Detection of (pre)cancerous colorectal lesions in Lynch syndrome patients by microsatellite instability liquid biopsy.

Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close endoscopic surveillance is the only option available to reduce CRC morbidity and mortality. However, it may fail to intercept interval cancers and patients' compliance to such an invasive procedure may decrease over the years. The development of a minimally invasive test able to detect (pre)cancerous colorectal lesions, could thus help tailor surveillance programs in LS patients. Taking advantage of an endoscopic surveillance program, we retrospectively assessed the instability of five microsatellites (BAT26, BAT25, NR24, NR21, and Mono27) in liquid biopsies collected at baseline and possibly at two further endoscopic rounds. For this purpose, we tested a new multiplex drop-off digital polymerase chain reaction (dPCR) assay, reaching mutant allele frequencies (MAFs) as low as 0.01%. Overall, 78 plasma samples at the three time-points from 18 patients with baseline (pre)cancerous lesions and 18 controls were available for molecular analysis. At baseline, the MAFs of BAT26, BAT25 and NR24 were significantly higher in samples of patients with lesions but did not differ with respect to the grade of dysplasia or any other clinico-pathological characteristics. When all markers were combined to determine MSI in blood, this test was able to discriminate lesion-bearing patients with an AUC of 0.80 (95%CI: 0.66; 0.94).

Modulation of faecal miRNAs highlights the preventive effects of a Mediterranean low-inflammatory dietary intervention.

BACKGROUND: Dietary interventions have been proposed as therapeutic approaches for several diseases, including cancer. A low-inflammatory Mediterranean dietary intervention, conducted as a pilot study in subjects with Familial Adenomatous Polyposis (FAP), reduced markers of local and systemic inflammation. We aim to determine whether this diet may modulate faecal microRNA (miRNA) and gene expression in the gut. METHODS: Changes in the faecal miRNome were evaluated by small RNA sequencing at baseline (T0), after the three-month intervention (T1), and after an additional three months (T2). Changes in the transcriptome of healthy rectal mucosa and adenomas were evaluated by RNA sequencing at T0 and T2. The identification of validated miRNA-gene interactions and functional analysis of miRNA targets were performed using in silico approaches. RESULTS: Twenty-seven subjects were included in this study. It was observed that the diet modulated 29 faecal miRNAs (p < 0.01; |log2 Fold Change|>1), and this modulation persisted for three months after the intervention. Levels of miR-3612-3p and miR-941 correlated with the adherence to the diet, miR-3670 and miR-4252-5p with faecal calprotectin, and miR-3670 and miR-6867 with serum calprotectin. Seventy genes were differentially expressed between adenoma and normal tissue, and most were different before the dietary intervention but reached similar levels after the diet. Functional enrichment analysis identified the proinflammatory ERK1/2, cell cycle regulation, and nutrient response pathways as commonly regulated by the modulated miRNAs and genes. CONCLUSIONS: Faecal miRNAs modulated by the dietary intervention target genes that participate in inflammation. Changes in levels of miRNAs and genes with oncogenic and tumour suppressor functions further support the potential cancer-preventive effect of the low-inflammatory Mediterranean diet. CLINICAL TRIAL NUMBER REGISTRATION: NCT04552405, Registered in ClinicalTrials.gov.

De novo germline pathogenic variant in Lynch Syndrome: A rare event or the tip of the iceberg?

Lynch Syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants or epimutation in one of the DNA mismatch repair genes. De novo pathogenic variants in mismatch repair genes have been described as a rare event in Lynch Syndrome (1-5%), although the prevalence of de novo pathogenic variants in Lynch Syndrome is probably underestimated. The de novo pathogenic variant was identified in a 26-year-old woman diagnosed with an adenocarcinoma of the caecum with mismatch repair protein deficiency at immunohistochemistry and a synchronous neuroendocrine tumor of the appendix with normal expression of mismatch repair proteins. DNA testing revealed deletion of exon 6 of the MLH1 gene. It appeared to be a de novo event, as the deletion was not detected in the patient's parents. The presence of a mosaicism in the patient was excluded and haplotype analysis demonstrated the paternal origin of the chromosome harboring the deletion. The de novo deletion probably originated either from a very early postzygotic or a single prezygotic mutational event, or from a gonadal mosaicism. In conclusion, the identification of de novo pathogenic variants is crucial to allow proper genetic counseling and appropriate management of the patient's family.

Quality of life after prophylactic surgery for colorectal adenomatous polyposis.

PURPOSE: Colorectal adenomatous polyposis is characterized by the onset of tens to thousands of adenomas in the colorectal epithelium and, if not treated, leads to a lifetime increased risk of developing colorectal cancer compared to the general population. Thus, prophylactic surgery is recommended. This study aims to investigate the quality of life of colorectal adenomatous polyposis patients following prophylactic surgery and indirectly compares these findings with those of healthy adults of the normative sample. METHODS: All patients who underwent prophylactic surgery for polyposis and were in follow-up at the hereditary digestive tract tumors outpatient department of our institute were eligible for the study. The Short Form-36 questionnaire and 21 ad hoc items were used at the time of clinical evaluation. RESULTS: A total of 102 patients were enrolled. For the SF-36 domains, mean values ranged from 64.18 for vitality to 88.49 for physical functioning, with the highest variability for role-physical limitations; the minimum value of functioning was reached for role-physical limitations, role-emotional limitations, and social functioning. The maximum value of functioning was reached for role-emotional limitations (73.96%) and role-physical limitations (60.42%). In total, 48.96% and 90.63% of patients reported no fecal or urinary incontinence episodes, respectively; 69.79% of patients did not have problems in work/school resumption or the personal sexual sphere. CONCLUSION: Quality of life following prophylactic surgery for these patients seems to be good when indirectly compared to HP-normative samples'. Young adult patients appear to quickly manage and adapt to changes in bowel functioning. A minority of patients may experience social and sexual issues.

Efficacy of laparoscopic Toupet fundoplication compared to endoscopic and surgical procedures for GERD treatment: a randomized trials network meta-analysis.

PURPOSE: We aim to review and quantitatively compare laparoscopic Toupet fundoplication (LTF), Nissen fundoplication (LNF), anterior partial fundoplication (APF), magnetic augmentation sphincter (MSA), radiofrequency ablation (RFA), transoral incisionless fundoplication (TIF), proton pump inhibitor (PPI), and placebo for the treatment of GERD. A number of meta-analyses compared the efficacy of surgical and endoscopic procedures for recalcitrant GERD, but considerable debate on the effectiveness of operative strategies remains. METHODS: A systematic review of MEDLINE databases, EMBASE, and Web of Science for randomized controlled trials (RCTs) comparing the aforementioned surgical and endoscopic GERD treatments was performed. Risk ratio and weighted mean difference were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to assess relative inference. RESULTS: Thirty-three RCTs were included. Surgical and endoscopic treatments have similar RR for heartburn, regurgitation, bloating. LTF has a lower RR of post-operative dysphagia when compared to APF (RR 3.3; Crl 1.4-7.1) and LNF (RR 2.5; Crl 1.3-4.4). The pooled network meta-analysis did not observe any significant improvement regarding LES pressure and pH < from baseline. LTF, APF, LNF, MSA, RFA, and TIF had have a similar post-operative PPI discontinuation rate. CONCLUSION: LTF has a lower rate of post-operative dysphagia when compared to APF and LNF. The pre-post effects, such as GERD-HQRL, LES pressure, and pH <4, should be avoided in meta-analyses because results may be biased. Last, a consensus about the evaluation of GERD treatments' efficacy and their outcomes is needed.

The neglected role of preimplantation genetic testing for Lynch syndrome.

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.

Association between Pancreatoblastoma and Familial Adenomatous Polyposis: Review of the Literature with an Additional Case.

BACKGROUND: Adult pancreatoblastoma (PBL) is a rare pancreatic malignancy, with recent evidence suggesting a possible link to familial adenomatous polyposis (FAP). This study aims to review the latest evidence and explore a possible association between adult PBL and FAP. METHODS: Two independent literature reviews were conducted: (1) on PBL and FAP, and (2) on PBL in the adult population not diagnosed with FAP. RESULTS: Out of 26 articles on PBL and FAP screened, 5 were selected for systematic review, including 1 additional case. We identified eight FAP-related PBL cases, with a median age of 40 (IQR: 34-50). Of these, seven (87%) occurred in adults. We found 65 cases of adult PBL not FAP-related; thus, 7 out of 65 cases (10.7%) of adult PBL reported in the literature are associated with a clinical diagnosis of FAP or were carriers of APC germline pathogenic variants (GPVs). CONCLUSION: Data suggest a non-random association between adult PBL and FAP. Further research is essential to optimise surveillance protocols and develop more effective treatment strategies.

Gynecological Cancers in Lynch Syndrome: A Comparison of the Histological Features with Sporadic Cases of the General Population.

Introduction: About 5% of endometrial cancers (ECs) are attributed to an inherited predisposition, for which Lynch syndrome (LS) accounts for the majority of cases. Women with LS have a 40−60% predicted lifetime risk of developing EC, in addition to a 40−80% lifetime risk of developing colorectal cancer and other cancers. In this population, the lifetime risk of developing ovarian cancer (OC) is 10−12%. Object: to compare the histopathological features of LS-associated EC and OC with sporadic cancers in order to evaluate whether there are differences in terms of age at diagnosis, site of occurrence in the uterus, histological type, stage at diagnosis, and tumor grading. Materials and methods: we compared data obtained from 96 patients with LS-associated gynecological cancers (82 with EC and 14 with OC) to a control group (CG) of 209 patients who developed sporadic EC, and a CG of 187 patients with sporadic OC. Results: The mean age at diagnosis of LS-associated EC and OC was much lower than in the control groups. In both groups with EC, the endometrioid histotype was the most frequently occurring histotype. However, among LS women there was a significantly higher incidence of clear cell tumors (11% versus 2.4% in the CG, p = 0.0001). Similar to the sporadic cancer cases, most of the LS-associated ECs presented at an early stage (89% of cases at FIGO I-II stage). In the LS group, the tumor frequently involved only the inner half of the endometrium (77% of cases, p < 0.01). In the LS group, 7.3% of ECs were localized to the lower uterine segment (LUS), whereas no cancer developed in the LUS in the CG. No serous OCs were diagnosed in the LS group (versus 45.5% in the CG, p = 0.0009). Most of the LS-associated OCs presented at an early stage (85% of cases at FIGO I-II stages, p < 0.01). Conclusion: LS-associated EC and OC seem to have peculiar features, occurring at a younger age and at an earlier stage. In LS, EC less frequently involves the outer half of the endometrium, with a more frequent occurrence in the LUS. The presence of clear cell EC was more frequently observed, whereas in OC, the predominant histotype was endometrioid.

Reply to Serrano et al. Comment on "Colletti et al. Prevalence and Management of Cancer of the Rectal Stump after Total Colectomy and Rectal Sparing in Patients with Familial Polyposis: Results from a Registry-Based Study. Cancers 2022, 14, 298".

We carefully read the comment by Serrano et al. [...].

Prevalence and Management of Cancer of the Rectal Stump after Total Colectomy and Rectal Sparing in Patients with Familial Polyposis: Results from a Registry-Based Study.

BACKGROUND: The balance between quality of life and colorectal cancer risk in familial adenomatous polyposis (FAP) patients is of primary importance. A cut-off of less than 30 polyps under 1 cm of diameter in the rectum has been used as an indication for performing ileo-rectal anastomosis (IRA) in terms of lower rectal cancer risk. This study aimed to assess clinical and surgical features of FAP patients who developed cancer of the rectal stump. METHODS: This retrospective study included all FAP patients who underwent total colectomy/IRA from 1977 to 2021 and developed subsequent rectal cancer. Patients' features were reported using descriptive statistics by considering the overall case series and within pre-specified classes of age (<20, 20-30, and >30 years) at first surgery. RESULTS: Among the 715 FAP patients, 47 (6.57%, 95% confidence interval: 4.87; 8.65) developed cancer in the rectal stump during follow-up. In total, 57.45% of the population were male and 38.30% were proband. The median interval between surgery and the occurrence of rectal cancer was 13 years. This interval was wider in the youngest group (p-value: 0.012) than the oldest ones. Twelve patients (25.53%) received an endoscopic or minimally invasive resection. Amongst them, 61.70% were Dukes stage A cancers. CONCLUSIONS: There is a definite risk of rectal cancer after total colectomy/IRA; however, the time interval from the index procedure to cancer developing is long. Minimally invasive and endoscopic treatments should be the procedures of choice in patients with early stage cancers.

Hereditary colorectal cancer syndromes and the COVID-19 pandemic: results from a survey conducted in patients enrolled in a dedicated registry.

PURPOSE: The coronavirus 2019 (COVID-19) pandemic has had profound consequences also for non-infected patients. This study aimed to evaluate the impact of the pandemic on the quality of life of a population with hereditary gastrointestinal cancer predisposition syndromes and on the surveillance/oncological care program of patients enrolled in a dedicated registry. METHODS: The study was conducted by means of an online self-report survey during the first Italian national lockdown. The survey comprised four sections: demographics; perception/knowledge of COVID-19; impact of the COVID-19 pandemic on surveillance and cancer care; health status (SF-12 questionnaire). RESULTS: 211 complete questionnaires were considered. 25.12% of respondents reported being not at all frightened by COVID-19, 63.98% felt "not at all" or "a little" more fragile than the healthy general population, and 66.82% felt the coronavirus to be no more dangerous to them than the healthy general population. 88.15% of respondents felt protected knowing they were monitored by a team of dedicated professionals. CONCLUSION: Patients with hereditary gastrointestinal cancer predisposition syndromes reported experiencing less fear related to COVID-19 than the healthy general population. The study results suggest that being enrolled in a dedicated registry can reassure patients, especially during health crises.

Preventive Anti-inflammatory Diet to Reduce Gastrointestinal Inflammation in Familial Adenomatous Polyposis Patients: A Prospective Pilot Study.

Familial adenomatous polyposis (FAP) is an autosomal-dominant hereditary condition associated with germline mutations in the adenomatous polyposis coli gene. Patient management involves prophylactic surgery and intensive life-long endoscopic surveillance. Diet is a major concern for patients with FAP, who are generally free of symptoms before surgery but tend to have issues related to bowel function postoperatively. We hypothesized that a low-inflammatory diet based on the principles and recipes of the Mediterranean diet would reduce markers of local and systemic inflammation. Twenty-eight patients with FAP over 18 years of age who underwent rectum-sparing prophylactic colectomy and were included in our surveillance program participated in a pilot dietary intervention study. Blood and stool samples at baseline (T0), at the end of the dietary intervention (T1, three months), and at the end of the study (T2, six months after T0) were collected. Gastrointestinal inflammation markers including fecal calprotectin, cyclooxygenase-2, and 15-hydroxyprostaglandin dehydrogenase were evaluated. Serum calprotectin, insulin, insulin-like growth factor-1, C-reactive protein, and glycated hemoglobin were also assessed. Significant changes in serum calprotectin, insulin, and insulin-like growth factor-1 levels occurred over time. Borderline significant changes were observed in the neutrophil-lymphocyte ratio. These changes were noticeable immediately at the end of the 3-month active dietary intervention (T1). A significant increase in 15-hydroxyprostaglandin dehydrogenase expression in the normal crypts of matched samples was also observed between T0 and T2. This pilot study supports the hypothesis that a low-inflammatory diet can modulate gastrointestinal markers of inflammation in individuals with FAP. PREVENTION RELEVANCE: Cancer is known to be related to inflammatory conditions. This study suggests that anti-inflammatory dietary intervention may potentially prevent adenomas and cancer in FAP patients by reducing systemic and tissue inflammatory indices.

Management of serious complications in intra-abdominal desmoid-type fibromatosis.

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.

Gardner-associated fibroma of the neck: role of a multidisciplinary evaluation for familial adenomatous polyposis diagnosis.

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 <5 mm) diffusely present on the large bowel. Genetic testing revealed a pathogenic germline variant in the APC gene. The predictive genetic test on the patient's parents and sister was negative for the identified APC mutation; therefore, the patient carried an apparent de novo germline mutation. 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.

Definition and management of colorectal polyposis not associated with APC/MUTYH germline pathogenic variants: AIFEG consensus statement.

An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarità ed Ereditarietà 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).

Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long-term?

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.

Risk factors for metachronous colorectal cancer in Lynch syndrome patients: a registry-based observational mono-institutional study cohort.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Familial adenomatosis polyposis-related desmoid tumours treated with low-dose chemotherapy: results from an international, multi-institutional, retrospective analysis.

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.

Long-term survival between total colectomy versus proctocolectomy in patients with FAP: a registry-based, observational cohort study.

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.