Claudia Mescoli

The Potential of Restaging in the Prediction of Pathologic Response After Preoperative Chemoradiotherapy for Rectal Cancer

BackgroundWe performed this study to prospectively evaluate the postchemoradiotherapy performance of transrectal ultrasonography (TRUS), pelvic computed tomography (CT) scan and magnetic resonance imaging (MRI), and endoscopic biopsies for predicting the pathologic complete response of rectal cancer patients.MethodsFour weeks after completion of preoperative chemoradiotherapy, 46 consecutive patients with mid to low rectal cancer were prospectively evaluated by proctoscopy, TRUS, and pelvic CT scan and MRI. On the basis of T and N status, patients were classified as T0 or T1–4 and N-negative or N-positive. For each staging modality used, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Findings were compared with the pathologic tumor-node-metastasis stage.ResultsOn histopathologic analysis, 12 patients had pT0 and 34 had pT1–4 lesions; out of 45 assessable patients, 9 were N-positive. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting T status (T0 vs. T ≥1) were 77%, 33%, 74%, 36%, and 64%, respectively, for TRUS; 100%, 0%, 74%, not assessable, and 74% for CT; and 100%, 0%, 77%, not assessable, and 77% for MRI. The corresponding figures in predicting N status (N-negative vs. N-positive) were, respectively, 37%, 67%, 21%, 81%, and 61% for TRUS; 78%, 58%, 32%, 91%, and 62% for CT; and 33%, 74%, 25%, 81%, and 65% for MRI.ConclusionsCurrent rectal cancer staging modalities after chemoradiotherapy allow good prediction of node-negative cases, although none of them is able to predict the pathologic complete response on the rectal wall.

PDCD4 nuclear loss inversely correlates with miR-21 levels in colon carcinogenesis

Programmed cell death 4 (PDCD4) has recently been demonstrated to be a new tumor suppressor gene involved in colon carcinogenesis. PDCD4 immunohistochemical expression was assessed in 300 polypoid lesions of the colon mucosa (50 hyperplastic polyps [HP], 50 serrated adenomas [SA], 50 tubular adenomas with low-grade-intraepithelial neoplasia [LG-IEN], 50 tubular adenomas with high-grade-IEN [HG-IEN]), and in 50 colon adenocarcinomas (CRC). As normal controls, we considered 50 biopsy samples obtained from patients with irritable bowel syndrome (N). We further investigated PDCD4 messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (PCR) in a different series of N, LG-IEN, HG-IEN, and CRC biopsy samples. miR-21 expression (an important PDCD4-expression regulator) was also determined by quantitative real-time PCR and in situ hybridization. Normal colocytes and HP featured strong PDCD4 nuclear immunostaining whereas a significantly lower PDCD4 nuclear expression was observed in dysplasia (low- and high-grade adenomas and SA) and invasive CRC. PDCD4 immunostaining and mRNA levels decreased significantly as the phenotypic changes occurring during colon carcinogenesis progressively increased (p < 0.001). As expected, miR-21 expression was significantly upregulated in preneoplastic/neoplastic samples, consistent with PDCD4 downregulation. These results consistently support the use of nuclear PDCD4 immunohistochemical downregulation as a novel biomarker for the diagnosis of dysplastic/neoplastic lesions in colon biopsy samples.

Nuclear Expression of S100A4 Calcium-Binding Protein Increases Cholangiocarcinoma Invasiveness and Metastasization

Cholangiocarcinoma (CCA) carries a severe prognosis because of its strong invasiveness and early metastasization. In several patients, otherwise eligible for surgical resection, micrometastasis are already present at the time of surgery. The mechanisms responsible for CCA invasiveness are unclear. S100A4, a member of the S100 family of small Ca2+‐binding proteins, is expressed in mesenchymal cells, regulates cell motility in several cell types, and is expressed in some epithelial cancers. Thus, we aimed to study the role of S100A4 in CCA invasiveness and metastasization. The expression of S100A4 was studied by immunohistochemistry in 93 human liver samples of CCA patients undergoing surgical resection and correlated with metastases development (67 cases) and patient survival following surgery using log rank tests and multivariate analysis. S100A4 expression was studied in EGI‐1 and TFK‐1, human CCA cell lines with and without nuclear S100A4 expression, respectively. Metastatic properties of CCA cells were assessed by xenotransplantation in severe combined immunodeficiency (SCID) mice after transduction with lentiviral vectors encoding firefly luciferase gene. Proliferation, motility (wound healing), invasiveness (Boyden chamber), and metalloproteinases (MMPs) secretion were studied in CCA cells, with or without lentiviral silencing of S100A4. Nuclear expression of S100A4 by neoplastic ducts was a strong predictor of metastasization and reduced survival after resection (P < 0.01). EGI‐1 CCA cells showed stronger metastatic properties than TFK‐1 when xenotransplanted in SCID mice. S100A4‐silenced EGI‐1 cells showed significantly reduced motility, invasiveness, and MMP‐9 secretion in vitro, without changes in cell proliferation. Conclusion: Nuclear S100A4 identifies a subset of CCA patients with a poor prognosis after surgical resection. Nuclear expression of S100A4 increases CCA cells invasiveness and metastasization, indicating that S100A4 may also represent a potential therapeutic target. (HEPATOLOGY 2011; 54:890–899)

PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis

Inflammatory bowel diseases (IBDs; both ulcerative colitis [UC] and Crohn’s colitis [CC]) are well-established predisposing pathological conditions for colorectal cancer (CRC) development. In IBDs, both the endoscopy and the histology assessment of CRC precursors (i.e., dysplasia, also defined as intraepithelial neoplasia) are associated with low interobserver consistency, and no reliable dysplasia-specific biomarker is available. The programmed cell death 4 (PDCD4) tumor suppressor gene is involved in sporadic colorectal oncogenesis, but scanty information is available on its involvement in IBD-associated colorectal oncogenesis. One hundred twenty tissue samples representative of active and inactive IBD and of flat dysplasia were obtained from 30 cases of UC and 30 of CC who undergone colectomy. Twenty additional biopsy samples obtained from patients with irritable bowel syndrome acted as normal controls. PDCD4 expression was assessed by immunohistochemistry; the expression of miR-21 (a major PDCD4 regulator) was investigated by quantitative real-time PCR and in situ hybridization in different series of a hundred samples. Tissue specimens from both controls and inactive IBD consistently featured strong PDCD4 nuclear immunostain; conversely, lower PDCD4 nuclear expression was featured by both active IBD and IBD-associated dysplastic lesions. Significant PDCD4 down-regulation distinguished IBD-associated dysplasia (p < 0.001) versus active IBD. In both active IBD and dysplasia, PDCD4 down-regulation was significantly associated with miR-21 up-regulation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. PDCD4 nuclear expression may be usefully applied as ancillary maker in the histological assessment of IBD-associated dysplastic lesions.

Telomerase is an independent prognostic marker of overall survival in patients with colorectal cancer.

Background:Colorectal cancer (CRC) is an important cause of cancer-related death. Prediction of recurrence is an important issue in the treatment of disease, particularly for stage II patients. The level of telomere-specific reverse transcriptase (hTERT), the catalytic component of the telomerase complex, increases along with CRC progression, but its prognostic value is still unclear.Methods:One hundred and thirty-seven CRC patients were studied for hTERT expression in tumour cells by real-time PCR. hTERT level was evaluated as a prognostic factor of overall survival (OS) in all patients and of disease recurrence in a subgroup of 50 stage II patients.Results:The median hTERT level was 93.8 copies (interquartile range 48–254). Patients with high hTERT levels (above the median) showed a significantly worse survival than those with low hTERT levels (below the median; log-rank test P<0.0001; hazard ratio (HR)=3.30 (95% confidence interval (CI) 1.98–5.52); P<0.0001). The negative prognostic value of high hTERT level is independent of the pathological stage and microsatellite instability (HR=2.09 (95% CI 1.20–3.64), P=0.009). Moreover, in stage II CRC, high hTERT levels identified patients with a higher risk of disease recurrence (HR=3.06 (95% CI 1.03–9.04), P=0.043) and death (HR=3.24 (95% CI 1.37–7.71), P=0.008).Conclusion:hTERT level is an independent prognostic marker of OS in CRC patients. In addition, assessment of hTERT level could improve stratification of stage II CRC patients for the risk of disease recurrence.

Isolated Tumor Cells in Regional Lymph Nodes as Relapse Predictors in Stage I and II Colorectal Cancer

PURPOSE Lymph node (LN) involvement is the most important prognostic factor in colorectal cancer (CRC), and pN-positive status identifies patients who require adjuvant chemotherapy. Approximately 15% to 20% of patients without nodal metastases (pN0) develop recurrent disease. In this study, we tested the prognostic significance of isolated tumor cells (ITCs) in LNs of patients with pN0 CRC (stages I and II). PATIENTS AND METHODS ITCs in LNs regional to CRC were assessed in 312 consecutive patients with pN0 CRC who were followed up clinically and/or endoscopically for at least 6 months after surgery (mean, 67 months; median, 64 months; range, 8 to 102 months). LNs were dissected from gross surgical specimens according to a standardized protocol (with a mean of 17 LNs per patient; range, five to 107 LNs). In all, 5,313 pN0 LNs were collected and assessed by using cytokeratin immunostaining in two serial histology sections from each LN, which amounting to a total of 10,626 specimens. The correlation between ITC status and cancer recurrence was tested by using univariate and multivariate statistics. RESULTS ITCs were documented in 185 of 312 patients (59%). CRC relapsed in 31 of 312 patients (10%), and 25 of 31 recurrences (81%) were documented among ITC-positive patients. CRC recurrence rates among ITC-positive and ITC-negative patients were 14% (25 of 185 patients) and 4.7% (six of 127 patients), respectively. In both univariate and multivariate analyses, ITC status was the only variable significantly associated with cancer relapse (Cox model; hazard ratio, 3.00; 95% CI, 1.23 to 7.32; P = .013). CONCLUSION In patients with pN0 CRC, cancer relapse was significantly associated with ITCs in regional LNs. ITCs should be considered among the clinicobiologic variables that identify high-risk patients who can benefit from adjuvant chemotherapy.

The histopathological approach to inflammatory bowel disease: a practice guide.

Inflammatory bowel diseases (IBDs) are lifelong disorders predominantly present in developed countries. In their pathogenesis, an interaction between genetic and environmental factors is involved. This practice guide, prepared on behalf of the European Society of Pathology and the European Crohn’s and Colitis Organisation, intends to provide a thorough basis for the histological evaluation of resection specimens and biopsy samples from patients with ulcerative colitis or Crohn’s disease. Histopathologically, these diseases are characterised by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the cell types present, but these features frequently overlap. If a definitive diagnosis is not possible, the term indeterminate colitis is used for resection specimens and the term inflammatory bowel disease unclassified for biopsies. Activity of disease is reflected by neutrophil granulocyte infiltration and epithelial damage. The evolution of the histological features that are useful for diagnosis is time- and disease-activity dependent: early disease and long-standing disease show different microscopic aspects. Likewise, the histopathology of childhood-onset IBD is distinctly different from adult-onset IBD. In the differential diagnosis of severe colitis refractory to immunosuppressive therapy, reactivation of latent cytomegalovirus (CMV) infection should be considered and CMV should be tested for in all patients. Finally, patients with longstanding IBD have an increased risk for the development of adenocarcinoma. Dysplasia is the universally used marker of an increased cancer risk, but inter-observer agreement is poor for the categories low-grade dysplasia and indefinite for dysplasia. A diagnosis of dysplasia should not be made by a single pathologist but needs to be confirmed by a pathologist with expertise in gastrointestinal pathology.

Long-Term Follow-up of Barrett’s Epithelium: Medical Versus Antireflux Surgical Therapy

BackgroundBarrett’s esophagus (BE) is the most serious complication of GERD. In BE patients, this observational study compares the effects of antireflux surgery versus antisecretory medical therapy.MethodsOverall, 89 BE patients (long BE = 45; short BE = 44) were considered: 45 patients underwent antireflux surgery and 44 underwent medical therapy. At both initial and follow-up endoscopy, symptoms were assessed using a detailed questionnaire; BE phenotypic changes [intestinal metaplasia (IM) presence/type, Cdx2 expression] were assessed by histology (H&E), histochemistry (HID), and immunohistochemistry. Surgical failures were defined as follows: (1) abnormal 24-h pH monitoring results after surgery, (2) endoscopically evident recurrent esophagitis, and (3) recurrent hiatal hernia or slipped fundoplication on endoscopy or barium swallow.ResultsReversion of IM was observed in 12/44 SSBE and 0/45 LSBE patients (p < 0.01). Reversion was more frequently observed after effective antireflux surgery than after medical treatment (p = 0.04). In patients with no further evidence of IM after therapy, Cdx2 expression was also absent (p = 0.02). The extent of IM was reduced, and the IM phenotype improved in SSBE patients after surgery.ConclusionsPatients with short BE (but not those with long BE) may benefit from surgically reducing the esophagus’ exposure to GE reflux; among these patients, successful surgery carries a higher IM reversion rate than medical treatment.

Different hemodynamic patterns of alcoholic and viral endstage cirrhosis: analysis of explanted liver weight, degree of fibrosis and splanchnic Doppler parameters.

Objective. In cirrhosis, portal hemodynamics is usually considered independently of the disease etiology. The objective of this study was to investigate the role of the etiology of liver disease on the relationship between liver blood flow and liver pathology in endstage cirrhosis. Material and methods. Portal blood velocity and volume, congestion index of the portal vein, and hepatic and splenic pulsatility indices were evaluated with echo-Doppler in cirrhotic patients immediately before liver transplantation. When a patent paraumbilical vein was present, its blood flow was measured and effective portal liver perfusion was calculated as portal blood flow minus paraumbilical blood flow. The hemodynamic parameters were correlated with liver weight and the pattern of the liver fibrosis morphometrically assessed in explanted livers. A total of 131 patients with alcoholic or viral cirrhosis were included in the study. Results. In alcoholic cirrhosis, liver weight was higher than that in viral disease (1246±295 g versus 1070±254 g, p=0.001), portal liver perfusion per gram of liver tissue was lower (0.49±0.36 ml g−1 min−1 versus 0.85±0.56 ml g−1 min−1, p=0.004) and hepatic pulsatility indices were higher (1.45±0.31 versus 1.26±0.30, p=0.018). The degree of liver fibrosis was similar in alcoholic and viral cirrhosis (11.7±5.5% versus 11.0±4.4%, p=NS). An inverse relationship between liver weight and Child-Pugh score was disclosed in viral (p<0.001) but not in alcoholic disease. Conclusions. A different hemodynamic pattern characterizes the advanced stage of cirrhosis of alcoholic and viral origin. A more severe alteration of intrahepatic portal perfusion, probably coexisting with a more severe hepatocyte dysfunction, and a higher liver weight can be detected in alcoholic cirrhosis.

Magnetic Resonance Enterography for Crohn’s Disease: What the Surgeon Can Take Home

BackgroundCrohn’s disease (CD) is a life-long, chronic, relapsing condition requiring often morphological assessment. MR enterography (MRE) offers advantages of not using ionizing radiation and yielding intraluminal and intra-abdominal informations. The aim of our study was to identify how MRE can be useful in planning surgical procedures.Patients and MethodsIn this retrospective study, 35 patients who underwent MRE and then surgery for CD were enrolled from 2006 to 2010. MRE findings were compared to intraoperative findings. Histology of operative specimens, systemic inflammatory parameters, and fecal lactoferrin were also evaluated. Cohen’s κ agreement test, sensitivity and sensibility, uni-/multivariate logistic regression, and non-parametric statistics were performed.ResultsMRE identified bowel stenosis with a sensitivity of 0.95 (95% CI 0.76–0.99) and a specificity of 0.72 (95% CI 0.39–0.92). The concordance of MRE findings with intraoperative findings was high [Cohen’s κ = 0.72 (0.16)]. Abscesses were detected at MRE with a sensitivity of 0.92 (95% CI 0.62–0.99) and a specificity of 0.90 (95% CI 0.69–0.98) with a Cohen’s κ = 0.82 (0.16). The grade of proximal bowel dilatation resulted to be a significant predictor of the possibility of using strictureplasty instead of/associated to bowel resection either at univariate or at multivariate analysis.ConclusionOur study confirmed that MRE findings correlate significantly with disease activity. Detailed information about abscess could suggest percutaneous drainage that could ease the following surgery or avoid emergency laparotomy. Proximal bowel dilatation can suggest the possibility to perform bowel sparing surgery such as strictureplasty.