Oncological Safety and Potential Cost Savings of Routine vs Selective Histopathological Examination After Appendectomy: Results of the Multicenter, Prospective, Cross-Sectional FANCY Study.

OBJECTIVE: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. BACKGROUND: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. METHODS: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. RESULTS: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients. CONCLUSIONS: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Safety and economic analysis of selective histopathology following cholecystectomy: multicentre, prospective, cross-sectional FANCY study.

BACKGROUND: There is ongoing debate concerning the necessity of routine histopathological examination following cholecystectomy. In order to reduce the pathology workload and save costs, a selective approach has been suggested, but evidence regarding its oncological safety is lacking. METHODS: In this multicentre, prospective, cross-sectional study, all gallbladders removed for gallstone disease or cholecystitis were systematically examined by the surgeon for macroscopic abnormalities indicative of malignancy. Before sending all specimens to the pathologist, the surgeon judged whether histopathological examination was indicated. The main outcomes were the number of patients with hypothetically missed malignancy with clinical consequences (upper limit two-sided 95 per cent c.i. below 3:1000 considered oncologically safe) and potential cost savings of selective histopathological examination. RESULTS: Twenty-two (2.19:1000) of 10 041 specimens exhibited malignancy with clinical consequences. In case of a selective policy, surgeons would have held back 7846 of 10041 (78.1 per cent) gallbladders from histopathological examination. Malignancy with clinical consequences would have been missed in seven of 7846 patients (0.89:1000, upper limit 95% c.i. 1.40:1000). No patient benefitted from the clinical consequences, while two were harmed (futile additional surgery). Of 15 patients in whom malignancy with clinical consequences would have been diagnosed, one benefitted (residual disease radically removed), two potentially benefitted (palliative systemic therapy), and four experienced harm (futile additional surgery). Estimated cost savings established by replacing routine for selective histopathological examination were €703 500 per 10 000 patients. CONCLUSION: Selective histopathological examination following cholecystectomy is oncologically safe and could reduce pathology workload, costs, and futile re-resections.

Tumour-stroma ratio outperforms tumour budding as biomarker in colon cancer: a cohort study.

The tumour-stroma ratio (TSR) and tumour budding (TB) are two high-risk factors with potential to be implemented in the next TNM classification. The aim of the current study was to evaluate the practical application of the two biomarkers based on reproducibility, independency and prognostic value. Patients diagnosed with stage II or III colon cancer who underwent surgery between 2005 and 2016 were included. Both TSR and TB were scored on haematoxylin and eosin-stained tissue sections. The TSR, based on the relative amount of stroma, was scored in increments of 10%. TB was scored following the consensus guidelines; a bud was defined as ≤ 4 tumour cells. For analysis, three categories were used. Cohen's kappa was used for reproducibility. The prognostic value was determined with survival analysis. In total, 246 patients were included. The TSR distribution was N = 137 (56%) stroma-low and N = 109 (44%) stroma-high. The TB distribution was TB-low N = 194 (79%), TB-intermediate N = 35 (14%) and TB-high N = 17 (7%). The reproducibility of the TSR was good (interobserver agreement kappa = 0.83 and intraobserver agreement kappa = 0.82), whereas the inter- and intraobserver agreement for scoring TB was moderate (kappa 0.47 and 0.45, respectively). The survival analysis showed an independent prognostic value for disease-free survival for TSR (HR 1.57; 95% CI 1.01-2.44; p = 0.048) and for TB-high (HR 2.01; 95% CI 1.02-3.96; p = 0.043). Based on current results, we suggest the TSR is a more reliable parameter in daily practice due to better reproducibility and independent prognostic value for disease-free survival.

An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B.

BACKGROUND & AIMS: Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients. METHODS: We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA <2000 IU/ml, alanine aminotransferase normalization after 1 year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT-qPCR. RESULTS: Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non-responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for eight selected genes. A 2-gene subset (HLA-DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype and baseline HBsAg level correctly classified 90% of all patients, in which HLA-DPB1 and SERPIN-E1 were independent predictors of response. CONCLUSION: We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment.

Non-invasive evaluation of liver fibrosis: a comparison of ultrasound-based transient elastography and MR elastography in patients with viral hepatitis B and C.

OBJECTIVE: To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy. METHODS: One hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade ≥ F2 and ≥F3. We defined cutoff values for selection of patients with F0-F1 (sensitivity >95%) and for significant fibrosis F2-F4 (specificity >95%). RESULTS: Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (n = 3), F1 (n = 53), F2 (n = 15), F3 (n = 8) and F4 (n = 6). TE and MRE accuracy were comparable [AUROCTE ≥ F2: 0.914 (95% CI: 0.857-0.972) vs. AUROCMRE ≥ F2: 0.909 (0.840-0.977), P = 0.89; AUROCTE ≥ F3: 0.895 (0.816-0.974) vs. AUROCMRE ≥ F3: 0.928 (0.874-0.982), P = 0.42]. Cutoff values of <5.2 and ≥8.9 kPa (TE) and <1.66 and ≥2.18 kPa (MRE) diagnosed 64% and 66% of patients correctly as F0-F1 or F2-F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80%. CONCLUSION: TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80%. KEY POINTS: • Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis. • Both have comparable accuracy for detecting liver fibrosis in viral hepatitis. • The individual techniques reliably detect or exclude significant liver fibrosis in 66 %. • A conditional strategy for inconclusive findings increases the number of correct diagnoses.

A 3D in vitro model of differentiated HepG2 cell spheroids with improved liver-like properties for repeated dose high-throughput toxicity studies.

Immortalized hepatocyte cell lines show only a weak resemblance to primary hepatocytes in terms of gene expression and function, limiting their value in predicting drug-induced liver injury (DILI). Furthermore, primary hepatocytes cultured on two-dimensional tissue culture plastic surfaces rapidly dedifferentiate losing their hepatocyte functions and metabolic competence. We have developed a three-dimensional in vitro model using extracellular matrix-based hydrogel for long-term culture of the human hepatoma cell line HepG2. HepG2 cells cultured in this model stop proliferating, self-organize and differentiate to form multiple polarized spheroids. These spheroids re-acquire lost hepatocyte functions such as storage of glycogen, transport of bile salts and the formation of structures resembling bile canaliculi. HepG2 spheroids also show increased expression of albumin, urea, xenobiotic transcription factors, phase I and II drug metabolism enzymes and transporters. Consistent with this, cytochrome P450-mediated metabolism is significantly higher in HepG2 spheroids compared to monolayer cultures. This highly differentiated phenotype can be maintained in 384-well microtiter plates for at least 28 days. Toxicity assessment studies with this model showed an increased sensitivity in identifying hepatotoxic compounds with repeated dosing regimens. This simple and robust high-throughput-compatible methodology may have potential for use in toxicity screening assays and mechanistic studies and may represent an alternative to animal models for studying DILI.

Comparison of interobserver agreement of magnetic resonance elastography with histopathological staging of liver fibrosis.

PURPOSE: MR elastography (MRE) can serve as an accurate surrogate marker of liver fibrosis. For any diagnostic test that is to replace the current reference standard, interobserver agreement should be at least as good and preferably better. The objective of this study was to perform a head-to-head comparison of the interobserver agreements of MRE and liver fibrosis staging on biopsy in a single cohort of hepatitis patients. METHODS: One hundred and three patients with viral hepatitis B or C who had a liver biopsy underwent MRE. Two readers independently selected a region-of-interest (ROI) in the liver to derive elasticity values. Two pathologists first independently staged fibrosis on biopsies using the METAVIR classification and subsequently held a consensus meeting. Interobserver agreements of elasticity values and fibrosis stages were assessed with intraclass correlation coefficients (ICC). RESULTS: MRE and biopsy data were available for 85/103 patients. ICC of pathologists staging fibrosis was almost perfect at 0.91 (95% CI 0.86-0.94). ICC for MRE readers was significantly (P < 0.0001) higher at 0.99 (95% CI 0.98-1.00). CONCLUSIONS: Interobserver agreement for liver fibrosis staging was almost perfect for both histopathology and MRE, with a significant higher agreement for MRE. Its high interobserver agreement and reliable accuracy support the use of MRE as a non-invasive screening tool for liver fibrosis.

Efficacy of EUS-guided keyhole biopsies in diagnosing subepithelial lesions of the upper gastrointestinal tract.

Background and study aims Tissue acquisition is required for diagnosis of subepithelial lesions (SELs). However, obtaining adequate tissue remains challenging. This study investigated an EUS-guided technique using a forceps to create a channel and take multiple biopsies from the center of the lesion, therefore called endoscopic ultrasound-guided keyhole biopsy (EUS-KB). Patients and methods A retrospective cohort study was conducted in 56 patients with SELs in the upper gastrointestinal tract who were scheduled to undergo EUS-KB. The primary aim was to assess diagnostic yield, defined as the percentage of procedures where EUS-KB resulted in a definitive histopathological diagnosis. Furthermore, factors influencing diagnostic yield were investigated. Additional outcomes included technical success and adverse events. Results Technical success was achieved in 55 of 60 biopsies (91.7%). EUS-KB provided a diagnosis in 44 of 55 biopsies (80.0%), histology mostly showing gastrointestinal stromal tumor or leiomyoma. The diagnostic yield was not significantly influenced by the size or location of the SEL. Adverse events occurred in one patient (1.7%). Conclusions EUS-KB is a feasible and safe technique for obtaining a classifying diagnosis for SELs in the upper gastrointestinal tract. It could offer an alternative diagnostic modality, especially in lesions smaller than 20 mm.

Clinical characteristics and survival outcomes of patients with primary central nervous system lymphoma treated with high-dose methotrexate-based polychemotherapy and consolidation therapies.

Given the rarity of primary central nervous system lymphoma (PCNSL), evaluations of different high-dose methotrexate-(HD-MTX)-based treatment regimens is sparse. This retrospective, multicenter study evaluates clinical characteristics and outcomes (progression-free, overall and disease-specific survival) after five HD-MTX-based polychemotherapeutic regimens and two consolidation therapies. 346 patients with histologically confirmed PCNSL, treated with ≥ 1 cycle HD-MTX-based strategies (≥3g/m2/cycle) were included. The regimens included MATRIX (HD-MTX, HD-AraC, thiotepa, and rituximab), (R)MBVP±HD-AraC (HD-MTX, teniposide/etoposide, carmustine, prednisolone, ± HD-AraC, ± rituximab), (R)MP (HD-MTX, procarbazine, ± rituximab), and a combination of HD-MTX and HD-AraC. The overall response rate after induction was 69 %, 28 % complete remission and progressive disease was observed in 100 (29 %) patients. 126 (36 %) patients received consolidation, including high-dose-BCNU-thiotepa with autologous stem cell transplantation (HD-BCNU-TT/ASCT, n = 59 (17 %)) or whole brain radiotherapy (WBRT, n = 67 (19 %)). Clinical characteristics associated with adverse mortality risk by multivariable prognostication contained age > 60 years (HR 1.61, p = 0.011), elevated LDH (HR 1.75, p = 0.004) and WHO status ≥ 2 (HR 1.56, p = 0.010). Independently, induction regimens containing HD-AraC demonstrated survival benefit compared to induction regimens without HD-AraC (HR 0.59, p = 0.002). Without preference for HD-BCNU-TT/ASCT or WBRT, a favorable effect of consolidation (HR 0.44 and HR 0.42, p < 0.001) was confirmed, also with consolidation as time-dependent variable. Competing risk analysis showed similar low incidence of lymphoma-unrelated deaths in consolidated and unconsolidated patients. This study confirms that age, elevated LDH and WHO status increase the mortality risk. HD-AraC containing treatment regimens and consolidation with HD-BCU-TT/ASCT or WBRT were associated with superior survival, including a favorable low incidence of lymphoma-unrelated deaths.

Real-world routine diagnostic molecular analysis for TP53 mutational status is recommended over p53 immunohistochemistry in B-cell lymphomas.

Previous studies in patients with mature B-cell lymphomas (MBCL) have shown that pathogenic TP53 aberrations are associated with inferior chemotherapeutic efficacy and survival outcomes. In solid malignancies, p53 immunohistochemistry is commonly used as a surrogate marker to assess TP53 mutations, but this correlation is not yet well-established in lymphomas. This study evaluated the accuracy of p53 immunohistochemistry as a surrogate marker for TP53 mutational analysis in a large real-world patient cohort of 354 MBCL patients within routine diagnostic practice. For each case, p53 IHC was assigned to one of three categories: wild type (staining 1-50% of tumor cells with variable nuclear staining), abnormal complete absence or abnormal overexpression (strong and diffuse staining > 50% of tumor cells). Pathogenic variants of TP53 were identified with a targeted next generation sequencing (tNGS) panel. Wild type p53 expression was observed in 267 cases (75.4%), complete absence in twenty cases (5.7%) and the overexpression pattern in 67 cases (18.9%). tNGS identified a pathogenic TP53 mutation in 102 patients (29%). The overall accuracy of p53 IHC was 84.5% (95% CI 80.3-88.1), with a robust specificity of 92.1% (95% CI 88.0- 95.1), but a low sensitivity of 65.7% (95% CI 55.7-74.8). These results suggest that the performance of p53 IHC is insufficient as a surrogate marker for TP53 mutations in our real-world routine diagnostic workup of MBCL patients. By using p53 immunohistochemistry alone, there is a significant risk a TP53 mutation will be missed, resulting in misevaluation of a high-risk patient. Therefore, molecular analysis is recommended in all MBCL patients, especially for further development of risk-directed therapies based on TP53 mutation status.

Targeted next-generation sequencing has incremental value in the diagnostic work-up of patients with suspect pancreatic masses; a multi-center prospective cross sectional study.

BACKGROUND: The diagnostic process of patients with suspect pancreatic lesions is often lengthy and prone to repeated diagnostic procedures due to inconclusive results. Targeted Next-Generation Sequencing (NGS) performed on cytological material obtained with fine needle aspiration (FNA) or biliary duct brushing can speed up this process. Here, we study the incremental value of NGS for establishing the correct diagnosis, and subsequent treatment plan in patients with inconclusive diagnosis after regular diagnostic work-up for suspect pancreatic lesions. METHODS: In this prospective cross-sectional cohort study, patients were screened for inclusion in four hospitals. NGS was performed with AmpliSeq Cancer Hotspot Panel v2 and v4b in patients with inconclusive cytology results or with an uncertain diagnosis. Diagnostic results were evaluated by the oncology pancreatic multidisciplinary team. The added value of NGS was determined by comparing diagnosis (malignancy, cystic lesion or benign condition) and proposed treatment plan (exploration/resection, neoadjuvant chemotherapy, follow-up, palliation or repeated FNA) before and after integration of NGS results. Final histopathological analysis or a 6-month follow-up period were used as the reference standard in case of surgical intervention or non-invasive treatment, respectively. RESULTS: In 50 of the 53 included patients, cytology material was sufficient for NGS analysis. Diagnosis before and after integration of NGS results differed in 24% of the patients. The treatment plan was changed in 32% and the diagnosis was substantiated by the NGS data in 44%. Repetition of FNA/brushing was prevented in 14% of patients. All changes in treatment plan were correctly made after integration of NGS. Integration of NGS increased overall diagnostic accuracy from 68% to 94%. INTERPRETATION: This study demonstrates the incremental diagnostic value of NGS in patients with an initial inconclusive diagnosis. Integration of NGS results can prevent repeated EUS/FNA, and can also rigorously change the final diagnosis and treatment plan.

Diagnostic accuracy of MRI in differentiating hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value of gadoxetate disodium.

OBJECTIVE: The purpose of this article is to prospectively determine the sensitivity of hepatobiliary phase gadoxetate disodium-enhanced MRI combined with standard MRI in differentiating focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). SUBJECTS AND METHODS: Patients suspected of having FNH or HCA larger than 2 cm underwent gadoxetate disodium-enhanced MRI. Standard MRI was evaluated separately from the additional hepatobiliary phase by two blinded radiologists. For the largest lesion in each patient, findings were compared with histologic diagnosis. Sensitivity, positive predictive value (PPV), and distinctive features were analyzed using McNemar and analysis of variance tests. RESULTS: Fifty-two patients completed the study. Histologic diagnosis revealed 24 HCAs and 28 FNHs. Characterization on standard MRI was inconclusive in 40% (21/52) and conclusive in 60% (31/52) of lesions. The sensitivity of standard MRI for HCA was 50% (12/24) with a PPV of 100% (12/12). The sensitivity for FNH was 68% (19/28) with a PPV of 95% (18/19). After review of hepatobiliary phase, the sensitivity for HCA improved to 96% (23/24) with a PPV of 96% (23/24). The sensitivity for FNH improved to 96% (27/28) with a PPV of 96% (27/28). Features with significant predictive value for diagnosis in HCA included bleeding (p < 0.001), fat (p = 0.010), and glycogen (p = 0.024). The presence of a central scar was predictive for FNH (p < 0.001). CONCLUSION: This study shows high sensitivity of gadoxetate disodium-enhanced MRI when standard series are combined with the hepatobiliary phase for differentiation of FNH and HCA in lesions larger than 2 cm.

Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir.

BACKGROUND AND AIM: We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg-interferon and adefovir for 48 weeks. METHODS: Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment. RESULTS: Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA < 2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow-up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg ≤ 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%. CONCLUSIONS: At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of < 7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR.

Frequent mutated B2M, EZH2, IRF8, and TNFRSF14 in primary bone diffuse large B-cell lymphoma reflect a GCB phenotype.

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. A total of 103 patients with O-DLBCL were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended)-NanoString/Lymph2Cx analysis. Mutational profiles were identified with targeted next-generation deep sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCLs, were predominantly classified as GCB phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx revealed significantly different GEP clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P < .001). Expression levels of 23 genes of 2 different targeted GEP panels indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB exhibited a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes (ie, B2M, EZH2, IRF8, TNFRSF14) compared with NO-DLBCL-GCB (P = .031, P = .010, P = .047, and P = .003, respectively). PB-DLBCL, with its corresponding specific mutational profile, was significantly associated with a superior survival compared with equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P = .016). This study is the first to show that PB-DLBCL is characterized by a GCB phenotype, with a centrocyte-like GEP pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity, and its specific mutational landscape offers potential for targeted therapies (eg, EZH2 inhibitors).

Focal nodular hyperplasia and hepatic adenoma: epidemiology and pathology.

Focal nodular hyperplasia (FNH) and hepatic adenoma (HA) represent the most frequent non-vascular benign liver tumors. They are often asymptomatic. The widespread use of high-resolution imaging modalities leads to an increase of incidental detection of FNH and HA. Physicians are thus increasingly confronted with these formerly rarely recognized conditions, stressing the need for concise but adequate information on the optimal clinical strategies for these patients. FNH is the most common non-vascular benign tumor of the liver. It probably arises as a polyclonal, hyperplastic response to a locally disturbed blood flow. It is typically found in asymptomatic women. Histologically, FNH can be described as a focal form of cirrhosis. Complications of FNH are extremely rare and surgical resection is generally not advised. HA is a rare monoclonal, but benign liver tumor primarily found in young females using estrogen-containing contraceptives. Although its exact etiology is unknown, a direct link between sex steroid exposure and the uncontrolled hepatocellular growth is suspected. Complications of HA are spontaneous bleeding and malignant transformation. Withdrawal of estrogen treatment and excision of large tumors (>5 cm) are established therapeutic strategies. In conclusion, although FNH and HA are reasonably well-described clinical and histopathological entities, their epidemiology and pathophysiology need to be further unraveled.

Safety and cost analysis of selective histopathological examination following appendicectomy and cholecystectomy (FANCY study): protocol and statistical analysis plan of a prospective observational multicentre study.

INTRODUCTION: Routine histopathological examination following appendicectomy and cholecystectomy has significant financial implications and comprises a substantial portion of the pathologists' workload, while the incidence of unexpected pathology is low. The aim of the selective histopathological examination Following AppeNdicectomy and CholecystectomY (FANCY) study is to investigate the oncological safety and potential cost savings of selective histopathological examination based on macroscopic assessment performed by the surgeon. METHODS AND ANALYSIS: This is a Dutch multicentre prospective observational study, in which removed appendices and gallbladders will be systematically assessed by the operating surgeon for macroscopic abnormalities suspicious for malignant neoplasms. After visual inspection and digital palpation of the removed specimen, the operating surgeon will report whether macroscopic abnormalities suspicious for a malignant neoplasm are present, and if he or she believes additional microscopic examination by the pathologist is indicated. Regardless of the surgeon's assessment, all specimens will be sent for histopathological examination. In this way, routine histopathological examination can be compared with a hypothetical situation in which specimens are routinely examined by surgeons and only sent to the pathologist on indication. The two main outcomes are oncological safety and potential cost savings of a selective policy. Oncological safety of selective histopathological examination will be assessed by calculating the number of patients in whom a histopathological diagnosis of an appendiceal neoplasm or gallbladder cancer with clinical consequences benefitting the patient would have been missed. A cost analysis will be performed to quantify the potential cost savings. ETHICS AND DISSEMINATION: The study protocol was reviewed by the Institutional Review Board of the Amsterdam UMC, location AMC, which decided that the Dutch Medical Research Involving Human Subjects Act is not applicable. In all participating centres, approval for execution of the FANCY study has been obtained from the local Institutional Review Board before the start of inclusion of patients. The study results will be disseminated through peer-reviewed publications and conference presentations. Guidelines will be revised according to the findings of the study. TRIAL REGISTRATION NUMBER: NCT03510923.

Acute Clinical Manifestation of Mesenteric Heterotopic Pancreatitis: A Pre- and Postoperative Confirmed Case.

Heterotopic pancreas is a relatively uncommon congenital anomaly, defined as pancreatic tissue in ectopic sites without an anatomic and vascular continuity with the main body of the pancreas. We report the case of a 58-year-old woman who was admitted to the hospital with the clinical suspicion of a mild, acute pancreatitis. Computed tomography, magnetic resonance imaging, transabdominal ultrasound, and endoscopic ultrasound revealed a normal orthotopic pancreas and the suspicion of a large heterotopic pancreas in the small bowel mesentery with signs of acute inflammation. The diagnosis of mesenteric heterotopic pancreatitis was preoperatively confirmed by endoscopic ultrasound-guided fine-needle aspiration and consequently histologically established after surgical resection.

Noncirrhotic Portal Hypertension in Perinatally HIV-infected Adolescents Treated With Didanosine-containing Antiretroviral Regimens in Childhood.

BACKGROUND: Noncirrhotic portal hypertension (NCPH) has been reported in HIV-infected adults. Antiretroviral drugs, as well as genetic and thrombophilic predisposition, have been suggested as possible etiologic factors. METHODS: Clinical data were collected from 6 HIV-infected patients attending the Infectious Diseases Departments at respectively Emma Children's Hospital Academic Medical Centre in Amsterdam, The Thai Red Cross AIDS Research Centre, Bangkok, Imperial College Healthcare NHS Trust, London who were diagnosed with NCPH. All underwent extensive blood analysis, liver ultrasound, liver elastography, esophagogastroduodenoscopy and percutaneous needle liver biopsy for histological evaluation. RESULTS: We describe 6 perinatally HIV-infected adolescents, all female, who developed NCPH after prolonged exposure during childhood to a didanosine-containing antiretroviral regimen. Histology and electron microscopy showed periportal fibrosis and mitochondrial damage as key findings in their liver biopsies. One of these 6 patients required surgical intervention, the remainder have been managed conservatively to date. CONCLUSIONS: Thus, symptomatic NCPH may present in adolescence after perinatally acquired HIV-1 infection. In this case series, risk factors included female sex and prolonged exposure to antiretroviral regimens that included the nucleoside-analogue didanosine in childhood.