Search

Descriptive statistics of the primary and secondary endpoint measurements.

Boxplot reflecting the distribution of 15-PGDH expression at baseline (T0) and at six months (T2) according to the Aperio ScanScope Cytoplasm Algorithm V2. Each box indicates the 25th and 75th percentiles of the distribution. The horizontal line inside the box indicates the median and the whiskers indicate the extreme measured values; the mean value is represented by a black diamond.

Panel A-1: COX-2 IHC performed on normal FAP biopsies collected before the dietary intervention (T0) and after six months of diet (T2). Panel A-2: COX-2 IHC performed on adenoma FAP biopsies at T0 and T2. Panel B-1: COX-2 IHC performed on normal colon mucosa collected from surgery for sporadic colon cancer. Panel B-2: 15-PGDH IHC performed on normal colon mucosa collected from surgery for sporadic colon cancer.

Supplementary Legends

Preimplantation genetic testing for monogenic/single-gene disorders (PGT-M) is a procedure employed in the field of assisted reproductive technology to avoid the transmission of genetic diseases to the offspring. Hereditary cancer syndromes represent a diffuse and accepted indication for PGT-M, but take-up differs among the different disorders. Its use is markedly lower for the genes causing Lynch syndrome compared with the breast cancer type 1 or 2 susceptibility genes (BRCA1/2), despite the similar prevalence and severity of the two conditions. Reasons to explain this difference have not been explored. First, Lynch syndrome may be more frequently undiagnosed compared with hereditary breast and ovarian cancer syndrome. In addition, the different take-up may be due to different patient perceptions of the conditions and of the management options. Finally, this distinct attitude may depend on the awareness and sensibility of the professionals caring for affected patients. The authors' considerations are, however, speculative, and specific studies aimed at disentangling the causes of the different receptions of PGT-M are warranted to understand how to tackle this gap. In the meantime, we believe that empowerment regarding PGT-M of all individuals with hereditary cancer syndromes, including Lynch syndrome, is ethically due, and plead for a more active involvement of caregivers.

Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection. Patient’s clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan–Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated. In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively). Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.

ObjectiveWomen with Lynch syndrome have a risk up to 40–60% of developing endometrial cancer, which is higher than their risk of developing colorectal or ovarian cancer. To date, no data on the outcomes of patients with Lynch syndrome diagnosed with non-endometrioid endometrial cancer are available. The goal of this study was to evaluate the outcome of patients with Lynch syndrome diagnosed with non-endometrioid endometrial cancer.MethodsData from consecutive patients diagnosed with Lynch syndrome and with a histological diagnosis of non-endometrioid endometrial cancer were retrospectively collected in two referral institutes in Italy. A case–control comparison (applying a propensity matching algorithm) was performed in order to compare patients with proven Lynch syndrome and controls. Inclusion criteria were: (a) histologically-proven endometrial cancer; (b) detection of a germline pathogenic variant in one of the MMR genes; (c) adequate follow-up. Only carriers of pathogenic or likely pathogenic variants (ie, class 5 and 4 according to the InSiGHT classification) were included in the study. Survival outcomes were assessed using KaplanMeier and Cox models.ResultsOverall, 137 patients with Lynch syndrome were collected. Mean patient age was 49.2 (10.9) years. Genes involved in the Lynch syndrome included MLH1, MSH2, and MSH6 in 43%, 39%, and 18% of cases, respectively. The study population included 27 patients with non-endometrioid endometrial cancer, who were matched 1:2 with patients with sporadic cancers using a propensity matching algorithm. After a median follow-up of 134 months (range 1–295), 2 (7.4%) of the 27 patients developed recurrent disease (3 and 36 months) and subsequently died of disease (7 and 91 months). Patients diagnosed with Lynch syndrome experienced better disease-free survival (HR 7.86 (95% CI 1.79 to 34.5); p=0.006) and overall survival (HR 5.33 (95% CI 1.18 to 23.9); p=0.029) than controls.ConclusionsNon-endometrioid endometrial cancer occurring in patients with Lynch syndrome might be associated with improved oncologic outcomes compared with controls. Genetic/molecular profiling should be investigated in order to better understand the mechanism underlying the prognosis.

Benefits of neoadjuvant chemo-radiotherapy (CRT) are well known for locally advanced and/or node-positive rectal cancer, but the best timing for CRT has been less explored for cT3N0 patients. The aim of the present study was to compare the 5-year disease-free survival (DFS) probability between neoadjuvant CRT and upfront surgery in patients affected by cT3N0 rectal cancer. A retrospective review of 105 patients affected by cT3N0 rectal cancer, staged by pelvic magnetic resonance imaging and treated at the National Cancer Institute of Milan between 2011 and 2017, was performed: 42 (40.0%) were treated by neoadjuvant CRT and 63 (60.0%) by upfront surgery. Propensity score matching was performed to avoid selection bias, and Cox multivariate regression was used to analyze outcomes. The 5-year DFS probability was 87.5% in neoadjuvant CRT patients vs. 90.0% in upfront surgery cases (Log-rank p = 0.76). The 5-year loco-regional recurrence-free survival probability was respectively 96.8% vs. 96.3% (Log-rank p = 0.954). On multivariate analysis, neoadjuvant CRT had no impact on DFS when compared to upfront surgery (adjusted HR 0.71, 95%CI 0.18–2.70, p = 0.613), but 61.9% of upfront surgery cases were treated by adjuvant chemo-radiation (adjusted HR 0.41, 95%CI 0.11–1.57, p = 0.196). The only independent predictor of improved DFS was age at diagnosis (adjusted HR 0.95, p = 0.017). CRT should be considered for cT3N0 patients, but its timing (neoadjuvant vs. adjuvant) seems not to affect the disease-free survival in the present cohort of patients.

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Introduction: Familial adenomatous polyposis (FAP) is a hereditary autosomal dominant disorder characterized by the development of multiple adenomas in the colon and rectum with a lifetime risk of 80%–100% to develop colorectal cancer if undetected or untreated. Gardner-associated fibroma (GAF) is a rare, benign soft tissue lesion with uncertain pathogenesis. GAF is generally associated with FAP in its clinical variant, called Gardner syndrome (GS). Case Description: A 16-year-old boy with no comorbidities and no significant medical history was referred to the Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, for genetic counselling after surgical removal of a right anterior cervical paramedian fibroma. The histopathology on the specimen led to the diagnosis of GAF. He had no family history for colorectal cancer or gastrointestinal polyposis and denied any gastrointestinal symptoms. Physical examination showed a small frontal osteoma and colonoscopy showed the presence of multiple small sessile polyps (>100 polyps, diameter Conclusions: GAF may represent a sentinel sign of FAP, preceding gastrointestinal symptoms and endoscopic findings. A careful multidisciplinary approach is determinant for correct and early diagnosis of FAP.

Background Desmoid fibromatosis (DF) is a rare and locally infiltrative monoclonal fibroblastic proliferation arising from connective tissues, with lack of metastatic potential. About 10% of all DF cases are intra‐abdominally sited. Complications in this site, due to the locally infiltrative nature of the disease, may be severe and potentially life threatening. However, data on incidence, management, and outcome of these complications are limited. Aim Data of patients with sporadic or FAP‐related intra‐abdominal DF treated at Istituto Nazionale dei Tumori (INT) in Milano from 2005 to 2020 who developed a serious complication during the course of their disease were retrospectively collected and analyzed with a descriptive statistics. Methods and Results Out of 72 intra‐abdominal DF, 8 cases were identified (M/F: 5/3, median age: 35 years, FAP‐related/sporadic: 2/6): 3 with bowel obstruction, 5 with bowel perforation. In 4 cases the serious complication was the first evidence of disease; in the other 4 cases it occurred at a time interval from diagnosis in the range of 4–44 months (during an active surveillance program in one case and during chemotherapy in the other 3 cases). A surgical treatment was feasible and successful in 5 cases. In 3 surgically unmanageable patients, all progressing and experiencing acute complications while on chemotherapy, a non‐surgical approach with intensive supportive treatment and with a prompt change of chemotherapy regimen was implemented, being successful in two, the other patient dying due to a concomitant progressive lymphoma thereafter. Conclusion In this series of intra‐abdominal DF, the incidence of serious complications was 11%. Most patients were successfully treated with surgery. When surgery was deemed to be unfeasible, a conservative management with intensive supportive care and a careful choice of chemotherapy was adopted, ensuring a favorable outcome in most.

Although duodenal adenomas and cancer appear to occur significantly less frequently in autosomal recessive MUTYH-associated polyposis (MAP) than in autosomal dominant familial adenomatous polyposis (FAP),1 current guidelines recommend similar endoscopic surveillance for both disorders.2-4 This involves gastro-duodenoscopy starting at 25 to 35 years of age and repeated at intervals determined by Spigelman staging based on the number, size, histological type and degree of dysplasia of adenomas, and by ampullary staging. Case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced Spigelman stage benign disease and even without coexisting adenomas.1 Recent molecular analyses suggest thatMAPduodenal adenomashave a higher mutational burden than FAP adenomas and are more likely to harbor oncogenic drivermutations, such as those in KRAS.5 These apparent differences in the biology and natural history of duodenal polyposis in FAP and MAP challenge the assumption that the same surveillance should be applied in both conditions.

Introduction Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) wingless-related integration site (WNT) subtype, the course of which has only recently been described. Methods We retrieved all patients with documented germline APC mutations and a diagnosis of MBL to examine their outcome, late effects of treatment, and further oncological events. Results Between 2007 and 2016, we treated six patients, all with a pathogenic APC variant mutation and all with MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine, and vincristine for a maximum of eight courses. Five of six diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Methylation profile score (in two cases) and copy number variation analysis (chromosome 6 deletion in two cases) performed on four of six retrieved samples confirmed WNT molecular subgroup. Four out of six patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other two cases. Four patients developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion Our data confirm a good prognosis for patients with MBL associated with FAP. Patients' secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarita ed Ereditarieta dei Tumori Gastrointestinali, AIFEG) reviewed the literature and agreed on a number of position statements regarding the definition and management of polyposis coli without an identified pathogenic mutation on the APC or MUTYH genes, defined in the document as NAMP (non-APC/MUTYH polyposis).

Introduction. Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) WNT subtype as well, the course of which has only recently been described. Methods. We retrospectively retrieved all patients with documented germline APC mutations and a centrally-reviewed diagnosis of MBL to examine the outcome of their MBL, late effects of its treatment, and further oncological events. Results. Between 2007-2016 we diagnosed and treated 6 patients, all with a pathogenic APC variant mutation, who all had MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine and vincristine for a maximum of 8 courses. Five of 6 diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Four of 6 patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other 2 cases. Four patients had developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion. Our data confirm a good prognosis for patients with MBL associated with FAP. Patients’ secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

[Introduction] Desmoid tumour (DT) is a locally aggressive fibroblastic proliferative disease representing the most common extraintestinal manifestation of familial adenomatosis polyposis (FAP). As data on the activity of chemotherapy in these patients are limited, we examined the outcomes of patients treated with low-dose methotrexate (MTX)+vinca alkaloids (vinorelbine or vinblastine)., [Patients and methods] We retrospectively reviewed clinical and outcome data from all patients with confirmed FAP-associated DTs treated with weekly MTX+vinca alkaloids in seven European sarcoma reference centres between January 2000 and December 2018. Radiological responses were assessed using RECIST V.1.0 and V.1.1. The Kaplan-Meier method associated to the log-rank test was used to estimate and compare survival curves., [Results] We identified 37 patients (median age 29 years, range 7–44). According to RECIST, 20/37 (54.1%) patients achieved partial response (PR), 15/37 (40.5%) patients had stable disease and 2/37 (5.4%) had progressive disease as best response. Overall, the median progression-free survival (PFS) was 6.5 years (range, 0.3–12.1 years). In the subset of patients achieving PR as best response, the median PFS was not reached. In a subset of 11 patients with progressive disease offered MTX+vinca alkaloids rechallenge (after chemotherapy withdrawal following prolonged disease control), the disease control rate was 100%, resulting in a median PFS after rechallenge of 5.8 years., [Conclusions] This is the largest series on the activity of low-dose chemotherapy in patients with FAP-related DT. In this population, MTX+vinca alkaloids is an active combination, as already reported in patients with sporadic DT.

Background: The best surgical choice for patients with familial adenomatous polyposis (FAP) is still debated. No prospective trials have been carried out to evaluate the pros and cons of the recommended procedures: total colectomy (ileorectal anastomosis [IRA]) vs restorative proctocolectomy (ileal pouch–anal anastomosis [IPAA]). The aim of this study was to provide a basis for tailored precision surgery in patients with FAP. Methods: We conducted a retrospective review of patients with FAP who underwent surgery and were registered in a dedicated database in Milan, Italy. Twenty-year survival related to surgical approach and prognostic factors were investigated using a Cox regression model. Results: A total of 925 patients underwent surgery between 1947 and 2015: 340 (36.8%) IPAA and 585 (63.2%) IRA. Colorectal cancer (CRC) at surgery was diagnosed in 28.6% of patients and a pathogenic APC variant was identified in 88%. During a median follow-up of 129 months, 150 patients died. The survival probability was significantly higher in the IRA than the IPAA group: 0.82 vs 0.75 (hazard ratio [HR] 0.6, 95% confidence interval [CI] 0.42–0.84). Multivariable regression modeling adjusted for propensity scores showed a similar difference, although no longer significant. Multivariable analysis indicated as independent risk factors CRC (HR 4.68, 95% CI 3.04–7.20) and age at surgery (HR 1.03, 95% CI 1.02–1.06). Among patients without cancer, the main risk factor for shorter survival was older age (HR 1.06, 95% CI 1.04–1.09). Conclusion: The study confirms excellent long-term results of surgical approaches with IRA and IPAA, suggesting that the best surgical choice may be an individually and clinically tailored approach, preferably at a young age.

Background APC gene pathogenic variants are characterized by a lifetime risk of nearly 100% to develop a colorectal carcinoma. International guidelines suggest a prophylactic surgery in the second decade. Methods A descriptive analysis was performed evaluating a surgical series of adolescent patients with familial adenomatous polyposis (FAP) enrolled in the prospectively maintained hereditary polyposis registry. Results Thirty-eight adolescent patients (median age 16 years; range, 7-19) underwent laparoscopic prophylactic surgery. APC gene pathogenic variants were detected in all patients, and six patients were proband. No patients were converted to open surgery. Median postoperative stay was five days (4-16). Early postoperative complications were one dural puncture and one anastomotic leakage. Regarding late complications, we observed one patient having small bowel obstruction 56 months after surgery. Pathological reports showed one patient with pTis adenocarcinoma in two separate sites; 33 patients with low-grade dysplasia, four with high-grade dysplasia. One patient developed a desmoid tumor 37 months after surgery. After a median follow-up of 40.5 months, no patients died or had a second abdominal surgery because of cancer in rectal stump. Conclusions Rectal sparing surgery was the first choice in the major respect of patients' quality of life. Laparoscopic prophylactic surgery for FAP is well accepted from adolescents. It represents a safe option due to the low incidence of post-surgical desmoids and quick postoperative recovery.

Introduction: Recent advances in technology and research are rapidly changing the diagnostic approach to hereditary gastrointestinal cancer (HGIC) syndromes. Although the practice of clinical genetics is currently transitioning from targeted criteria-based testing to multigene panels, important challenges remain to be addressed. The aim of this study was to develop and technically validate the performance of a multigene panel for HGIC. Methods: CGT-colon-G14 is an amplicon-based panel designed to detect single nucleotide variants and small insertions/deletions in 14 well-established or presumed high-penetrance genes involved in HGIC. The assay parameters tested were sensitivity, specificity, accuracy, and inter-run and intra-run reproducibility. Performance and clinical impact were determined using 48 samples of patients with suspected HGIC/polyposis previously tested with the targeted approach. Results: The CGT-colon-G14 panel showed 99.99% accuracy and 100% inter- and intra-run reproducibility. Moreover, panel testing detected 1 actionable pathogenic variant and 16 variants with uncertain clinical impact that were missed by the conventional approach because they were located in genes not previously analyzed. Conclusion: Introduction of the CGT-colon-G14 panel into the clinic could provide a higher diagnostic yield than a step-wise approach; however, results may not always be straightforward without the implementation of new genetic counseling models.

Patients with familial adenomatous polyposis (FAP) depend on a lifelong endoscopic surveillance programme and prophylactic surgery, and usually suffer nutritional problems. Intestinal inflammation has been linked to both FAP and colorectal cancer. Epidemiological studies show a relationship between diet and inflammation. Preventive dietary recommendations for FAP patients are so far lacking. We have designed a nonrandomized prospective pilot study on FAP patients to assess whether a low-inflammatory diet based on the Mediterranean diet principles and recipes, by interacting with the microbiota, reduces gastrointestinal markers of inflammation and improves quality of life. This report describes the scientific protocol of the study and reports the participants’ adherence to the proposed dietary recommendations. Thirty-four FAP patients older than 18 years, bearing the APC pathogenic variant, who underwent prophylactic total colectomy with ileo-rectal anastomosis were eligible into the study. During the 3-month dietary intervention, they reported improvements in their consumption of Mediterranean foods (vegetables, fruits, fish, and legumes), and a reduction in pro-inflammatory foods (red/processed meat and sweets); this led to a significant increase in their adherence to the Mediterranean diet. The improvement was accompanied by a decrease in the number of diarrhoeal discharges. These preliminary results are encouraging with regard to feasibility, dietary outcome measures, and safety.

Objective: To investigate the performance of tumor testing approaches in the identification of Lynch syndrome (LS) in a single-center cohort of people with colorectal cancer (CRC). Methods: A retrospective analysis of data stored in a dedicated database was carried out to identify patients with CRC suspected for LS who were referred to Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, between 1999 and 2014. The sensitivity and specificity of immunohistochemistry (IHC) for mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis (alone or combined) were calculated with respect to the presence of causative MMR germline variants. Results: A total of 683 patients with CRC suspected for LS were identified. IHC results of MMR protein analysis and MSI were assessed in 593 and 525 CRCs, respectively, while germline analysis was performed in 418 patients based on the IHC or MSI test result and/or clinical features. Univariate and multivariate analysis revealed a significant correlation of pathogenic MMR germline variants with all clinicopathologic features including Amsterdam criteria, presence of endometrial cancer, CRC site, age at onset, stage, and grade. The highest odds ratio values were observed for IHC and MSI (17.1 and 8.8, respectively). The receiver operating characteristic curve and area under the curve values demonstrated that IHC alone or combined with other clinicopathologic parameters was an excellent test for LS identification. Conclusions: This study confirms the effectiveness of tumor testing to identify LS among patients with CRC. Although IHC and MSI analysis were similarly effective, IHC could be a better strategy for LS identification as it is less expensive and more feasible.

Aims and background Guidelines for surveillance in patients with familial adenomatous polyposis (FAP) recommend mutation carriers to undergo periodic colorectal examination starting in the early teens. Performing colonoscopy in children may lead to complications. Wireless capsule endoscopy (WCE) has been introduced recently to evaluate both the upper and lower gastrointestinal tract, and seems suitable as a first screening examination for adolescents. The aim of this study was to evaluate the pros and cons of WCE. Methods This was a retrospective review of a single institution database of adolescent patients with FAP identified through the Hereditary Colorectal Tumor Registry between 2007 and 2013. The main outcomes were identification of upper and lower gastrointestinal tract polyps, tolerance of the examination, and number and size of polyps. Results Of 46 adolescent patients with FAP, 14 (30.4%) patients carrying adenomatous polyposis coli gene ( APC) mutation, 6 male and 8 female, age (median, range) 12 (10-17) years, body mass index 19 (13-24), underwent WCE as first screening examination. The examination was completed in 13 patients (93.3%). Wireless capsule endoscopy identified the duodenal papilla in 4 patients and colonic and rectal polyps in all 13 patients. In 7 patients, fewer than 25 polyps were identified. No complications were recorded related to the use of the video capsule. Conclusions Wireless capsule endoscopy is feasible and well-tolerated as a first screening examination in adolescent patients. It cannot be used as alternative to the colonoscopy, but could improve compliance with colonoscopy, and increase early adherence to a surveillance program.

Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6,858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a “classical” polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions vs. point mutations in the APC-5' regulatory region. This article is protected by copyright. All rights reserved.

Background Gastrointestinal (GI) carcinomas are very rare in the pediatric and adolescent age range. We report the clinical features, treatment, and outcome of a series of children and adolescents with GI carcinoma prospectively registered in the Italian Tumori Rari in Eta Pediatrica (TREP) project. Methods The TREP project developed diagnostic and therapeutic guidelines based on recommendations currently in use for adults. Clinical data were centrally registered and reviewed. Results Fifteen patients were registered over the years 2000–2016. Most of the tumors were colorectal carcinomas (12 cases). All but one patient had advanced-stage disease (American Joint Committee on Cancer stages III–IV), and the majority of patients had aggressive histological subtypes, i.e. poorly differentiated (G3) (five patients), mucinous (four patients), and signet ring (two patients) adenocarcinomas. Surgery was performed in 13 of 15 patients, and was radical in nine of 13 patients. Only one patient received postoperative radiotherapy. All patients received chemotherapy, with the addition of bevacizumab in two cases. Nine patients were still alive at the time of the present report, but two of them had only just completed their treatment program and one patient is still on treatment. Six patients died due to disease progression. Conclusions This prospective report on pediatric GI tract carcinomas confirms the rarity and biological aggressiveness of these diseases in pediatric and adolescent age. Further prospective studies are needed to explore the distinct biology of tumor in this age group in order to find new therapeutic targeted agents.

Purpose. The purpose of the study was to evaluate the feasibility and safety of performing laparoscopic intestinal surgery using local anesthesia and intravenous sedation with instruments 2 pneumoperitoneum was maintained using pressure of 3 to 5 mm Hg. Commercially available instruments, sizes 2 insufflation pressure under local anesthesia and intravenous sedation. This methodology holds promise in the development of new approaches to intestinal surgery and disease diagnosis.

Aim The natural history and appropriate management of anastomotic sinus has not been clearly defined. The aim of this study was to evaluate the incidence, management and outcomes of anastomotic sinus. Method The medical records of all patients who underwent a low anterior resection (LAR) or an ileal pouch– anal anastomosis (IPAA) with a diverting loop ileostomy (LI) and with contrast enema performed before planned stoma closure between 2001 and 2011 were retrospectively reviewed. The radiological features of the sinus tract, treatment and outcome of anastomotic sinus were studied. Results Twenty patients (8.2%) were found to have anastomotic sinuses out of the total of 244 patients who had undergone LAR (n = 146) or IPAA (n = 98) with LI. Of these, 13 (65%) had prior symptomatic leaks, while seven did not. Twelve patients (60%) were found to have simple sinus tracts, while eight had complex sinuses (associated with either pelvic cavities or severe strictures). Five patients with simple tracts were treated with observation alone. Fifteen patients underwent surgical interventions. Overall, with a median follow-up of 28 (6–73) months, 16 patients (80%) had resolution of their sinuses. All of 12 patients (100%) with simple sinus tracts and four of eight patients (50%) with complex sinuses underwent successful stoma reversals after 8 (3.5–24) months following the initial surgery (P = 0.01). Conclusion Patients with simple tracts are significantly more likely to have complete resolution of sinuses than patients with complex sinuses. Persistent sinus associated with either a pelvic cavity or severe stricture despite surgical intervention is likely to lead to a permanent

Background Androgen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described. Case presentation Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers. Conclusions By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s40880-016-0115-1) contains supplementary material, which is available to authorized users.

Background Prophylactic surgery is still considered the standard treatment for patients with Familial Adenomatous Polyposis (FAP). Laparoscopic (Lap) surgery has been introduced as an alternative approach. The aim was to evaluate the feasibility and short- to long-term outcomes after prophylactic FAP surgery in adolescent. Procedures A retrospective review of a database of adolescent patients with FAP identified through the Hereditary Colorectal Tumor Registry in a single Institution between 2005 and 2011. Patients underwent Lap total colectomy (TC) with ileo-rectal anastomosis (IRA) or proctocolectomy (PC) with ileal-pouch anal anastomosis (IPAA). The main outcomes were: Hospital stay, postoperative complications, desmoid tumor rates, tumor recurrence, long-term complications. Results Sixteen consecutive patients with median age 16 (range 13–19) and median BMI 22 (17–29) underwent surgery. [correction made here after initial online publication]. Of them 14 patients had LAP TC with IRA and 2 had PC with IPAA. Operative time (median, range) was TC/IRA 270 (210–330) minutes; PC/IPAA 370 (360–380) minutes. Length of extraction site was cm (median, range) 6(5–8). Lymph Node harvest (median, range) 81 (32–139). Postoperative stay days (median, range) were 6 (4–24). Five patients (31.2%) showed dysplasia on the pathological report and 3 of them showed severe dysplasia. Median follow-up time (FU) was 39 months, range (10–82). The anastomotic leak rate for 30 days was 2 (12.5%). Pouch failure was 0. Post-surgical desmoid tumors rate was 1 (6.2%) and there was no tumor recurrence. Anastomotic stricture, SBO and mortality were zero. Conclusions Lap approach is feasible and shows acceptable postoperative outcomes. Lap surgery can be an appealing alternative for prophylactic surgery in adolescent FAP patients. Pediatr Blood Cancer 2012; 59: 1223–1228. © 2012 Wiley Periodicals, Inc.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome. Risk of cancer begins to increase after age 20 years if not treated. The purpose of this study was to evaluate the feasibility and short- and long-term outcomes after laparoscopic prophylactic surgery for FAP. Fifty-five patients with FAP were identified through the Hereditary Colorectal Tumor Registry from 2003 to 2009. Patients with laparoscopic total colectomy (TC)/IRA or proctocolectomy (TPC)/ileal pouch-anal anastomosis IPAA were included. Patients with previous colon or abdominal major surgery, malignancy, and desmoids before surgery were excluded. Main outcomes were: 30 days anastomotic leak and pouch failure; long-term desmoids and malignant recurrence. Of the 55 patients, 32 were men, median age was 28 years, and mean body mass index was 23. Median follow-up time was 36 (range, 5–77) months. Forty-four patients had laparoscopic TC/IRA and ten had laparoscopic TPC/IPAA. One patient was converted to open surgery and received an open TPC/IPAA. Incision length was 7 (range, 5–14) cm. Anastomotic leak was 3 (5.4%: 2 laparoscopic and 1 open), and pouch failure was 0. Median postsurgical length of stay was 7 (range, 4–24) days. Desmoids occurred in three patients (5.4%), and there was no malignant recurrence within the follow-up period. Pathology revealed severe dysplasia in ten patients and adenocarcinoma in nine (8 laparoscopic and 1 open). Long-term small-bowel obstruction was 2 (3.6%). One mortality due to liver metastases occurred at 24 months. Laparoscopic prophylactic treatment of FAP appears to be safe and feasible and may be an appealing alternative to open surgery. If the goal of prophylactic FAP surgery is to avoid cancer occurrence, laparoscopic surgery could be an important advancement.

11556Background: Desmoid tumours (DTs) are monoclonal neoplasms with fibroblastic-myofibroblastic differentiation and they represent the most common extra-intestinal manifestation of familial adeno...

The treatment of tumors of the distal rectum continues to be a matter of great controversy among oncologic surgeons. There are increasingly promising indications that functionally conservative surgery may be a valid therapeutic alternative to conventional therapy in patients with tumours of the lower rectum, traditionally treated by abdomino-perineal resection and definitive colostomy. Many points are presently under evaluation and we want to discuss some of the most relevant topics that are now permitting to change the guide lines of therapy of this disease. Our view of the problem is based on a personal experience cumulated in fourteen years of activity in a specialized unit and this paper reports the main results of a complex and diversified study carried out during this period at the National Cancer Institute of Milan.

Background Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. Methods The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. Results A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0–516) months in the open group and 60 (12–108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. Conclusion Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

Rectal cancer incidence is increasing among the elderly who are more often considered for palliation rather than for surgical cure. Moreover, sphincter-sparing surgery is often avoided when treating the elderly. We report our experience on a consecutive series of 38 subjects, suffering from a lower third rectal tumour with a median distance of 5.6 cm from the anal verge (7 Dukes' A, 6 Dukes' B, 17 Dukes' C, 3 Dukes' D, 3 anastomotic recurrences and 2 large villous adenomas). All subjects were prospectively collected in a 2-year period and treated with total resection and colo-anal hand-sewn anastomosis on a J colic reservoir. 20 patients younger than 65 years and 18 over 65 years were matched for surgical complications, late morbidity, oncological and functional results but no statistical difference was found. Our hope is that a conservative approach in treating the low rectal tumours will progressively be accepted for elderly patients.

From March 1990 to December 1992, 47 patients with primary or recurrent low rectal cancer under-went total rectal resection and a coloendoanal anastomosis. Rectal resection was extended downward to the ano-rectal junction. The restorative technique included a colo-endoanal anastomosis between the dentate line and a J-shaped colic reservoir. All lesions were located within 7 cm of the anal verge (within 6 cm in 33 primary cases). Macroscopic and histological radicality was documented in all cases. Pelvic recurrence occurred in six patients and was para-anastomotic in one case. Post-operative morbidity was low. Perfect continence was documented in 36 patients and 72 of the cases had one or two bowel movements a day. All but four patients are alive at a follow-up ranging from 6 to 40 months (median 20 months). This approach is a safe option to conventional total rectal excision with permanent colostomy for lower third rectal carcinoma.