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Patients with ulcerative colitis (UC) are at risk of developing a colorectal cancer. The aim of this study was to examine our experience in the treatment of ulcerative Colitis Cancer (CC), the role of the ileal pouch–anal anastomosis (IPAA), and the clinical outcome of the operated patients. Data from 417 patients operated on for ulcerative colitis were reviewed. Fifty-two (12%) were found to have carcinoma of the colon (n = 43) or the rectum (n = 9). The indication to surgery, the histopathological type, the cancer stage, the type of surgery, the oncologic outcome, and the functional result of IPAA were examined. The majority of the patients had a mucinous or signet-ring carcinoma. An advanced stage (III or IV) was present in 28% of the patients. Early (stage I or II) CC was found in all except one patient submitted to surgery for high-grade dysplasia, low-grade dysplasia, or refractory colitis. Thirty-nine (75%) of the 52 patients underwent IPAA, 10 patients were treated with a total abdominal proctocolectomy with terminal ileostomy. IPAA was possible in 6/9 rectal CC. Cumulative survival rate 5 and 10 years after surgery was 61% and 53%, respectively. The survival rate was significantly lower for mucinous or signet-ring carcinomas than for other adenocarcinoma. No significant differences of the functional results and quality of life were observed between IPAA patients aged less than or more than 65 years. Failure of the pouch occurred in 5 of 39 (12.8%) patients for cancer of the pouch (2 pts) or for tumoral recurrence at the pelvic or peritoneal level. Early surgery must be considered every time dysplasia is discovered in patients affected by UC. The advanced tumoral stage and the mucous or signet-ring hystotype influence negatively the response to therapy and the survival after surgery. IPAA can be proposed in the majority of the patients with a functional result similar to that of UC patients not affected by CC. Failures of IPAA for peritoneal recurrence or metachronous cancer of the pouch can be observed when CC is advanced, moucinous, localized in the distal rectum, or is associated with primary sclerosing cholangitis.

Context Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine cancer syndrome. Multiple gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) affect 30% to 80% of MEN1 patients, with the most common functioning GEP-NET being gastrinoma. Biochemical identification of hypergastrinemia may help to recognize the presence of gastrinomas before they are detectable by instrumental screening, enabling early diagnosis and start of therapy, preferably before tumor progression and metastases occurrence. Objective Evaluate the effectiveness of secretin stimulation test to precociously diagnose the presence of gastrin-secreting tumors. Design Results of secretin stimulation tests, performed between 1991 and February 2020, were retrospectively analyzed, as aggregate, in a cohort of MEN1 patients with GEP-NETs. Setting Data were extracted from the MEN1 Florentine database. Patients The study included 72 MEN1 patients with GEP-NETs who underwent a secretin stimulation test for the evaluation of gastrin secretion. Outcomes A positive secretin stimulation test was assumed with a difference between basal fasting serum gastrin (FSG) and the maximum stimulated value of gastrin over 120 pg/mL. Results The secretin stimulation test showed a secretin-induced hypergastrinemia in 27.8% (20/72) of patients with GEP-NETs, and a positive test in 18 cases. The test allowed the identification of a positively stimulated hypergastrinemia in 75.0% (3/4) of patients who presented a basal FSG within the normal range. Conclusions Diagnosis of gastrinoma is complex, difficult, and controversial. Results of this study confirm that a positive secretin stimulation test allows early diagnosis of gastrinomas, even in the presence of borderline or normal levels of nonstimulated FSG.

Leonardo da Vinci set out to produce a true treatise of anatomy, since in his time no such work existed. His drawing of the spine is a formidable example of his genius. Since artworks by Leonardo are appreciated for their accuracy and careful adherence to the subject represented, we examined Leonardo’s spine as one would a radiograph, looking for evidence of osteoporotic fractures or signs of osteoarthritis. The dorsal and lumbar vertebrae show a slightly wedge-shaped deformity without “radiological” signs of fracture. Instead, signs of osteoarthritis can be noted at the lumbar vertebrae. With his extraordinary eye for detail, Leonardo produced an image that foreshadows those that radiology would later make available to clinicians for the diagnosis of problems linked to vertebral degeneration.

The COVID-19 pandemic and its consequences have demonstrated that viral infections still pose great challenge to health systems worldwide. The immune system plays a primary role in fighting infections, and non-specific innate immunity, in particular, is a key defense mechanism engaged during the first phases of an infection. The subsequent triggered immune response, characterized by specific cytokine patterns, can be exaggerated and lead to a cytokine storm, causing multiorgan damage and intravascular disseminated coagulation. Calcitriol, the active form of vitamin D, a key player in mineral homeostasis, is able to control the immune response by favoring the production of antimicrobial peptides (e.g., cathelicidin), decreasing viral shedding, and modulating the inflammatory process. A poor vitamin D status has been demonstrated to be associated with increased risk of infections, especially in fragile subjects, as also recently shown in COVID-19 disease. Unfortunately, this does not demonstrate that supplementation with vitamin D is significantly linked to prevention or modulation of the course of viral infections. Large intervention trials are necessary to produce evidence that vitamin D supplementation is linked to decreased rates of infections and related complications. At present, cholecalciferol and calcidiol regimens commonly employed in clinical practice to prevent and correct musculoskeletal abnormalities are advisable, at least in fragile, vitamin D-deficient individuals, in order to reach a target of serum 25(OH)D of 30–50 ng/ml, avoiding large doses, which can be responsible for hypercalciuria-hypercalcemia or increased falls.

Purpose: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant cancer syndrome characterized by the development of multiple neuroendocrine tumors. The condition requires lifelong surveillance and multiple medical and surgical therapies throughout the patient’s life. For all these reasons, a diagnosis of MEN1 can be a psychological shock for the patient, as well as his/her relatives. Over the past two decades, clinicians have started to consider the emotional, psychological, relational and social aspects of MEN1 patients’ lives, as these may be important considerations in the clinical and therapeutic management of these patients. Methods: This paper reviews and critically analyzes perceptions of MEN1-related quality of life (QoL) in patients diagnosed with the syndrome and in relatives, highlighting the unique features of MEN1 syndrome compared with a single tumor diagnosis. Results: Interestingly, studies in MEN1 patients have shown that a relatively high percentage of them, despite having a complex multi-tumor syndrome, were moderately optimistic (50%), self-reporting a normal QoL. This positive response correlated with the fact that these patients were cared for at dedicated referral centers, where personalized care and constant follow-up provide them with reassurance that they are receiving high quality of management of their disorder. Conclusions: The possibility of having access to a clinical referral center for this complex rare disease, together with the support of a dedicated patient association, emerged as the ideal model for the management of post-diagnosis shock, and appeared to contribute to the preservation of good health-related quality of life in MEN1 patients.

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited syndrome, caused by heterozygote inactivating mutation of the MEN1 tumor suppressor gene, and characterized by the development of mult...

Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.

BACKGROUND Crohn’s disease (CD) is a complex disorder resulting from the interaction of genetic, environmental, and microbial factors. The pathogenic process may potentially affect any segment of the gastrointestinal tract, but a selective location in the terminal ileum was reported in 50% of patients. AIM To characterize clinical sub-phenotypes (colonic and/or ileal) within the same disease, in order to identify new therapeutic targets. METHODS 14 consecutive patients undergoing surgery for ileal CD were recruited for this study. Peripheral blood samples from each patient were collected and the main polymorphisms of the gene Card15/Nod2 (R702W, G908R, and 1007fs) were analyzed in each sample. In addition, tissue samples were taken from both the tract affected by CD and from the apparently healthy and disease-free margins (internal controls). We used a multiplex gene assay in specimens obtained from patients with ileal localization of CD to evaluate the simultaneous expression of 24 genes involved in the pathogenesis of the disease. We also processed surgery gut samples with routine light microscopy (LM) and transmission electron microscopy (TEM) techniques to evaluate their structural and ultrastructural features. RESULTS We found a significant increase of Th17 (IL17A and IL17F, IL 23R and CCR6) and Th1 (IFN-γ) gene expression in inflamed mucosa compared to non-inflamed sites of 14 CD patients. DEFB4 and HAMP, two genes coding for antimicrobial peptides, were also strongly activated in inflamed ileal mucosa, suggesting the overwhelming stimulation of epithelial cells by commensal microbiota. IFN-γ and CCR6 were more expressed in inflamed mucosa of CD patients with ileal localization compared with patients with colonic localization suggesting a more aggressive inflammation process in this site. Morphological analysis of the epithelial lining of Lieberkün crypts disclosed enhanced release activity from goblet mucocytes, whereas the lamina propria contained numerous cells pertaining to various lines. CONCLUSION We observed that the expression of ileal genes related to Th1 and Th17 activity is strongly activated as well as the expression of genes involved in microbiota regulation.

Background and Aims Crohn’s disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn’s disease-associated small bowel carcinoma prognosis. Methods As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn’s disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. Results Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn’s disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. Conclusions The improved distinction of lower- from higher-grade Crohn’s disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.

Background Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. Patients and Methods In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. Results We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. Conclusions Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy. Graphic Abstract

Background. CARD15/NOD2 is the most significant genetic susceptibility in Crohn’s disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. Methods. 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. Results. CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases ( p < 0.05 ). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery ( p = 0.0344 ). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine ( p = 0.012 ), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. Conclusions. 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.

Most Crohn’s disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies. Supplementary Information The online version contains supplementary material available at 10.1007/s00428-021-03109-2.

We describe the second- and third-order nonlinear response of monolayer transition metal dichalcogenides, demonstrating their potential for phase-matched nonlinear wave mixing thanks to their atomic-layer thickness implying a surface-like nonlinear interaction.

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a “logbook” for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn’s disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

The oscillation of neutrons $n$ into mirror neutrons $n'$, their mass degenerate partners from dark mirror sector, can have interesting implications for neutron stars: an ordinary neutron star could gradually transform into a mixed star consisting in part of mirror dark matter. Mixed stars can be detectable as twin partners of ordinary neutron stars: namely, there can exist compact stars with the same masses but having different radii. For a given equation of state (identical between the ordinary and mirror components), the mass and radius of a mixed star depend on the proportion between the ordinary and mirror components in its interior which in turn depends on its age. If $50 \% - 50\%$ proportion between two fractions can be reached asymptotically in time, then the maximum mass of such "maximally mixed stars" should be $\sqrt2$ times smaller than that of ordinary neutron star while the stars exceeding a critical mass value $M^{\rm max}_{NS}/\sqrt2$ should collapse in black holes after certain time. We evaluate the evolution time and discuss the implications of $n-n'$ transition for the pulsar observations as well as for the gravitational waves from the neutron star mergers and associated electromagnetic signals., Comment: 18 pages, 6 figures

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant endocrine tumor syndrome, caused by inactivating mutations of the MEN1 tumor suppressor gene at 11q13 locus, which predisposes to develop tumors in target neuroendocrine tissues. As the positional cloning and identification of the causative gene in 1997, genetic diagnosis, by the sequencing-based research of gene mutations, has become an important tool in the early and differential diagnosis of the disease. Application of the genetic test, in MEN1 index cases and in first-degree relatives of mutated patients, has been constantly increasing during the last two decades, also thanks to the establishment of multidisciplinary referral centers and specific genetic counseling, and thanks to the wide availability of high throughput instruments for gene sequencing and gene mutation identification. The MEN1 genetic test helps the specific diagnosis of probands, and allows the early identification of asymptomatic carriers, strongly contributing, together with progressions in tumor diagnostic techniques and in pharmacological and surgical therapeutic approaches, to the reduction of morbidity and mortality associated with the syndrome. International clinical guidelines for MEN1 have been drafted by panels of specialists in the field, with the main goal to improve the management of the disease and grant patients a better quality of life. Here, we review main recommendations and suggestions derived by the last published general guidelines in 2012, and by most recent published studies about MEN1 syndrome diagnosis, clinical management, therapeutic approaches and patients’ quality of life.

Summary Crohn's disease (CD) is a multifactorial immunologically mediated disease. In this study we explored, for the first time, the efficacy of the Multiplex Gene Assay technology for detecting mRNA expression profile of 24 selected CD related genes in endoscopic biopsies and surgical specimens from CD patients with colonic localization of the disease. The polymorphisms of genes most frequently associated with CD were also analysed in DNA samples from the same patients. The analysis of endoscopic samples showed increased expression of 7 genes in inflamed mucosa compared to non-inflamed mucosa and suggests the activation of the autophagy process and of a Th17 adaptive response. The analysis of surgical specimens showed increased expression of 16 genes in inflamed tissue compared to non-inflamed internal controls and revealed the activation of immune-adaptive Th17 response in association with a Th1 response. Furthermore, an increased expression of genes involved in ionic transport and signal transduction was found in inflamed mucosa compared to non-inflamed internal controls. This study confirms the activation of Th17 and Th1 adaptive-immune response also in colonic CD. It should be stressed that these responses have been disclosed in biopsy tissue, while only Th17 differentiation is revealed in endoscopic tissue. Interestingly, the polymorphisms analysis revealed that a homozygous genotype is associated to a more complicated clinical course.

To retrospectively evaluate the age of onset of MEN1-associated lesions in a group of affected children and adolescents and to compare the clinical features of our series with the evidence derived from the literature.The study population consisted of 22 Italian children and adolescents (age 6-31 years at the time of the inclusion in this study) all with a clinical and/or a genetic diagnosis of MEN1 performed before the age of 16 who have been followed-up regularly from 1998 to 2016 at the Regional Referral Center for Hereditary Endocrine Tumors. Clinical, biochemical, imaging and genetic data have been collected for each patient.Ten subjects (45.5%) have not yet presented any clinical/biochemical/radiological manifestation of MEN1 disease, whereas 12 patients (54.5%) developed at least one MEN1-associated endocrine manifestation. The second group of patients was significantly older than the first one. The most frequent manifestation was primary hyperparathyroidism (50%), followed by pituitary tumors (prolactinomas) (31.8%) and nonfunctioning pancreatic neuroendocrine tumors (9%). The earliest cases of primary hyperparathyroidism and prolactinoma were a 12-year-old girl and a 13-year-old boy, respectively.MEN1 disease seems to present with different features in children and adolescents from those in adults. Our study confirms the fundamental importance of screening for tumors in young MEN1 patients beginning in early childhood, in order to avoid diagnostic and therapeutic delays.

Background and aims An increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC]. Methods A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations. Results CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications. Conclusions In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.

Background Distal pancreatectomy is the most frequent operation for insulinomas complicating multiple endocrine neoplasia type 1 insulinoma, although there are conditions for which a different operative approach might be preferable. In this article, we report the operative experience of a referral center for multiple endocrine neoplasia type 1 insulinoma. Methods Twelve patients underwent operations between 1992 and 2015: 8 underwent a distal pancreatic resection, and 4 underwent a pancreatoduodenectomy. Enucleation of other macroadenomas present in the remnant pancreas was performed in 9 out of these 12 patients. Results Operative complications (2 pancreatic fistulas and 2 cases of pancreatitis) occurred in 4 of the 8 distal pancreatic resections. In 1 patient, reoperation was required to resolve the complications of the first operation. At pathologic analysis, multiple insulinomas were found in 5 patients, lymph-nodal metastasis positive for insulin in 2 patients, multiple nonfunctioning pancreatic tumors in all patients, glucagonoma in 4 patients, and gastrinoma in the duodenum or lymph nodes in 4 patients. All the patients were treated successfully for the hypoglycemic/hyperinsulinemic syndrome with no clinical recurrence at a mean follow-up of 85 months (range 4–242 months). Recurrent nonfunctioning pancreatic tumor macroadenomas in the remnant pancreas occurred in only 1 of the 12 patients, and no progression of the gastrinomas was observed. None of the patients developed diabetes mellitus. Conclusion Resection of the most severely affected part of the pancreas, whether left or right, associated with enucleation of concomitant macroadenomas in the preserved pancreas is recommended for the treatment of hypoglycemic/hyperinsulinemic syndrome and to prevent malignant progression of nonfunctioning pancreatic tumors in patients with multiple endocrine neoplasia type 1. If the head of the pancreas is the most affected site and the Zollinger-Ellison syndrome is concomitant, then pancreatoduodenectomy should be preferred over distal pancreatectomy.

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are the second most common tumors in multiple endocrine neoplasia type 1 (MEN1), mainly occurring in pancreatic islets and duodenum, usually as multiple tumors. They can manifest as both nonfunctioning and functioning tumors. Currently, surgical removal of GEP-NETs in MEN1 represents the gold standard curative approach. Conventional medical therapies for sporadic GEP-NETs showed to be effective also in a percentage of MEN1 patients. Innovative medical therapies, that have demonstrated to be effective on sporadic GEP-NETs, still need to be evaluated on MEN1 patients in prospective clinical trials and long-term follow-up. This review resumes current knowledge of MEN1 GEP-NETs, discussing surgical and medical approaches, genetic and molecular bases of tumorigenesis, and presenting novel possible drug therapies.

Leonardo da Vinci's analysis and artistic representation of the hepatic vascular anatomy, performed more than 500 years ago, has not yet been fully recognized nor appreciated. Leonardo modified the anatomic concepts of Galen, up until then in vogue, and described for the first time the intrahepatic distribution of the proper hepatic artery, the portal vein, and the hepatic veins. The depiction of these structures is surprising for its clarity and perspective and reproduces the anatomic situation almost exactly. The segmentary division of the liver which several centuries later became the basis of modern resection hepatic surgery was extremely clear in Leonardo's mind.

Approximately 300 cases of sporadic parathyroid cyst (PCs) have been reported to date. Only two cases have been described in MEN1 so far. Detection by imaging could be challenging, especially in multiglandular primary hyperparathyroidism (HPT) and clinical outcome could be different. During the period 1990-2014, 71 MEN1 patients were operated for primary hyperparathyroidism in our centre. We report three cases of PCs in MEN1 patients affected by HPT, who underwent a total or subtotal parathyroidectomy with transcervical thymectomy. In our series, all three patients had an unsatisfactory postoperative course, at variance with the high percentage (over 90 %) of long-term success in MEN1 patients operated at our centre. One patient affected by cystic degeneration of all the four parathyroid glands reported persistent hypoparathyroidism, despite autografts of parathyroid tissue. For the other two cases, surgery failed to cure hyperparathyroidism, perhaps because of the presence of undetected ectopic parathyroid tissue. In the context of a multiglandular disease such as MEN1 syndrome, PCs seem rare but our experience shows about a 4 % incidence. Furthermore their presence, even in expert hands, could affect the preoperative identification of the parathyroid glands due to the difficult differential diagnosis between PC and other cystic lesions of the neck, and intraoperative detection of the glands as well as the postoperative outcome.

Background: DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study. Methods: Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up. Results: DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-? and apoptosis signaling, were found to be most significantly affected. Conclusions: Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.

Background No previous study describes the postoperative outcome and functional results after ileal pouch-anal anastomosis (IPAA), performed in ulcerative colitis by the same surgical team with the different anastomotic techniques adopted in a 27-year period. Methods Prospectively, consecutive 333 ulcerative colitis patients operated adopting different IPAA techniques during the open surgery period 1984-2011 were enrolled. IPAA was performed using single stapling (SS) technique in 38 patients, double stapling (DS) technique in 235 patients (TIA stapler 42 patients, Endo-GIA 131 patients, Contour 62 patients) and handsewn IPAA in 60 patients. Results Statistically different early and late complications were recorded among the different IPAA techniques. A lower frequency of daily and nocturnal defecations and a higher level of continence were observed in the DS-IPAA compared to handsewn IPAA. The distance between the anastomotic line and the anal verge was significantly lower in DS Endo-GIA or DS Contour groups than in the DS TIA and SS. In SS IPAA group, 31.6% developed cuffitis compared to 14.4% belonging to DS group, at a mean follow-up of 140.4 months. Conclusions Technical improvements changed the IPAA technique. Stapled IPAA is characterized by better functional outcome than handsewn IPAA. DS Endo-GIA and Contour IPAA are followed by lower risk of cuffitis.

Estrogens behave as protective agents on the development of colorectal cancer, and hormonal-replacement therapy is associated with an increased survival rate in women with this disease, indicating that estrogenic therapy correlates with a better prognosis. The protective effect of estrogens on Fcolorectal cancer development and progression is presumably related to the expression of estrogen receptors in colon mucosa, with the estrogen receptor-β isoform being the predominant one. This observation suggests that estrogen receptor-β could have an inhibitory effect on colorectal cancer cell proliferation and a regulatory effect on colonic mucosa cell growth, opening the discussion on a pharmacologic approach to colorectal cancer prevention and therapy based on estrogenic compounds.

The original version of this article unfortunately contained a mistake in Table 2. The table 2 was truncated in the original publication. The full table 2 is given below.

Background: The choice of surgical treatment for patients with Multiple Endocrine Neoplasia type 1 (MEN1)-related primary hyperparathyroidism (PHPT) remains controversial and it has not been specifically addressed in young patients. Methods: This is a retrospective case series study. The study includes the surgical data and the follow-up of 38 patients younger than 30 years of age, all diagnosed with MEN1, collected and followed-up between 1991 and 2017 at the Regional Referral Center for Inherited Endocrine Tumors of the Tuscany Region, and operated by parathyroidectomy. Genetic and/or clinical MEN1 diagnosis was made before surgery in all patients. Subtotal (9/38 patients) or total parathyroidectomy with auto-transplantation (28/38 patients) were performed in all patients but one, in whom a single mediastinal adenoma was excised from the aorto-pulmonary window. All patients but one, who was operated in 2017, had a post-operatory follow-up of at least 12 months. Results: Total parathyroidectomy (TPTX), with auto-transplantation, was the most frequently adopted operation both as primary (20/38 patients) and secondary (8/38 patients) surgery, followed by subtotal parathyroidectomy (SPTX; 9/38 patients) and limited parathyroidectomy (1/38 patient). At follow-up, lasting a mean of 11.8 ± 6.6 years (range 0-23 years), no persistent PHPT was observed. PHPT recurred in 4/28 TPTX (14%) and in 2/9 SPTX (22%). Permanent hypoparathyroidism showed no statistically significant difference between the procedures (2/9 in SPTX and 5/28 in TPTX). Conclusions: Data from this retrospective study showed the efficacy of TPTX for the treatment of MEN1-PHPT, also in adolescent and young patients, showing, in our series, no risk of PHPT permanence and a longer disease-free period and, subsequently, the possibility to postpone re-intervention with respect to both limited PTX and SPTX. The risk of permanent hypoparathyroidism in TPTX was comparable to STPX, and could be mitigated over the years.

Background To assess outcomes of patients operated on for rectal cancer (RC) by analysing the trends of disease free survival curves (DFSc) after a very long-term follow-up. Methods All patients treated with curative intent for RC from 1986 to 2005 were retrospectively analyzed. Other than demographics, disease characteristics and treatment-related factors were considered. The DFSc were compared between patients who had neoadjuvant therapy (NAT) and those who had surgery alone. Results Median age of 319 patients included in the study was 66.3 years (range 23-89) and 140 (57.6%) of them were males. Moreover, NAT was given in 24 (11.8%) patients, and adjuvant therapy in 40 (19.7%) patients. Median follow-up was of 150 months (60-240). In patients who had NAT the mean age was higher (P=0.05), RC were located lower (P=0.009) and higher positive lymph-nodes were found (P=0.003), whereas the number of both local (P=0.4) and distant recurrences (P=0.7) was not significantly lower, compared to the other group. Comparing trends of DFSc a more progressive decrease was shown in patients treated with surgery alone. Even if the differences of DSFc between groups at the end of follow-up were not significant (95% CI: 0.609-2.963, P=0.46), patients who had NAT displayed better survival up to 180 months. Conclusions Overall, these results showed comparable outcomes between both groups over such a long lasting follow-up. This time frame might be used more extensively for increasing our knowledge of RC biological behaviour as well.

Primary hyperparathyroidism (HPT) is the most common endocrinopathy in Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. Supernumerary and/or ectopic parathyroid glands, potentially causes of persistent or recurrent HPT after surgery, have been previously described. However, this is the first ever described case of ectopic parathyroid gland localized in the aortopulmunary window causing HPT in MEN1. After a consistent concordant pre-operative imaging assessment the patient, a 16 years old male affected by a severe hypercalcemia, underwent surgery. The parathyroid was found very deeply near the tracheal bifurcation, hidden by the aortic arch itself and for this reason not visible at the beginning of the dissection but only after being identified by palpation for its typical consistence. The intraoperative PTH decreased at normal level 10 min after removal of the ectopic gland. The patient remained with normal value of calcemia and PTH during the 10 months of follow-up.

In multiple endocrine neoplasia syndrome type 2A (MEN 2A), early total thyroidectomy (TT; performed before the age of 5 years) is the best option to prevent medullary thyroid carcinoma (MTC) development, but the management of MEN 2A patients diagnosed after childhood is still under debate. Seventeen consecutive patients diagnosed with MEN 2A after the age of 5 years (mean age, 23.3 years) with a pathologic diagnosis of micro-MTC without nodal involvement were enrolled. All patients underwent TT with thymectomy and central compartment lymph node dissection. During surgery, parathyroid tissue removal occurred in 14 patients. No major postoperative complications nor persistent hypoparathyroidism was observed. After a mean follow-up of 16.6 years, no patient developed primary hyperparathyroidism or disease recurrence. Even if TT is recommended before the age of 5, when MEN 2A diagnosis is performed after this age in micro-MTC without nodal involvement, TT with thymectomy and central compartment lymphadenectomy can provide good oncologic and functional results.