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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.

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, >=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 >=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 >=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.

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.

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.

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.

At present, abdominoperineal resection remains the most diffuse method of treatment of very low rectal cancer. Today, we can avoid this method in some patients by using a sphincter-saving procedure. From March 1990 to January 1999, 273 consecutive total rectal resections and coloendoanal anastomoses were performed at our Institute; this study concerns 141 consecutive patients treated for a primary adenocarcinoma of the distal rectum, from 3.5 to 8 cm from the anal verge. Patient stratification, based on definitive pathological report, was 31 Dukes' stage A (T2N0), 44 stage B (T3N0), and 66 stage C (T2N+-T3N+). Overall recurrence rate was 9.2%; postoperative morbidity attributable to the procedure was low. A perfect continence was documented in 61% of cases. The only pathological factor related to local recurrence rate is peritumoral lymphocytic reaction inside and around the tumor (P = .0005 and .031) independently from the number of metastatic lymph nodes, depth of fatty tissue infiltration, and lymphatic and venous neoplastic emboli. The minimum follow-up time is 12 months. Our data, in accordance with other authors, seem to highlight the relevant role that a well-practiced surgery, together with accurate information on the spreading of this disease, has in achieving an optimal local control of cancer.

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.

Recent reports suggest that a distal clearance (DC) of 10 mm at the lower surgical margin may be considered adequate in the surgical treatment of rectal cancer, but there are no data on the possible adequacy of a < 10-mm DC in N0 patients in whom a good prognosis can otherwise be expected, that is, those with negative surgical margins and negative lymph nodes. Between November 1991 and December 1998, 154 consecutive patients with adenocarcinoma of the lower third of the rectum had a total rectal resection with total mesorectal excision and coloendoanal anastomosis. Among 76 N0 patients, there were 35 with <10-mm DC and 41 with > or =10-mm DC. Each group was divided into two subgroups depending on whether the surgical margins were involved or not, and the rate of local recurrence in the various categories was compared. All B2 Astler-Coller stage patients in the series received postsurgical chemoradiotherapy. The local recurrence rate in the 35 patients with DC < 10 mm was 11.4% and that of the 41 patients with DC > or =10 mm was 7.3%. When only patients with negative surgical margins were considered, the local recurrence rate was 3.4% for those with < 10-mm DC and 5.1% for those with > or =10-mm DC. Our results suggest that a radical surgery with <10-mm DC followed by chemoradiotherapy may be adequate in N0 patients, provided that a careful pathologic examination of the surgical specimen excludes the presence of lymph node metastases and that the distal rectal and mesorectal resection margins fall in healthy tissue.

The number of examined lymph nodes and metastases in lymph nodes smaller than 5 mm (small lymph nodes) are a determining factor in the stage of rectal cancer although the clinical significance of occult micrometastases is controversial. We are reporting our preliminary results on the identification and prognostic utility of metastases in small lymph nodes and occult micrometastases. We searched small metastatic lymph nodes in 101 cases of adenocarcinoma of the lower third of the rectum. We used the manual technique to dissect mesorectal fat and occult micrometastases in the lymph nodes of 52 Dukes' A and B patients, using a pool of anticytokeratin antibodies. Forty-five percent of the metastatic lymph nodes were smaller than 5 mm in diameter and determined the Dukes' stage in 15 (30.6%) of 49 Dukes' C patients. Occult micrometastases were found in 21 (40.4%) patients: five recurred but vascular invasion, positive distal margin of the rectum, and positive circumferential margin of the mesorectum were present. Small metastatic lymph nodes, vascular invasion, positive distal margin of the rectum, and positive circumferential margin of the mesorectum were found to be more important than occult micrometastases in predicting early recurrence of rectal cancer.