Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors.

BACKGROUND: An increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors. METHODS: We measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610-650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence. RESULTS: The fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610-650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman's rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83. CONCLUSIONS: These results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are maximally effective in early-stage colorectal cancer peritoneal metastases (CRC-PM); however, the use of HIPEC to treat subclinical-stage PM remains controversial. This prospective two-center study assessed adjuvant HIPEC in CRC patients at high risk for metachronous PM ( www.clinicaltrials.gov NCT02575859). METHODS: During 2006-2012, a total of 22 patients without systemic metastases were prospectively enrolled to receive HIPEC simultaneously with curative surgery, plus adjuvant systemic chemotherapy (oxaliplatin/irinotecan-containing ± biologics), based on primary tumor-associated criteria: resected synchronous ovarian (n = 2) or minimal peritoneal (n = 6) metastases, primaries directly invading other organs (n = 4) or penetrating the visceral peritoneum (n = 10). A control group retrospectively included 44 matched (1:2) patients undergoing standard treatments and no HIPEC during the same period. The cumulative PM incidence was calculated in a competing-risks framework. RESULTS: Patient characteristics were comparable for all groups. Median follow-up was 65.2 months [95 % confidence interval (CI) 50.9-79.5] in the HIPEC group and 34.5 months (95 % CI 21.1-47.9) in the control group. The 5-year cumulative PM incidence was 9.3 % in the HIPEC group and 42.5 % in the control group (p = 0.004). Kaplan-Meier estimated 5-year overall survival (OS) was 81.3 % in the HIPEC group versus 70.0 % in the control group (p = 0.047). No operative death occurred. Grade 3-4 [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4] morbidity rates were 18.2 % in the HIPEC group and 25 % in controls (p = 0.75). At multivariate analysis, HIPEC correlated to lower PM cumulative incidence [hazard ratio (HR) 0.04, 95 % CI 0.01-0.31; p = 0.002], and better OS (HR 0.25, 95 % CI 0.07-0.89; p = 0.039) and progression-free survival (HR 0.31, 95 % CI 0.11-0.85; p = 0.028). CONCLUSION: Adjuvant HIPEC may benefit CRC patients at high-risk for peritoneal failure. These results warrant confirmation in phase III trials.

Epidural analgesia does not influence anastomotic leakage incidence after open colorectal surgery for cancer: A retrospective study on 1,474 patients.

BACKGROUND: Anastomotic leakage is a major cause of morbidity after colorectal surgery. Epidural analgesia is the most effective method for postoperative pain relief after major abdominal surgery. Anyhow, its effect on anastomotic leakage rate is still controversial. This study aimed to compare epidural versus intravenous analgesia as risk factor for anastomotic leakage requiring reoperation in patients undergoing open colorectal surgery for cancer. METHODS: A retrospective study on 1,474 patients was performed. The Cox proportional hazards model was used to study the relation between primary and secondary factors of risk and anastomotic leakage occurrence within 30 days after elective operation. RESULTS: Overall 30-day anastomotic leakage requiring reoperation was 4.9% (95%CI: 3.8-6.0%). No difference in anastomotic leakage occurrence was observed between the epidural analgesia group and the intravenous analgesia group (Hazard ratio: 0.94; 95%CI: 0.53-1.67%; P = 0.8338). Females had a rate of anastomotic leakage 43% lower than males (P = 0.0301). The diverting stoma resulted to be protective for anastomotic leakage occurrence (P = 0.0052). AL significantly increased postoperative median length of stay but not in-hospital mortality. CONCLUSIONS: Epidural analgesia does not influence the AL risk after open colorectal surgery for cancer.

Wall defects after abdominoperineal resection: a modified tension-free technique.

BACKGROUND: The treatment of wall defects after abdominoperineal resection has yet to be defined. In this study we report the outcome of a modified prosthetic technique for the treatment of combined large incisional and parastomal hernia performed after abdominoperineal resection. MATERIAL AND METHODS: Between January 2005 and July 2008, 21 consecutive patients who underwent abdominoperineal resection for low rectal cancer received surgical repair for large incisional hernias with a modified mesh technique consisting of a tension-free attachment of the prosthetic material to the posterior sheath of the rectus abdominis muscle. The surgical outcome was assessed mainly as the recurrence rate of abdominal hernia and postoperative complications. RESULTS: Among the 21 patients we reported two minor complications: partial necrosis of the skin flap (4.8%) and a seroma (4.8%). One major complication occurred: extensive necrosis of the skin flap (4.8%). We reported one death due to stroke 20 days after surgery. The mean postoperative hospital stay was 6.1 days (SD, 2.3). CONCLUSIONS: This study encourages the use of a tension-free modified prosthetic technique for the repair of combined wall defects after abdominoperineal resection. The technique does not lead to an increase in the incidence of complications, offering a considerable advantage to the patient.

Diagnosis of rectal cancer by Tissue Resonance Interaction Method.

BACKGROUND: Since population screening has the potential to reduce mortality from rectal cancer (RC), novel methods with improved cost-effectiveness warrant consideration. In a previous pilot study, we found that the rapid, inexpensive and non-invasive electromagnetic detection of RC is a highly specific and sensitive technique. The aim of the present prospective study was to evaluate the prediction accuracy of electromagnetic detection of RC. METHODS: 304 eligible subjects were consecutively enrolled in our Institute and subjected to electromagnetic detection followed by colonoscopy and histopathologic analysis of biopsies. A putative RC carrier status was attributed to subjects showing an electromagnetic signal < 50 units (U). RESULTS: RC patients showed a significantly lower electromagnetic signal (40.9 +/- 0.9 U; mean +/- S.E.) than did non-RC subjects (79.2 +/- 1.4 U; P < 2.2e-16). At a threshold < 50 U, electromagnetic detection identified 103 putative patients, whereas colonoscopy detected 108 patients, with an overlap of 91 patients between the two methods. The 15.7% false-negative rate by electromagnetic detection was brought to zero by raising the threshold value to 70 U; on the other hand, such a threshold increased the false-positive rate to 30%. CONCLUSION: Electromagnetic detection of RC at a signal threshold < 70 U appears to eliminate false-negative results. Although colonoscopy would still be required in examining the false-positives associated with the < 70 U electromagnetic threshold, the need for this method would be reduced. Thus, electromagnetic detection represents a new accurate, rapid, simple, and inexpensive tool for early detection of RC that merits testing in large population-based programs.

Integrative approach for prioritizing cancer genes in sporadic colon cancer.

The current multistep carcinogenesis models of colon cancer do not fully capture the genetic heterogeneity of the disease, which is additionally complicated by the presence of passenger and driver genetic alterations. The aim of this study was to select in the context of this significant heterogeneity additional genes functionally related to colon cancer development. High-throughput copy number and gene expression data of 36 microsatellite stable sporadic colon cancers resected from patients of a single institution characterized for mutations in APC, KRAS, TP53 and loss of 18q were analyzed. Genes whose expression correlated with the underlying copy number pattern were selected, and their association with the above listed mutations and overall survival was evaluated. Gain of 20q was strongly associated with TP53 mutation, and overall survival with alterations on 7p, 8p, 13q, 18q, and 20q. An association with 18q loss and gain of 8q24 was also observed. New candidate genes with a potential role in colon cancer are PLCG1 on 20q, DBC1 on 8q21, and NDGR1 on 8p24. In addition, an unexpected pattern of loss and mutability was found in the region upstream of the KRAS gene. By integrating copy number alterations with gene expression and mutations in colon cancer associated genes, we have developed a strategy that identifies previously known molecular features and additional players in the molecular landscape of colon cancer.

Hospital bodies: the genesis of Italian National Health Service.

Hospital public bodies were instituted in Italy in 1968. Their creation represents a fundamental step forward in the evolution of the national healthcare system and has allowed improvements in social equity in hospitals. The lack of independent funding beyond the insurance-type healthcare system existing at the time, hindered its success. The hospital body has however left a trace in the modern national healthcare system with the introduction of the hospital corporation.

Diagnosis of rectal cancer by electromagnetic interactions: preliminary results.

OBJECTIVES: Although colonoscopy is effective in screening for colorectal cancer, its high cost and low compliance rates have encouraged a search for different methods. Our study was designed to evaluate the feasibility of rectal cancer detection using a nonlinear tuneable oscillator (TRIMprob), a recently developed device for detecting differences in electromagnetic properties of cancerous and normal tissues. METHODS: We tested 228 patients (115 male and 113 female) between March and September 2006: 114 patients with rectal cancer diagnosed on colonoscopy and 114 patients with negative colonoscopy results. The TRIMprob probe was moved over the surface of the pelvic area from the back and the front, with the patient standing, normally dressed, between the operator and the system receiver. The signal variation of three spectral lines, for 465-MHz, 930-MHz, and 1395-MHz frequencies was recorded for each of six probe positions. RESULTS: Analysis of resonance values showed that only the 465-MHz frequency differentiated patients with rectal cancer from those without cancer at all six probe positions (P < 0.001). With a cutoff value of 50 arbitrary units, the area under the receiver operating characteristic curve was 0.94 (specificity, 85 percent; sensitivity, 94 percent). CONCLUSIONS: The TRIMprob test discriminates well between patients with normal rectal tissue and those with malignant lesions. These preliminary results confirm that electromagnetic detection of rectal cancer is possible and suggest this method of extracorporeal scanning may be useful as a first-level screening tool.

Distal clearance margin of 1 cm or less: a safe distance in lower rectum cancer surgery.

PURPOSE: The purpose of this study was to investigate the prognostic role of distal clearance margin (DCM) in lower rectum cancer surgery. MATERIALS AND METHODS: Two-hundred-three cancer patients underwent total rectal resection, possibly followed by adjuvant chemoradiotherapy. DCM was classified as positive or negative (<1, > or =1 cm) and investigated with multivariable proportional hazard models. RESULTS: A total of 52 deaths, 19 local relapses, 40 distant metastases, and three second primaries were observed as first events. Five-year survival with positive, negative <1, or negative > or =1 cm DCM was 51%, 81%, and 69%, respectively (p = 0.018). The difference was significant between positive and negative DCM (p = 0.031), not between negative <1 and > or =1 cm (p = 0.106). Local and distant 5-year incidences according to DCM were 30%, 8%, and 8% (p = 0.006) and 38%, 26%, and 19% (p = 0.857), respectively. CONCLUSIONS: DCM, but not tumor size, is a prognostic factor after sphincter-saving surgery, which is safe whenever a negative margin is achieved.

Pelvic lymphedema: truth or fiction?

Pelvis is a functional shell-like unit consisting of the pelvic floor and perineum. The patients, who underwent a radical operation of the pelvis due to an oncological disease, often develop pelvic disorders. These disorders do not depend on the type of surgery or any presence of postoperative treatment (radio- and chemotherapy). The reason for this is still mostly unknown. These disorders without an appropriate treatment of rehabilitation always result in the following symptoms: fatty tissue hypertrophy and fibrosis as well as functional chronic disorders. Lymphedema is described as a progressive pathological condition with retention of protein-rich liquid in the interstitial space, fatty tissue hypertrophy and fibrosis. It is possible to assume that lymphadenectomy related to pelvic surgery results in a localized lymphedema in the pelvis developing disorders of perineum and pelvic floor: a pelvic lymphedema, or rather a blind lymphedema, i.e. with symptoms but with no signs. The clinical evidence shows that the lymphatic vessels play a relevant role in the pathology of the pelvic floor and perineum. The study of pelvic lymphedema could be the key when choosing the therapies for pelvic disorders resulting from surgery.

Health authority: the Italian experience.

The healthcare reform, introduced in Italy in 1992, has completely changed the structure of the national healthcare system (NHS) , including the introduction of the concept of "business firm" applied to public health service providers. The aim of this study was to outline the history of healthcare "firms" (azienda sanitaria) and evaluate the impact of this change on the NHS in terms of health expenditure, and corporate effectiveness and efficiency. Self regulation and correction are the abilities to which the success of healthcare companies can be attributed. The benefits of creating healthcare firms include preventing those problems associated with healthcare models based on the principles of the private insurance type model and preferring instead a cost-effectiveness approach.

Colorectal carcinoma in children and adolescents: the experience of the Istituto Nazionale Tumori of Milan, Italy.

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common tumors in adults, but extremely rare in young age. This study retrospectively reports on a group of 27 patients <30 years of age, and particularly on 7 cases <18 years old, treated at the Istituto Nazionale Tumori, Milan, Italy, between 1985 and 2005. PATIENTS AND METHODS: Among the children/adolescents (age 9-18, median 12 years), 5/7 had unfavorable CRC histotypes (poorly differentiated or mucinous adenocarcinoma) and all but one had advanced disease at onset. Initial surgical resection was complete in 5/7 cases, and all patients received postoperative chemotherapy. RESULTS: In the subset of patients <18 years, 6/7 had tumor progression or relapse, and 5 died of their tumor: overall survival (OS) was 23% at 5 years. In the group of 19- to 29-year-olds (young adults), 5-year OS was 72.6%. CONCLUSIONS: This study confirms the rarity and poor prognosis of CRC in children and adolescents: advanced stage and an aggressive biology are hallmarks of this tumor in pediatric age, while clinical findings and outcome in young adults seem more similar to those observed in adult series. Therapeutic recommendations should stay the same as for adults. Surgery remains the mainstay of treatment and early diagnosis is crucial: it is important for pediatricians to be aware that CRC does occur in children, in order to refer suspected cases to expert physicians professionally dedicated to the management of this cancer in adults.

Natural fluorescence spectroscopy of human blood plasma in the diagnosis of colorectal cancer: feasibility study and preliminary results.

AIM AND BACKGROUND: Fluorescence spectroscopy of biomolecules is considered a promising method to discriminate in vivo normal tissue from malignant tissue at various sites including breast, cervix, lung, and colon. However, only few studies have been reported on the feasibility of exploiting fluorescence spectroscopy of blood to characterize pathological changes usable in diagnostic oncology. In this study, the fluorescence characteristics of human blood plasma have been studied in the visible spectral range in an attempt to discriminate patients with colorectal cancer from subjects of a control population. PATIENTS AND METHODS: The study involved 341 subjects, including 169 blood donors with no evidence of disease, 143 patients bearing colorectal adenocarcinomas (36 in the colon, 38 in the sigmoid colon and 69 in the rectum), 11 patients with local relapse, 10 patients with familial adenomatous polyposis and 8 with single adenomas. Blood samples were collected from all subjects and plasma fluorescence spectrum was analyzed using a conventional spectrofluorometer. RESULTS: The intensity of a fluorescence emission peak around 615-635 nm, which could reasonably be ascribed to endogenous porphyrins, was significantly different between patients bearing colorectal cancer and blood donors. The diagnostic capacity of the method was tested by ROC analysis, which resulted in an area under the curve of 0.72, close to that reported for the CEA test. CONCLUSION: These results, although preliminary, suggest the potential of fluorescence measurements of blood plasma as an additional method for diagnostic application in colon cancer.

MIF/CD74 axis is a target for novel therapies in colon carcinomatosis.

BACKGROUND: Strategies aimed at obtaining a complete cytoreduction are needed to improve long-term survival for patients with colorectal cancer peritoneal carcinomatosis (CRC-pc). METHODS: We established organoid models from peritoneal metastases of two naïve CRC patients. A standard paraffin inclusion was conducted to compare their 3D structure and immunohistochemical profile with that of the corresponding surgical samples. RNA expression levels of the CRC stem cell marker LGR5 was measured by in situ hybridization. The secretome of organoids was profiled by mass spectrometry. Energy homeostasis of organoids was interfered with 4-IPP and metformin. Biochemical and metabolic changes after drug treatments were investigated by western blot and mass spectrometry. Mitochondria impairment was evaluated by electron microscopy and mitotraker staining. RESULTS: The two organoids recapitulated their corresponding clinical samples in terms of 3D structure and immmunoistochemical profile and were positive for the cancer stem cells marker LGR5. Proteomic analyses of organoids highlighted their strong dependence on energy producing pathways, which suggest that their targeting could be an effective therapeutic approach. To test this hypothesis, we treated organoids with two drugs that target metabolism acting on AMP-activated protein kinase (AMPK), the main regulator of cellular energy homeostasis, which may act as metabolic tumour suppressor in CRC. Organoids were treated with 4-IPP, an inhibitor of MIF/CD74 signalling axis which activates AMPK function, or metformin that inhibits mitochondrial respiratory chain complex I. As a new finding we observed that treatment with 4-IPP downregulated AMPK signalling activity, reduced AKT phosphorylation and activated a JNK-mediated stress-signalling response, thus generating mitochondrial impairment and cell death. Metformin treatment enhanced AMPK activation, decreasing the activity of the anabolic factors ribosomal protein S6 and p4EBP-1 and inducing mitochondrial depolarization. CONCLUSION: We provide evidence that the modulation of AMPK activity may be a strategy for targeting metabolism of CRC-pc organoids.

Potential pathological understaging of pT3 rectal cancer with less than 26 lymph nodes recovered: a prospective study based on a resampling of 50 rectal specimens.

The aim of the paper was to establish if the 12 lymph nodes recommended by tumor-node-metastasis (TNM) system are sufficient for a correct staging of rectal cancer. For this purpose, we first compared the mean number of lymph nodes recovered in the same surgical specimen at the routine sampling and at a resampling performed by a second expert gastrointestinal pathologist. The study was performed on 50 cases of pT2N0 and pT3N0 rectal cancers, with a minimum number of 12 lymph nodes recovered at first sampling, histologically negative for metastases. Resampling retrieved a variable number (1 to 24) of nodes missed at first sampling. The final pN0 status was maintained in pT2 patients, whereas in 18.7% of pT3 patients, metastatic lymph nodes were detected if the mean number of lymph nodes increased from 17.8 to 26.8 after the second sampling. Interestingly, all pN1 patients had only a single metastatic lymph node measuring less than 4.9 mm. As we have shown that most (five out of six) missed metastatic lymph nodes were detected in specimens in which a maximum number of 19 lymph nodes had been originally recovered, we strongly suggest a resampling of pT3N0 rectal specimens if less than 20 lymph nodes have been recovered.

Quantitative analysis of plasma DNA in colorectal cancer patients: a novel prognostic tool.

Extracellular DNA in the plasma or serum of cancer patients has been recently proposed as a source of analyzable cancer-related gene sequences (qualitative approach). Furthermore, patients with different tumor types show high levels of cell-free circulating DNA both in plasma and serum (quantitative approach) at the time of surgery. Our aim was to verify whether the level of cell-free DNA in plasma might help in detecting recurrences during follow-up of colorectal cancer (CRC) patients. We studied 70 patients undergoing surgery for primary CRC. Plasma samples were obtained at the time of surgery and during follow-up. The cell-free circulating DNA in plasma was quantified by the Dipstick Kit method. At the time of surgery, in all patients, cell-free DNA levels in plasma were about 25 times higher in comparison with 20 healthy donors. In contrast, the carcinoembryonic antigen (CEA) value of this cohort of patients was altered in only about 37% of cases. During follow-up, cell-free DNA levels decreased progressively in tumor-free patients, while it increased in those developing recurrences or metastases. The results were further supported by qualitative analysis of circulating tumor-specific DNA, such as K-Ras mutations and p16(INK4a) promoter hypermethylation. These preliminary data confirm that plasma tumor DNA levels (i) are significantly higher in patients with CRC, (ii) decrease progressively in the follow-up period in tumor-free patients, and (iii) increase in patients with recurrence or metastasis. We suggest, therefore, that the quantification of plasma cell-free DNA might represent a useful tool for monitoring of CRC and, prospectively, for identifying high-risk individuals.

The art of decision-making in surgery. To what extent does economics influence choice?

Traditionally most surgeons have paid little attention to the costs of healthcare treatments. With the increase in the number of efficacious surgical alternatives, a distinct scarcity of available resources has emerged. Since the Eighties, the impact of surgical expenditure has been increasing everywhere. The causes are: medical progress, increased life expectancy, escalating costs and decreasing revenues. The surgeon has been increasingly forced to weigh up theories, doctrines and techniques of economics and management. This created new problems of choice. In any event, the surgeon's decision-making could lead to negative consequences if the primary concern is with the financial constraints and he is prompted simply to act rather than to achieve his therapeutic goal. In conclusion, although the impact of economic considerations is inevitable in the choice of surgery, the terms and methods involved in the process are rather ambiguous. In other words, surgeons face with the dilemma of the patient to whom the economist denies treatment. To be aware of this issue is the first step, but there is still much more to do in order to define the terms of action.

The apoptosis inhibitor protein survivin induces tumor-specific CD8+ and CD4+ T cells in colorectal cancer patients.

The identification of tumor-associated antigens expressed by colorectal carcinoma remains one of the major goals for designing novel immunological treatments for this tumor. By using a reverse-immunology approach, we show here that the inhibitor of apoptosis protein, survivin, is immunogenic in colorectal cancer patients. In particular, we found that survivin elicited CD8(+) T cell-mediated responses in peripheral blood or in tumor-associated lymphocytes from patients at different disease stage. Colorectal carcinoma cells were recognized by survivin-specific T lymphocytes, and the survivin-specific, class-I HLA-restricted T lymphocytes were fully activated and released interleukin-2 in response to HLA/survivin-peptide complexes expressed by tumor cells. In addition to CD8-mediated responses, survivin specifically stimulated CD4+ T-cell reactivity in peripheral blood lymphocytes from the same patients, thus suggesting that a complete activation of the immune system may occur in response to this antiapoptotic protein. These findings indicate that survivin could be considered a valuable tumor-associated antigen for immune-based clinical approaches in colorectal cancer.

Abdominosacral resection for locally recurring rectal cancer.

AIM: To investigate feasibility and outcome of abdominal-sacral resection for treatment of locally recurrent rectal adenocarcinoma. METHODS: A population of patients who underwent an abdominal-sacral resection for posterior recurrent adenocarcinoma of the rectum at the National Cancer Institute of Milano, between 2005 and 2013, is considered. Retrospectively collected data includes patient characteristics, treatment and pathology details regarding the primary and the recurrent rectal tumor surgical resection. A clinical and instrumental follow-up was performed. Surgical and oncological outcome were investigated. Furthermore an analytical review of literature was conducted in order to compare our case series with other reported experiences. RESULTS: At the time of abdomino-sacral resection, the mean age of patients was 55 (range, 38-64). The median operating time was 380 min (range, 270-480). Sacral resection was performed at S2/S3 level in 3 patients, S3/S4 in 3 patients and S4/S5 in 4 patients. The median operating time was 380 ± 58 min. Mean intraoperative blood loss was 1750 mL (range, 200-680). The median hospital stay was 22 d. Overall morbidity was 80%, mainly type II complication according to the Clavien-Dindo classification. Microscopically negative margins (R0) is obtained in all patients. Overall 5-year survival after first surgical procedure is 60%, with a median survival from the first surgery of 88 ± 56 mo. The most common site of re-recurrence was intrapelvic. CONCLUSION: Sacral resection represents a feasible approach to posterior rectal cancer recurrence without evidence of distant spreading. An accurate staging is essential for planning the best therapy.

Different genetic features associated with colon and rectal carcinogenesis.

PURPOSE: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers. EXPERIMENTAL DESIGN: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18. RESULTS: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN- SCRCs. All MIN- SCRCs showed beta-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN- SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q. CONCLUSIONS: The APC-beta-catenin pathway is inactivated in MIN- SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN- SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.