Association between Ustekinumab Trough Levels, Serum IL-22, and Oncostatin M Levels and Clinical and Biochemical Outcomes in Patients with Crohn's Disease.

Background: Ustekinumab (UST) has demonstrated effectiveness in treating patients with Crohn's disease. Monitoring treatment response can improve disease management and reduce healthcare costs. We investigated whether UST trough levels (TLs), serum IL22, and Oncostatin M (OSM) levels could be early indicators of non-response by analysing their correlation with clinical and biochemical outcomes in CD. Methods: Patients with CD initiating UST treatment from October 2018 to September 2020 were enrolled at six Italian centres for inflammatory bowel disease (IBD). Clinical and biochemical data were collected at four time points: baseline, second subcutaneous (SC) dose, fourth SC dose, and 52 weeks. TLs were measured during maintenance, at the second SC dose, and at the fourth SC dose. IL-22 and OSM serum levels were assessed at baseline and the second SC dose. We analysed whether TLs, IL22 levels, and OSM serum levels were associated with clinical response, clinical remission, biochemical remission, and endoscopic remission using the appropriate statistical tests. Results: Out of eighty-four initially enrolled patients, five were lost to follow-up, and eleven discontinued the drug before 52 weeks. At the 52-week time point, 47% achieved biochemical remission based on faecal calprotectin levels, and 61.8% achieved clinical remission. TLs at the second SC dose significantly correlated with biochemical remission at the same time point (p = 0.011). However, TLs did not correlate with clinical remission. Baseline OSM levels did not correlate with biochemical or clinical remission or response. IL22 levels notably decreased during UST therapy (p = 0.000), but its values did not correlate with biochemical or clinical remission. Conclusions: UST is an effective therapy for patients with CD. TLs measured at the second SC dose significantly correlated with biochemical remission, emphasising their potential role in treatment monitoring. Levels of OSM and IL-22, despite a significant decrease in the latter during therapy, did not exhibit correlations with clinical or biochemical outcomes in our study. Further studies are needed to confirm these findings.

Rectal sparing approach after preoperative radio - and/or Chemo-therapy (ReSARCh): a prospective, multicentre, observational study.

BACKGROUND: Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer, however their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes. METHODS: This prospective, multicentre, observational study investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal local excision or watch-and-wait approach, based on tumor response (major or complete) and patient/surgeon choice. The primary endpoint of the study was rectum preservation at a minimum follow-up of two years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at three years. RESULTS: Of 178 patients enrolled in 16 centres, 112 (62.9%) were managed with local excision and 66 (37.1%) with watch-and-wait. At a median (interquartile range) follow-up of 36.1 (30.6-45.6) months, the rectum was preserved in 144 (80.9%) patients. The 3-year rectum-sparing, overall, disease-free, local recurrence-free, distant recurrence-free survival was 80.6% (95%CI 73.9-85.8), 97.6% (95%CI 93.6-99.1), 90.0% (95%CI 84.3-93.7), 94.7% (95%CI 90.1-97.2), and 94.6% (95%CI 89.9-97.2), respectively. The 3-year stoma-free survival was 95.0% (95%CI 89.5-97.6). The 3-year regrowth-free survival in the watch-and-wait group was 71.8% (95%CI 59.9-81.2). CONCLUSIONS: In rectal cancer patients with major or complete clinical response after neoadjuvant therapy, the rectum can be preserved in about 80% of cases, without compromise the outcomes.

Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study.

BACKGROUND: Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown. OBJECTIVE: The study aims to analyze the innate immunity microenvironment in ileal mucosa according to the duration of Crohn's disease. DESIGN: A prospective cohort study. SETTINGS: Tertiary referral center for IBD surgery. PATIENTS: A total of 88 consecutive patients with Crohn's disease undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public data set were analyzed as an external validation cohort. MAIN OUTCOME MEASURES: Neutrophil infiltration was evaluated by histological asessment and macrophage subpopulation was assessed by immunohistochemistry. Expressions of TLR2 , TLR4 , TLR5 , DEFB1 , DEFB4A , DEFB103 , DEFA5 , and DEFA6 were quantified by real-time quantitative polymerase chain reaction. Concentrations of BDNF, CCL-11, ICAM-1, IL-1A, IL-1ß, IL-1RN, IL-12p40, IL-12p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, and VEGFA were determined with an immunometric assay. RESULTS: Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease ( p = 0.07). A higher number of macrophages expressed CD163 at low intensity in late-stage Crohn's disease ( p = 0.04). The concentration of IL-15 ( p = 0.02) and IL-23A ( p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expressions of DEFB1 ( p = 0.03), DEFB4A ( p = 0.01), IL-2 ( p = 0.04), and IL-3 ( p = 0.03) increased in patients with late-stage Crohn's disease. LIMITATIONS: A relatively small number of patients, especially in the newly diagnosed group. CONCLUSIONS: In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in the healthy mucosa of patients with late-stage Crohn's disease, suggesting that reparative and profibrotic processes are predominant in the long term, and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract . ACTIVACIN DE LA INMUNIDAD INNATA EN LA RECIENTEMENTE DIAGNOSTICADA ENFERMEDAD DE CROHN ILEOCLICA UN ESTUDIO DE COHORTE: ANTECEDENTES:Estudios recientes demostraron que la cirugía temprana para la enfermedad de Crohn (EC) conduce a una menor tasa de recurrencia. Sin embargo, se desconoce el mecanismo subyacente.OBJETIVO:El estudio tiene como objetivo analizar el microambiente de la inmunidad innata en la mucosa ileal según la duración de la EC.DISEÑO:Un estudio de cohorte prospectivo.AJUSTES:Centro terciario de referencia para cirugía de EII.PACIENTES:Fueron registrados de manera prospectiva y consecutiva 88 pacientes con EC sometidos a resección ileocolónica. Se obtuvieron muestras de mucosa ileal, tanto del íleon sano como del íleon inflamado. Los datos se analizaron como una cohorte de validación externa.PRINCIPALES MEDIDAS DE RESULTADO:Fueron evaluados la infiltración de neutrófilos por histología y la subpoblación de macrófagos por inmunohistoquímica. La expresión de TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 y DEFA6 fueron cuantificados mediante qPCR en tiempo real. Las concentraciones de BDNF, CCL-11, ICAM-1, IL-1A, IL-1B, IL-1RN, IL-12 p40, IL-12 p70, IL-15, IL-17A, IL-23A, MMP-3, CCL-3, KITLG, VEGFA se determinaron con ensayo inmunométrico.RESULTADOS:La infiltración de neutrófilos se correlaciona inversamente con la duración de la enfermedad. La expresión del ARNm de DEFB4A mostro una tendencia a ser mayor en la EC en etapa tardía ( p = 0,07). Un mayor número de macrófagos expresaron CD163 a baja intensidad en la etapa tardía ( p = 0,04). La concentración de IL15 ( p = 0,02) e IL23A ( p = 0,05) fue mayor en la mucosa ileal sana de pacientes en estadio temprano. En la cohorte externa, la expresión de DEFB1 ( p = 0,03) y DEFB4A ( p = 0,01), IL2 ( p = 0,04) e IL3 ( p = 0,03) aumentó en pacientes en etapa tardía.LIMITACIONES:Un número relativamente pequeño de pacientes, especialmente en el grupo recién diagnosticado.CONCLUSIONES:En la EC recién diagnosticada, los altos niveles de IL-15 e IL-23 en la mucosa sana sugieren que la inmunidad innata es el promotor de la inflamación aguda. Además, los macrófagos M2 aumentan en la mucosa sana de pacientes con EC en etapa tardía, lo que sugiere que los procesos reparadores y profibróticos son predominantes a largo plazo y en esta fase, la terapia antiinflamatoria puede ser menos eficiente. (Traducción-Dr. Osvaldo Gauto ).

Multiple colorectal adenomas syndrome: The role of MUTYH mutation and the polyps' number in clinical management and colorectal cancer risk.

BACKGROUND & AIMS: Multiple colorectal adenomas (MCRAs) can result from APC (AFAP) or biallelic MUTYH (MAP) mutations, but most patients are wild type and referred to as non-APC/MUTYH polyposis (NAMP). We aim to examine the risk of colorectal cancer (CRC) and the role of endoscopy in managing patients with MCRAs, with a specific focus on clinical features and genotype. METHODS: Records of MRCAs between 2000 and 2022 were retrospectively analysed. Patients were divided according to the genotype (MAP vs. NAMP) and the number of categorised polyps' burden (group 1: 10-24, group 2: 25-49, and group 3: 50-99 adenomas). Predictors of outcome were CRC-free survival (CRC-FS) and Surgery free-survival (S-FS). RESULTS: 220 patients were enrolled (NAMP n = 178(80.0%)). CRC at diagnosis was more frequent in group 3 (p = 0.01), without significant differences between the genotypes (p = 0.20). At a follow-up of 83(41-164) months, 15(7%) patients developed CRC during surveillance. CRC-FS was not correlated to genotype (p = 0.07) or polyps' number (p = 0.33), while S-FS was similar in MAP and NAMP (p = 0.22) and lower in groups 2 and 3 (p = 0.0001). CONCLUSIONS: MAP and NAMP have the same CRC risk and no difference in treatment. Endoscopic surveillance compared favorably with surgery in avoiding CRC risk, even in patients with more severe colorectal polyposis.

Leaving behind a diseased small bowel during surgery for Crohn's disease: Long-term outcomes.

PURPOSES: Stricture is a common complication of Crohn's disease (CD) and may be treated with bowel-sparing procedures. Our study analyzed what happens in terms of intestinal and systemic inflammation when the diseased bowel is left behind following surgery. METHODS: In this retrospective study, we enrolled 42 consecutive patients who underwent strictureplasty (alone or with resection) for stricturing CD. Control patients who underwent complete diseased bowel resection were identified and propensity score-matched for the sex, age, and history of abdominal surgery. Biohumoral values were collected at follow-up examinations at 1, 6, and 12 months after surgery. Magnetic resonance imaging (MRI) was performed before and after strictureplasty in 19 patients. RESULTS: In the strictureplasty group, fecal calprotectin levels were decreased at 12 months (p = 0.03), whereas in the resectiongroup, they were decreased at 6 months (p = 0.02). On MRI, the ADC [apparent diffusion coefficient] (p < 0.001), wall thickness (p = 0.046) and Magnetic Resonance Index of Activity (MaRIA) (p < 0.001) and Clermont (p < 0.001) scores were improved after strictureplasty. Surgical recurrence was more frequent in the strictureplasty group than in the resection group (p = 0.003). CONCLUSIONS: Our retrospective study showed that even if the diseased bowel was left behind after surgery, the intestinal inflammatory activity still decreased. However, the permanence of the diseased bowel still increased the risk of reoperation, probably because of the fibrotic nature of the stenosis and the multifocality of CD.

IMMUNOREACT 0: Biopsy-based immune biomarkers as predictors of response to neoadjuvant therapy for rectal cancer-A systematic review and meta-analysis.

BACKGROUND: The main therapy for rectal cancer patients is neoadjuvant therapy (NT) followed by surgery. Immune biomarkers are emerging as potential predictors of the response to NT. We performed a meta-analysis to estimate their predictive significance. METHODS: A systematic literature search of PubMed, Ovid MEDLINE and EMBASE databases was performed to identify eligible studies. Studies on patients with rectal cancer undergoing NT in which the predictive significance of at least one of the immunological markers of interest was assessed by immunohistochemistry (IHC) in pretreatment biopsies were included. RESULTS: Seventeen studies reporting sufficient data met the inclusion criteria for meta-analysis. High levels of total CD3+, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs), as well as stromal and intraepithelial CD8+ compartments, significantly predicted good pathological response to NT. Moreover, high levels of total (tumoral and immune cell expression) PD-L1 resulted associated to a good pathological response. On the contrary, high levels of intraepithelial CD4+ TILs were correlated with poor pathological response. FoxP3+ TILs, tumoral PD-L1 and CTLA-4 were not correlated to the treatment response. CONCLUSION: This meta-analysis indicated that high-density TILs might be predictive biomarkers of pathological response in patients that underwent NT for rectal cancer.

Predictors of urinary tract infection after lower gastrointestinal surgery.

BACKGROUND: Urinary tract infections (UTIs) cause postoperative morbidity in patients undergoing lower gastrointestinal (GI) surgery that can prolong postoperative hospital stays. In patients with a fever of unknown origin (FUO), clinicians ignore what to do while waiting for the results of the urine culture test. This study aimed to develop a nomogram predicting UTI in the case of postoperative FUO. METHODS: This observational, retrospective study included all consecutive patients from 1 November 2020 to 1 November 2021 undergoing lower-GI surgery at the Chirurgia Generale 3, University Hospital of Padua, Italy. A nomogram was created and externally validated in 90 consecutive patients undergoing urine culture tests for FUO at the Chirurgia Oncologica Unit, Veneto Institute of Oncology. RESULTS: In the development cohort, 109 (N = 109) patients performed a urine culture test for FUO, and 39 were diagnosed with UTI. In a multivariate analysis of patients who underwent urine culture tests for FUO, UTI was associated with female sex, older age, and duration of catheterization at the date of the urine culture test. We developed a nomogram to predict UTI in surgical patients with a C-index of 0.76. In the validation cohort, 90 consecutive patients, who had lower-GI surgery, underwent a urine culture test for FUO and were tested with this nomogram. In the validation cohort, the C-index of the nomogram for predicting a positive urine culture test was 0.71. CONCLUSIONS AND RELEVANCE: UTIs are a common problem in patients undergoing lower-GI surgery. A nomogram including the major risk factors may help to reduce the inappropriate use of antibiotics during the period awaiting the result of the urine culture test.

Extraintestinal Cancers in Inflammatory Bowel Disease: A Literature Review.

BACKGROUND: Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis. AIMS: The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs. RESULTS: IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy. CONCLUSIONS: Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.

Collagen VI promotes recovery from colitis by inducing lymphangiogenesis and drainage of inflammatory cells.

Despite a number of studies providing evidence that the extracellular matrix (ECM) is an active player in the pathogenesis of intestinal inflammation, knowledge on the actual contribution of specific ECM molecules in the progression of inflammatory bowel disease (IBD) remains scant. Here, we investigated the role of a major ECM protein, collagen VI (ColVI), in gut homeostasis and elucidated the impact of its deregulation on the pathophysiology of IBD. To this end, we combined in vivo and ex vivo studies on wild type and ColVI-deficient (Col6a1-/- ) mice both under physiological conditions and during experimentally induced acute colitis and its subsequent recovery, by means of gut histology and immunostaining, gene expression, bone marrow transplantation, flow cytometry of immune cell subpopulations, and lymph flow assessment. We found that ColVI displayed dynamic expression and ECM deposition during the acute inflammatory and recovery phases of experimentally induced colitis, whereas the genetic ablation of ColVI in Col6a1 null mice impaired the functionality of lymphatic vessels, which in turn affected the resolution of inflammation during colitis. Based on these findings, we investigated ColVI expression and deposition in ileal specimens from two cohorts of patients affected by Crohn's disease (CD) and correlated ColVI abundance to clinical outcome. Our results show that high ColVI immunoreactivity in ileal biopsies of CD patients at diagnosis correlates with increased risk of surgery and that ColVI expression in biopsies taken at the resection margin during surgery, and showing inactive disease, predict disease recurrence. Our data unveil a key role for ColVI in the intestinal microenvironment, where it is involved in lymphangiogenesis and intestinal inflammation. Altogether, these findings point at the dysregulation of ColVI expression as a novel factor contributing to the onset and maintenance of inflammation in CD via mechanisms impinging on the modulation of inflammatory cell recruitment and function. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Accuracy comparisons of fingerprint based song recognition approaches using very high granularity.

Music and song recognition is an activity of wide interest for researchers and companies due to the intrinsic challenges and the possible economical profits it can give. Despite basic algorithms about song recognition are simple in principle, it is quite difficult to obtain an efficient and robust approach able to generate an effective algorithm for identifying short piece of audio on the fly. In this paper, we compare the results obtained using a new algorithm we recently proposed against several baseline approaches in terms of accuracy when very short pieces of audio are processed. Experimental results, performed using both a subset of the MTG-Jamendo dataset and a proprietary audio corpus containing 7000 songs, show our approach outperform the others in particular for excerpts of audio shorter than 3s.

Role of Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Could It Be Considered a Predictor of Prognosis?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. METHODS: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. RESULTS: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). CONCLUSIONS: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management.

The impact of COVID-19 pandemic on access to medical services and its consequences on emergency surgery.

Background: On March 9, 2020, the Italian Prime Minister announced the lockdown, which was officially closed on May 4. This extraordinary measure was necessary to contain the COVID-19 pandemic spread in Italy. During this phase, a significant decrease in patients' access to Emergency Department (ED) was observed. Delayed access to treatment determined a delay in the diagnosis of acute surgical conditions, as already documented in other clinical areas, with consequences on surgical outcome and survival. Aim of this study is to provide a detailed description of abdominal urgent-emergent conditions surgically treated and surgical outcomes during the lockdown in a tertiary referral Italian hospital, compared with historical data. Methods: A retrospective review of urgent-emergent patients surgically treated in our department was conducted in order to compare patients' characteristics and surgical outcomes during the period March 9th-May 4th, 2020 with the same period of the previous year. Results: 152 patients were included in our study, 79 patients in 2020 group and 77 patients in 2019. We found no significant differences between the groups regarding ASA score, age, gender, and disease prevalence. Significant differences were found in symptom duration before ER access and abdominal pain as the main symptom in non-traumatic conditions. We also performed a sub-analysis on peritonitis which showed significant differences in: hospital length of stay, presence of colostomy vs. ileostomy, and fatal events in 2020. No differences were found in the use of laparoscopy. Conclusions: While the overall number of ER accesses has decreased in 2020 group, the number of patients surgically treated in emergency-urgency conditions has not decreased. However, those patients waited significantly more before the hospital access. This diagnostic delay was associated with a more severe clinical condition and a consequent significantly worse prognosis.

Impact of DNA mismatch repair proteins deficiency on number and ratio of lymph nodal metastases in colorectal adenocarcinoma.

BACKGROUND: Approximately 15 % of colorectal adenocarcinomas (CRCs) are characterized by an altered expression of DNA mismatch repair (MMR) proteins (i.e. MMR deficiency [MMRd]). Lymph node ratio (LNR) represents one of the most important prognostic markers in non-advanced CRCs. No significant data are available regarding LNR distribution depending on MMR status. PURPOSE OF THE STUDY: The aim of the present work was to compare pathological and clinical characteristics of MMRd tumors versus MMR proficient (MMRp) cases. Particular attention was paid to how these molecular sub-groups relate to the LNR. MATERIALS AND METHODS: A mono-Institutional series of 1037 consecutive surgically treated stage I-IV CRCs were retrospectively selected and data were obtained from pathological reports. Cases were characterized for MMR/MSI status by means of immunohistochemistry or for microsatellite instability (MSI) analysis. RESULTS: MMRd/MSI tumors (n = 194; 18.7 %) showed significant differences in comparison to MMRp lesions for sex (female prevalence 50.5 % vs 40.7 %; p = 0.013), age (74.2 vs 69.2; p < 0.001), location (right side; p < 0.001), diameter (larger than MMRp; p < 0.001), growth pattern (expansive pattern of growth; p < 0.001), peri- (p = 0.0002) and intra-neoplastic (p = 0.0018) inflammatory infiltrate, presence of perineural invasion (p < 0.001), stage (lower stage at presentation; p < 0.001), grade (higher prevalence of high-grade tumors; p < 0.001), and LNR (lower; p < 0.001). CONCLUSIONS: MMRd/MSI tumors are a distinct molecular CRC subtype characterized by a significantly lower LNR in comparison to MMRp lesions. These data further support the prognostic impact of MMRd/MSI status in early-stage CRCs.

Treatment and Prognosis of Fibrolamellar Hepatocellular Carcinoma: a Systematic Review of the Recent Literature and Meta-analysis.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare disease and current efforts are focused on the prognosis and on the development of efficient and specific treatments. This study aimed to review the latest evidence regarding FL-HCC treatment and prognosis. METHODS: A systematic review of the literature over the past 10 years regarding FL-HCC, and meta-analysis of 1-, 3-, and 5-year overall survival (OS) comparing FL-HCC and conventional HCC were performed. RESULTS: Overall, 1567 articles were screened, of them 21 were selected for the systematic review, and 6 for meta-analysis. Twenty-one studies included a total of 2168 patients with FL-HCC, with a median age ranging from 11 to 56 years. The majority of patients underwent surgical resection or liver transplantation. After a median follow-up ranging from 24 to 58 months, 1-year OS was 67-100% and 5-year OS was 28-65%. A total of 743 patients with FL-HCC and 163,472 with conventional HCC were included in the meta-analysis. There was a significantly improved 1-, 3-, and 5-years OS in the FL-HCC group compared to the conventional HCC group, although high heterogeneity was found. When excluding population-based studies, and including 96 FL-HCC and 221 conventional HCC patients, the heterogeneity was low, and the meta-analysis showed a significantly longer 1-year OS in patients with FL-HCC than conventional HCC; however, there were no differences at 3- and 5-years OS. CONCLUSIONS: Surgical resection for FL-HCC is currently the only curative treatment available. FL-HCC is plagued by high-recurrence rates and poor long-term outcomes which may be related to the absence of specific treatment for advanced and recurrent disease.

Vedolizumab is superior to infliximab in biologic naïve patients with ulcerative colitis.

There are no prospective, head-to-head, controlled trials comparing the efficacy and safety of Infliximab (IFX) and Vedolizumab (VDZ) for the treatment of moderate-to-severe ulcerative colitis (UC), while only a few real-life retrospective studies have been published so far. We assessed the efficacy of IFX vs. VDZ in two cohorts of biologic-naïve outpatients with moderate-to-severe UC or mild, but refractory, disease. Data were extracted from patients' files and reviewed. The duration of follow-up (FU) was 52 weeks. The primary endpoint was the clinical remission (CR) at the end of FU. Secondary endpoints were: drug persistency, time to obtain CR, clinical response at the end of the induction phase (IP), steroid-free CR (compared to patients who used steroids at baseline) at the end of FU, need for drug optimization, adverse events (AEs), and normalization of C-reactive protein (CRP). We also analyzed the causes of dropping out (primary non-response), or secondary loss of response (immunogenic or not), for each group. We enrolled 82 patients (50 IFX and 32 VDZ) who met the inclusion criteria. At the end of FU, CR was obtained in 32% of the patients on IFX and 75% on VDZ (p = 0.0003). Drug persistency was superior for VDZ compared to IFX (78% vs. 52%, p = 0.033). Clinical response at the end of induction was reached in 54% and in 81% in the IFX and VDZ group, respectively (p = 0.014). Steroid-free clinical remission at the end of FU was 62% and 94% in the IFX vs. VDZ group, respectively (p = 0.036). The need for drug optimization was higher for VDZ than for IFX (28% vs. 57%, p = 0.009), while the time to obtain CR, the incidence of AEs, mean duration of FU, and rate of CRP normalization at the end of IP were comparable between the two groups. There was a prevalence of patients dropping out because of primary non-response in IFX group (p = 0.027), while the incidence of secondary loss of response was similar in the two groups. At the multivariate analysis, CRP and Partial Mayo Score (PMS) at T0 did not correlate with CR at the end of FU in both groups. In this retrospective, real world data study in biologic-naïve patients, VDZ was superior to IFX in CR, clinical response rate at the end of IP, drug persistency, steroid-free remission, and need for optimization at the end of FU.

Rectal Sparing Approaches after Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-Analysis Comparing Local Excision and Watch and Wait.

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

Tumor immune microenvironment in therapy-naive esophageal adenocarcinoma could predict the nodal status.

BACKGROUND: Currently, preoperative staging of esophageal adenocarcinoma (EAC) has modest reliability and accuracy for pT and pN stages prediction, which heavily affects overall survival. The interplay among immune checkpoints, oncogenes, and intratumoral and peritumoral immune infiltrating cells could be used to predict loco-regional metastatic disease in early EAC. METHODS: We prospectively evaluated immune markers expression and oncogenes status as well as intratumoral and peritumoral immune infiltrating cells populations in esophageal mucosa samples obtained from neoadjuvant therapy-naïve patients who had esophagectomy for EAC. RESULTS: Vascular invasion and high infiltration of lamina propria mononuclear cells resulted associated with nodal metastasis. Low infiltration of activated CD8+ CD28+ T cells was observed in both intratumoral and peritumoral mucosa of patients with nodal metastasis. Low levels of CD69, MYD88, and TLR4 transcripts were detected in the intratumoral specimen of patients with lymph node involvement. Receiver operating characteristic curve analysis showed good accuracy for detecting nodal metastasis for all the markers tested. Significant lower infiltration of CD8 T cells and M1 macrophages and a lower expression of CD8A, CD8B, and TBX21 were found also in Esophageal Adenocarcinoma TCGA panCancer Atlas in the normal tissue of patients with nodal metastasis. CONCLUSIONS: Our data suggest that immune surveillance failure is the main driver of nodal metastasis onset. Moreover, nodal metastasis containment also involves the immune microenvironment of the peritumoral healthy tissue.

Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma.

BACKGROUND: Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY: According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES: More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.

Validation of the Padova Prognostic Score for Colitis in Predicting Long-Term Outcome After Restorative Proctocolectomy.

Background: In 10%-20% of cases it is impossible to make a differential diagnosis between ulcerative colitis and Crohn's colitis. A 50% failure rate of J pouch ilea-anal anastomosis is observed in Crohn's colitis. In 2009, we created the Padua Prognostic Score for Colitis (PPSC) to predict the long-term clinical and functional outcome and quality of life of patients undergoing restorative proctocolectomy with J pouch. The aim of the present study is to establish and validate the accuracy of a prognostic score for chronic inflammatory bowel diseases (IBD). Patient population and methods: The PPSC was created in 2009 by integrating clinical and histological information of patients undergoing RPC. It included preoperative perianal abscess or fistula, rectal sparing, terminal ileum involvement, skip lesions and histological diagnosis of indeterminate colitis or Crohn's colitis on the operative specimen. The validity of this score was tested in predicting postoperative abscess or fistula, anal canal disease, pouchitis, pouch failure and new diagnosis of Crohn's disease. Correlation analysis, ROC curve analysis and survival analysis were used to validate the PPSC in a different cohort from the previous one. Results: We retrospectively enrolled in this study 138 consecutive patients undergoing CPR for ulcerative colitis (n = 127) or indeterminate colitis (n = 11) in our institution since 2005 to 2020. In this period, we observed 11 patients with postoperative abscess or fistula, 3 with anal canal disease, 40 with pouchitis, 6 with pouch failure and 6 with new diagnosis of Crohn's disease. In the new validation cohort, the PPSC confirmed to have a good accuracy in predicting the onset of postoperative CD (AUC = 74.5%, p = 0.018). Kaplan Meier curves demonstrate how a PPSC over 1 can reliably predicts the long-term onset of, pouchitis (p = 0.002) and anal abscess or fistulae (p = 0.04). Conclusions: In this validation study we confirmed the accuracy of the PPSC in predicting postoperative fistulas or abscesses and pouchitis. Therefore, we believe that in clinical practice patients with a PPSC score greater than 1 should be warned of this risk of possible Crohn's disease diagnosis and pouch failure.

Chemoradiation vs. local excision in the management of early squamous cell carcinoma of the anus: a systematic review.

PURPOSE: Squamous cell carcinoma of the anus (SCCA) suffers a constant increase each year in the last decades. Recent studies suggested the possibility of local excision (LE) as an option for early-stage SCAC patients. This systematic review aims to summarize the available evidence on the comparison of LE vs. chemoradiotherapy (CRT) in the treatment of early SCCA patients. METHODS: We conducted a literature review including MEDLINE/PubMed, EMBASE, SCOPUS, clinicaltrials.gov, and the Cochrane Database of Systematic Reviews through June 2022. MOOSE guidelines were followed. We used the methodological index for non-randomized studies (MINORS) tool to assess quality. Data on survival and procedure-associated costs were extracted. RESULTS: Four retrospective studies including 3323 patients were included. They were all comparative retrospective cohort studies (three were registry-based studies, either NCDB or SEER) with a MINORS score of 16-19 points. Overall survival (OS) was comparable between LE and CRT patients in three studies, with a 5-year OS of 85.3-100% in LE patients and 85-91.6% in CRT patients. One study investigated cancer-specific survival (CSS) and reported similar 5-year CSS in LE (98%) and CRT patients (96%). One investigated progression-free survival (PFS) and did not report any statistically significant difference in 5-year PFS between LE (91%) and CRT patients (83%). Only one study considered the mean costs associated with the two approaches (29,210 USD with LE and 46,350 USD with CRT). CONCLUSIONS: LE may potentially be considered a valid alternative to CRT for patients with early-stage SCAA. Results of prospective randomized long-term trials comparing LE with CRT are warranted to draw definitive conclusions and consider LE as a true cost-effective strategy for T1N0 SCCA with similar oncologic results offered by CRT, which-to date-remains the "gold standard." PROSPERO REGISTRATION: CRD42022338750.