IMMUNOREACT 7: Regular aspirin use is associated with immune surveillance activation in colorectal cancer.

BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.

IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer.

BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.

IMMUNOREACT 5: female patients with rectal cancer have better immune editing mechanisms than male patients - a cohort study.

BACKGROUND: Studies evaluating sex differences in colorectal cancer (CRC) tumor microenvironment are limited, and no previous study has focused on rectal cancer patients' constitutive immune surveillance mechanisms. The authors aimed to assess gender-related differences in the immune microenvironment of rectal cancer patients. METHODS: A systematic review and meta-analysis were conducted up to 31 May 2021, including studies focusing on gender-related differences in the CRC tumor microenvironment. Data on the mutational profile of rectal cancer were extracted from the Cancer Genome Atlas (TCGA). A subanalysis of the two IMMUNOREACT trials (NCT04915326 and NCT04917263) was performed, aiming to detect gender-related differences in the immune microenvironment of the healthy mucosa in patients with early (IMMUNOREACT 1 cohort) and locally advanced rectal cancer following neoadjuvant therapy (IMMUNOREACT 2 cohort). In the retrospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 442 patients (177 female and 265 male), while in the retrospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), we enrolled 264 patients (80 female and 184 male). In the prospective IMMUNOREACT 1 cohort (therapy naive), the authors enrolled 72 patients (26 female and 46 male), while in the prospective IMMUNOREACT 2 cohort (patients who had neoadjuvant therapy), the authors enrolled 105 patients (42 female and 63 male). RESULTS: Seven studies reported PD-L1 expression in the CRC microenvironment, but no significant difference could be identified between the sexes. In the TGCA series, mutations of SYNE1 and RYR2 were significantly more frequent in male patients with rectal cancer. In the IMMUNOREACT 1 cohort, male patients had a higher expression of epithelial cells expressing HLA class I, while female patients had a higher number of activated CD4+Th1 cells. Female patients in the IMMUNOREACT 2 cohort showed a higher infiltration of epithelial cells expressing CD86 and activated cytotoxic T cells (P=0.01). CONCLUSIONS: Male patients have more frequent oncogene mutations associated with a lower expression of T-cell activation genes. In the healthy mucosa of female patients, more Th1 cells and cytotoxic T cells suggest a potentially better immune response to the tumor. Sex should be considered when defining the treatment strategy for rectal cancer patients or designing prognostic scores.

Pancreaticoduodenectomy for dysplastic duodenal adenoma in a patient with familial adenomatous polyposis.

Colorectal polyposis is the main feature of familial adenomatous polyposis (FAP), but benign and malignant lesions have also been described in the stomach, duodenum, small bowel, biliary tract and pancreas. There are few reports on FAP patients with duodenal polyps that developed at a younger age and even fewer on cases with dysplastic degeneration. The progression to carcinoma usually presents quite late in the clinical history of FAP patients, typically at least 20 to 25 years after proctocolectomy. This report described the rare case of a patient presenting with duodenal adenomas with dysplastic changes and tumor infiltration as the first sign of FAP, who was treated by pancreaticoduodenectomy followed by proctocolectomy for subsequent dysplastic changes in colonic polyps.

Hepatic metastases of colorectal cancer: locoregional intra-arterial treatment.

A radical resection alone of colorectal hepatic metastases is possible in only 10-20% of the patients but, when resection and ablation are combined, the rate of radicalism can improve. A regional hepatic intra-arterial chemotherapy infusion (HAI) has been introduced in the clinical practice, as a possible alternative approach to systemic chemotherapy. Nevertheless, the introduction of new systemic therapies with monoclonal antibodies, combined to irinotecan or oxaliplatin, recently improved response rates and overall survival ia these patients. Aiming to evaluate a possible influence of HAI in these new treatments, the most important studies underlining the evolution of intrahepatic administration in recent years are reviewed.

Arteroportal fistulas between the accessory right hepatic, gastroduodenal and superior mesenteric arteries and portal vein: a difficult technical problem to overcome in liver transplantation.

BACKGROUND: Fistulous communications between the accessory right hepatic (ARHA), gastroduodenal (GD), and superior mesenteric (SMA) arteries and the portal vein (PV) may represent a contraindication for liver transplantation (LT). MATERIAL: A patient with HCV-related liver cirrhosis and progressive liver decompensation underwent preoperative LT work-up. Doppler ultrasound (DU), Angiography and MRI revealed arteroportal fistulas (APF) and diversion of mesenteric-splenoportal flow through spontaneous splenorenal shunts (SSRS) in the systemic circulation. The patient was transplanted and the ARHA and GDA were distally sectioned; the HA was anastomosed to the donor HA; the superior mesenteric vein (SMV) was detached from the splenopancreatic venous bed by sectioning and ligating the Henle trunk, by ligating an posterior-inferior pancreatic vein and, finally, by positioning an iliac vein interposition graft between the SMV and the donor PV. The postanastomotic SMV trunk and recipient PV were ligated below and above the pancreatic head, respectively. RESULTS: Reperfusion and late liver function were good. DU and MRI studies showed an effective portal flow and the maintenance of a normal splenopancreatic vein outflow through the SSRS. DISCUSSION: APF represent a serious clinical problem, particularly in patients who need LT. The persistence of arterial flow into the PV is dangerous for the long-term liver function. A particular surgical strategy, strictly tailored to the hemodynamic conditions, has to be planned. CONCLUSIONS: Extrahepatic multiple APF would no longer to represent a contraindication to LT, although this claim needs to be confirmed in the light of further experience and a longer-term follow-up.

A comparative prospective study of two available solutions for kidney and liver preservation.

BACKGROUND: Viaspan (University of Wisconsin [UW]) solution is the gold standard for abdominal organ preservation. Celsior (CEL) is an extracellular-type, low-potassium, low-viscosity solution, initially used for heart and lung preservation. We have performed a prospective multicenter study to compare the role of these cold-storage solutions on kidney and liver recovery after transplantation. PATIENTS AND METHODS: From March 15, 2000 to December 31, 2001, 441 (172 CEL and 269 UW) renal transplants (RT) and 175 (79 CEL and 96 UW) liver transplants (LT) were included in the study. RESULTS: Perfusate volume used was significantly lower in the UW group, being 4,732 +/- 796 mL versus 5,826 + 834 mL in the CEL group (P < 0.001). In LT, median total bilirubin serum levels were significantly higher at 5 and 7 posttransplant days in the UW group (90.6 and 92.3 micromol/L, respectively) as compared with CEL (51.3 and 63.4 micromol/L, respectively). After LT, primary nonfunction (PNF) rates in the CEL and UW groups were 3.8% and 4.2% (P = NS) respectively, with 1-year graft and patient survival being 83.3% versus 85.4% (P = NS) and 89.9% versus 90.6% (P = NS). After RT, delayed graft function (DGF) rates were 23.2% and 22.7% (P = NS), respectively; PNF rates were 1.9% and 1.7% (P = NS) respectively, with 1-year graft and patient survival being 92.3% versus 94.2% (P = NS) and 99.4% versus 97.7% (P = NS). CONCLUSIONS: CEL solution was shown to be as effective as UW in both liver and kidney preservation. In LT patients, biliary function recovery is significantly better in the CEL group. CEL solution represents an efficacious option in multiorgan harvesting.

Preoperative selective portal vein embolization (PSPVE) before major hepatic resection. Effectiveness of Doppler estimation of hepatic blood flow to predict the hypertrophy rate of non-embolized liver segments.

Hepatocellular carcinoma may be unresectable for volumetric reasons. The future remaining liver after hepatectomy might be too small to ensure survival. Preoperative selective portal vein embolization of the tumorous lobe can induce hypertrophy of the future remaining liver and enable safer surgery. A 76-year-old patient with hepatocellular carcinoma needed right lobectomy however, the future remaining liver was judged insufficient to ensure an uneventful postoperative course. The left lobe to whole liver volumetric ratio was to small (29.7%) and a preoperative selective portal vein embolization of the right portal branch via a percutaneous, transhepatic, contralateral approach was performed without side effects. A Doppler estimation of left branch portal blood flow and velocity was carried out before and after preoperative selective portal vein embolization. After 21 days the left lobe volume increased by about 44.2% with a safe left lobe/whole liver ratio of 40.8%. The portal blood flow and portal blood flow velocity showed an increase of 253% and 122%, respectively. A right lobectomy was performed without complications. Three months later, computed tomography scan showed no hepatocellular carcinoma recurrence. Preoperative selective portal vein embolization is a safe technique which can enable major hepatectomy to be performed in situations otherwise judged unresectable for a life-threatening volumetric insufficiency. The portal blood flow and portal blood flow velocity evaluations can easily predict the hypertrophy rate of non-embolized liver segments.

A rare surgical case of metachronous double carcinoma of the biliary tract.

We report on a rare case of metachronous double carcinoma of the biliary tract, occurring in a 65-year-old male. The patient was admitted to the hospital with jaundice in March 2004. Ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) scans of the abdomen showed a minimally dilated intrahepatic biliary tree with normal-appearing choledocus. Obstruction of the common hepatic duct was revealed by endoscopic retrograde cholangiopancreatography (ERCP). The patient underwent a resection of the middle third of the extrahepatic duct and cholecystectomy (cholangiocarcinoma, pT1N0M0), with the surgical margins of resection showing as negative. After 2 years, during follow-up, the findings of a positron emission tomography (PET)-CT scan suggested a possible cholangiocarcinoma of the distal part of the biliary tract; CT and MRI scanning of the abdomen showed mild dilatation of the distal common hepatic duct; an ERCP showed mild dilatation of the retropancreatic remnant of the biliary tree with endoluminal defects. Eventually the patient underwent pancreaticoduodenectomy. The histopathological diagnosis of the resected specimen confirmed a cholangiocarcinoma; 10 lymph nodes were negative (pT1N0M0). At 6 months post-op after the second operation the patient is progressing well with no signs of recurrence. Patients with cholangiocarcinoma - in whom survival is prolonged with surgical resection - should undergo careful follow-up for both recurrence and second primary cancer. PET scanning seems to play the most important diagnostic role.

Different hemodynamic patterns of alcoholic and viral endstage cirrhosis: analysis of explanted liver weight, degree of fibrosis and splanchnic Doppler parameters.

OBJECTIVE: In cirrhosis, portal hemodynamics is usually considered independently of the disease etiology. The objective of this study was to investigate the role of the etiology of liver disease on the relationship between liver blood flow and liver pathology in endstage cirrhosis. MATERIAL AND METHODS: Portal blood velocity and volume, congestion index of the portal vein, and hepatic and splenic pulsatility indices were evaluated with echo-Doppler in cirrhotic patients immediately before liver transplantation. When a patent paraumbilical vein was present, its blood flow was measured and effective portal liver perfusion was calculated as portal blood flow minus paraumbilical blood flow. The hemodynamic parameters were correlated with liver weight and the pattern of the liver fibrosis morphometrically assessed in explanted livers. A total of 131 patients with alcoholic or viral cirrhosis were included in the study. RESULTS: In alcoholic cirrhosis, liver weight was higher than that in viral disease (1246+/-295 g versus 1070+/-254 g, p=0.001), portal liver perfusion per gram of liver tissue was lower (0.49+/-0.36 ml g(-1) min(-1) versus 0.85+/-0.56 ml g(-1) min(-1), p=0.004) and hepatic pulsatility indices were higher (1.45+/-0.31 versus 1.26+/-0.30, p=0.018). The degree of liver fibrosis was similar in alcoholic and viral cirrhosis (11.7+/-5.5% versus 11.0+/-4.4%, p=NS). An inverse relationship between liver weight and Child-Pugh score was disclosed in viral (p<0.001) but not in alcoholic disease. CONCLUSIONS: A different hemodynamic pattern characterizes the advanced stage of cirrhosis of alcoholic and viral origin. A more severe alteration of intrahepatic portal perfusion, probably coexisting with a more severe hepatocyte dysfunction, and a higher liver weight can be detected in alcoholic cirrhosis.

Influence of steroids on HCV recurrence after liver transplantation: A prospective study.

BACKGROUND/AIMS: To assess the effect of long-term maintenance of steroids on HCV recurrence after liver transplantation (LT), that is still controversial, a prospective multicentre trial was conducted at the centres of Bologna and Padua, Italy. METHODS: From September 2002, 47 eligible HCV positive LT recipients were randomized to receive 2 different steroid schedules in association with tacrolimus: group A: rapid tapering and withdrawal 91 days after LT group B: slow tapering and withdrawal 25 months after LT. Thirty-nine patients were assessable: 23 in group A and 16 in group B. Donor and recipient characteristics were similar in the two groups. Median follow-up was 841 days (130-1376). One hundred liver biopsies were performed, and every patient had a biopsy at month 12. RESULTS: Twenty-two out of 23 (95, 65%) patients in group A and 15 out of 16 (93, 75%) in group B had histologically-confirmed HCV recurrence. Twelve-month histology showed advanced fibrosis (score 3 or 4) in 42.1% of the patients in group A versus 7.6% in group B (P=0.03). One-and 2-year advanced fibrosis-free survival were 65.2 and 60.8 in group A and 93.7% in group B (P=0.03 and =0.02, respectively). CONCLUSIONS: Slow tapering of steroids reduced the progression of recurrent hepatitis C after LT.

Acute liver rejection: accuracy and predictive values of doppler US measurements--initial experience.

PURPOSE: To prospectively evaluate accuracy and predictive values of Doppler ultrasonographic (US) measurement of portal blood velocity (PBV) and splenic pulsatility index (SPI) in diagnosis of clinically relevant acute rejection in patients with clinicobiochemical hepatic dysfunction after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Study was approved by the institutional review board, and protocol conformed to ethical guidelines of Declaration of Helsinki. Patient informed consent was obtained. In 27 patients with OLT (23 men, four women; mean age, 48 years; range, 27-64 years), PBV and SPI were measured at Doppler US within 48 hours before or after liver biopsy for clinically suspected acute rejection. Biopsy specimens were assigned scores according to Banff method, and rejection activity index (RAI) was calculated. RAI score of 4 or greater was considered clinically relevant acute rejection. Doppler US parameters were analyzed as absolute values and as percentage point changes with respect to values obtained at last examination before rejection was suspected. Information from two Doppler US parameters was combined; Doppler US composite index was calculated. Statistical tests were conducted to assess accuracy, sensitivity, specificity, and predictive values of Doppler US parameters in diagnosis of graft rejection. RESULTS: Clinically relevant acute rejection was diagnosed in nine patients. Median time from OLT until histologic diagnosis of acute rejection was 8 days (range, 5-20 days). Rejection was associated with a marked reduction in mean PBV (-43% +/- 5 [standard error of the mean]) and a slight increase in SPI (+12% +/- 16). The calculated Doppler US composite index was strictly related to severity of rejection (P < .001). When applied retrospectively, this index had good accuracy (88%) for prediction of rejection (specificity, 89%; sensitivity, 86%; negative predictive value, 94%). CONCLUSION: During the first weeks after OLT, a marked decrease in PBV associated with increased SPI supports suspicion of clinically relevant acute rejection.

Change in portal flow after liver transplantation: effect on hepatic arterial resistance indices and role of spleen size.

Information on changes in splanchnic hemodynamics after liver transplantation is incomplete. In particular, data on long-term changes are lacking, and the relationship between changes in arterial and portal parameters is still under debate. The effect of liver transplantation on splanchnic hemodynamics was analyzed with echo-Doppler in 41 patients with cirrhosis who were followed for up to 4 years. Doppler parameters were also evaluated in 7 patients transplanted for acute liver failure and in 35 controls. In cirrhotics, portal blood velocity and flow increased immediately after transplantation (from 9.1 plus minus 3.7 cm/sec to 38.3 plus minus 14.6 and from 808 plus minus 479 mL/min to 2,817 plus minus 1,153, respectively, P <.001). Hepatic arterial resistance index (pulsatility index) also augmented (from 1.36 plus minus 0.32 to 2.34 plus minus 1.29, P <.001) and was correlated with portal blood velocity and flow. The early changes in these parameters were related, in agreement with the hepatic buffer response theory. Portal flow returned to normal values after 2 years. Superior mesenteric artery flow normalized after 3 to 6 months. Splenomegaly persisted after 4 years, when spleen size was related to portal blood flow. In 7 patients transplanted for acute liver failure, portal flow, and hepatic arterial resistance index were normal after transplantation. In conclusion, a high portal flow was present in cirrhotics until 2 years after transplantation, probably because of maintenance of elevated splenic flow. An early increase in hepatic arterial resistance indices is a common finding, but it is transient and is related to the increase in portal blood flow. A normal time course of portal-hepatic hemodynamics was detected in patients transplanted for acute liver failure.

Cavoportal hemitransposition: a successful way to overcome the problem of total portosplenomesenteric thrombosis in liver transplantation.

Orthotopic liver transplantation (OLT) may be feasible even in the presence of diffuse portal vein thrombosis (PVT) in the recipient, providing hepatopetal portal flow to the graft can be ensured. Cavoportal hemitransposition was used in selected cases in which no other salvage solutions were technically possible. We report our experience of two patients with diffuse thrombosis of the entire portal system. One patient also had thrombosis of a previous portacaval shunt with a synthetic interposition graft. Portal pedicle dissection and native hepatectomy (with or without vena cava removal) appeared difficult. Bleeding from the exposed area was severe, and in one case, a new laparotomy was necessary to stop the abdominal hemorrhage. The postoperative course was complicated by severe ascites (with fluid infection and surgically drained suprahepatic abscess in one case), renal insufficiency (requiring dialysis in one case), esophagogastric variceal bleeding (needing several sessions of endoscopic treatment), and bronchopneumonic infections (in one case, superinfection with Aspergillus fumigatus despite amphotericin B lipid complex therapy led to the patient's death from multiorgan failure). Our experience was compared with 17 other cases in the literature. Etiologic factors, preoperative diagnostics, surgical problems, and postoperative complications are focused on and discussed. Diffuse PVT no longer appears to be an absolute contraindication to OLT, although cavoportal hemitransposition needs further experience and long-term follow-up.

Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: a controlled clinical trial.

Intravenous methylprednisolone is used in most liver transplant centers as first-line therapy of acute hepatic cellular rejection in patients who undergo liver transplant. However, no controlled study has been performed to date to define the optimal dose and duration of the steroid regimen. The schedules that actually are used in most transplant centers are drawn from those that were developed empirically for the treatment of acute renal graft rejection. Thus, the aim of the study was to compare two schedules of steroid treatment of acute hepatic cellular rejection among those most widely used. Thirty-eight eligible patients with grade II or III acute hepatic cellular rejection were randomized to receive two different high-dose methylprednisolone schedules. Eighteen patients were randomized in group A (intravenous dose of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d). Twenty patients were randomized in group B (intravenous dose of 1,000 mg of methylprednisolone for three consecutive days). The response to treatment was evaluated by means of a second liver biopsy. The treatment of group A proved to be more effective than treatment of group B. The resolution of acute hepatic cellular rejection was observed in 83.3% of cases in group A and 50.0% of cases in group B (P <.05). The treatment of group A proved to be safer also than treatment of group B. Patients randomized in group B showed a higher prevalence of infections (90.0% of cases versus 55.5% of cases; P <.01) mainly because of bacterial (80.0% versus 50.0%; P <.05) and viral (50.0% versus 16.6%; P <.05) agents. In conclusion, the study shows that intravenous administration of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d is more effective and safer than intravenous dose of 1,000 mg of methylprednisolone for three consecutive days in the treatment of acute cellular rejection in patients with liver transplantation.