 fusion on Ipilimumab- Nivolumab immunotherapy. A case study and review of the literature.

Renal cell carcinoma still carries a poor prognosis despite therapeutic advancements. Detection of genetic mutations is vital in improving our understanding of this disease as well as potential role in targeted therapy. Here we present a case of a 49 year old man with an aggressive renal cell carcinoma bearing a novel pathogenic KAT6A::NRG1 fusion. We will explore the clinical presentation, histological and molecular diagnostics, treatment and disease progression. We will discuss the relevance of this unique fusion and comparisons with cancer cases with similar genetic mutations. Further research is warranted for such cases, in order to facilitate better targeted treatments.

Defining the origin, evolution, and immune composition of SDH-deficient renal cell carcinoma.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma represents a rare subtype of hereditary kidney cancer. Clinical diagnosis can be challenging and there is little evidence to guide systemic therapeutic options. We performed genomic profiling of a cohort of tumors through the analysis of whole genomes, transcriptomes, as well as flow cytometry and immunohistochemistry in order to gain a deeper understanding of their molecular biology. We find neutral evolution after early tumor activation with a lack of secondary driver events. We show that these tumors have epithelial derivation, possibly from the macula densa, a specialized paracrine cell of the renal juxtaglomerular apparatus. They subsequently develop into immune excluded tumors. We provide transcriptomic and protein expression evidence of a highly specific tumor marker, PAPPA2. These translational findings have implications for the diagnosis and treatment for this rare tumor subtype.

Lumpfish (Cyclopterus lumpus) Is Susceptible to Renibacterium salmoninarum Infection and Induces Cell-Mediated Immunity in the Chronic Stage.

Renibacterium salmoninarum is a Gram-positive, intracellular pathogen that causes Bacterial Kidney Disease (BKD) in several fish species in freshwater and seawater. Lumpfish (Cyclopterus lumpus) is utilized as a cleaner fish to biocontrol sea lice infestation in Atlantic salmon (Salmo salar) farms. Atlantic salmon is susceptible to R. salmoninarum, and it can transfer the infection to other fish species. Although BKD outbreaks have not been reported in lumpfish, its susceptibility and immune response to R. salmoninarum is unknown. In this study, we evaluated the susceptibility and immune response of lumpfish to R. salmoninarum infection. Groups of lumpfish were intraperitoneally (i.p.) injected with either R. salmoninarum (1×107, 1×108, or 1×109 cells dose-1) or PBS (control). R. salmoninarum infection kinetics and mortality were followed for 98 days post-infection (dpi). Transcript expression levels of 33 immune-relevant genes were measured in head kidney (n = 6) of fish infected with 1×109 cells/dose and compared to the control at 28 and 98 dpi. Infected lumpfish displayed characteristic clinical signs of BKD. Lumpfish infected with high, medium, and low doses had a survival rate of 65%, 93%, and 95%, respectively. Mortality in the high-dose infected group stabilized after 50 dpi, but R. salmoninarum persisted in the fish tissues until 98 dpi. Cytokines (il1ß, il8a, il8b), pattern recognition receptors (tlr5a), interferon-induced effectors (rsad2, mxa, mxb, mxc), and iron regulation (hamp) and acute phase reactant (saa5) related genes were up-regulated at 28 dpi. In contrast, cell-mediated adaptive immunity-related genes (cd4a, cd4b, ly6g6f, cd8a, cd74) were down-regulated at 28 dpi, revealing the immune suppressive nature of R. salmoninarum. However, significant upregulation of cd74 at 98 dpi suggests induction of cell-mediated immune response. This study showed that R. salmoninarum infected lumpfish in a similar fashion to salmonid fish species and caused a chronic infection, enhancing cell-mediated adaptive immune response.

Oral Immunization of Larvae and Juvenile of Lumpfish (Cyclopterus lumpus) against Vibrio anguillarum Does Not Influence Systemic Immunity.

Vibrio anguillarum, a marine bacterial pathogen that causes vibriosis, is a recurrent pathogen of lumpfish (Cyclopterus lumpus). Lumpfish is utilized as a cleaner fish in the Atlantic salmon (Salmo salar) aquaculture in the North Atlantic region because of its ability to visualize and prey on the ectoparasite sea lice (Lepeophtheirus salmonis) on the skin of Atlantic salmon, and its performance in cold environments. Lumpfish immunity is critical for optimal performance and sea lice removal. Oral vaccine delivery at a young age is the desired method for fish immunization because is easy to use, reduces fish stress during immunization, and can be applied on a large scale while the fish are at a young age. However, the efficacy of orally delivered inactivated vaccines is controversial. In this study, we evaluated the effectiveness of a V. anguillarum bacterin orally delivered to cultured lumpfish and contrasted it to an intraperitoneal (i.p.) boost delivery. We bio-encapsulated V. anguillarum bacterin in Artemia salina live-feed and orally immunized lumpfish larvae. Vaccine intake and immune response were evaluated by microscopy and quantitative polymerase chain reaction (qPCR) analysis, respectively. qPCR analyses showed that the oral immunization of lumpfish larvae resulted in a subtle stimulation of canonical immune transcripts such as il8b, il10, igha, ighmc, ighb, ccl19, ccl20, cd8a, cd74, ifng, and lgp2. Nine months after oral immunization, one group was orally boosted, and a second group was both orally and i.p. boosted. Two months after boost immunization, lumpfish were challenged with V. anguillarum (7.8 × 105 CFU dose-1). Orally boosted fish showed a relative percentage of survival (RPS) of 2%. In contrast, the oral and i.p. boosted group showed a RPS of 75.5% (p < 0.0001). V. anguillarum bacterin that had been orally delivered was not effective in lumpfish, which is in contrast to the i.p. delivered bacterin that protected the lumpfish against vibriosis. This suggests that orally administered V. anguillarum bacterin did not reach the deep lymphoid tissues, either in the larvae or juvenile fish, therefore oral immunization was not effective. Oral vaccines that are capable of crossing the epithelium and reach deep lymphoid tissues are required to confer an effective protection to lumpfish against V. anguillarum.

Biosorbent derived from coffee husk for efficient removal of toxic heavy metals from wastewater.

In this study, we investigated the feasibility on the utilization of coffee husk as biosorbents for the removal of heavy metal ions such as Pb2+ and Cd2+ from wastewater. Biochar was produced from coffee wastes and modified with sodium hydroxide to create functional groups on the surface and increase the specificic surface area. The resultant products were characterized by using various analytical methods such as scanning electron microscopy, specific area, surface functional group and zeta potential analysis. The as-prepared materials were employed as adsorbent to remove Pb2+ and Cd2+ ions from wastewater. The maximum sorption capacities of biosorbents were measured to be 116.3 and 139.5 mg g-1 for Cd2+ and Pb2+, respectively, which is comparable to the conventional adsorbents. Kinetic studies showed that the sorption of Pb2+ and Cd2+ on biosorbents can be described by the Freundlich isotherm and second-order kinetic model. The coffee husk-derived biosorbent was capable of removing 89.6% of Pb2+ and 81.5% Cd2+ ions from wastewater, and therefore can be considered as low-cost and efficient adsorbent to remove heavy metal ions from wastewater.

Enhanced recovery of phosphate as a value-added product from wastewater by using lanthanum modified carbon-fiber.

The aim of this study is to present the potential of activated carbon fiber (CF) impregnated with lanthanum (La) as a novel adsorbent (La-CF) of phosphate-phosphorus (P) and to assess the value-added due to P-recovery from wastewater using La-CF. The CF were loaded with La and the loaded CF was then calcined at 500 °C. The La-CF adsorbent was used in a series of batch experiments to characterize the adsorption of P at pH of 6-10 and P concentrations of 1-200 mg/L. Physical-chemical properties such as surface morphology, surface charge, surface area, and surface chemistry were determined for the La-CF. The La-CF exhibited adsorption capacity of 196.5 mg/g, fast sorption kinetics and high selectivity for P removal from aqueous solution. La-CF removed 97.3% of P from wastewater and achieved P-level to below 2 mg/L. It was repetitively reused over 10 times in successive cycles to remove P from wastewater. The value-added by recovery of P from wastewater was calculated at around 0.12 US$/L, demonstrating economic benefits of La-CF. In conclusion, the successful removal, recycling, and recovery value-added of P using La-CF adsorbent displayed good potential for developing the technology for treatment of wastewaters to recover valuable compounds such as phosphorus.

Impact of the first surge of the COVID-19 pandemic on a tertiary referral centre for kidney cancer.

OBJECTIVE: To analyse the impact of the COVID-19 pandemic on a centralized specialist kidney cancer care pathway. MATERIALS AND METHODS: We conducted a retrospective analysis of patient and pathway characteristics including prioritization strategies at the Specialist Centre for Kidney Cancer located at the Royal Free London NHS Foundation Trust (RFH) before and during the surge of COVID-19. RESULTS: On 18 March 2020 all elective surgery was halted at RFH to redeploy resources and staff for the COVID-19 surge. Prioritizing of patients according to European Association of Urology guidance was introduced. Clinics and the specialist multidisciplinary team (SMDT) meetings were maintained with physical distancing, kidney surgery was moved to a COVID-protected site, and infection prevention measurements were enforced. During the 7 weeks of lockdown (23 March to 10 May 2020), 234 cases were discussed at the SMDT meetings, 53% compared to the 446 cases discussed in the 7 weeks pre-lockdown. The reduction in referrals was more pronounced for small and asymptomatic renal masses. Of 62 low-priority cancer patients, 27 (43.5%) were deferred. Only one (4%) COVID-19 infection occurred postoperatively, and the patient made a full recovery. No increase in clinical or pathological upstaging could be detected in patients who underwent deferred surgery compared to pre-COVID practice. CONCLUSION: The first surge of the COVID-19 pandemic severely impacted diagnosis, referral and treatment of kidney cancer at a tertiary referral centre. With a policy of prioritization and COVID-protected pathways, capacity for time-sensitive oncological interventions was maintained and no immediate clinical harm was observed.

Growth and renal function dynamics of renal oncocytomas in patients on active surveillance.

OBJECTIVES: To study the natural history of renal oncocytomas and address indications for intervention by determining how growth is associated with renal function over time, the reasons for surgery and ablation, and disease-specific survival. PATIENTS AND METHODS: The study was conducted in a retrospective cohort of consecutive patients with renal oncocytoma on active surveillance reviewed at the Specialist Centre for Kidney Cancer at the Royal Free London NHS Foundation Trust (2012 to 2019). Comparison between groups was performed using Mann-Whitney U-tests and chi-squared tests. A mixed-effects model with a random intercept for patient was used to study the longitudinal association between tumour size and estimated glomerular filtration rate (eGFR). RESULTS: Longitudinal data from 98 patients with 101 lesions were analysed. Most patients were men (68.3%) and the median (interquartile range [IQR]) age was 69 (13) years. The median (IQR) follow-up was 29 (26) months. Most lesions were small renal masses, and 24% measured over 4 cm. Over half (64.4%) grew at a median (IQR) rate of 2 (4) mm per year. No association was observed between tumour size and eGFR over time (P = 0.871). Nine lesions (8.9%) were subsequently treated. Two deaths were reported, neither were related to the diagnosis of renal oncocytoma. CONCLUSION: Natural history data from the largest active surveillance cohort of renal oncocytomas to date show that renal function does not seem to be negatively impacted by growing oncocytomas, and confirms clinical outcomes are excellent after a median follow-up of over 2 years. Active surveillance should be considered the 'gold standard' management of renal oncocytomas up to 7cm.

Pattern, timing and predictors of recurrence after surgical resection of chromophobe renal cell carcinoma.

PURPOSE: Currently there are no specific guidelines for the post-operative follow-up of chromophobe renal cell carcinoma (chRCC). We aimed to evaluate the pattern, location and timing of recurrence after surgery for non-metastatic chRCC and establish predictors of recurrence and cancer-specific death. METHODS: Retrospective analysis of consecutive surgically treated non-metastatic chRCC cases from the Royal Free London NHS Foundation Trust (UK, 2015-2019) and the international collaborative database RECUR (15 institutes, 2006-2011). Kaplan-Meier curves were plotted. The association between variables of interest and outcomes were analysed using univariate and multivariate Cox proportional hazards regression models with shared frailty for data source. RESULTS: 295 patients were identified. Median follow-up was 58 months. The five and ten-year recurrence-free survival rates were 94.3% and 89.2%. Seventeen patients (5.7%) developed recurrent disease, 13 (76.5%) with distant metastases. 54% of metastatic disease diagnoses involved a single organ, most commonly the bone. Early recurrence (< 24 months) was observed in 8 cases, all staged ≥ pT2b. 30 deaths occurred, of which 11 were attributed to chRCC. Sarcomatoid differentiation was rare (n = 4) but associated with recurrence and cancer-specific death on univariate analysis. On multivariate analysis, UICC/AJCC T-stage ≥ pT2b, presence of coagulative necrosis, and positive surgical margins were predictors of recurrence and cancer-specific death. CONCLUSION: Recurrence and death after surgically resected chRCC are rare. For completely excised lesions ≤ pT2a without coagulative necrosis or sarcomatoid features, prognosis is excellent. These patients should be reassured and follow-up intensity curtailed.

Aeromonas salmonicida infection kinetics and protective immune response to vaccination in sablefish (Anoplopoma fimbria).

Effective vaccine programs against Aeromonas salmonicida have been identified as a high priority area for the sablefish (Anoplopoma fimbria) aquaculture. In this study, we established an A. salmonicida infection model in sablefish to evaluate the efficacy of commercial vaccines and an autogenous vaccine preparation. Groups of 40 fish were intraperitoneally (ip) injected with different doses of A. salmonicida J410 isolated from infected sablefish to calculate the median lethal dose (LD50). Samples of blood, head kidney, spleen, brain, and liver were also collected at different time points to determine the infection kinetics. The LD50 was estimated as ~3 × 105 CFU/dose. To evaluate the immune protection provided by an autogenous vaccine and two commercial vaccines in a common garden experimental design, 140 fish were PIT-tagged, vaccinated and distributed equally into 4 tanks (35 fish for each group, including a control group). Blood samples were taken every 2 weeks to evaluate IgM titers. At 10 weeks post-immunization, all groups were ip challenged with 100 times the calculated LD50 for A. salmonicida J410. A. salmonicida was detected after 5 days post-infection (dpi) in all collected tissues. At 30 days post-challenge the relative percentage survival (RPS) with respect to the control group was calculated for each vaccine. The RPS for the bacterin mix was 65.22%, for Forte Micro 4® vaccine was 56.52% and for Alpha Ject Micro 4® was 30.43%, and these RPS values were reflected by A. salmonicida tissue colonization levels at 10 days post-challenge. Total IgM titers peaked at 6-8 weeks post-immunization, where the autogenous vaccine group showed the highest IgM titers and these values were consistent with the RPS data. Also, we determined that the A. salmonicida A-layer binds to immunoglobulins F(ab)' in a non-specific fashion, interfering with immune assays and potentially vaccine efficacy. Our results indicate that vaccine design influences sablefish immunity and provide a guide for future sablefish vaccine programs.

Type 2 Diabetic Retinopathy Screening in a General Practice: A Five-Year Retrospective Analysis.

Aim To assess current standards of diabetic retinopathy screening in primary care against the National Institute of Clinical Excellence (NICE) guidelines for type 2 diabetes mellitus. Moreover, to determine whether individuals with diabetes were screened for diabetic retinopathy no later than three months from referral to the local eye screening service and no later than one year from their last retinal screen. Materials and methods A single-center, retrospective audit was undertaken at a small general practice. Data was collected from the health records of individuals placed on the type 2 diabetes register from 01/01/2013 to 01/01/2018. Individuals who were diagnosed with diabetes whilst registered at a different practice, who had pre-diabetic retinal screening or were referred onto a different screening pathway were excluded. A total of 50 records were audited and data collection involved demographics, dates individuals were placed on the diabetes register and dates of attendance and non-attendance to screening. Results 16.0% of individuals with type 2 diabetes underwent retinal screening which adhered to the NICE guidelines. Of the cohort which did not adhere, 59.5% experienced an interval greater than three months between diagnosis and first retinal screening and 64.3% experienced a screening interval greater than one year. Conclusions Diabetic retinopathy screening of individuals must be improved to meet the NICE standards. Interventions should be implemented to increase the awareness within general practitioners and practice nurses to ensure all people with diabetes receive their first retinal screen within the first three months of diagnosis with regular annual screening thereafter.

Recurrent swelling and pain in the abdomen and joints in a patient with hereditary angioedema and Ehlers-Danlos syndrome.

A 23-year-old woman was referred to the allergy and immunology clinic for recurrent abdominal, cutaneous and joint swelling and pain with a history of mucosal infections since childhood. Her history and clinical findings were suggestive of two rare and complex disorders, hereditary angioedema (HAE) and Ehlers-Danlos syndrome (EDS). Her recurrent episodes of abdominal and joint pain were initially misattributed to more common diagnoses such as esophagitis, depression and chronic pain syndrome. However, the coexistence of HAE and EDS likely contributed to a delay in diagnoses as the combination of these two rare but overlapping disorders is less understood by physicians. She had persistently low levels of C4 and C1-esterase inhibitor (C1-INH) with low to low-normal C1-esterase function, normal C1Q and no C1Q antibodies. In the setting of recurrent abdominal pain with cutaneous swelling, this supported the diagnosis of HAE type I. The increase in joint extensibility with recurrent shoulder subluxations since childhood was a manifestation of EDS. Although no known genetic mutations were identified for EDS, her diagnosis was confirmed by a geneticist based on her clinical phenotype. Before the diagnosis of HAE and EDS, our patient had at least 100 visits/year to the emergency department/hospitalisations for these recurrent symptoms. After starting on C1-INH replacement therapy, the frequency has decreased 10-fold. She also noted a 70% improvement in her quality of life. Familiarity with these rare disorders will assist healthcare providers in recognising HAE and EDS and include them as part of their differential diagnoses. Early diagnosis is important for a patient's well-being as both these chronic disorders have been associated with poor quality of life. Additionally, proper diagnoses will reduce healthcare costs by preventing unnecessary procedures due to misdiagnoses. Proper treatment will help to decrease hospitalisations and avoidance of life-threatening consequences (such as asphyxiation from fatal laryngeal attacks of HAE and rupture of aneurysms in EDS).

First-in-human in vivo non-invasive assessment of intra-tumoral metabolic heterogeneity in renal cell carcinoma.

Intratumoral genetic heterogeneity and the role of metabolic reprogramming in renal cell carcinoma (RCC) have been extensively documented. However, the distribution of these metabolic changes within the tissue has not been explored. We report on the first-in-human in vivo non-invasive metabolic interrogation of RCC using hyperpolarized carbon-13 (13C) magnetic resonance imaging (HP-MRI) and describe the validation of in vivo lactate metabolic heterogeneity against multi-regional ex vivo mass spectrometry. HP-MRI provides an in vivo assessment of metabolism and provides a novel opportunity to safely and non-invasively assess cancer heterogeneity.