NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice.

The interleukin-1 family members, IL-1ß and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1ß processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

Trends in thyroid function testing, neck ultrasound, thyroid fine needle aspiration, and thyroidectomies in North-eastern Italy.

PURPOSE: Evidence of an increased diagnostic pressure on thyroid has emerged over the past decades. This study aimed to provide estimates of a wide spectrum of surveillance indicators for thyroid dysfunctions and diseases in Italy. METHODS: A population-based study was conducted in North-eastern Italy, including 11.7 million residents (20% of the total Italian population). Prescriptions for TSH testing, neck ultrasound or thyroid fine needle aspiration (FNA), surgical procedures, and drugs for hypo- or hyperthyroidism were extracted from regional health databases. Proportions and rates of selected examinations were calculated from 2010 to 2017, overall and by sex, calendar years, age, and region. RESULTS: Between 2010 and 2017 in North-eastern Italy, 24.5% of women and 9.8% of men received at least one TSH test yearly. In 2017, 7.1% of women and 1.5% of men were prescribed drugs for thyroid dysfunction, 94.6% of whom for hypothyroidism. Neck ultrasound examinations were performed yearly in 6.9% of women and 4.6% of men, with a nearly two-fold variation between areas. Thyroid FNA and thyroidectomies were three-fold more frequent in women (394 and 85 per 100,000) than in men (128 and 29 per 100,000) with a marked variation between areas. Both procedures decreased consistently after 2013. CONCLUSIONS: The results of this population-based study describe recent variations over time and between surrounding areas of indicators of 'diagnostic pressure' on thyroid in North-eastern Italy. These results emphasize the need to harmonize practices and to reduce some procedures (e.g., neck ultrasound and total thyroidectomies) in certain areas.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Abnormal ankle-brachial index (ABI) predicts primary and secondary cardiovascular risk and cancer mortality.

BACKGROUND: An abnormal ankle-brachial pressure index (ABI) is a marker of the risk for increased total and cardiovascular (CV) mortality. However, it is not clear whether it is associated with an even worse prognosis in patients with previous CV events or with cancer mortality. MATERIALS AND METHODS: Consecutive subjects undergoing ABI assessment for suspected peripheral artery disease or for stratification of CV risk in ten centers in the Veneto Region (northeast Italy), between 2011 and 2014 were enrolled. The ABI was expressed as normal ≥0.9 to ≤1.3, and abnormal <0.9 or >1.3. All-cause mortality and CV or cancer mortality and hospitalizations for CV disease were collected from administrative databases up to December 2018. RESULTS: The study enrolled 1,177 patients. ABI was abnormal in 57.2%. Median follow-up was 61.6 months (53.4-70.1). All-cause, CV and cancer mortality were higher in patients with abnormal than normal ABI, with hazard ratios (HR) respectively 2.0 (95% CI 1.48-2.69), 1.98 (95% CI 1.24-3.17) and 1.85 (95% CI 1.09-3.15). Among subjects with abnormal ABI, the risk of overall mortality, HR 1.57 (95% CI 1.17-2.12), and CV mortality, HR 2.39 (95% CI 1.43-3.99), was higher in those with previous CV events. These latter also had a higher risk of hospitalization for myocardial infarction and stroke: HR 1.85 (95% CI 1.023.37) and 2.17 (95% CI 1.10-4.28). CONCLUSIONS: The co-existence of abnormal ABI and a history of CV events identifies subjects at higher risk, who call for a more aggressive approach. Abnormal ABI is also a predictor of cancer mortality.

The German Hodgkin Study Group risk model is useful for Hodgkin lymphoma patients receiving radiotherapy after autologous stem cell transplant.

PURPOSE: To apply the German Hodgkin Study Group (GHSG) risk model in patients with recurrent/refractory Hodgkin lymphoma receiving involved-field radiotherapy after autologous stem cell transplantation. MATERIAL AND METHODS: The study consisted in the retrospective analysis of 30 consecutive patients with recurrent/refractory Hodgkin lymphoma who received involved-field radiotherapy after autologous stem cell transplantation. Our policy was of adding involved-field radiotherapy for patients with positive PET scan before autologous stem cell transplantation (23 out of 30 patients, 77%), and/or irradiating sites of bulky disease at relapse (11 out of 30 patients, 37%). Patients were stratified into four risk groups according to the presence of the five clinical risk factors identified by the GHSG; (1) stage IV disease; (2) time to relapse≤3 months; (3) ECOG-PS≥1; (4) bulk≥5cm; and (5) inadequate response to salvage chemotherapy. RESULTS: The median interval from autologous stem cell transplantation to involved-field radiotherapy was 3 months (range, 1-7 months), and the median involved-field radiotherapy dose was 35Gy (range, 12-40Gy). At a median follow-up of 35 months (range, 1-132 months), the 2-year progression-free survival in the entire series was 60%. When examining the four different GHSG risk groups, the progression-free survival rate at 2 years was 86%, 83%, 50%, and 36% for patients with score=0, score=1, score=2, and score=3 to 5, respectively (P=0,01). Among the 12 patients havingat leastthree risk factors who underwent thoracic involved-field radiotherapy, three (25%) developed pneumonitis. CONCLUSION: The adoption of the GHSG risk model at the time of recurrence/progression is a useful prognostic tool to select patients with Hodgkin lymphoma for consolidative involved-field radiotherapy after autologous stem cell transplantation.

Multidisciplinary treatment approach for primary thyroid spindle cell sarcoma: A case report.

A 25-year-old female with high-grade spindle cell sarcoma of the thyroid persistent after thyroidectomy performed at another hospital was referred to our institute. Chemotherapy followed by surgery with intraoperative radiotherapy and postoperative intensity-modulated radiotherapy were planned within the sarcoma board. Chemotherapy was discontinued after two cycles because of local disease progression and surgery with intraoperative radiotherapy, was anticipated. The treatment was completed with postoperative radiotherapy. After 36 months off-therapy, the patient was free of disease without significant late effects. Thyroid sarcomas are very rare and there is no consensus on their clinical management. Hence, case reports are useful to share treatment options. In this patient case, the histotype and the high-grade disease required a combined therapy program, managed in a multidisciplinary setting.

Long-term Follow-up and Post-relapse Outcome of Patients with Localized Retroperitoneal Sarcoma Treated in the Italian Sarcoma Group-Soft Tissue Sarcoma (ISG-STS) Protocol 0303.

BACKGROUND: This study was designed to assess patterns of recurrence and long-term outcomes of patients undergoing surgery for localized retroperitoneal sarcoma (RPS) after neoadjuvant high dose long-infusion ifosfamide (HLI) and radiotherapy (RT). METHODS: Patients received three cycles of HLI (14 g/m2). RT was started in combination with II cycle up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. The primary endpoint was relapse-free survival (RFS) after surgery. Secondary endpoints were overall survival (OS), crude cumulative incidence of local recurrence (CCI-LR), and distant metastases (CCI-DM). For patients who relapsed, progression-free survival (PFS) and post-relapse OS were estimated. The trial was registered with ITASARC_*II_2004_003. RESULTS: Between 2003 and 2010, 83 patients were recruited. At a median follow-up of 91.7 months, 42 (56%) of 75 operated patients developed LR (n = 27) or DM (n = 10) or both LR and DM (n = 5) relapse. Seven-year RFS was 46.6% [95% confidence interval (CI) 29.6-52.4]. Thirty-two patients died. Seven-year OS rate was 63.2% (95% CI 42.7-66.0). The corresponding CCI of LR and DM were 37.4% [standard error (SE) 5.5%] and 20.0% (SE 12.6%), respectively. The only factor significantly associated with LR was FNCLCC grading, whereas histological subtype resulted associated with DM. At recurrence, 24 patients (57%) underwent surgery. Two-year post-relapse PFS and OS rates for patients developing LR or DM were 14.8, 41.0, 27.3, and 63.6%, respectively. CONCLUSIONS: LR after neoadjuvant CT-RT for RPS were predominantly infield. While almost one half of relapsed patients underwent further surgery, prognosis was poor.

Rectal sparing approach after preoperative radio- and/or chemotherapy (RESARCH) in patients with rectal cancer: a multicentre observational study.

BACKGROUND: Rectum-sparing approaches appear to be appropriate in rectal cancer patients with a major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The aim of the present study is to evaluate the effectiveness of rectum-sparing approaches at 2 years after the completion of neoadjuvant treatment. STUDY DESIGN: Patients with rectal adenocarcinoma eligible to receive neoadjuvant therapy will be prospectively enrolled. Patients will be restaged 7-8 weeks after the completion of neoadjuvant therapy and those with mCR (defined as absence of mass, small mucosal irregularity no more than 2 cm in diameter at endoscopy and no metastatic nodes at MRI) or cCR will be enrolled in the trial. Patients with mCR will undergo local excision, while patients with cCR will either undergo local excision or watch and wait policy. The main end point of the study is to determine the percentage of rectum preservation at 2 years in the enrolled patients. CONCLUSION: This protocol is the first prospective trial that investigates the role of both local excision and watch and wait approaches in patients treated with neoadjuvant therapy for rectal cancer. The trial is registered at clinicaltrials.gov (NCT02710812).

Bowel function and quality of life after local excision or total mesorectal excision following chemoradiotherapy for rectal cancer.

BACKGROUND: Local excision for rectal cancer is expected to offer a better functional outcome than conventional surgery. The aim of the present study was to compare quality of life and bowel function in patients with rectal cancer who underwent either local excision or conventional surgery after chemoradiotherapy. METHODS: This was a retrospective multicentre study. Patients who underwent local excision were compared with those who had mesorectal excision. Quality of life and bowel function were investigated using validated questionnaires (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29 and Memorial Sloan-Kettering Cancer Center Bowel Function Instrument) at a median follow-up of 49 (range 13-95) months. Further analysis was undertaken of data from patients who underwent local excision alone compared with those requiring subsequent radical surgery. Statistical significance was set at P < 0·010. RESULTS: The mean constipation score was significantly better in the local excision group than in the mesorectal excision group (3·8 (95 per cent c.i. 0·3 to 7·2) versus 19·8 (12·1 to 27·4); P < 0·001). Compared with patients who underwent mesorectal excision, those who had local excision had less sensation of incomplete emptying (mean score 3·7 (3·4 to 4·0) versus 2·8 (2·5 to 3·1); P < 0·001) and second bowel movements within 15 min (mean score 3·6 (3·3 to 3·9) versus 3·0 (2·7 to 3·3); P = 0·006). Patients who underwent local excision alone scored better than those who had mesorectal excision, particularly for bowel function, who, in turn, scored better than patients requiring subsequent radical surgery following local excision. CONCLUSION: Patients who underwent local excision had a better quality of life and bowel function than those who underwent mesorectal excision.

Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.

BACKGROUND: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS). METHODS: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. RESULTS: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively. CONCLUSIONS: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).

Treatment efficacy with electrochemotherapy: A multi-institutional prospective observational study on 376 patients with superficial tumors.

BACKGROUND: Cutaneous metastases represent a therapeutic challenge. An increasing body of experience suggests that electrochemotherapy (ECT) provides effective tumor control, although its evidence basis should be strengthened. METHODS: This prospective, multicenter, observational study enrolled patients with superficial metastases, who underwent ECT at 10 centers between 2008 and 2013. Outcomes included adherence to European Standard Operating Procedures of ECT (ESOPE), tumor response, local progression-free survival (LPFS), toxicity and patient-reported outcomes (PROs, EORTC QLQ-C30 plus an 8-item questionnaire). RESULTS: We enrolled 376 eligible patients. Tumor histotype distribution was as follows: melanoma, 56%; squamous cell carcinoma, 11%; Kaposi sarcoma, 11%; breast carcinoma, 8%; basal cell carcinoma, 6%; soft tissue sarcomas, 3%; others, 5%. We registered 1304 target tumors (median size 1 cm). Treatment adhered to ESOPE in 88% of patients as to the route of drug administration, and in 70% as to electrode application. The procedure was mainly performed under sedation (64.6%) and by using intravenous chemotherapy (93.4%). Tumor response rate at 60 days was 88% (complete, 50%). Small tumor size predicted complete response achievement (OR 2.24, p = 0.003), higher LPFS (HR 0.68, p = 0.004) and improved PROs (Global Health Status, p < 0.001; wound bleeding, p < 0.001; healing, p = 0.002; and aesthetics, p < 0.001). Skin toxicity (grade ≥3, 7.8%) was lower in patients with tumors <2 cm (p≤0.001). One-year LPFS was 73.7% (95%CI 68.4-78.3). CONCLUSIONS: ECT represents a valuable skin-directed therapy across a range of malignancies. The most frequently applied treatment modality is intravenous chemotherapy under sedation. Small tumor size predicts durable tumor control, fewer side-effects and better PROs.

An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts.

Despite some success with certain hematological malignancies and in contrast with the strong pro-apoptotic effects measured in vitro, the overall response rate of acute lymphoblastic leukemia (ALL) to histone deacetylase inhibitors (HDACis) is low. With the aim to improve the understanding of how HDACis work in vivo, we investigated the therapeutic efficacy of the clinically approved HDACi Givinostat in a collection of nine pediatric human T-ALL engrafted systemically in NOD/SCID mice. We observed highly heterogeneous antileukemia responses to Givinostat, associated with reduction of the percentage of infiltrating blasts in target organs, induction of apoptosis and differentiation. These effects were not associated with the T-ALL cytogenetic subgroup. Transcriptome analysis disclosed an immediate transcriptional signature enriched in genes involved in cell-cycle regulation and DNA repair, which was validated by quantitative RT-PCR and was associated with in vivo response to this HDACi. Increased phospho-H2AX levels, a marker of DNA damage, were measured in T-ALL cells from Givinostat responders. These results indicate that the induction of the DNA damage response could be an early biomarker of the therapeutic effects of Givinostat in T-ALL models. This information should be considered in the design of future clinical trials with HDACis in acute leukemia.

Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005).

BACKGROUND: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma. PATIENTS AND METHODS: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement. RESULTS: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions. CONCLUSION: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists. CLINICAL TRIALS NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab.

BACKGROUND: AMP-activated protein kinase (AMPK) has a central role in cellular energy sensing and is activated in preclinical tumour models following anti-vascular endothelial growth factor (VEGF) therapy. The possible predictive or prognostic role of AMPK status in cancer patients treated with anti-VEGF drugs has not been investigated so far. METHODS: Expression of components of the AMPK pathway including phosphorylated AMPK (pAMPK), phosphorylated acetyl-Coa carboxylase (pACC) and liver kinase B1 (LKB1) was investigated by immunohistochemistry in 48 colorectal cancers treated with FOLFIRI plus bevacizumab. Correlation between pAMPK and pACC and associations between the AMPK pathway scores and clinico-pathological characteristics were assessed. Overall survival (OS) was estimated through Kaplan-Meier method, whereas hazard ratios were computed to identify prognostic factors. RESULTS: Fourteen patients (29.2%) were included in the pAMPK-negative group (score ≤5), whereas 34 patients (70.8%) were included in the pAMPK-positive group (score >5). The Spearman's coefficient for the correlation between pAMPK and pACC scores in primary tumour samples was 0.514 (P=0.0002). Low pAMPK levels were associated with worse OS (P-value 0.0002) but not with PFS, whereas low pACC levels were associated both with worse OS and PFS (P-value 0.0007 and 0.01, respectively). CONCLUSIONS: Our findings suggest that high tissue AMPK activation is a prognostic biomarker in this cohort of metastatic colorectal cancer patients.

Interobserver variability of clinical target volume delineation in soft-tissue sarcomas.

PURPOSE: The present observational study reports the results of a multi-institutional dummy-run designed to estimate the consistency of interobserver variability in clinical target volume delineation in two different cases of soft-tissue sarcomas in which postoperative and preoperative radiotherapy were prescribed, respectively. The purpose of this work was to quantify interobserver variability in routine clinical practice. PATIENTS AND METHODS: Two different cases of soft-tissues sarcomas were chosen: a case of postoperative and a case of preoperative radiation therapy. Participating centres were requested to delineate clinical target volumes according to their experience in both cases. Descriptive statistic was calculated for each variable (volume, diameters) separately for two cases. Box-whiskers plots were used for presentation of clinical target volume. A Shapiro-Wilk's test was performed to evaluate the departures from normality distribution for each variable. The comparison between relative variations of diameters was evaluated using the Student's t test. RESULTS: Several variations affecting both volumes and diameters were observed. Main variations were observed in the craniocaudal and laterolateral diameters. Each case showed similar dispersion, indicating a lack of reproducibility in volumes definition. CONCLUSIONS: This observational study highlighted that, in the absence of specific instructions or guidelines, the interobserver variability can be significant both in postoperative and preoperative radiotherapy of soft-tissue sarcomas.

Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups.

BACKGROUND: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004. PATIENTS AND METHODS: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS). RESULTS: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%. CONCLUSIONS: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall.

BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure.

Validity and reliability of the MSKCC Bowel Function instrument in a sample of Italian rectal cancer patients.

AIMS: The purpose of this study was to translate the Memorial Sloan Kettering Cancer Centre (MSKCC) Bowel Function Instrument into Italian and to test its psychometric validity and reliability in a sample of Italian rectal cancer patients. METHODS: The MSKCC questionnaire was translated into Italian using a standard procedure of double-back translation. Construct validity was tested using a factor analysis and internal reliability was estimated using the Cronbach's alpha coefficient. Concurrent validity was determined by correlations with European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 quality of life scales. A non-parametric analysis of variance was used to establish the discriminant validity of the questionnaire. Test-retest reliability was assessed using the intra-class correlation coefficient. RESULTS: 124 rectal cancer patients participated in the validation study. The number of missing items was 2.2%. The factorial structure was found to be quite similar to the original one and the internal reliability was 0.7 for urgency, 0.6 for frequency, and 0.7 for dietary subscale. The test-retest reliability was acceptable with one exception: the dietary subscale showed a low reproducibility (ICC = 0.4). All three subscales showed a significant correlation with the QLQ-C30 and QLQ-CR38 domains and were able to discriminate several groups of clinical relevance. CONCLUSIONS: The Italian version of the MSKCC Bowel Function Instrument shows acceptable psychometric properties and can be considered a valuable and specific instrument to assess bowel functions in rectal cancer patients, both for research purposes and in clinical practise.

Multimodality approach in extra cervical locally advanced cervical cancer: chemoradiation, surgery and intra-operative radiation therapy. A phase II trial.

BACKGROUND: The goal of this study was to determine the rational of radical surgery with intra-operative high-dose radiotherapy after chemoradiation (RT-CT) in extra cervical locally advanced cervical cancer (LACC) patients. METHODS: Between 2000 and 2007, 42 LACC (stage IIA bulky-IVA) patients were treated at the Gynecologic Oncology Unit of the C.R.O. of Aviano in a Phase II Clinical Trial. Radiotherapy was administered to the whole pelvic region (50.4 Gy in 28 fractions) in combination with cisplatin (60 mg/mq) plus 5FU (750 mg/mq for 4 days) on first and fifth week of RT. Radical surgery with Intra-Operative Radiation Therapy (IORT) was performed 6-8 weeks after the end of RT-CT treatment. RESULTS: After RT-CT, 35/42 patients (83%) underwent radical surgery and IORT treatment. At pathologic examination 8/35 (23%) patients showed complete response, while the rest (27/35) had residual disease either microscopic (17/27) or gross (10/27). The 5-year disease free survival (DFS) and the 5-year overall survival (OS) were 46% and 49% respectively. There were significant better DFS and OS when residual tumor was absent or limited to the cervix, respectively 78% versus 16% and 81% versus 20% (p < 0.001). All recurrences occurred within 24 months from treatment. CONCLUSIONS: RT-CT followed by surgery and IORT in LACC patients seems to be active in a subgroup of patients with pathological complete response to treatment or partial response with residual tumor limited to the cervix.