Analysing cause of death during follow-up for non-muscle-invasive bladder cancer: is there a role for watchful waiting?

INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) patients often require multiple invasive procedures during follow-up. Surveillance guidelines do not adjust for increasing frailty or competing comorbidity. We aim to evaluate the influence of these factors on the natural history of NMIBC and whether this may have implications for appropriate follow-up schedules. METHODS: NMIBC patients who died in a 3-year period while on cystoscopic surveillance were identified. Frailty was assessed using the Rockwood Clinical Frailty Scale (CFS): 1-3, no frailty; 4, vulnerable; 5-9, mild/severe frailty. Similarly, three-tier categorisations were performed for comorbidity (Charlson Comorbidity Index) and for anaesthetic risk (American Society of Anesthesiologists' [ASA] score). RESULTS: Of the 69 patients, 26 were categorised as no frailty, 20 as vulnerable and 13 as frail. There was no difference in the proportions of those with higher risk NMIBC between the categories. Increasing frailty was associated with reduced overall survival (median 59, 29 and 13 months; p < 0.05) but not recurrence-free survival (p = 0.98) or progression-free survival (p = 0.58). Similar results were obtained using the Charlson Comorbidity Index or ASA score. No frail patients with low/intermediate-risk NMIBC had clinically significant disease progression prior to death. Frail patients with CFS ≥ 4 were found to have similar complications due to bladder cancer itself (p = 0.48) yet almost three times as many complications following cystoscopic procedures during follow-up (p < 0.05). CONCLUSIONS: For frail patients with low risk of progression, protocol-driven cystoscopic surveillance may not improve survival and watchful waiting may be more appropriate. Further investigation is required to determine the feasibility of this approach.

Role of fibrogenic markers in chronic hepatitis C and associated hepatocellular carcinoma.

Detection and follow up of fibrogenesis in chronic hepatitis C (CHC) is mandatory for early treatment and risk stratification. The current study included 120 patients with CHC, of whom 30 had liver cirrhosis (LC) and 30 had hepatocellular carcinoma (HCC). 15 wedge liver biopsies, taken during laparoscopic cholecystectomy, were included as normal controls. Cases were subjected to laboratory investigations, serologic markers for viral hepatitis and assessment of circulating levels of hyaluronic acid (HA) and platelet-derived growth factor (PDGF). Immunohistochemical expression of connective tissue growth factor (CTGF), PDGF and transforming growth factor-ß1 (TGF-ß1) was also carried out. A significant increase (p < 0.01) in serum HA was noticed in CHC, LC and HCC compared to controls. Although, a significant decrease in serum PDGF was detected in CHC and LC compared to controls, HCC values were comparable. A significant up-regulation of CTGF was detected in CHC, LC and HCC (p < 0.01) in contrast to its limited mild expression in normal livers. Intense PDGF positive staining was noticed in CHC, LC and HCC compared to scattered faint expression in controls. The significant expression and marked intensity of PDGF staining matched the progress to tumorigenesis. A positive TGF-ß1 immunostaining was also noticed in CHC, LC and HCC. An intense and extensive cytoplasmic expression of TGF-ß1 was encountered in patients with LC revealing that CTGF, PDGF and TGF-ß1 act synergistically in LC. Data revealed that HA and CTGF may be implicated as important diagnostic parameters for assessment of hepatic fibrosis and PDGF for monitoring malignant transformation in CHC.

Effect of splenectomy on liver regeneration and function following partial hepatectomy: experimental study.

The presence of enough remaining functioning liver parenchyma to avoid life-threatening post-operative liver failure is a major prerequisite for hepatic resection in patients with hepato-biliary carcinoma. There are clinical reports which confirm the beneficial clinical effects of splenectomy on integrity of the residual liver following liver resection for hepatocellular carcinoma in cirrhotic patients with hypersplenism and portal hypertension. This experimental study was designed on hamsters to evaluate the proliferative capacity and function of the remaining liver lobes; in which splenectomy was done simultaneously with partial hepatectomy compared with those in which splenectomy was not done. Forty hamsters were divided into two groups: GI; in which partial hepatectomy was performed without splenectomy and the GII; in which animals were subjected to partial hepatectomy with prior splenectomy. Animals from each group were subjected to liver biopsy from the remaining lobes 48, 72 hours and one week after surgery. Also, serum alanine aminotransferase (ALT) and total bilirubin were tested before, 48, 72 hours and one week after hepatectomy. Hepatic regeneration in the remaining lobes was assessed through histo-pathological study, DNA ploidy of the hepatic nuclei using computerized image analysis system and determining of the labeling index of the nuclear factor NF Kappa B (P105), a novel monoclonal antibody specific for P105 protein by immunohistochemistry. In GII: induction of NK kappa B (P105) labeling index showed maximum expression depending on the regenerative capacity of the remaining liver lobes. In contrast, in GI; liver regeneration was slow. Also, changes in liver function of GII indicated that splenectomy prior hepatecotomy may minimize dysfunction in the remaining hypertrophied liver lobes.

Immunohistochemical expression of CD95 (Fas), c-myc and epidermal growth factor receptor in hepatitis C virus infection, cirrhotic liver disease and hepatocellular carcinoma.

Gene product expression in normal and chronic hepatitis C virus infection was determined in an attempt to improve our understanding of the molecular events leading to the development of cirrhosis and liver carcinoma. Activation of CD95 (Fas) causes apoptosis of cells and liver failure in mice and has been associated with human liver disorders. c-myc is involved in cell proliferation and EGFR in regeneration of cells. The material of the current study included 50 cases of chronic hepatitis C (CHC) (and negative hepatitis B virus infection), 29 cases of liver cirrhosis and HCV (LC), and 19 cases of hepatocellular carcinoma and HCV (HCC) admitted to the Theodor Bilharz Research Institute (TBRI) during the years 2003-2004. Ten wedge liver biopsies - taken during laparoscopic cholecystectomy - were included in the study as normal controls. Laboratory investigations, including liver function tests, serological markers for viral hepatitis and serum alpha fetoprotein level (alpha-FP), were determined for all cases. Histopathological study and immunohistochemistry using monoclonal antibodies for CD95, c-myc and EGFR were also done. In CHC cases, the histological activity index (HAI) revealed more expression of Fas antigen in liver tissues with active inflammation than in those without active inflammation (p < 0.01). EGFR and c-myc act synergistically in liver tumorigenesis. Upregulation of Fas in chronic hepatitis C infection and of c-myc & EGFR in malignant transformation was concluded from this study. c-myc expression may obstruct the induction of apoptosis of HCC cells and lead to uncontrolled cell growth.

Effect of a broad spectrum antiparasitic drug "ivermectin" in acute and chronic experimental giardiasis using different dose regimens.

In this study, the maximal excretion of Giardia lamblia cysts was three weeks post infection (p.i). Administration of ivermectin subcutaneously proved to be effective in treating hamsters infected for 2 and 3 weeks respectively. It was found that the dose of 300 microg/kg b.w. was much more efficient than 200 mg/kg b.w. The cure rate was 99.1% in the former, and 98.7% in the later. The difference was statistically significant. In chronic giardiasis where infection was kept for 6 weeks, the cure rate was 99.5% two weeks after treatment with 300 g/kg b.w. of ivermectin. Assessment of cure was performed also by histopathological examination of upper 2/3 of small intestine of the hamsters. Localization and counting of the parasite were carried out immunohistochemically. The mean number of trophozoites decreased markedly after treatment with the large dose either acute or chronic giardiasis.