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Kathrin Ludwig,
Matteo Fassan,
Claudia Mescoli,
Marco Pizzi,
Mariangela Balistreri,
Laura Albertoni, Salvatore Pucciarelli,
Marco Scarpa,
Giacomo Carlo Sturniolo,
Imerio Angriman,
Massimo Rugge
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ABSTRACT: 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.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2012; · 2.49 Impact Factor
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ABSTRACT: OBJECTIVE:: To investigate the risk of metachronous colorectal cancer (CRC), its impact on survival, and the risk of rectal cancer in a cohort of probands meeting the Amsterdam criteria. BACKGROUND:: Several determinants of decision-making for the management of CRC in patients with a putative diagnosis of Lynch syndrome are scarcely defined, and many of them undergo segmental bowel resection instead of the advised total colectomy. METHODS:: A retrospective cohort study was conducted on 65 probands of the Amsterdam-positive families who had surgery for primary CRC and at least 5-year surveillance thereafter. The rates of metachronous CRC and of rectal cancer were evaluated, together with their association with preoperatively available clinical predictors. Differences in overall survival between patients with and without metachronous CRC were evaluated using a time-dependent Cox model. RESULTS:: Seventeen patients (26.2%) had metachronous CRC. No clinical feature was associated with an increased risk of its development. The risk of death in patients with metachronous CRC was 6-fold increased. Neither a 2-year interval endoscopic surveillance after surgery, nor total colectomy was associated with a significant reduction in metachronous CRC. Eighteen patients (23.7%) had rectal cancer at first presentation, 5 patients of the remainder (10.6%) developed rectal cancer after primary colon resection. Two patients undergoing total colectomy developed a metachronous rectal cancer (18.2%). A first-degree family history of rectal cancer was associated with an increased risk of rectal cancer. CONCLUSIONS:: Probands of families fulfilling the Amsterdam criteria carry a high risk of rectal cancer and of metachronous CRC. Total proctocolectomy, or total colectomy and a 1-year interval of proctoscopic surveillance should be advised when a high risk of rectal cancer can be predicted.
Annals of surgery 09/2012; · 7.90 Impact Factor
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ABSTRACT: We have previously demonstrated the prognostic significance of rectal cancer pathologic response to neoadjuvant chemoradiation. Recent studies in other cancers have reported that hypoxia influences response to neoadjuvant chemoradiation.
This study aimed to 1) characterize hypoxia-related protein expression in locally advanced rectal cancer before neoadjuvant chemoradiation, 2) determine the comodulation of hypoxia-related protein expression, and 3) evaluate the relationship between hypoxia-related protein expression and overall survival, time to recurrence, and tumor regression grade.
Immunohistochemical analysis of 4 hypoxia-related proteins (HIF-1α, CA-IX, VEGF, and GLUT-1) was performed on archival pretreatment rectal cancer biopsies.
: Eighty-five patients with locally advanced rectal cancer treated with neoadjuvant radiation and 5-fluorouracil-based chemotherapy were included.
The impact of hypoxia-related protein expression on outcome was evaluated by use of Cox proportional hazards model. Hypoxia-related protein expression was correlated with tumor regression grade by use of Spearman correlation coefficients.
Median follow-up was 54 months. CA-IX expression was associated with overall survival (p = 0.01). HIF-1α expression was weakly correlated with VEGF (r = 0.26, p = 0.02) and GLUT-1 (r = 0.35, p = 0.001). Hypoxia-related protein expression was not associated with time to recurrence or Mandard tumor regression grade.
Elevated CA-IX expression may be associated with poorer overall survival in locally advanced rectal cancer treated by neoadjuvant chemoradiation and resection. The expression of the hypoxia-related proteins HIF-1α, VEGF, and GLUT-1 may be comodulated in locally advanced rectal cancer. Further studies are needed to evaluate the mechanisms governing hypoxia regulation and the role of hypoxia in rectal cancer response to neoadjuvant chemoradiation.
Diseases of the Colon & Rectum 09/2012; 55(9):990-5. · 3.13 Impact Factor
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ABSTRACT: OBJECTIVES: The aim of this study was to compare volume measurements on computed tomography (CT) images with histopathological assessments of chemoradiotherapy (CRT)-induced tumor regression in locally advanced rectal cancer (RC). METHODS: In 25 patients (13 males, 12 females; median age, 63years; age range, 44-79years) with locally advanced RC treated with preoperative CRT and surgery, two radiologists measured tumor volume on CT images before and after CRT. CT-based tumor volumetry and the modified response evaluation criteria in solid tumors (mRECISTs) were compared with T and N downstaging after CRT, and with the tumor regression grade (TRG). RESULTS: Tumor volumes were significantly smaller on CT images after CRT. The tumors regressed in 52% (13/25), 36% (9/25) and 40% (10/25) of patients, based on T downstaging, TRG and mRECIST findings, respectively. In terms of T downstaging, the pre- and post-CRT tumor volumes of responders and non-responders to the treatment differed statistically, while their tumor volume reduction rates and volume reductions according to the 65% mRECIST threshold did not. In terms of N downstaging and TRG, the differences between the responders' and the non-responders' pre- and post-CRT tumor volumes, tumor volume reduction rates, and mRECIST thresholds were never statistically significant. CONCLUSION: Measuring tumor size on CT images is of limited value in predicting the histopathological response to preoperative CRT in RC patients, so it may be unwise to select surgical treatment strategies based on CT volumetry.
European journal of radiology 08/2012; · 2.65 Impact Factor
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Emanuele D L Urso,
Riccardo Nascimbeni, Salvatore Pucciarelli,
Marco Agostini,
Claudio Casella,
Dario Moneghini,
Diego Di Lorenzo,
Isacco Maretto,
Maribel Sullivan,
Isabella Mammi,
Alessandra Viel,
Donato Nitti
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ABSTRACT: BACKGROUND: Currently, no guidelines exist for the treatment of patients with multiple colorectal adenomas (MCRAs) (>10 but <100 synchronous nondiminutive polyps of the large bowel). This retrospective study aimed to investigate the clinical and molecular factors related to different treatments for MCRAs. METHODS: Patients with MCRAs were consecutively enrolled from January 2003 to June 2011. Sequencing of their APC and MutYH genes was performed. The clinical, molecular, and family histories of the patients were collected using the Progeny database. The patient treatments were divided into three groups of increasing clinical weight: endoscopic polypectomy, segmental resection, and total colectomy. A logistic regression analysis of clinicomolecular factors related to different treatment options was performed. RESULTS: The study comprised 80 patients (32 women, 40 %) with a median age of 53 years (range 13-74 years). The median number of polyps was 33 (range 10-90).The cases included 62 diffuse polyposis, 18 segmental polyposis coli and synchronous colorectal carcinomas (CRC; 34 cases, 43%). The pathogenetic mutations were biallelic MutYH (n = 19, 24 %) and APC (n = 4, 5 %). The mean follow-up period was 74 months (median 43 months, range 1-468 months). Endoscopic polypectomy was performed in 25 cases (31 %), segmental resection in 16 cases (20 %), and total colectomy in 39 cases (49 %). The logistics regression analysis, considering all the patients, showed that the number of polyps, the presence of CRC, and mutation were correlated with more intensive treatment. For the patients without CRC, only the number of polyps was correlated with the severity of the treatment (p > 0.0166). "On the ROC (receiver operating characteristic) curve, 25 was the number of polyps that best discriminated between surgical and endoscopic therapy. CONCLUSIONS: The majority of patients with MCRAs undergo surgery. For patients without CRC, only the number of polyps, and not the presence of a disease-causing mutation, is correlated with increased heaviness of treatment. Patients with more than 25 polyps are more likely to undergo a surgical resection.
Surgical Endoscopy 07/2012; · 4.01 Impact Factor
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Enzo Mammano,
Francesca Galdi,
Mariaelena Pierobon,
Emanuela Tessari,
Jianghong Deng, Salvatore Pucciarelli,
Marco Agostini,
Francesco De Marchi,
Vincenzo Canzonieri,
Antonino De Paoli,
Claudio Belluco,
Lance Liotta,
Emanuel Petricoin,
Pierluigi Pilati,
Donato Nitti
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ABSTRACT: BACKGROUND: Currently there is no reliable technique for predicting clinical or pathologic complete tumor response after radiochemotherapy (RCT) in patients with rectal cancer. We applied reverse phase protein microarray (RPMA) technology to find a signal pathway that may predict the response to preoperative treatment. PATIENTS AND METHODS: Fifteen rectal cancer samples were collected during preoperative RCT. Seven patients had a good response to preoperative therapy (Mandard grade I-II) and 8 patients had a poor response (Mandard grade III-V). Using laser capture microdissection (LCM) and RPMA analysis, we measured the phosphorylation level of nearly 80 end points and analyzed the signaling pathways. RESULTS: We identified 4 signaling proteins whose phosphorylation levels were significantly different (P < .05) between the good vs. poor responders; CHK2 and β-catenin were more highly phosphorylated in poor responders, whereas PDK1 and glycogen synthase kinase (GSK)-3α/β had lower phosphorylation levels in poor responders. Interestingly GSK-3α/β, β-catenin, and PDK1 are all present in the phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway. CONCLUSIONS: Based on our results, we hypothesize that the activating state of the PI3K-AKT pathway can stratify patients who could benefit most from neoadjuvant treatment. Moreover, identification of theranostic targets has the potential to pinpoint new therapeutic strategies for the nonresponsive population.
Clinical Colorectal Cancer 06/2012; · 1.68 Impact Factor
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ABSTRACT: Radiographically small pulmonary nodules (PNs) in patients with colorectal cancer are troublesome because their discovery raises concern about metastases. This study sought to establish the appropriate timing of radiological follow-up for PNs detected at initial staging evaluation of colorectal carcinoma patients.
The medical records of 376 consecutive colorectal cancer patients who underwent curative surgery and had baseline and follow-up chest X-rays (CXR) and computed tomography (CT) were reviewed.
The study included 92 patients who had all CXR and chest CT available for review, at least one PN found on baseline imaging, and no synchronous neoplasms. On baseline chest CT, these 92 patients had 170 PNs altogether and 77 (45.2 %) of them were greater than 5 mm in size. Baseline CXR detected 13 PNs in 12 patients and all but 2 were larger than 5 mm. Nodule size greater than 5 mm and irregular margins were predictors of nodule growth. The mean doubling time of 24/170 (14.1 %) growing PNs was about 4 months.
Our findings suggest that baseline and follow-up CXR are pointless, and short-interval CT follow-up is warranted when PNs larger than 5 mm with irregular margins are detected on preoperative chest CT.
• Pulmonary nodules in colorectal cancer patients raise concern about metastasis. • Baseline and follow-up chest X-ray in colorectal cancer can be abandoned. • CT is the best technique for assessing PNs in colorectal cancer. • Short-interval CT follow-up advisable for PNs larger than 5 mm with irregular margins.
European Radiology 04/2012; 22(8):1680-6. · 3.22 Impact Factor
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Salvatore Pucciarelli,
Enrica Rampazzo,
Marta Briarava,
Isacco Maretto,
Marco Agostini,
Maura Digito,
Sonia Keppel,
Maria Luisa Friso,
Sara Lonardi,
Antonino De Paoli,
Claudia Mescoli,
Donato Nitti,
Anita De Rossi
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ABSTRACT: To investigate whether the plasma levels of cell-free RNA (cfRNA) and telomere-specific reverse transcriptase mRNA (hTERT) are associated with tumor response in rectal cancer patients who received preoperative chemoradiotherapy (pCRT).
Patients who underwent pCRT for rectal cancer and for whom baseline and paired post-pCRT blood samples were available were studied. On the basis of tumor regression score, patients were classified as having response or having no response. Clinical variables and plasma levels of cfRNA and hTERT before and after the pCRT were evaluated. The association between each predictor and tumor response was assessed by univariate and multivariate analyses.
Of 98 eligible patients, 45 were determined to respond to therapy, and 53 did not respond to therapy. In univariate analysis, gender (P = 0.040), baseline levels of cfRNA (P = 0.026), post-pCRT levels of both hTERT and cfRNA (P < 0.0001 and P = 0.001, respectively), and the difference between the post- and pre-pCRT levels of both hTERT and cfRNA (P = 0.009 and P = 0.001, respectively) were found to be significant predictors of tumor response. In multivariate analysis, using variables that were available before pCRT, cfRNA levels and gender independently predicted the tumor response, while in multivariate analysis, which used all of the variables available before the surgical procedure, the post-pCRT levels of cfRNA and the difference between the post- and pre-pCRT levels of cfRNA independently predicted tumor response.
Plasma levels of cfRNA and hTERT are promising markers of tumor response to pCRT for rectal cancer.
Annals of Surgical Oncology 03/2012; 19(9):3089-96. · 4.17 Impact Factor
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ABSTRACT: 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).
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.
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).
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.
Journal of Clinical Oncology 02/2012; 30(9):965-71. · 18.37 Impact Factor
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Marco Agostini,
Chiara Bedin, Salvatore Pucciarelli,
Mariavittoria Enzo,
Marta Briarava,
Roberta Seraglia,
Eugenio Ragazzi,
Pietro Traldi,
Laura Molin,
Emanuele Damiano Urso,
Isabella Mammi,
Alessandra Viel,
Mario Lise,
Ennio Tasciotti,
Alessandra Biasiolo,
Patrizia Pontisso,
Donato Nitti
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ABSTRACT: Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS).
An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated.
Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients.
Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.
The International journal of biological markers 12/2011; 27(1):13-9. · 1.48 Impact Factor
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Marco Agostini, Salvatore Pucciarelli,
Maria Vittoria Enzo,
Paola Del Bianco,
Marta Briarava,
Chiara Bedin,
Isacco Maretto,
Maria Luisa Friso,
Sara Lonardi,
Claudia Mescoli,
Paola Toppan,
Emanuele Urso,
Donato Nitti
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ABSTRACT: The circulating cell-free DNA (cfDNA) in plasma has been reported to be a marker of cancer detection. The aim of this study was to investigate whether the cfDNA has a role as response biomarker in patients receiving preoperative chemoradiotherapy (CRT) for rectal cancer.
Sixty-seven patients (median age 61 years; male/female 42/25) who underwent CRT for rectal cancer were evaluated. After tumor regression grade (TRG) classification was made, the patients were classified as having disease that responded (TRG 1-2) and that did not respond (TRG 3-5) to therapy. Plasma samples were obtained from patients before and after CRT. The cfDNA levels were analyzed by quantitative real-time polymerase chain reaction of β-globin. On the basis of the Alu repeats, the cfDNA was considered as either total (fragments of 115 bp, Alu 115) or tumoral (fragments of 247 bp, Alu 247). The association between the pre- or post-CRT levels and between variations during CRT of the Alu 247, Alu 115 repeat, and Alu 247/115 ratio (cfDNA integrity index) and the pathologic tumor response was analyzed.
The baseline levels of cfDNA were not associated with tumor response. The post-CRT levels of the cfDNA integrity index were significantly lower in responsive compared to nonresponsive disease (P = 0.0009). Both the median value of the Alu 247 repeat and the cfDNA integrity index decreased after CRT in disease that responded to therapy (P < 0.005 and P < 0.005, respectively) compared to disease that did not respond to therapy (P = 0.83 and P = 0.726, respectively). The results of the multivariable logistic regression analysis showed that only the cfDNA integrity index was significantly and independently associated with tumor response to treatment.
The plasma levels of the longer fragments (Alu 247) of cfDNA and the cfDNA integrity index are promising markers to predict tumor response after preoperative CRT for rectal cancer.
Annals of Surgical Oncology 03/2011; 18(9):2461-8. · 4.17 Impact Factor
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ABSTRACT: To prospectively describe patient-reported outcomes (PROs) after preoperative chemoradiotherapy (pCRT) for rectal cancer.
Little evidence is available on PROs after pCRT for rectal cancer.
Patients with rectal cancer, candidates to receive pCRT, were enrolled in a multicenter prospective observational trial. Health-related quality of life was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and its colorectal cancer module (QLQ-CR38), and fecal incontinence and bowel function were evaluated using the fecal incontinence score questionnaire and a set of ad hoc questions. Questionnaires were filled out before CRT (t₀), 2 to 3 weeks after completion of CRT (t₁), and at 6 (t₂) and 12 months (t₃) after surgery. Primary analysis of selected scales included: global quality of life, physical functioning, social functioning, fatigue, body image, future prospective, and gender-related sexual problems.
Of 149 eligible patients, questionnaires were completed in 100%, 95%, 88% and 77% of cases at t0, t₁, t₂, and t₃, respectively. At t₃, 78% of patients reported stool fractionation and 72% sensation of incomplete defecation. Only 14% of patients had optimal continence. Physical/social functioning, fatigue, and body image showed a decrease just after pCRT and returned to baseline levels at 1 year after treatment. Global quality of life was stable over time. Male sexual problems were greatly impaired throughout the study period (P < 0.001) with major clinically meaningful changes between baseline and 1 year after treatment.
These findings add to the body of evidence available regarding pCRT and help clinicians to make more informed treatment decisions.
Annals of surgery 01/2011; 253(1):71-7. · 7.90 Impact Factor
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ABSTRACT: 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.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2011; 458(4):413-9. · 2.49 Impact Factor
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ABSTRACT: Locally advanced rectal cancer is currently treated with pre-operative radiochemotherapy (pRCT), but the response is not uniform. Identification of patients with higher likelihood of responding to pRCT is clinically relevant, as patients with resistant tumors could be spared exposure to radiation or DNA-damaging drugs that are associated with adverse side effects. To highlight predictive biomarkers of response to pRCT, a systematic search of PubMed was conducted with a combination of the following terms: "rectal", "predictive", "radiochemotherapy", "neoadjuvant", "response" and "biomarkers". Genetic polymorphisms in epithelial growth factor receptor (EGFR) and thymidylate synthase (TS) genes, the expression of several markers, such as EGFR, bcl-2/bax and cyclooxygenase (COX)-2, and circulating biomarkers, such as serum carcinoembryonic antigen (CEA) level, are promising as predictor markers, but need to be further evaluated. The majority of the studies did not support the predictive value of p53, while the values of Ki-67, TS and p21 is still controversial. Gene expression profiles of thousands of genes using microarrays, microRNA studies and the search for new circulating molecules, such as human telomerase reverse transcriptase mRNA and cell-free DNA, are providing OPEN ACCESS Cancers 2011, 3 2177 interesting results that might lead to the identification of new useful biomarkers. Evaluation of biomarkers in larger, prospective trials are required to guide therapeutic strategies.
Cancers. 01/2011; 3:2176-21943390.
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ABSTRACT: The risk of cancer or severe polyposis of the rectal stump after total colectomy for MutYH-associated polyposis is scarcely defined. To evaluate this risk, we describe the findings of endoscopic surveillance of the rectal stump in a series of patients with biallelic MutYH mutations and polyposis.
This is a retrospective, observational, multicenter case series derived from 2 familial cancer registries. Biallelic, germ-line MutYH mutations were found in 14 patients with no adenomatous polyposis coli gene mutations. Eleven of them underwent total colectomy with ileorectal anastomosis and yearly proctoscopic surveillance thereafter. Phenotype and histology of rectal polyps were recorded at diagnosis and during follow-up. Development of adenomas and carcinomas during endoscopic surveillance of the rectal stump was observed.
At diagnosis, 6 patients had attenuated polyposis (10-100 adenomas), 5 patients had classical polyposis, 8 patients had colon carcinoma, and no patient had rectal carcinoma. The mean number of rectal polyps at diagnosis was 2.64 ± 2.11 (range, 0-6). No patients had rectal cancer. The most frequent MutYH mutations were Y165C/Y165C and G382D/G382D in 6 and 2 patients, respectively. During surveillance of the rectal stump after surgery (median duration, 5 y; range, 2-23 y), no patient developed rectal cancer. The mean number of adenomas per proctoscopy was 1.23 ± 2.19 (range, 0-10 adenomas per proctoscopy). This study was limited by the small size and retrospective nature of the case series.
Total colectomy with ileorectal anastomosis may be appropriate for patients with MutYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.
Diseases of the Colon & Rectum 12/2010; 53(12):1670-5. · 3.13 Impact Factor
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Elisabetta Rossi,
Umberto Basso,
Romina Celadin,
Francesca Zilio, Salvatore Pucciarelli,
Michele Aieta,
Carmen Barile,
Teodoro Sava,
Giorgio Bonciarelli,
Salvatore Tumolo,
Cristina Ghiotto,
Cristina Magro,
Antonio Jirillo,
Stefano Indraccolo,
Alberto Amadori,
Rita Zamarchi
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ABSTRACT: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment.
An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer.
M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings.
M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers.
Clinical Cancer Research 10/2010; 16(21):5233-43. · 7.74 Impact Factor
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Monique Maas,
Patty J Nelemans,
Vincenzo Valentini,
Prajnan Das,
Claus Rödel,
Li-Jen Kuo,
Felipe A Calvo,
Julio García-Aguilar,
Rob Glynne-Jones,
Karin Haustermans,
Mohammed Mohiuddin, Salvatore Pucciarelli,
William Small,
Javier Suárez,
George Theodoropoulos,
Sebastiano Biondo,
Regina G H Beets-Tan,
Geerard L Beets
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ABSTRACT: Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15-27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR.
In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test.
484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0-277). 5-year crude disease-free survival was 83.3% (95% CI 78.8-87.0) for patients with pCR (61/419 patients had disease recurrence) and 65.6% (63.6-68.0) for those without pCR (747/2263; HR 0.44, 95% CI 0.34-0.57; p<0.0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0.54 (95% CI 0.40-0.73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0.91 (95% CI 0.73-1.12). The effect of pCR on disease-free survival was not modified by other prognostic factors.
Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival.
None.
The lancet oncology 09/2010; 11(9):835-44. · 14.47 Impact Factor
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ABSTRACT: Numerous miRNAs are deregulated in human cancers and experimental evidence indicates that they can play roles as oncogenes or tumor suppressor genes. Colorectal cancer represents a wide and exciting area of research for molecular biology, due to the growing need of a molecular classification as well as prognostic and predictive molecular factors that may guide oncologists in the clinical management of patients. The aim of this review is to analyze the state of art of the miRNA expression profiles in colorectal cancer to explore some perspectives in this research field.
Clinica chimica acta; international journal of clinical chemistry 05/2010; 411(17-18):1181-6. · 2.54 Impact Factor
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ABSTRACT: The aim of the study was to assess the accuracy of imaging techniques in predicting pathologic tumor (ypT), node (ypN) stages and the circumferential resection margin (ypCRM) status of rectal cancers after preoperative chemoradiotherapy (CRT).
Using pelvic computed tomography (CT), magnetic resonance imaging (MRI), and endorectal ultrasound (ERUS), 90 consecutive patients with locally advanced mid-to-low rectal cancer were prospectively assessed. Postirradiation T and N stages and infiltration of the CRM, as assessed by CT, MRI and ERUS, were compared with histopathologic findings.
The accuracy of ypT staging was low, whatever the imaging technique used (37% by CT, 34% by MRI, and 27% by ERUS), the most frequent inaccuracy being overstaging. Imaging showed a good specificity and good negative predictive values (NPV) when mural staging was grouped into ypT ≤ 3 and ypT4 categories; in particular, ERUS achieved a 92% specificity and 95% NPV. CRM involvement was correctly predicted in 71% of patients by CT (74% specificity; 93% NPV) and in 85% by MRI (88% specificity; 95% NPV). The accuracy for nodal staging was 62%, 68%, and 65% by CT, MRI and ERUS, respectively; the corresponding NPV were 88%, 78%, and 76%.
Current imaging techniques are inaccurate in restaging rectal cancer after CRT but are useful in predicting T ≤ 3 tumors, cases with negative nodes and tumor-free CRM. These findings may be of clinical relevance for planning less invasive surgery.
Surgery 05/2010; 149(1):56-64. · 3.10 Impact Factor
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ABSTRACT: The aim of this cross-sectional study was to evaluate psychological well-being outcomes in disease-free survivors who previously underwent radical surgery for rectal adenocarcinoma.
All patients with rectal adenocarcinoma who underwent primary surgery at a single institution from 1990 to 2002 were considered for inclusion in the study. We identified and sent questionnaires to 145 patients after excluding those who had died or had recurrent disease. One hundred and seventeen patients (men/women: 74/43; median age: 65 years) returned the questionnaires. Patients' well being was evaluated using the Psychological General Well-Being Index (PGWBI) questionnaire. The mean PGWBI score was compared with normative data of the general population. The impact of patient-, tumor- and treatment-related factors on patients' long-term psychological well-being status was also evaluated.
Compared with the general population, study patients had significantly better anxiety, depressed mood, positive well being, general health, vitality scales and global index scores. On multivariate analysis, positive well being was independently affected by time from diagnosis (36 months; p=0.025) and occurrence of early major complications (p=0.024). Variables that were independently associated with worse self-control included primary education (p=0.04) and the presence of fecal urgency (p=0.049). General health was negatively affected by time from diagnosis (36 months; p=0.047) and fecal urgency (p=0.009).
Patients who have survived cancer are likely to re-evaluate the importance of everyday events and this may explain why they had better PGWBI scores. This study also identified that a short time from diagnosis, early adverse events and bowel dysfunction had a negative impact on patients' well being.
Psycho-Oncology 05/2010; 20(7):706-14. · 3.34 Impact Factor
