PURPOSE:In some situations, the pathological diagnosis of neuroendocrine neoplasms (NEN) remains challenging, with direct consequences for treatment decisions. ENDOCAN-TENpath, the French national expert network for NEN pathology, established monthly virtual "third-reading" sessions for collegial review of difficult cases. We evaluated the diagnostic outcomes and clinical impact of this process. METHODS:All cases submitted to third-reading sessions from March 2022 to December 2023 were retrospectively reviewed. We analyzed diagnostic difficulties, diagnostic modifications, and their expected therapeutic impact. RESULTS:Of 3239 cases received by ENDOCAN-TENpath, 126 (3.9%) were submitted to third-reading by 22 of 33 network pathologists (median turnaround: 20 days). Diagnostic difficulties fell into four categories: high-grade NEN classification (33.3%), mixed neuroendocrine/non-neuroendocrine neoplasm diagnosis (36.5%), incomplete neuroendocrine phenotypes (23.0%), and unfamiliar entities (7.1%). Consensus or majority diagnosis was reached in 102 cases (81%). Unresolved cases were due to lack of consensus (n = 13) or insufficient material (n = 10). Critically, the process yielded decisions with major therapeutic consequences: 20/46 presumed NENs were reclassified as non-neuroendocrine malignancies and 5/25 presumed adenocarcinomas as NENs, fundamentally altering treatment strategy. Furthermore, 32/42 ambiguous high-grade NENs were definitively classified as tumor or carcinoma, directly determining first-line chemotherapy regimen. These findings also prompted internal guidelines to reduce diagnostic variability. CONCLUSION:The ENDOCAN-TENpath third-reading process yields a high rate of clinically actionable diagnostic decisions directly altering treatment strategy, while identifying unmet needs and providing a framework for reducing diagnostic variability in complex NEN cases.

Hepatitis E virus (HEV) is an RNA virus with 1 serotype and 4 main genotypes.1 Genotype 1 and 2 are transmitted via the fecal-oral route in developing countries. Genotype 3 or 4 infection is a zoonosis, mainly observed in developed countries.1 In immunocompetent patients, it is mainly responsible for self-limiting infection. In immunocompromised patients, especially in transplant patients, it can lead to chronic hepatitis in up to 60% of patients.1 Infection with HEV genotype 1 or 2 in pregnancy, especially in the third trimester, may lead to severe illness and fulminant liver failure. Poor maternal and fetal outcomes have been reported with up to 30% mortality.2 Few cases of HEV genotype 3 infection during pregnancy were reported in immunocompetent patients.3,4 No poor outcome was observed in this setting. Only 1 case of HEV genotype 3 infection that occurred during the first trimester in a kidney transplant patient was reported.5 Herein, we report the case of a female liver transplant patient who developed an acute HEV genotype 3 infection 2 wk before delivery. CASE REPORT A 34-y-old non-HLA-sensitized woman had undergone a first orthotopic liver transplantation for autoimmune hepatitis. She was given induction therapy with basiliximab followed by a triple maintenance immunosuppression based on tacrolimus (target trough level of 5–6 ng/mL), mycophenolic acid (500 mg bid.), and low-dose steroids (5 mg/d). The posttransplant period was uneventful and her liver enzyme levels were always within the normal range. Eighteen months after transplantation, the mycophenolic acid was replaced by azathioprine (100 mg/d) because of her desire to have a child. At 26 mo posttransplant, she got pregnant. At 34 wk of gestation, systematic control of her blood parameters revealed a slight increase in liver enzyme levels. She was completely asymptomatic. No anti-HLA antibodies or autoimmune antibodies were detected. Nuclear acid tests for hepatitis B and C as well as cytomegalovirus were negative. Conversely, HEV RNA was positive in the serum (7.13 log IU/mL) and in the stools. Retrospective analysis of a serum obtained 1 mo earlier did not reveal the presence of HEV RNA. Phylogenetic analysis revealed that the strain belonged to genotype 3c. Anti-HEV IgG and IgM, which were negative at transplantation, were positive: IgG concentration was at 1.59 IU/mL (limit of detection at 0.3 IU/mL) and IgM index was at 20.05. Total lymphocyte, CD4+ T-cell, and CD8+ T-cell counts were 200, 75, and 64/mm3, respectively. The prothrombin test was 100%. No liver biopsy was performed because autoimmune antibodies were negative and HEV RNA was detected. The cause of HEV infection was not clearly identified, but it was likely related to the consumption of pork products. She did not receive any blood product transfusion, did not travel abroad, and was not in contact with animals. After the HEV diagnosis, no modification in the immunosuppressive regimen was done because the tacrolimus trough level was already at 5 ng/mL and the patient had a history of autoimmune disease. Despite the lack of fetal distress and growth retardation, the baby was delivered by cesarean section 2 wk later (at 36 wk of gestation) because of a persistent increase in liver enzyme levels and a decreased platelet count (from 105 000 to 55 000/mm3; Figure 1). No obstetrical complications occurred. The placenta tested positive for HEV RNA. Anti-HEV staining was done and was strongly positive (Figure 2). The breast milk tested positive for HEV RNA at days 2 and 20 after delivery. Consequently, breastfeeding was contraindicated.FIGURE 1.: Outcome of liver enzyme and HEV RNA concentrations during and after pregnancy. *Superscripts correspond to HEV RNA in the stools. ALT, alanine transaminase; AST, aspartate transaminase; HEV, hepatitis E virus.FIGURE 2.: Anti-HEV staining of the placenta: positive cytoplasmic anti-HEV staining in trophoblastic cells. The control placenta was obtained from a woman not infected by HEV. The patient and control woman had given their informed consent to perform HEV staining on their placenta and tissue samples were stored in a biobank (CRB BB-0033-00014). HEV, hepatitis E virus. The arrow shows the positive staining.The newborn was a boy weighing 2885 g. The Apgar score was 10/10. He was tested for HEV RNA at days 1–5, 15 d, and 1 mo. All tests were negative. Liver enzyme levels remain within the normal ranges. Anti-HEV IgM was not detected. Conversely, anti-HEV IgG was positive (37 IU/mL). Regarding the infected mother, tacrolimus level was maintained <5 ng/mL to obtain HEV clearance and azathioprine was stopped. Because of the lack of HEV clearance, ribavirin was started 3 mo after delivery at the initial dose of 800 mg/d, and the dose was then increased to 1000 mg/d because of the good hematological tolerance (estimated glomerular filtration rate according to the Chronic Kidney Disease-Epidemiology Collaboration formula was 63 mL/min). At the initiation of ribavirin, anti-HEV IgG concentration was 3.21 IU/mL and IgM index was 19.39. Liver enzyme levels returned to normal as soon as 1 mo after starting ribavirin and remained unchanged until the last follow-up (Figure 1). HEV RNA concentration also decreased rapidly. It remained detectable at very low levels for a long period. Ribavirin was stopped once HEV RNA was undetectable in the serum and the stools on 2 occasions at 1 mo apart. Thus, the total duration of ribavirin was 16 mo. At 1 y after ceasing ribavirin, HEV RNA is still undetectable in the serum and stools. Anti-HEV IgG concentration was 38 IU/mL and IgM index was 8. Hence, we can consider that she achieved a sustained virological response. DISCUSSION HEV genotype 1 infection during pregnancy, especially during the third trimester, is associated with a high viral load compared with acute hepatitis6 and an increased risk of fulminant hepatic failure, which results in a high mortality rate ranging from 20% to 30%.2 Miscarriage and stillbirths were also reported. In vitro data have shown that progesterone is crucial to maintaining HEV replication in human liver cells during pregnancy.7 In pregnant Indian women infected by HEV, a reduction in the expression of progesterone receptor has been observed, leading to a predominance of T-helper type 1 lymphocytes. This immunologic shift results in an increase in the cytotoxic T-cell reaction responsible for fetal and maternal injury.6 Here, we report the case of a liver transplant patient who developed a genotype 3 HEV infection during the third trimester of pregnancy. In a large cohort from India, Patra et al8 reported that pregnant women with jaundice and acute viral hepatitis caused by HEV infection had a higher maternal mortality rate and worse obstetric and fetal outcomes than pregnant women with jaundice and acute viral hepatitis caused by other types of viral hepatitis. Elective preterm delivery is historically reserved for HEV-positive pregnant patients if obstetric complications occur. In the present case, because the patient was already at 36 wk of amenorrhea, had a persistent increase in liver enzyme levels, and a decreased platelet count, her baby was delivered by cesarean section despite the lack of fetal distress and growth retardation. Interestingly, although the HEV RNA viral load was high in the mother and HEV was detected in high levels in the placenta, the newborn was not infected. The anti-HEV IgG detected in the baby was probably transmitted by his mother. The lack of transmission of genotype 3 HEV infection from mother to child is in line with previous small case series and case reports. In a study from Vietnam, no transmission to children from 4 immunocompetent pregnant women with HEV genotype 3a replication at delivery was observed.4 To our knowledge, no delivery with replication HEV has been reported in solid organ transplant patients. Mallet et al5 reported the case of a kidney transplant patient who was infected by HEV (unknown genotype) at 8 wk of gestation. She cleared the virus after the reduction of immunosuppression at the beginning of the third trimester and had no replication at delivery.5 The newborn was not infected. The risk of vertical transmission that can influence the decision for early fetal delivery still needs to be studied. Bertuzzo et al9 reported the case of an Asian nontransplant pregnant woman who was infected by HEV (unknown genotype) and developed acute hepatic failure. After delivery, she required a liver transplantation.9 In the present case, liver enzyme tests increased after delivery. The reasons for a delayed increase in transaminases are unclear because of the lack of published data in this setting. This may be related to the changes in the hormonal or immunological status. After delivery, she developed chronic hepatitis that required long-term ribavirin therapy to obtain viral clearance both in the serum and stools. We observed that the detection of HEV RNA in the stools when stopping ribavirin is associated with an increased risk of relapse, even if HEV RNA is not detected in the serum.10 Prolonging ribavirin therapy enables a sustained virological response.11 In summary, this case report highlights that despite HEV genotype 3 infection in the third trimester of pregnancy, the outcome was good and the newborn infection was not systematic. Although HEV genotype 1, which occurs during pregnancy, can induce acute liver injury and is associated with an increased risk of mother and child mortality, it does not seem to be the case for HEV genotype 3 infection. In this setting, there is a risk of developing chronic hepatitis.

The outcome of stage II–III colorectal cancer (CRC) is highly variable and therapeutic choice is currently based on TNM staging with a few additional biomarkers. However, studies show that some stage III patients have a better prognosis than some stage II patients. A promising consensus molecular (CMS) classification with prognostic relevance has been developed, but it is not used in daily practice. Our team developed CINSARC, a 67-gene expression prognostic signature, whose prognostic value has been demonstrated in many cancer types. It is applicable to formalin-fixed, paraffin-embedded (FFPE) blocks using NanoString® technology. We investigated whether it could predict outcome in stage II–III CRC. We established the CINSARC classification on the TCGA retrospective cohort comprising 297 stage II–III CRC patients using RNA sequencing and on a second independent cohort comprising 169 cases using NanoString® technology. We compared its recurrence-free and overall survival prognostic value with TNM staging and CMS classification. In the TCGA cohort, we showed that CINSARC significantly splits the population of stage II–III CRC into two groups with different progression-free interval (P = 1.68 × 10−2; HR = 1.87 [1.11–3.16]) and overall survival (P = 3.73 × 10−3; HR = 2.45 [1.31–4.59]) and is a strong prognostic factor in multivariate analysis, outperforming TNM staging and CMS classification. We validated these results in the second cohort by applying CINSARC on FFPE samples with Nanostring® technology. CINSARC is a ready-to-use tool with a robust independent prognostic value in stage II–III CRC.

Abstract Primary intestinal lymphangiectasia is an unusual cause of protein losing enteropathy due to either congenital malformation or obstruction of lymphatics of intestine. The disease can affect all or only a small part of the small intestine. Peripheral lymphedema may be associated. The diagnosis is based on endoscopic and histopathological findings. A 30-year-old woman presents lower extremity edema with hypoproteinemia, hypoalbuminemia, and hypogammaglobulinemia. 99mTc-labeled human serum albumin nanocolloid lymphoscintigraphy of the lower extremity demonstrated a dermal backflow in the right extremity consistent with lymphedema and an unusual ileal uptake on SPECT/CT. Diagnosis is confirmed on histopathological evaluation of biopsy of ileum.

Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.

Colonic macrophages are considered to be major effectors of inflammatory bowel diseases (IBDs) and the control of gut inflammation through C-type lectin receptors is an emerging concept. We show that during colitis, the loss of dectin-1 on myeloid cells prevents intestinal inflammation, while the lack of mannose receptor (MR) exacerbates it. A marked increase in dectin-1 expression in dextran sulfate sodium (DSS)-exposed MR-deficient mice supports the critical contribution of dectin-1 to colitis outcome. Dectin-1 is crucial for Ly6ChighCCR2high monocyte population enrichment in the blood and their recruitment to inflamed colon as precursors of inflammatory macrophages. Dectin-1 also promotes inflammasome-dependent interleukin-1β (IL-1β) secretion through leukotriene B4 production. Interestingly, colonic inflammation is associated with a concomitant overexpression of dectin-1/CCL2/LTA4H and downregulation of MR on macrophages from IBD patients. Thus, MR and dectin-1 on macrophages are important mucosal inflammatory regulators that contribute to the intestinal inflammation.

After liver transplantation (LT), the role of preformed donor‐specific anti–human leukocyte antigen antibodies (pDSAs) remains incompletely understood. We conducted a retrospective, case‐control analysis to determine the impact of pDSAs after LT in 3 French transplant centers (Bordeaux, Lyon, and Toulouse). Among the 1788 LTs performed during the study period, 142 (7.9%) had at least 1 pDSA. The patient survival rate was not different between patients who received an LT with pDSAs and the matched‐control group. A liver biopsy was performed 1 year after transplantation in 87 recipients. The metavir fibrosis score did not differ between both groups (1 ± 0.8 versus 0 ± 0.8; P = 0.80). However, undergoing a retransplantation (hazard ratio [HR] = 2.6, 95% confidence interval [CI], 1.02‐6.77; P = 0.05) and receiving induction therapy with polyclonal antibodies (HR = 2.5; 95% CI, 1.33‐4.74; P = 0.01) were associated with a higher risk of mortality. Nonetheless, high mean fluorescence intensity (MFI) donor‐specific antibodies (ie, >10,000 with One Lambda assay or >5000 with Immucor assay) were associated with an increased risk of acute rejection (HR = 2.0; 95% CI, 1.12‐3.49; P = 0.02). Acute antibody‐mediated rejection was diagnosed in 10 patients: 8 recipients were alive 34 (1‐125) months after rejection. The use of polyclonal antibodies or rituximab as an induction therapy did not reduce the risk of acute rejection, but it increased the risk of infectious complications. In conclusion, high MFI pDSAs increase the risk of graft rejection after LT, but they do not reduce medium‐term and longterm patient survival. The use of a T or B cell–depleting agent did not reduce the risk of acute rejection.

Background MMR testing is performed to screen Lynch Syndrome, evaluate the prognosis of colorectal cancer (CRC) and predict the efficacy of PD1/PDL1 blockade in all tumor types. Two methods are available: immunohistochemistry (IHC) using antibodies against MMR proteins and molecular biology (MB) for assessing microsatellite instability (MSI). Classically, dMMR tumor corresponds to loss of expression of two proteins (MLH1 and PMS2 or MSH2 and MSH6) associated with MSI. Atypical profiles of dMMR tumors have sporadically been described. The aim of our study was to describe the frequency and characteristics of these atypical cases. Methods All MMR testing performed in our center between 2007 and 2017 were checked to select cases with both available IHC and MB. Then, all dMMR cases were reviewed to identify atypical cases which were defined by: isolated loss of expression of one protein, loss of expression of two proteins without MSI, normal expression of the four proteins with MSI, aberrant loss of proteins, or MSI-low. Biological data of atypical cases were controlled and clinical data were collected for each case. Results 4948 MMR tests were performed, 3800 had both available IHC and MB data, and 585 were dMMR (15 %). Among them, 97 cases were atypical and after biological control, 8 cases were re-classified typical; allowing to finally identify 89 atypical cases: 60 CRC, 10 endometrial carcinoma, 8 digestive non CRC and 11 others types of cancers. A strong correlation with genetic syndromes was observed for those atypical profiles. Table . 2015P Isolated PMS2 or MSH6 loss n = 53 Expression of the four proteins n = 5 MSH2/MSH6 or MLH1/PMS2 loss n = 16 Aberrant loss of proteins n = 15 MSI 43 3 - 13 MSI low 1 2 8 - MSS * 9 - 8 2 Clinical characteristics Predominantly CCR Genetic predisposition syndrome (73%) Exclusively CCR or endometrial Genetic predisposition syndrome (≥40%) Predominantly Non CRC (63%) None (* MSS: microsatellite stability) Conclusions Even using controlled IHC and MB, 15% of dMMR tumors have an atypical profile. These atypical cases mainly involve non CRC cancer with a strong prediction for Lynch syndrome. Their therapeutic impact particularly for immunotherapy should be now evaluated. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

To the Editor: Juvenile polyposis of infancy (OMIM 612242) is a hamartomatous polyposis including macrocephaly, facial dysmorphism, hypotonia, developmental delay; rectal bleeding occurred during the first 2 years of life (1,2). It results from a microdeletion of chromosome 10q23 involving PTEN (phosphatase and tensing homolog) and BMPR1A (bone morphogenetic protein receptor type 1A) tumour-suppressor genes (1,2). A protein-losing enteropathy can lead to colectomy in the first years of life (1,2) and to an early death (2). Later on, there is an increased risk of colorectal cancer (2). In mice, the conditional deletion of Bmpr1a induces the development of numerous polyps mimicking human juvenile polyposis (3). BMP signalling promotes cell differentiation and thus balances the intestinal stem cell renewal under the control of the Wnt/Apc/β-catenin pathway. In adenomatous polyposis coli (Apc) deficient mice, the inducible loss of Pten leads to an increased tumourigenesis because of an increased activation of PI3K/Akt/mTOR (phosphatidyl-inositol 3 kinase/Protein kinase B/mammalian target of rapamycin) pathway (4). mTOR is a downstream effector of the PI3K negatively regulated by PTEN. Its expression is increased in intestinal polyps of Apc deficient mice; its inhibition reduced the number of polyps and their size (5), and also delayed the apparition of dysplasia (6). The wider use of the mTOR inhibitor sirolimus in clinical trials of cancer therapy and the severity of the phenotype of our young patient led us to consider this drug as a new therapeutic option. An 11-year old girl was followed since birth for macrocephaly (+5 SD), mild hypotonia, motor and developmental delay. When she was 18 months old, she had rectal bleeding. Her colonoscopy revealed numerous juvenile polyps, up to 3 cm of diameter (Fig. 1 A and B). Genetic analysis found a de novo germline deletion encompassing PTEN and BMPR1A. Follow-up endoscopies confirmed a severe form of polyposis with 30 to 50 polyps, mainly located in the colon but also in the stomach and the small bowel. She had a failure to thrive, mild anaemia and protein-losing enteropathy. A colonic perforation occurred after resection of large polyps when she was 5 years old. In emergency, a transient ileostomy was performed.FIGURE 1: Juvenile polyps under sirolimus treatment. Prior to treatment, there were large pediculated or sessile polyps with exudative loss on their heads (A and B). The number and size of polyps decreased after 1 and 3 years of treatment (C and D respectively).Instead of performing a colectomy, which could exacerbate watery and stool losses and increase the risk of dehydration, we decided to start a treatment with sirolimus when she was 6-year-old, targeting a blood concentration of 5 ng/mL. We found a decrease in number and size of polyps during yearly endoscopic follow-up (Fig. 1C and D). After more than 4-year of follow-up, she showed a weight improvement and normal serum albumin level without recurrence of anaemia or adverse event. When she was 11-year-old no polyp was detected, even in the rectum where few small polyps were previously present. Importantly, an immunostaining of phospho-S6 ribosomal protein, a target of mTOR, showed a marked decreased expression after sirolimus initiation (Fig. 2).FIGURE 2: mTOR activity in sirolimus-treated polyps. Immunostaining of phospho-S6 ribosomal protein (left panels) was performed to measure mTOR activity under sirolimus treatment. Nuclei staining (DAPI, right panels) and the whole sections (boxes) of the polyps are shown. Despite a strong and large decrease in phospho-S6 ribosomal protein labelling, demonstrating mTOR inhibition, some polyps areas remained positive (see box).In conclusion, this report suggests that sirolimus is effective in the treatment of severe juvenile polyposis of infancy and could be considered as a therapeutic option, instead of colectomy.

AIM To investigate the role of tacrolimus intra-patient variability (IPV) in adult liver-transplant recipients. METHODS We retrospectively assessed tacrolimus variability in a cohort of liver-transplant recipients and analyzed its effect on the occurrence of graft rejection and de novo donor-specific antibodies (dnDSAs), as well as graft survival during the first 2 years posttransplantation. Between 02/08 and 06/2015, 116 patients that received tacrolimus plus mycophenolate mofetil (with or without steroids) were included. RESULTS Twenty-two patients (18.5%) experienced at least one acute-rejection episode (BPAR). Predictive factors for a BPAR were a tacrolimus IPV of > 35% [OR = 3.07 95%CI (1.14-8.24), P = 0.03] or > 40% [OR = 4.16 (1.38-12.50), P = 0.01), and a tacrolimus trough level of < 5 ng/mL [OR=3.68 (1.3-10.4), P =0.014]. Thirteen patients (11.2%) developed at least one dnDSA during the follow-up. Tacrolimus IPV [coded as a continuous variable: OR = 1.1, 95%CI (1.0-1.12), P = 0.006] of > 35% [OR = 4.83, 95%CI (1.39-16.72), P = 0.01] and > 40% [OR = 9.73, 95%CI (2.65-35.76), P = 0.001] were identified as predictors to detect dnDSAs. IPV did not impact on patient- or graft-survival rates during the follow-up. CONCLUSION Tacrolimus-IPV could be a useful tool to identify patients with a greater risk of graft rejection and of developing a de novo DSA after liver transplantation

BACKGROUND AND AIM:Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. METHOD:Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. RESULTS:Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). CONCLUSION:In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection.

In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.

L’octréotide, un analogue de la somatostatine, peut être une option thérapeutique pour contrôler les hypoglycémies des patients atteints d’un insulinome, lorsque la chirurgie (seul traitement curatif) n’est pas réalisable. L’octréotide agit via le sous-type 2 des récepteurs de somatostatine (sst2) et le 5 (sst5) dans une moindre mesure. De nombreux cas cliniques ont démontré que malgré l’expression de sst2, la réponse thérapeutique (normalisation de la glycémie) n’était pas systématique après traitement à l’octréotide. Nous avons donc évalué la relation entre l’efficacité thérapeutique de l’octréotide et la présence de sst2. Une analyse protéique (immunohistochimie (IHC) et western blot (WB)) et de l’ARNm (RT-qPCR) de sst2 a été réalisée pour 32 patients traités par octréotide dans le cadre d’un insulinome. La présence de la protéine sst2 (IHC et/ou WB) a été retrouvée chez 17 patients dont 13 répondent au traitement (taux de réponse de 76 % en présence de sst2). La réponse à l’octréotide est indépendante de la localisation membranaire et/ou cytosolique de sst2. À l’inverse, moins de 14 % des patients répondent en l’absence d’expression protéique de sst2 (2/15 patients). Enfin, en dessous d’un certain seuil d’amplification de l’ARN sst2 (DeltaCt > à 7,1), il n’y a plus de réponse thérapeutique. Le prolongement de cette étude permettra de caractériser les autres sous-types de récepteur de somatostatine (sst5, 3 et 1) présentant une forte affinité pour les analogues de somatostatine de deuxième génération (pasiréotide). Ces derniers pourraient alors être proposés comme traitement aux patients n’exprimant pas sst2.

e14629 Background: Lynch syndrome (LS) is the most frequent inherited colorectal cancer (CRC) syndrome, due to germline mutations in one of the mismatch repair (MMR) genes. Out of the 15% of CRCs associated with deficient DNA mismatch repair system (dMMR) that are characterized by high levels of microsatellite instability (MSI-H), only 3% are attributable to Lynch syndrome. The other 12% are sporadic, with acquired dMMR phenotype caused in tumors by hypermethylation of the promoter of gene hMLH1, often associated with BRAF V600E mutation. A probably underestimated group does not respond to any of these definitions and is called Lynch-like syndrome (LLS). The aim of the study was to compare the pathological and clinical features of the LS, LLS, and sporadic CRCs and to evaluate the contribution of somatic tools to the screening of potential LS patients. Methods: Two hundred and twelve patients with a dMMR CRC were included. The clinical, surgical, pathological and genetic data were retrieved. A complete MMR phenotype analysis of the tumor was realized, including MSI, expression of the MMR proteins, hypermethylation of the promoter of hMLH1 gene, and BRAF V600E mutation. Results: The only differentiating features between Sporadic (45.5% of the CRC), LLS (20.4%) and LS CRCs (34.1%) are the age of onset (68.5 vs 46 vs 47 years of age; p < 0.001) and the existence of cancers in the family (42.4% vs 42.4% vs 81.5%; p < 0.001). Detection of BRAF V600E is a sensitive (63%) and specific (100%) test in identifying sporadic tumors. The status of hypermethylation is also essential for sporadic diagnosis but can be traced in LS (3.5%). It turns out that the systematic use of these somatic tools in addition to basic clinical information (age of onset, location of the CRC, personal history of CRC or endometrial cancer) could save 25.5% of useless, expensive and time-consuming oncogenetic research, with a risk of error of 1.2%. Conclusions: No isolated clinical or pathological feature seems adequate to differentiate dMMR CRCs. In addition to MSI, a new algorithm including systematic BRAF V600E, hypermethylation of the promoter of the hMLH1 gene and clinical information may help to identify Lynch syndrome patients.

Goals and Background: Mutation of the KRAS oncogene is present in 75% to 95% of pancreatic cancer tissues. This study aimed to evaluate whether endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), combined with analysis of the KRAS mutation, improves the diagnosis of pancreatic cancer in cases of inconclusive or doubtful cytopathologic analysis.Patients and Methods: We prospectively included 186 patients with a pancreatic mass (103 men; mean age: 62 y). Cytopathology and KRAS mutations, using TaqMan MGB allelic discrimination, were performed on EUS-FNA material. A final diagnosis was obtained from EUS-FNA analysis and/or a subsequent biopsy if necessary, and/or surgery, and follow-up: these were pancreatic adenocarcinoma (n = 104), other malignant pancreatic tumors (n = 22), and benign lesions (n = 60, including 35 cases of chronic pancreatitis).Results: Inconclusive or doubtful (low-grade dysplasia or atypia) cytopathology was found in 68 cases. Of these, 29 patients who had adenocarcinoma were subsequently diagnosed, including 19 cases with a former KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone to diagnose adenocarcinoma were 73%, 100%, 100%, 75%, and 85%, respectively. When KRAS mutation analysis was combined with pathology, these values reached 88%, 99%, 99%, 89%, and 93%, respectively. The performance of EUS-FNA to diagnose malignancy was similarly improved after the KRAS-mutation assay (negative predictive value increased from 67% to 88%; accuracy increased from 85% to 94%).Conclusions: EUS-FNA plus KRAS-mutation analysis, using allelic discrimination, is accurate and improves the diagnosis of pancreatic adenocarcinoma when pathology is inconclusive or doubtful.

Le diagnostic topographique d’un insulinome est classiquement difficile. Évaluer la performance diagnostique des scanners hélicoïdaux monobarettes comparée aux scanners hélicoïdaux multibarettes dans le diagnostic topographique des hypoglycémies organiques par sécrétion innapropriée d’insuline (HOPSII). Étude rétrospective, monocentrique ayant inclus des patients avec une HOPSII symptomatique, prouvée biologiquement, ayant bénéficié d’un scanner pancréatique hélicoïdal multiphasique entre 1995 et 2014. Soixante-sept patients (40 femmes) d’âge médian 55 ans ont été inclus. L’insulinome a été confirmé à l’anatomopathologie chez 54 patients (pas d’histologie car absence de diagnostic topographique, n = 4 ; insulinome métastatique n = 3 ; refus ou contre-indication à la chirurgie, n = 6). Vingt-cinq patients ont eu un scanner monobarette et 42 patients un scanner multibarettes. Le scanner a permis de localiser l’insulinome chez 52 patients (78 %) dont 18/25 patients avec le scanner monobarette soit une sensibilité diagnostique de 72 % IC[0,5-0,86] versus 34/42 patients avec le scanner multibarettes soit une sensibilité de 81 % IC[0,69-0,93] (p = 0,3). Chez les 15 patients avec un scanner normal, l’insulinome a été localisé chez 11 patients (73 %) grâce à l’échographie abdominale transpariétale (n = 7), l’IRM (n = 2), l’échœndoscopie pancréatique (n = 2). Le scanner pancréatique hélicoïdal multiphasique permet de faire le diagnostic topographique de l’insulinome chez 78 % des patients. La sensibilité diagnostique du scanner multibarettes ne semble pas, dans cette série, statistiquement supérieure à celle du scanner monobarette. Les autres examens de localisation, et en particulier l’échographie abdominale transpariétale peuvent être utiles.