In-hospital mortality, 30-day readmission, and length of hospital stay after surgery for primary colorectal cancer: A national population-based study.

INTRODUCTION: The simultaneous assessment of multiple indicators for quality of care is essential for comparisons of performance between hospitals and health care systems. The aim of this study was to assess the rates of in-hospital mortality and 30-day readmission and length of hospital stay (LOS) in patients who underwent surgical procedures for colorectal cancer between 2005 and 2014 in Italy. METHODS: All patients in the National Italian Hospital Discharge Dataset who underwent a surgical procedure for colorectal cancer during the study period were included. The adjusted odd ratios for risk factors for in-hospital mortality, 30-day readmission, and LOS were calculated using multilevel multivariable logistic regression. RESULTS: Among the 353 941 patients, rates of in-hospital mortality and 30-day readmission were 2.5% and 6%, respectively, and the median LOS was 13 days. High comorbidity, emergent/urgent admission, male gender, creation of a stoma, and an open approach increased the risks of all the outcomes at multivariable analysis. Age, hospital volume, hospital geographic location, and discharge to home/non-home produced different effects depending on the outcome considered. The most frequent causes of readmission were infection (19%) and bowel obstruction (14.6%). CONCLUSIONS: We assessed national averages for mortality, LOS and readmission and related trends over a 10-year time. Laparoscopic surgery was the only one that could be modified by improving surgical education. Higher hospital volume was associated with a LOS reduction, but our findings only partially support a policy of centralization for colorectal cancer procedures. Surgical site infection was identified as the most preventable cause of readmission.

Surgical Unit volume and 30-day reoperation rate following primary resection for colorectal cancer in the Veneto Region (Italy).

BACKGROUND: The aim of this study was to evaluate the impact of Surgical Unit volume on the 30-day reoperation rate in patients with CRC. METHODS: Data were extracted from the regional Hospital Discharge Dataset and included patients who underwent elective resection for primary CRC in the Veneto Region (2005-2013). The primary outcome measure was any unplanned reoperation performed within 30 days from the index surgery. Independent variables were: age, gender, comorbidity, previous abdominal surgery, site and year of the resection, open/laparoscopic approach and yearly Surgical Unit volume for colorectal resections as a whole, and in detail for colonic, rectal and laparoscopic resections. Multilevel multivariate regression analysis was used to evaluate the impact of variables on the outcome measure. RESULTS: During the study period, 21,797 elective primary colorectal resections were performed. The 30-day reoperation rate was 5.5% and was not associated with Surgical Unit volume. In multivariate multilevel analysis, a statistically significant association was found between 30-day reoperation rate and rectal resection volume (intermediate-volume group OR 0.75; 95% CI 0.56-0.99) and laparoscopic approach (high-volume group OR 0.69; 95% CI 0.51-0.96). CONCLUSIONS: While Surgical Unit volume is not a predictor of 30-day reoperation after CRC resection, it is associated with an early return to the operating room for patients operated on for rectal cancer or with a laparoscopic approach. These findings suggest that quality improvement programmes or centralization of surgery may only be required for subgroups of CRC patients.

Systematic review of surgical treatment of subclinical Cushing's syndrome.

BACKGROUND: Subclinical Cushing's syndrome (SCS) is a condition of biochemical cortisol excess without the classical clinical features of overt hypercortisolism; it may be associated with some consequences of metabolic syndrome. The most appropriate treatment remains controversial. This study aimed to assess the outcomes of adrenalectomy for SCS. METHODS: A systematic review was performed. MEDLINE, Embase and Cochrane Databases (1980-2013) were searched for studies reporting the outcomes of unilateral adrenalectomy with respect to hypertension, diabetes, dyslipidaemia, obesity and osteoporosis in patients with SCS. Studies with a questionable diagnosis of SCS, bilateral adrenal involvement and insufficient data were excluded. RESULTS: Of the 105 papers screened, seven were selected; there were six retrospective studies and one randomized clinical trial, including 230 patients. Data analysis was limited by heterogeneity in definition of SCS and endpoints. Hypercortisolism was cured in all operated patients. Laparoscopy was the preferred approach, with a morbidity rate of 0·8 per cent. A beneficial effect of surgery on blood pressure, glucometabolic control and obesity was evident in all studies, with cure or improvement in 72, 46 and 39 per cent of patients respectively, compared with conservative management. The results for lipid metabolism were equivocal, because of a decrease in triglyceridaemia but discordant effects on cholesterol metabolism among the different studies. No beneficial effects on osteoporosis were found. CONCLUSION: Laparoscopic adrenalectomy seems to be beneficial in reversing several metabolic effects of hypercortisolism, with a low morbidity rate. However, the heterogeneity and low quality of the available studies preclude definitive recommendations.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

Histopathological characteristics of subsequent melanomas in patients with multiple primary melanomas.

BACKGROUND: Multiple primary melanomas (MPM) occur in up to 20% of melanoma patients, and subsequent tumours seem to have a favourable histopathological pattern. OBJECTIVE: A prospectively collected cohort of 194 patients with MPM was retrospectively reviewed to investigate clinical and histopathological features of first and subsequent melanomas. METHODS: Patients with MPM who were diagnosed at our Department (1985-2011) and who attended at least a follow-up control yearly were identified. RESULTS: The number of nevi was <10, 10-50 and >50 in 8.7%, 41% and 50.3% of patients respectively. Histopathological dysplastic nevi have been diagnosed in 105 patients. During a median follow-up of 58 months, 159 (81.9%), 24 (12.3%), 7 (3.6%) and 4 (2%) patients developed 2, 3, 4 and ≥ 5 melanomas, respectively. The median time to second primary melanoma was 45 months. The second primary melanoma was diagnosed within 1-year and after 5-year from the first melanoma in 36.6% and 17.3% of patients respectively. First and second primary melanomas were in situ in 41 (21%) and 104 (54%) patients respectively (P < 0.001). Among patients with ≥ 2 invasive melanomas (N = 80), median tumour thickness and ulceration of first and second primaries were 0.91 and 0.44 mm (P <0.001), and 32% and 7.7% (P = 0.001) respectively. CONCLUSIONS: Subsequent melanomas occurred within 1-year from the appearance of the first melanoma in 36% of patients with MPM, while a late melanoma diagnosis was detected in 17% of cases. Second primary melanoma had favourable histopathological features. Our findings support long-term skin surveillance to detect subsequent melanomas at an early stage.

Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n = 25 531).

BACKGROUND: Owing to its rarity, the published evidence on gastrointestinal (GI) carcinoid is often based on small series of patients or population-based studies regarding all neuroendocrine tumors. Here, we present a comprehensive epidemiological and survival analysis of the largest cohort of patients with GI carcinoid ever reported. PATIENTS AND METHODS: Patients with histological diagnosis of GI carcinoid (n = 25 531) were identified from the Surveillance Epidemiology End Results (SEER) database (including 18 USA cancer registries and spanning the 1973-2009 time frame). Demographic and disease data were used for epidemiological and survival analyses. RESULTS: The incidence of GI carcinoid is steadily increasing over the past three decades at a rate higher than any other cancer [annual percentage change (APC) = 4.4, 95% confidence interval (CI) 4.0-4.8]. These patients have a higher risk of further primary tumor (standardized incidence ratio, SIR = 1.15, 95% CI 1.10-1.21), but also a reduced risk of skin melanoma (SIR = 0.64, 95% CI 0.41-0.95). Despite the overall favorable prognosis (5-year disease-specific and relative survival rate: 91.3% and 87.4%, respectively), the mortality rate is increasing over time (APC = 3.5, 95% CI 3.0-4.0) and the 5-year survival rate of patients dying of GI carcinoid (28.5%), though better than that reported for GI cancers in general (8.4%), cannot be considered satisfactory. Finally, a nomogram is provided to predict patient survival on the basis of clinico-pathological factors independently associated with prognosis at multivariate analysis. CONCLUSIONS: These findings can be clinically useful for the management of patients with GI carcinoid and eagerly prompt the continuous effort to develop more effective therapeutic strategies against this slow-growing but chemoresistant tumor.

Adherence to treatment guidelines for primary sarcomas affects patient survival: a side study of the European CONnective TIssue CAncer NETwork (CONTICANET).

BACKGROUND: The impact of adherence to clinical practice guidelines (CPGs) for loco-regional treatment (i.e. surgery and radiotherapy) and chemotherapy on local disease control and survival in sarcoma patients was investigated in a European study conducted in an Italian region (Veneto). PATIENTS AND METHODS: The completeness of the adherence to the Italian CPGs for sarcomas treatment was assessed by comparing the patient's charts and the CPGs. Propensity score-adjusted multivariate survival analysis was used to assess the impact of CPGs adherence on patient clinical outcomes. RESULTS: A total of 151 patients were included. Adherence to CPGs for loco-regional therapy and chemotherapy was observed in 106 out of 147 (70.2%) and 129 out of 139 (85.4%) patients, respectively. Non-adherence to CPGs for loco-regional treatment was independently associated with AJCC stage III disease [odds ratio (OR) 1.77, P = 0.011] and tumor-positive excision margin (OR 3.55, P = 0.003). Patients not treated according to the CPGs were at a higher risk of local recurrence [hazard ratio (HR) 5.4, P < 0.001] and had a shorter sarcoma-specific survival (HR 4.05, P < 0.001), independently of tumor stage. CONCLUSIONS: Incomplete adherence to CPGs for loco-regional treatment of sarcomas was associated with worse prognosis in patients with non-metastatic tumors.

Multivariate analysis approach to the serum peptide profile of morbidly obese patients.

BACKGROUND: Obesity is currently epidemic in many countries worldwide and is strongly related to diabetes and cardiovascular disease. Mass spectrometry, in particular matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) is currently used for detecting different pattern of expressed protein. This study investigated the differences in low molecular weight (LMW) peptide profiles between obese and normal-weight subjects in combination with multivariate statistical analysis. MATERIALS: Serum samples of 60 obese patients and 10 healthy subjects were treated by cut-off membrane (30000 Da) to remove the most abundant proteins. The filtrates containing the LMW protein/peptides were analyzed by MALDI-TOF mass spectrometry. Dataset was elaborated to align and normalize the spectra. We performed cluster analysis and principal component analysis to detect some ionic species that could characterize and classify the subject groups. RESULTS: We observed a down-expression of ionic species at m/z 655.94 and an over-expression of species at m/z 1518.78, 1536.77, 1537.78 and 1537.81 in obese patients. Furthermore we found some ionic species that can distinguish obese patients with diabetes from those with normal glucose level. CONCLUSION: Serum peptide profile of LMW associate with multivariate statistical approach was revealed as a promising tool to discriminate and characterize obese patients and it was able to stratify them in relation to comorbidity that usually are associated with this disease. Further research involving a larger sample will be required to validate these findings.

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.

Clinical and molecular features of attenuated adenomatous polyposis in northern Italy.

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10-99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. METHODS: During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. RESULTS: MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the "no mutation" group). Clinical features rendered the "no mutation" group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. CONCLUSIONS: AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30-40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.

Circulating cell-free DNA: a promising marker of regional lymphonode metastasis in breast cancer patients.

PURPOSE: We undertook the current study with untreated breast cancer to (1) role the variations in the plasma levels of cfDNA and the size distribution in early stage, (2) determine the frequency in plasma of methylation of three candidate genes, RASSF1A, MAL, and SFRP1, and (3) to determine whether detection of cfDNA variations and methylation changes in plasma might have specific clinical utility. METHODS AND MATERIALS: Thirty-nine patients woman patients (median age 64 years; range, 36-90 years) who underwent surgery for primary BR and 49 healthy females' subjects (control group without any breast lesion) were evaluated. The cfDNA levels were analyzed using quantitative real-time polymerase chain reaction of ß-globin. Based on the ALU repeats, the cfDNA was considered as either total (fragments of 115 bp, ALU115) or tumoral (fragments of 247 bp, ALU247). The association between the levels of the ALU247, ALU115 repeat, and ALU 247/115and the pathologic tumor characteristics was analyzed. Used methylight qPCR method, cfDNA from plasma samples of healthy donors and patients with breast cancer were evaluated for the diagnotic value of the methylation status of three genes (RASSF1A, MAL, SFRP1) frequently methylated in breast cancer. RESULTS: The baseline levels of cfDNA were significantly higher in the patients with cancer, and the level of ALU247 was the most accurate circulating cfDNA marker in discriminating the cancer from non-cancer subjects. A high statistical significance was found by considering the T stage and patients with regional LN metastasis positive cancers showed significantly higher cfDNA level of ALU247. Moreover, patients with methylation of at least one of the gene under investigate showed a higher quantity of cfDNA ALU115 (p< 0.0001) and ALU247 level (p< 0.0001). CONCLUSIONS: We observed that necrosis could be a potential source of circulating tumour-specific cfDNA ALU247; and that cfDNA ALU247 and methylated cfDNA (RASSF1A, MAL and SFRP1) are both a phenotypic feature of tumour biology.

Cancer resistance to type II topoisomerase inhibitors.

Type II topoisomerases (TOPO2) are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. The class of compounds targeting TOPO2 includes some of the most active chemotherapy agents currently available for the treatment of patients with different cancer types. Therefore, understanding of the molecular mechanisms underlying resistance to these drugs is of pivotal importance to improve their efficacy and ultimately increase the life expectancy of cancer patients. The first aim of this review is to summarize the molecular biology of TOPO2 inhibitors, which is the key to understand cancer resistance to them; the second part of this work is dedicated to overview and discuss the available evidence on the mechanisms of resistance to these drugs, with special attention to the strategies that might be useful to circumvent this phenomenon on the clinical ground.

Soft tissue sarcoma and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome: formulation of an hypothesis.

Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder caused by mutation in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) which predisposes to colorectal cancer and other malignances, that not yet include sarcomas. For sustaining that soft tissue sarcomas could be HNPCC related malignances, we report on a HNPCC patient with leiomyosarcoma and review the English literature. Overall, we report on eleven cases of soft tissue malignant tumors involving HNPCC patients, with a mean age of 34 years at diagnosis of sarcomas. In the majority of these tumors loss of MSH2 expression can be found at immunohistochemistry (IHC) and in 10 patients a germline mutation in one of the MMR genes was found (7 cases were MSH2 defective and 3 cases MLH1 defective). Data for supporting our hypothesis are also experimental, epidemiologic, histopathological: excess of sarcomas in PMS2 defective mice; sporadic soft tissue sarcomas are rare, with mean age at onset of 56 years and normal IHC for MMR proteins. In conclusion, the data collected support the hypothesis that soft tissue sarcomas could be included in the spectrum of tumors that, even if rarely, depend on MMR genes deficiency.

Clinical and molecular detection of inherited colorectal cancers in northeast Italy: a first prospective study of incidence of Lynch syndrome and MUTYH-related colorectal cancer in Italy.

The reported incidence of hereditary colorectal cancers (CRCs) is widely variable. The principal aim of the study was to prospectively evaluate the incidence of familial CRCs in a region of northern Italy using a standardized method. Consecutive CRC patients were prospectively enrolled from October 2002 to December 2003. Patients underwent a structured family history, the microsatellite instability (MSI) test and a screen for MUTYH mutations. Following family history patients were classified as belonging to high, moderate and mild risk families. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins and investigation for MLH1/MSH2 mutations, for MLH1 promoter methylation and for the V600E hotspot BRAF mutation were performed in high MSI (MSI-H) cases. Of the 430 patients enrolled, 17 (4%) were high risk [4 hereditary non-polyposis colorectal cancer (HNPCC), 12 suspected HNPCC and 1 MUTYH-associated adenomatous polyposis coli (MAP)], 53 moderate risk and 360 mild risk cases. The MSI test was performed on 393 tumours, and 46 (12%) of them showed MSI-H. In these patients, one MLH1 pathogenetic mutations and two MSH2 pathogenetic mutations were found. Thirty-two (70%) MSI-H cases demonstrated MLH1 methylation and/or BRAF mutation: None of them showed MLH1/MSH2 mutation. Two biallelic germline MUTYH mutations were found, one with clinical features of MAP. A strong family history of CRC was present in 4% of the enrolled cases; incidence of MLH1/MSH2 or MUTHY mutations was 1.3% and of MSI-H phenotype was 12%. MLH1 methylation and BRAF mutation can exclude 70% of MSI-H cases from gene sequencing.

Validation of the new AJCC TNM staging system for gastric cancer in a large cohort of patients (n = 2,155): focus on the T category.

BACKGROUND: The prognostic value of T subclassification in patients with gastric carcinoma has been just implemented in the new AJCC TNM staging system, which has reclassified T2a and T2b into T2 and T3 tumors, respectively. The aim of the present study was to validate the prognostic significance of the new T categorization within the frame of the latest TNM staging system. METHODS: We retrospectively reviewed the records of 686 T2/T3 patients among 2155 subjects who underwent radical resection for gastric carcinoma at six Italian centers from 1988 through 2006. RESULTS: Upon multivariate analysis, the new T categories, extent of lymph node dissection (D) and patient's age were retained by the survival model as independent prognostic factors. In particular, the death risk for patients with T3 tumors was higher than that of patients with T2 tumors (HR: 1.42, P = 0.005). Among the 686 patients previously classified as having T2 tumors, patients with T2 and T3 disease were 270 (39.4%) and 416 (60.6%), respectively. After a median follow-up of 55 months, the 5-year overall survival rates were 67.3% and 52.3% for patients with T2 and T3 tumors, respectively (P < 0.001). The survival advantage for the T2 as compared to T3 category was maintained even when N0 and N+ patients were separately considered (P = 0.0154 and P < 0.001, respectively). CONCLUSIONS: Our data confirm the prognostic difference between the newly proposed T2 and T3 categories, which should be implemented in the routine clinical practice to improve risk stratification of patients with gastric cancer.

Maximizing the clinical usefulness of a nomogram to select patients candidate to sentinel node biopsy for cutaneous melanoma.

AIMS: Investigators from the Memorial Sloan Kettering Cancer Centre (MSKCC) have proposed a nomogram for predicting the sentinel node (SN) status in patients with cutaneous melanoma. The negative predictive value (NPV) of this test, which might help identify low-risk patients who might be safely spared SN biopsy (SNB), has not been yet investigated. METHODS: We tested the discrimination (area under the curve [AUC]), the calibration (linear regression) and the NPV of MSKCC nomogram in 543 patients treated at our institution. Different cut-off values were tested to assess the NPV, the reduction of SNB performed and the overall error rate obtained with the MSKCC nomogram. RESULTS: SN was positive in 147 patients (27%). Mean predicted probability was 17.8% (95%CI: 16.8-18.8%). Nomogram discrimination was significant (area under the curve = 0.68; P < 0.0001) and mean predicted probabilities of SN positivity well correlated with the observed risk (R(2) = 0.99). Cut-off values between 4% and 9% led to a NPV, SNB reduction and overall error rates ranging between 100 and 91.2%, 2.2 and 27.2%, and 0 and 2.3%, respectively. CONCLUSION: In our series, the nomogram showed a significant predictive accuracy, although the incidence of SN metastasis was higher than that observed in the MSKCC series (27% vs 16%). Using the nomogram, a NPV greater than 90% could be obtained, which would be associated with a clinically meaningful reduction of the SNB rate and an acceptable error rate. If validated in large prospective series, this tool might be implemented in the clinical setting for SNB patient selection.

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy.

The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C > G, which can affect radiosensitivity and MTHFR-677C > T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG ≤ 2 (OR = 0.46 95% CI 0.23-0.90, P = 0.024; and OR = 0.48 95% CI 0.24-0.96, P = 0.034; respectively). An association trend was observed for ABCB1-3435C > T, which is responsible for the multi-drug resistance (odds ratio (OR) = 1.96, 95% confidence interval (CI) 0.98-3.95, P = 0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245C > G as the most predictive factor. Other significant variables were: ABCB1-3435C > T, MTHFR-677C > T, ERCC1-8092C > A, ABCC2-1249G > A, XRCC1-28152G > A, XRCC3-4541A > G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG ≤ 2 as compared with low profiles (OR = 4.12 95% CI 1.46-11.65, P < 0.001 and OR = 12.44, 95% CI 5.52-28.04, P < 0.0001, respectively). This study evidences a major role of hOGG1-1245C > G and MTHFR-677C > T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.

Separate cavity margins excision as a complement to conservative breast cancer surgery.

BACKGROUND: Positive lumpectomy margins (LM) usually mandate re-excision. However, approximately half of these patients have no residual tumour in the re-excision specimen. The aim of this study was to investigate if separate cavity margin (CM) excision can safely reduce the need of re-operation. METHODS: Rate of re-operation for margin involvement and incidence of residual tumour in the re-excision specimen were retrospectively evaluated in 237 patients (group A) who underwent lumpectomy alone, and in 271 patients (group B) treated by lumpectomy and CM excision. Patients with positive LM (group A) or CM (group B) underwent re-excision. RESULTS: In the group A, 50/237 patients (21.1%) had LM+ and underwent re-excision. In the group B, 74/271 patients (27.3%) had LM+, but tumour was found within the CM specimen in 46 patients (17.0%), 24 LM+ and 22 LM-, and reached the CM cut edge in only 15 (5.5%), who finally underwent re-excision. Residual tumour was found in the re-excision specimen in 28/50 patients (56.0%) of the group A and in 7/15 patients (46.7%) of the group B. CONCLUSIONS: Separate CM excision strongly decreases the rate of re-operation for involved margin. However, the finding of various combinations of LM and CM status and the evidence that CM excision does not improve the positive predictive value of margin involvement suggest prudent conclusions. Only long term follow up of patients treated according to the CM status can exclude that the reduced rate of re-operations allowed by this procedure would expose to an increased risk of local recurrence.

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers.

BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process. PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR. RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (P<0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r=-0.24, P=0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P=0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P=0.03). CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.

Peptide-based anticancer vaccines: recent advances and future perspectives.

Anticancer active immunotherapy embodies the ideal antitumor therapy, as it theoretically combines target specificity with long-term disease control. Peptide-based cancer vaccines represent the most specific approach to polarize the immune system against malignant cells, since they are preparations made of single epitopes, the minimal immunogenic region of an antigen. Despite the strong rational, the promising preclinical results and the frequent induction of antigen-specific immune responses, peptide-based cancer vaccines have yielded relatively poor results in the clinical setting, a phenomenon likely due to the immunosuppressive properties of the tumor microenvironment that allow malignant cells to evade both naturally occurring and therapeutically induced immune surveillance. Nevertheless, advances in the engineering of peptides and in our understanding of the molecular mechanisms underlying an effective immune response against tumors have renewed the enthusiasm for peptide-based vaccination regimens in the setting of cancer, and a variety of clinical trials are being conducted based on the use of peptides. This review will describe the most recent insights in the rational design of peptide-based cancer vaccines, as well as the challenges to successful anticancer immunotherapy based on these short amino acid chains.