Cellular and Molecular Determinants of Biologic Drugs Resistance and Therapeutic Failure in Inflammatory Bowel Disease.

The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4ß7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities.

Whole liver transplantation in children under 10 kg: How to minimize the high risks of a still challenging procedure.

BACKGROUND: Whole liver transplantation in infants <10 kg is a rare procedure with moderate outcomes (67%-79% graft survival at 1 year) and high rates of vascular complications (hepatic artery thrombosis 5-26%). METHODS: Retrospective single-center analysis of whole liver transplantation in infants <10 kg and systematic review of the literature focused on survival rates and surgical complications. RESULTS: Between January 2005 and December 2020, 175 liver transplantations in 173 children were performed at our center. A total of 92 (53%) children weighed less than 10 kg; 19 (21%) of them underwent WLT and constitute the study population. Median age of the recipients was 10 months (21 days-24 months) and median body weight 6.5 (3.1-9.8) kg. Median age of the donors was 5 (1-84) months and median body weight 6.1 (4-21) kg. Median donor-to-recipient body weight ratio was 1.2 (range: 0.6-4.5). Postoperatively, neither hepatic artery nor portal vein thrombosis occurred. A biliary complication occurred in 4 cases: 1 bile leak (early), 3 anastomotic stenoses (1 delayed and 2 late), and 1 non-anastomotic stenosis (late). Patient survival rate at 1, 5, and 10 years was 100%, 92%, and 92%, respectively. Overall, death-censored graft survival after 1, 5, and 10 was 100%. CONCLUSION: Our results are excellent in terms of complications and graft and patient survival. This involves not only high-end surgical performance but also close interdisciplinary perioperative cooperation based on strong standard operating procedures and mainly focused on fluid management, hemostasiology, and strict monitoring of vessel patency.

MicroRNAs as Innovative Biomarkers for Inflammatory Bowel Disease and Prediction of Colorectal Cancer.

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn's disease (CD). These are autoimmune diseases of the gastrointestinal tract with a chronic relapsing and remitting course. Due to complex interactions between multiple factors in the etiology of IBD, the discovery of new predictors of disease course and response to therapy, and the development of effective therapies is a significant challenge. The dysregulation of microRNAs (miRNAs), a class of conserved endogenous, small non-coding RNA molecules with a length of 18-25 nucleotides, that regulate gene expression by an RNA interference process, is implicated in the complex pathogenetic context of IBD. Both tissue-derived, circulating, and fecal microRNAs have been explored as promising biomarkers in the diagnosis and the prognosis of disease severity of IBD. In this review, we summarize the expressed miRNA profile in blood, mucosal tissue, and stool and highlight the role of miRNAs as biomarkers with potential diagnostic and therapeutic applications in ulcerative colitis and Crohn's disease. Moreover, we discuss the new perspectives in developing a new screening model for the detection of colorectal cancer (CRC) based on fecal miRNAs.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

ALPPS for Locally Advanced Intrahepatic Cholangiocarcinoma: Did Aggressive Surgery Lead to the Oncological Benefit? An International Multi-center Study.

BACKGROUND: ALPPS is found to increase the resectability of primary and secondary liver malignancy at the advanced stage. The aim of the study was to verify the surgical and oncological outcome of ALPPS for intrahepatic cholangiocarcinoma (ICC). METHODS: The study cohort was based on the ALPPS registry with patients from 31 international centers between August 2009 and January 2018. Propensity score matched patients receiving chemotherapy only were selected from the SEER database as controls for the survival analysis. RESULTS: One hundred and two patients undergoing ALPPS were recruited, 99 completed the second stage with median inter-stage duration of 11 days. The median kinetic growth rate was 23 ml/day. R0 resection was achieved in 87 (85%). Initially high rates of morbidity and mortality decreased steadily to a 29% severe complication rate and 7% 90-day morbidity in the last 2 years. Post-hepatectomy liver failure remained the main cause of 90-day mortality. Multivariate analysis revealed insufficient future liver remnant at the stage-2 operation (FLR2) to be the only risk factor for severe complications (OR 2.91, p = 0.02). The propensity score matching analysis showed a superior overall survival in the ALPPS group compared to palliative chemotherapy (median overall survival: 26.4 months vs 14 months; 1-, 2-, and 3-year survival rates: 82.4%, 70.5% and 39.6% vs 51.2%, 21.4% and 11.3%, respectively, p < 0.01). The survival benefit, however, was not confirmed in the subgroup analysis for patients with insufficient FLR2 or multifocal ICC. CONCLUSION: ALPPS showed high efficacy in achieving R0 resections in locally advanced ICC. To get the most oncological benefit from this aggressive surgery, ALPPS would be restricted to patients with single lesions and sufficient FLR2.

Paradigm Shift in the Management of Irresectable Colorectal Liver Metastases: Living Donor Auxiliary Partial Orthotopic Liver Transplantation in Combination With Two-stage Hepatectomy (LD-RAPID).

OBJECTIVE: to report the first case of resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (RAPID) from living donor in a patient affected of irresectable colorectal liver metastases (i-CRLM) BACKGROUND:: A renaissance of liver transplantation (LT) for i-CRLM has been recently observed. The Norwegian SECA trial demonstrated a 5-year overall survival rate of approximately 60%, notwithstanding early tumor recurrence. The RAPID technique was recently introduced as alternative to whole deceased donor LT, but it is limited by poor availability of splittable organs and many organisational aspects. In this context left lateral living donor LT may be the ideal solution. METHODS: Report about the technique and results of living donor RAPID procedure. TECHNIQUE: A 49 years old woman affected with i-CRLM from adenocarcinoma of right colon, underwent a left hepatectomy with ligation of right portal vein maintaining the right hepatic artery patent. Subsequently, the left lateral lobe from her son was implanted as auxiliary partial orthotopic LT. Two weeks later completion of hepatectomy was performed. RESULTS: The donor postoperative course was uneventful. The recipient developed postoperatively a slight small for size syndrome which spontaneously resolved. No graft dysfunction and no rejection were observed. At POM 5 micrometastases occurred in bones and lungs, which were treated with radiotherapy and chemotherapy, respectively. Almost 2 years later the patient is alive, in good general condition, although slight progression of bone and lung metastases. CONCLUSIONS: LT poses a valid treatment option for i-CRLM. In times of organ paucity, "living donor-RAPID" procedure may represent a paradigm shift in the management of i-CRLM.

Auxiliary living donor liver transplantation combined with two-stage hepatectomy for unresectable colorectal liver metastases.

PURPOSE OF REVIEW: To review the role of liver transplantation for unresectable colorectal liver metastases (u-CRLM) and to describe the intial experience with auxiliary living donor liver transplantation combined with two-stage hepatectomy for u-CRLM (i.e. living donor RAPID). RECENT FINDINGS: Patients affected with u-CRLM have a poor prognosis with 5 years overall survival (OS) rate less than 10% under standard modern chemotherapy.There is an actual international consensus that liver transplantation for u-CRLM represents a viable option in highly selected patients with OS rate at 5 years up to 80% notwithstanding high recurrence rates. Due to the scarcity of whole liver graft from deceased donors, the RAPID procedure (i.e. resection and partial liver segment 2-3 transplantation from deceased donors with delayed total hepatectomy) has been introduced as possible alternative. The RAPID procedure represents the most actual and modern fusion of the two most challenging procedures of modern hepatobiliary and liver transplant surgery: that is auxiliary partial orthotopic liver transplantation and associating liver partition and portal vein ligation for staged hepatectomy. Although the deceased donor-RAPID procedure may show promising results, the basic problem of scarcity of organs from deceased donors and mainly the lack of splittable organs still remains. SUMMARY: The living donor RAPID, based on transplantation of left lateral segments from living donor, may represent the way out to this problem. It is feasible and safe (for both donor and recipient), but characterized by a very challenging high-end transplantological procedure.

Performance validation of the ALPPS risk model.

BACKGROUND: Based on the International ALPPS registry, we have recently proposed two easily applicable risk models (pre-stage1 and 2) for predicting 90-day mortality in ALPPS but a validation of both models has not been performed yet. METHODS: The validation cohort (VC) was composed of subsequent cases of the ALPPS registry and cases of centers outside the ALPPS registry. RESULTS: The VC was composed of a total of 258 patients including 70 patients outside the ALPPS registry with 32 cases of early mortalities (12%). Development cohort (DC) and VC were comparable in terms of patient and surgery characteristics. The VC validated both models with an acceptable prediction for the pre-stage 1 (c-statistic 0.64, P = 0.009 vs. 0.77, P < 0.001) and a good prediction for the pre-stage 2 model (c-statistic 0.77, P < 0.001 vs. 0.85, P < 0.001) as compared to the DC. Overall model performance measured by Brier score was comparable between VC and DC for the pre-stage 1 (0.089 vs. 0.081) and pre-stage 2 model (0.079 vs. 0087). CONCLUSION: The ALPPS risk score is a fully validated model to estimate the individual risk of patients undergoing ALPPS and to assist clinical decision making to avoid procedure-related early mortality after ALPPS.

Risk Adjustment in ALPPS Is Associated With a Dramatic Decrease in Early Mortality and Morbidity.

OBJECTIVE: To longitudinally assess whether risk adjustment in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) occurred over time and is associated with postoperative outcome. BACKGROUND: ALPPS is a novel 2-stage hepatectomy enabling resection of extensive hepatic tumors. ALPPS has been criticized for its high mortality, which is reported beyond accepted standards in liver surgery. Therefore, adjustments in patient selection and technique have been performed but have not yet been studied over time in relation to outcome. METHODS: ALPPS centers of the International ALPPS Registry having performed ≥10 cases over a period of ≥3 years were assessed for 90-day mortality and major interstage complications (≥3b) of the longitudinal study period from 2009 to 2015. The predicted prestage 1 and 2 mortality risks were calculated for each patient. In addition, questionnaires were sent to all centers exploring center-specific risk adjustment strategies. RESULTS: Among 437 patients from 16 centers, a shift in indications toward colorectal liver metastases from 53% to 77% and a reverse trend in biliary tumors from 24% to 9% were observed. Over time, 90-day mortality decreased from initially 17% to 4% in 2015 (P = 0.002). Similarly, major interstage complications decreased from 10% to 3% (P = 0.011). The reduction of 90-day mortality was independently associated with a risk adjustment in patient selection (P < 0.001; OR: 1.62; 95% CI: 1.36-1.93) and using less invasive techniques in stage-1 surgery (P = 0.019; OR: 0.39; 95% CI: 0.18-0.86). A survey indicated risk adjustment of patient selection in all centers and ALPPS technique in the majority (80%) of centers. CONCLUSIONS: Risk adjustment of patient selection and technique in ALPPS resulted in a continuous drop of early mortality and major postoperative morbidity, which has meanwhile reached standard outcome measures accepted for major liver surgery.

The ALPPS Risk Score: Avoiding Futile Use of ALPPS.

OBJECTIVES: To create a prediction model identifying futile outcome in ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) before stage 1 and stage 2 surgery. BACKGROUND: ALPPS is a 2-stage hepatectomy, which incorporates parenchymal transection at stage 1 enabling resection of extensive liver tumors. One of the major criticisms of ALPPS is the associated high mortality rate up to 20%. METHODS: Using the International ALPPS Registry, a risk analysis for futile outcome (defined as 90-day or in-hospital mortality) was performed. Futility was modeled using multivariate regression analysis and a futility risk score formula was computed on the basis of the relative size of logistic model regression coefficients. RESULTS: Among 528 ALPPS patients from 38 centers, a futile outcome was observed in 47 patients (9%). The pre-stage 1 model included age 67 years or older [odds ratio (OR) = 5.7], and tumor entity (OR = 3.8 for biliary tumors) as independent predictors of futility from multivariate analysis. For the pre-stage 1 model scores of 0, 1, 2, 3, 4 and 5 were associated with futile risk of 2.7%, 4.9%, 8.6%, 15%, 24%, and 37%. The pre-stage 2 model included major complications (grade ≥ 3b) after stage 1 (OR = 3.4), serum bilirubin (OR = 4.4), serum creatinine (OR = 5.4), and cumulative pre-stage 1 risk score (OR = 1.9). The model predicted futility risk of 5%, 10%, 20%, and 50% for patients with scores of 3.9, 4.7, 5.5, and 6.9, respectively. CONCLUSIONS: Both models have an excellent prediction to assess the individual risk of futile outcome after ALPPS surgery and can be used to avoid futile use of ALPPS.

Adverse Food Reactions in Inflammatory Bowel Disease: State of the Art and Future Perspectives.

Limited knowledge is available about the relationship between food allergies or intolerances and inflammatory bowel disease (IBD). Clinicians frequently encounter patients who report food allergies or intolerances, and gastroenterologists struggle distinguishing between patients with organic disorders and those with functional disorders, which the patients themselves may associate with specific dietary components. This task becomes even more arduous when managing patients with significant underlying organic conditions, like IBD. The aim of this review is to summarize and emphasize any actual associations between food allergies and intolerances and inflammatory diseases, such as ulcerative colitis and Crohn's disease. Through a narrative disceptation of the current literature, we highlight the increased prevalence of various food intolerances, including lactose, fructose, histamine, nickel, and non-celiac gluten sensitivity, in individuals with IBD. Additionally, we explore the association between increased epithelial barrier permeability in IBD and the development of food sensitization. By doing so, we aim to enhance clinicians' awareness of the nutritional management of patients with IBD when facing complaints or evidence of food allergies or intolerances.

Endoscopic Management of Strictures in Crohn's Disease: An Unsolved Case.

Crohn's disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs. It is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.

Revival of associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma: An international multicenter study with promising outcomes.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma has been considered to be contraindicated due to the initial poor results. Given the recent reports of improved outcomes, we aimed to collect the recent experiences of different centers performing associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma to analyze factors related to improved outcomes. METHODS: This proof-of-concept study collected contemporary cases of associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma and analyzed for morbidity, short and long-term survival, and factors associated with outcomes. RESULTS: In total, 39 patients from 8 centers underwent associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma from 2010 to 2020. The median preoperative future liver remnant volume was 323 mL (155-460 mL). The median future liver remnant increase was 58.7% (8.9% -264.5%) with a median interstage interval of 13 days (6-60 days). Post-stage 1 and post-stage 2 biliary leaks occurred in 2 (7.7%) and 4 (15%) patients. Six patients (23%) after stage 1 and 6 (23%) after stage 2 experienced grade 3 or higher complications. Two patients (7.7%) died within 90 days after stage 2. The 1-, 3-, and 5-year survival was 92%, 69%, and 55%, respectively. A subgroup analysis revealed poor survival for patients undergoing additional vascular resection and lymph node positivity. Lymph node-negative patients showed excellent survival demonstrated by 1-, 3-, and 5-year survival of 86%, 86%, and 86%. CONCLUSION: This study highlights that the critical attitude toward associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma needs to be revised. In selected patients with perihilar cholangiocarcinoma, associating liver partition and portal vein ligation for staged hepatectomy can achieve favorable survival that compares to the outcome of established surgical treatment strategies reported in benchmark studies for perihilar cholangiocarcinoma including 1-stage hepatectomy and liver transplantation.

Sedation with intranasal midazolam of Angolan children undergoing invasive procedures.

AIM: Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. METHODS: Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). RESULTS: Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). CONCLUSION: These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier.

Development and internal validation of the Comprehensive ALPPS Preoperative Risk Assessment (CAPRA) score: is the patient suitable for Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS)?

Background: Preoperative patient selection in Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is not always reliable with currently available scores, particularly in patients with primary liver tumor. This study aims to (I) to determine whether comorbidities and patients characteristics are a risk factor in ALPPS and (II) to create a score predicting 90-day mortality preoperatively. Methods: Thirteen high-volume centers participated in this retrospective multicentric study. A risk analysis based on patient characteristics, underlying disease and procedure type was performed to identify risk factors and model the Comprehensive ALPPS Preoperative Risk Assessment (CAPRA) score. A nonparametric receiver operating characteristic analysis was performed to estimate the predictive ability of our score against the Charlson Comorbidity Index (CCI), the age-adjusted CCI (aCCI), the ALPPS risk score before Stage 1 (ALPPS-RS1) and Stage 2 (ALPPS-RS2). The model was internally validated applying bootstrapping. Results: A total of 451 patients were included. Mortality was 14.4%. The CAPRA score is calculated based on the following formula: (0.1 × age) - (2 × BSA) + 1 (in the presence of primary liver tumor) + 1 (in the presence of severe cardiovascular disease) + 2 (in the presence of moderate or severe diabetes) + 2 (in the presence of renal disease) + 2 (if classic ALPPS is planned). The predictive ability was 0.837 for the CAPRA score, 0.443 for CCI, 0.519 for aCCI, 0.693 for ALPPS-RS1 and 0.807 for ALPPS-RS2. After 1,000 cycles of bootstrapping the C statistic was 0.793. The accuracy plot revealed a cut-off for optimal prediction of postoperative mortality of 4.70. Conclusions: Comorbidities play an important role in ALPPS and should be carefully considered when planning the procedure. By assessing the patient's preoperative condition in relation to ALPPS, the CAPRA score has a very good ability to predict postoperative mortality.

Resection for Klatskin tumors: technical complexities and results.

Klatskin's tumors, actually-redefined as perihilar cholangiocarcinoma (phCCA) do represent 50-70% of all CCAs and develop in a context of chronic inflammation and cholestasis of bile ducts. Surgical resection provides the only chance of cure for this disease but is technically challenging because of the complex, intimate and variable relationship between biliary and vascular structures at this location. Five years survival rates range between 25-45% (median 27-58 months) in case of R0 resection and 0-23% (median 12-21 months) in case of R1 resection respectively. It should be noted that the major costs of high radicality are represented by relative high morbidity and mortality rates (i.e., 20-66% and 0-9% respectively). Considering the fact that radical resection may represent the only curative treatment of phCCA, we focused our review on surgical planning and techniques that may improve resectability rates and outcomes for locally advanced phCCA. The surgical treatment of phCCA can be successful when following aspects have been fulfilled: (I) accurate preoperative diagnostic aimed to identify the tumor in all its details (localization and extension) and to study all the risk factors influencing a posthepatectomy liver failure (PHLF): i.e., liver volume, liver function, liver quality, haemodynamics and patient characteristics; (II) High end surgical skills taking in consideration the local extension of the tumor and the vascular invasion which usually require an extended hepatic resection and often a vascular resection; (III) adequate postoperative management aimed to avoid major complications (i.e., PHLF and biliary complications). These are technically challenging operations and must be performed in a high volume centres by hepato-biliary-pancreas (HBP)-surgeons with experience in microsurgical vascular techniques.

Living donor liver transplantation in Europe.

Living donor liver transplantation (LDLT) sparked significant interest in Europe when the first reports of its success from USA and Asia were made public. Many transplant programs initiated LDLT and some of them especially in Germany and Belgium became a point of reference for many patients and important contributors to the advancement of the field. After the initial enthusiasm, most of the European programs stopped performing LDLT and today the overall European activity is concentrated in a few centers and the number of living donor liver transplants is only a single digit fraction of the overall number of liver transplants performed. In this paper we analyse the present European activities and highlight the European contribution to the advancement of the field of LDLT.