SUMMARYChronic kidney disease (CKD) represents a major health burden1. Its central feature of renal fibrosis is not well understood. By whole exome resequencing in a model disorder for renal fibrosis, nephronophthisis (NPHP), we identified mutations of Fanconi anemia-associated nuclease 1 (FAN1) as causing karyomegalic interstitial nephritis (KIN). Renal histology of KIN is indistinguishable from NPHP except for the presence of karyomegaly2. FAN1 has nuclease activity, acting in DNA interstrand crosslinking (ICL) repair within the Fanconi anemia pathway of DNA damage response (DDR)3–6. We demonstrate that cells from individuals with FAN1 mutations exhibit sensitivity to the ICL agent mitomycin C. However, they do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from patients with Fanconi anemia. We complement ICL sensitivity with wild type FAN1 but not mutant cDNA from individuals with KIN. Depletion of fan1 in zebrafish revealed increased DDR, apoptosis, and kidney cysts akin to NPHP. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms of renal fibrosis and CKD.

Data on 709 patients who had a resection for colorectal carcinoma at Concord Hospital between 1971 and 1980 were studied to determine the independent effects on survival of several patient characteristics and pathological variables using the Cox regression model. Clinicopathological stage had the strongest association. Other variables ranked according to their relative importance independent of stage were: histological grade, level of direct spread, the presence of venous invasion, age and sex of the patient and the presence of obstruction.

The purpose of tumour staging for colorectal cancer (CRC) is to help define clinical management, facilitate communication between physicians, provide a basis for stratification and analysis of treatment results in prospective studies, and provide some prognostic information for patients and their families. The World Congresses of Gastroenterology, Digestive Endoscopy, and Coloproctology, Working Party on staging for CRC studied six commonly used systems to review their strengths and weaknesses. Although it was concluded that defining a new staging system was unnecessary, it was recognized that there is a need to define a terminology to describe the full anatomic extent of spread of CRC. Furthermore, we note that there are several additional features, derived from both clinical and pathology information, which have had prognostic significance shown by appropriately constructed multivariate analyses and which can be used to formulate a more accurate prognostic index than that provided by a description of anatomical tumour spread. Thus the Working Party came to two principal conclusions. First, a standard format should be adopted for the collection of the essential data required for prospective studies, and we recommend the 'International Documentation System (IDS) for CRC' for this purpose. Second, a nomenclature which describes the full anatomical extent of tumour spread and residual tumour status in CRC has been defined and should be adopted, from which all currently used staging systems can be derived. We have called this nomenclature the 'International Comprehensive Anatomical Terminology (ICAT) for CRC'. In the event that these recommendations are adopted, we envision that there will be improved clarity in the documentation of treatment outcome for patients with CRC and improved communication of results derived from prospective studies. Furthermore, an acceptance of IDS and ICAT would set the scene to develop a prognostic index for individual patients with CRC by the expansion of anatomical clinicopathology staging information to include additional factors which have independent prognostic significance.

These results following conventional surgery may be useful when evaluating new techniques.

Background. Patients with colorectal carcinoma found to have regional lymph node metastases after curative resection form a large and prognostically diverse group. This study aims to determine which pathology variables have independent prognostic effects. Methods. The data from the 579 patients used in this analysis were collected prospectively during a period of 21.5 years. The patients were from one institution, and the pathologic documentation was standardized. Patient follow‐up ranged between 6 months and 21.5 years. Survival analysis was by the Kaplan‐Meier method. Multivariate models were examined using Cox proportional hazards regression. Results. On univariate analysis, eight pathology variables had a significant association with survival. Six of these variables showed significant independent effects on survival on multivariate analysis. In diminishing potency, these variables were: apical lymph node involvement; spread involving a free serosal surface; invasion beyond the muscularis propria; location in the rectum; venous invasion; high tumor grade. Significant independent effects also were shown for patient age and gender. The number of involved lymph nodes added no significant independent prognostic information. Conclusion. Six pathology variables have been identified that act independently in determining the survival of patients with colorectal carcinoma and lymph node metastases. The most potent of these variables, apical lymph node involvement, was used by Dukes to subclassify Stage C tumors. Another variable, direct spread beyond the muscularis propria, defines the Astler‐Coller subclassification. It is recommended that all six independent variables be included in any future protocol for stratifying this prognostically diverse group of patients.