Apical Node Involvement Does Not Influence Prognosis After Potentially Curative Resection for Stage III Colorectal Cancer: A Competing Risks Analysis.

OBJECTIVE: To examine the independent prognostic value of ALN status in patients with stage III CRC. SUMMARY OF BACKGROUND DATA: Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. METHODS: Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. RESULTS: In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). CONCLUSIONS: No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Competing risks analysis of the effect of local residual tumour on recurrence and cancer-specific death after resection of colorectal cancer: implications for staging.

The pTNM staging system for colorectal cancer (CRC) is not entirely effective in discriminating between potentially curative and non-curative resections because it does not account for local residual tumour in patients with stages I, II or III. This study aimed to evaluate the prognostic importance of histologically verified tumour in any line of resection of the bowel resection specimen (TLR) in relation to pTNM stages and to demonstrate how TLR may be integrated into pTNM staging. Information on patients in the period 1995 to 2010 with complete follow-up to the end of 2015 was extracted from a prospective database of CRC resections. The outcome variables were the competing risks incidence of CRC recurrence and CRC-specific death. After exclusions, 2220 patients remained. In 1930 patients with pTNM stages I-III tumour, recurrence was markedly higher in those with TLR than in those without (HR 6.0, 95% CI 4.2-8.5, p < 0.001) and this persisted after adjustment for covariates associated with recurrence. CRC-specific death was markedly higher in the presence of TLR (HR 7.7, CI 5.3-11.2, p < 0.001), which persisted after adjustment for relevant covariates. These results justify removing patients with TLR from pTNM stages I to III and placing them in stage IV, thereby allowing the categorisation of all patients with any known residual tumour into three prognostically distinct groups. This study demonstrates how TLR may be integrated into pTNM staging, thus improving the definition of the three stages which are considered potentially curable (I, II and III).

Trends in pathology and long-term outcomes after resection of colorectal cancer: 1971-2013.

BACKGROUND: The aim of this study was to describe temporal trends in tumour pathology and long-term outcomes in 5217 patients recorded in a registry of colorectal cancer resections initiated at Concord Hospital, Sydney, Australia, in 1971. METHODS: This report is based on consecutive resections up to December 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of temporal trends was examined by least squares regression. RESULTS: The percentages of patients with local spread beyond the muscularis propria, nodal metastasis, distant metastasis and tumour in a line of resection all declined significantly. In consequence, the percentage of stage D patients fell, whereas the percentage in stage A rose. Other tumour variables that increased significantly were polypoid morphology, contiguous adenoma and invasion of a free serosal surface. Tumours in which an adherent adjacent structure was partly or completely removed also increased. There were significant declines in high-grade malignancy, venous invasion and tumour size. The recurrence rate for rectal cancers declined significantly, whereas for rectal and colonic cancers combined, both the overall 5-year survival rate and the 5-year cancer-specific survival rate increased markedly. CONCLUSION: These results show a reduction in adverse pathology findings and favourable trends in recurrence and survival after colorectal cancer resections in a high-incidence country over a period of 43 years.

Trends in short-term outcomes after resection of colorectal cancer: 1971-2013.

BACKGROUND: The aim of this study was to describe temporal trends in presentation, surgical management and immediate postoperative outcomes in patients recorded in a registry of colorectal cancer resections that was initiated at Concord Hospital, Sydney, Australia, in 1971. A companion paper describes tumour pathology and long-term recurrence and survival. METHODS: This report is based on 5217 consecutive resections up to 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of trends was examined by least squares regression. RESULTS: The percentage of asymptomatic patients increased over time, whereas urgent presentations declined. Tumour size declined. The percentage of rectal cancers fell but the percentage of low rectal tumours rose. Initially, restorative rectal resections increased rapidly but later remained stable. There was no trend in medical complications, whereas surgical complications declined. Anastomotic leakage after restorative rectal resections declined but it was low and stable for colonic tumours. The rate of early reoperation remained stable, whereas 30-day mortality declined. Neoadjuvant radiotherapy for rectal cancer and adjuvant chemotherapy for stages B and C were introduced in 1992 and applied increasingly thereafter. CONCLUSION: Our findings, based on a 43-year prospective study, indicate sustained trends towards the earlier diagnosis of colorectal cancer and favourable short-term outcomes following bowel resection.

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.

DNA ploidy of bladder cancer using bladder biopsy supernate specimens.

OBJECTIVE: To perform DNA image cytometry on 119 bladder biopsy supernate (BBS) specimens of transitional cell carcinoma (TCC) bladder to: (1) test the suitability of this cytologic specimen for use in DNA ploidy analysis, and (2) assess the value of DNA ploidy measured on this specimen as to the risk of tumor recurrence and survival. STUDY DESIGN: The histologic grade and cytologic grade were correlated, and the DNA ploidy produced was determined by image analysis of Feulgen-stained nuclei. Kaplan-Meier curves related age, sex, grade and DNA ploidy to recurrence of tumor and survival. Log rank analyses were used to ascertain the difference between the curves for each categorical variable. RESULTS: Urothelial cells derived from the BBS specimen were demonstrated to be representative of the tumor. The tumor recurrence rate was significantly higher (P = .0001) and the survival rate significantly lower (P = .0002) for patients with aneuploid tumors compared to those with diploid tumors. Patients with TCC 2 tumors had a significantly shorter time to recurrence (P = .003), although the relationship between ploidy and survival in this group was of marginal significance. CONCLUSION: The specimen was free of many of the problems associate with the other specimen types used for measuring DNA ploidy. The results show that the BBS specimen is diagnostically useful and suitable for DNA analysis, providing prognostically relevant information.