Karcinom sabirnih kanalića i endemska nefropatija - prikazi slučaja i pregled literature

Although collecting duct carcinoma is a subtype of renal cell carcinoma, several studies implicate association with urothelial carcinoma. The coexistence of collecting duct carcinoma and another renal neoplasm is rare. Endemic nephropathy is a renal disease causing chronic renal failure. It is highly associated with urothelial neoplasm and occurs in endemic villages in Bosnia, Croatia, Bulgaria, Romania and Serbia. Recent studies have confirmed the important role of exposure to aristolochic acid as an etiologic factor. We present three cases of collecting duct carcinoma with literature overview. In one case, we describe collecting duct carcinoma with metachronous urothelial carcinoma of the pyelon and urinary bladder in an endemic nephropathy patient. To our knowledge, this is the first case report describing this coexistence. Certain similarities between collecting duct carcinoma and urothelial carcinoma were found, e.g., higher incidence in female compared to male, higher mean age, and multifocal and multicentric occurrence of the tumor. Our observations support the hypothesis that collecting duct carcinoma and urothelial carcinoma could be connected.Iako je karcinom sabirnih kanalića podvrsta karcinoma bubrežnih stanica, određena istraživanja ukazuju na povezanost ovog entiteta s karcinomom prijelaznog epitela. Istodobna pojava karcinoma sabirnih kanalića i drugih bubrežnih neoplazma je rijetka. Endemska nefropatija je bubrežna bolest koja dovodi do kroničnog bubrežnog zatajenja. Vrlo je povezana s urotelnim tumorima i javlja se u endemskim selima u Bosni, Hrvatskoj, Bugarskoj, Rumunjskoj i Srbiji. Nedavna istraživanja potvrdila su značajnu ulogu izloženosti aristolohičnoj kiselini kao etiološkom čimbeniku. Predstavljamo tri slučaja karcinoma sabirnih kanalića s pregledom literature. U jednom slučaju opisujemo karcinom sabirnih kanalića s metakronom pojavom urotelnog karcinoma pijelona te mokraćnog mjehura u bolesnika s potvrđenom endemskom nefropatijom. Prema našim saznanjima ovo je prvi slučaj koji opisuje ovakvu koegzistenciju. Pronađene su određene sličnosti između karcinoma sabirnih kanalića i karcinoma prijelaznog epitela, a to su veća učestalost u ženskoj populaciji, viša prosječna dob, multifokalna i multicentrična pojava tumora. Naša zapažanja podupiru hipotezu o mogućoj povezanosti karcinoma sabirnih kanalića i karcinoma prijelaznog epitela

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence

The association of HLA region with endemic nephropathy and upper tract urothelial carcinoma in Croatia

Endemska nefropatija (EN) je kronična tubulointersticijska bolest bubrega kod koje se često javlja karcinom urotela gornjega urotrakta (UUC). Imunološki odgovor, u kojem ključnu ulogu imaju geni HLA, povezan je s nastankom brojnih bolesti. Cilj ovog rada bio je istražiti polimorfizam gena, alela i haplotipova lokusa HLA-A, -B i - DRB1 u skupini nesrodnih EN bolesnika (N=111; 52 bolesnika s UUC i 59 bolesnika bez UUC) u svrhu otkrivanja njihove moguće povezanosti s EN. Ispitana su i 52 zdrava srodnika i 190 zdravih nesrodnih osoba. Za određivanje polimorfizma HLA koristila se metoda lančane reakcije polimerazom u kombinaciji s oligunukleotidima specifičnih sekvenci (PCR-SSO) ili početnicama specifičnih sekvenci (PCR-SSP). Otkrivene su značajne razlike u zastupljenosti pojedinih alela HLA između skupine EN bolesnika i zdrave kontrole. U skupini EN bolesnika aleli HLA-A*01:01, B*57:01 i B*27:05 su bili značajno manje zastupljeni, dok je alel HLA-DRB1*04:02 bio značajno češće prisutan. Pozitivna povezanost s pojavom EN i UUC utvrđena je za haplotipove: HLA-B*18~DRB1*11 i HLA-B*44~DRB1*16 kao i produženi haplotip HLA-A*26:01~B*38:01~DRB1*04:02. Otkrivene su razlike u raspodjeli alela i haplotipova HLA s obzirom na dob pojave bolesti, kao i na preživljenje. Dobiveni rezultati ukazuju da su pojedini aleli i haplotipovi HLA potencijalno podložni, odnosno zaštitni genetski čimbenici za razvoj bolesti.Endemic nephropathy (EN) is a chronic tubulointerstitial kidney disease in which upper urothelial carcinoma (UUC) often occurs. The immune response and HLA genes have been linked with a number of diseases. Aim of this study was to analyze genes, alleles and haplotypes of HLA-A, -B and -DRB1 loci among EN patients (N=111; 52 patients with UUC and 59 patients without UUC) in order to investigate their possible role in EN etiology. In addition, analysis included 52 healthy relatives and 190 healthy unrelated individuals. HLA gene polymorphisms were determined by polymerase chain reaction methods in combination with oligonucleotides specific for HLA gene groups (PCR-SSO) or primers of specific sequences (PCR-SSP). Significant differences in distribution of several HLA alleles between EN patients and healthy controls were detected. The HLA-A*01:01, B*57:01 and B*27:05 alleles were significantly less present, while HLADRB1* 04:02 allele appeared significantly more frequently among EN patients. Positive corelation with the onset of EN and UUC was determined for HLAB* 18~DRB1*11 and HLA-B*44~DRB1*16 haplotypes, and HLAA* 26:01~B*38:01~DRB1*04:02 extended haplotype. Differences in distribution of alleles and haplotypes were also detected in correlation to age of disease onset and survival. Obtained data demonstrate that investigated HLA loci could be potential susceptibility/protection genetic markers for disesase development

Variation in Presentation and Presence of DNA Adducts and p53 Mutations in Patients with Endemic Nephropathy - an Environmental Form of the Aristolochic Acid Nephropathy

Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms

Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid

Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in the urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from nonendemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by 32P-postlabeling, the adduct was confirmed by mass spectrometry, and TP53 mutations in tumor tissues were identified by chip sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in nonendemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients

Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies