Low molecular weight heat shock protein HSP27 is a prognostic indicator in rectal cancer but not colon cancer.

OBJECTIVE: There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis. METHODS: HSP27 levels were determined using combined two-dimensional gel electrophoresis and tandem mass spectrometry (12 cases) and by immunohistochemistry using tissue microarrays of colorectal cancers sampled at surgery and 80 diagnostic rectal biopsies. RESULTS: HSP27 overexpression was strongly associated with poor cancer-specific survival in rectal cancer (n=205, p=0.0063) but not colon cancer (n=199, p=0.7385) in the cohort with a poor prognosis. Multivariate Cox regression confirmed nodal metastases (p=0.0001) and HSP27 expression (p=0.0233) as independent markers of survival in rectal cancer. HSP27 levels remained unchanged in the majority of cases (65/80, 81%) between diagnostic biopsies and matched surgical samples, regardless of whether patients had undergone preoperative radiotherapy. In the cohort with a good prognosis the association between HSP27 and survival was not observed in patients with either rectal (n=115; p=0.308) or colon cancer (n=200; p=0.713). CONCLUSION: In a large cohort of patients with a poor prognosis, HSP27 is an independent marker of poor outcome in rectal cancer; its expression is not altered by neoadjuvant radiotherapy. This finding requires validation in an independent similar cohort of patients with rectal cancer. HSP27 levels merit evaluation as a stratification factor for treatment of rectal cancer.

Smad4 loss is associated with fewer S100A8-positive monocytes in colorectal tumors and attenuated response to S100A8 in colorectal and pancreatic cancer cells.

S100A8 and its dimerization partner S100A9 are emerging as important chemokines in cancer. We previously reported that Smad4-negative pancreatic tumors contain fewer stromal S100A8-positive monocytes than their Smad4-positive counterparts. Here, we studied S100A8/A9-expressing cells in colorectal tumors relating their presence to clinicopathological parameters and Smad4 status. Two-dimensional gel electrophoresis (n = 12) revealed variation in the levels of S100A8 protein in colorectal cancer tumors, whereas immunohistochemical analysis (n = 313) showed variation in the numbers of stromal S100A8-positive and S100A9-positive cells. Loss of Smad4 expression was observed in 42/304 (14%) colorectal tumors and was associated with reduced numbers of S100A8-positive (P = 0.03) but not S100A9-positive stromal cells (P = 0.26). High S100A9 cell counts were associated with large tumor sizes (P = 0.0006) and poor differentiation grade (P = 0.036). However, neither S100A8 nor S100A9 cell counts predicted poor survival, except for patients with Smad4-negative tumors (P = 0.02). To address the impact of environmental S100A8/A9 chemokines on tumor cells, we examined the effects of exogenously added S100A8 and S100A9 proteins on cellular migration and proliferation of colorectal and pancreatic cancer cells. S100A8 and S100A9 enhanced migration and proliferation in Smad4-positive and Smad4-negative cancer cells. However, transient depletion of Smad4 resulted in loss of responsiveness to exogenous S100A8, but not S100A9. S100A8 and S100A9 activated Smad4 signaling as evidenced by phosphorylation of Smad2/3; blockade of the receptor for the advanced glycation end products inhibited this response. In conclusion, Smad4 loss alters the tumor's interaction with stromal myeloid cells and the tumor cells' response to the stromal chemokine, S100A8.

The acquisition and outcome of ICU-acquired Clostridium difficile infection in a single centre in the UK.

BACKGROUND: The clinical course and outcome of Clostridium difficile infection (CDI) in the intensive care unit (ICU) setting have been reported in a small number of studies in the US and Canada. However, no such study has been reported in the UK. Therefore, we aimed to study the acquisition rate and outcome of ICU-acquired CDIs in our unit. METHOD: Patient admissions to the ICU and nosocomial infection databases from April 2004 to April 2007 were reviewed to identify study groups, followed by retrospective case note review. Patients who acquired CDI prior to ICU admission were excluded. RESULTS: Sixty-two patients (31 males) who acquired CDI during their ICU stays were included in our study. The acquisition rate of CDI ranged from 1.52 to 4.78% per year. The median APACHE II score was 18, and the median interval between ICU admission and acquisition of CDI was 7 days. The median ICU stay was 16 days. Of the 62 patients, 13 (20.97%) died in the ICU. Of the 49 patients who were discharged, 41 were discharged ultimately from the hospital. Thus, the overall mortality attributable to CDI acquired in the ICU was 33.87%, compared to the average baseline mortality of 29% in our unit. Univariate analysis showed that increasing age (p = 0.004), APACHE II score (p=0.007), and male gender (p = 0.05) were significantly associated with ICU mortality in patients who acquired CDI in the ICU. Multivariate analysis showed that only increasing age (p = 0.031; OR 1.141, CI 1.013-1.287) was significantly associated with higher ICU mortality. CONCLUSION: Patients admitted to the ICU have a moderate risk of acquiring CDI. There is a small increase in mortality observed in patients who acquired CDI in the ICU. Increasing age is an independent predictor associated with mortality.

Diagnostic laparoscopy and management of the impalpable testis--a review of 10 years' practice at a non-paediatric specialist centre.

BACKGROUND: Laparoscopy is used for the diagnosis and treatment of impalpable testes. We reviewed practice and outcomes in our unit over the last 10 years. METHODS: Retrospective case-note review of patients undergoing laparoscopy with or without orchidopexy for impalpable testes. RESULTS: Eighty-three patients underwent laparoscopy. Twelve patients had bilateral impalpable testes; 25.3% of testes were identified intra-abdominally, 21% in the internal ring, and 29.5% of cases had vas and vessels entering the deep ring. A 76.5% success rate was achieved following diagnostic laparoscopy and standard open orchidopexy for testes in the region of the internal ring, compared to a 40.0% success rate following one-stage laparoscopic orchidopexy for 'low' intra-abdominal testes. CONCLUSION: Laparoscopy is useful in managing patients with an impalpable testis from both a diagnostic and therapeutic standpoint. The success rate following laparoscopic orchidopexy in our non-paediatric specialist centre is lower than in most reports from paediatric specialist centres. This suggests the importance of centralization of such complicated, less frequently performed surgical procedures to a specialist centre.