[Impact of partial nephrectomy in a hybrid operating room on the activity of kidney cancer surgery]. / Évaluation de l'utilisation de la salle hybride sur l'activité de chirurgie en cancérologie rénale.

INTRODUCTION: Partial nephrectomy (NP) after embolization of tumor vessels (NPESH) in a hybrid room combines embolization of tumor vessels and enucleation of the tumor under laparoscopy in the same operative time. The purpose of this study was to assess the impact of the use of NPESH in the management of patients treated with surgery for a localized kidney tumor. MATERIAL AND METHODS: Using the uroCCR database, we included all consecutive patients operated in a university hospital for localized kidney tumor. From 2011 to May 2015, patients were treated by Standard Partial Nephrectomy (NPS) Laparoscopic or Open and from May 2015 to May 2019 by NPESH. We evaluated characteristics of patients, tumors, perioperative data and complications. These data were compared by Student and Khi2 tests. RESULTS: 87 NPS were performed during Period 1 and 137 NPS were performed during period 2. The ASA score of patients undergoing NPESH was higher than NPS (P<0.0001). The tumor complexity and median tumor size were similar in the two groups (P=0.852 and P=0.48). The complication rate for NPS and NPESH was 55.2% and 33.6% (P=0.002). There were less severe complications in the NEPSH group (P=0.012). The median length of stay was 8 and 4 days for the NPS and NPESH groups (P<0.0001). Positive surgical margins were 2 (2.3%) and 6 (4.6%) for the NPS and NPESH group (P=0.713). DISCUSSION: NPESH is an efficient technique compared to NPS. It seems to be an interesting alternative to limit renal ischemia, complication rate and length of stay for the management of localized kidney tumors.

Circulating Cd34+ cell count differentiates primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms: a pragmatic study.

A high number of circulating CD34+ cells has been advocated to distinguish primary myelofibrosis from other Philadelphia-negative myeloproliferative neoplasms. We re-evaluated the diagnostic interest of measuring circulating CD34+ cells in 26 healthy volunteers and 256 consecutive patients at diagnosis for whom a myeloproliferative neoplasm was suspected. The ROC curve analysis showed that a number of CD34+ <10/µl excludes the diagnosis of primary myelofibrosis with a sensitivity of 97 % and a specificity of 90 % (area under the curve: 0.93 [0.89-0.98]; p < 0.001). Patients with PMF harboring a CALR mutation had more circulating CD34+ cells than patients with either a JAK 2 or MPL mutation (p = 0.02 and p < 0.01, respectively). These results suggest that this fast, simple, non-invasive, and standardized test is of particular interest to exclude the diagnosis of primary myelofibrosis.

Treatment of liver fibrosis: clinical aspects.

The main objective of antifibrotic treatment is to avoid the complications of chronic liver disease where its cause cannot be treated. Three main therapeutic endpoints can be targeted: cause; comorbidity; and fibrosis. Antifibrotic treatment is any intervention independent of cause that is intended to modify the course and/or level of fibrosis through direct action on the mechanisms of fibrosis. Several modalities are here considered: reduction of fibrosis course; reversion of fibrosis; and reversion of cirrhosis. Semiquantitative histological staging and morphometry are complementary techniques for monitoring fibrosis. The degree of fibrosis should preferentially be estimated by fibrosis progression based on measurements taken at baseline and during treatment, rather than by raw static measurements. Surrogate markers are the only tools for assessing drug efficacy in clinical practice, and are especially useful for checking compliance and identifying poor or non-responders. We propose to define non-response as no decrease in fibrosis progression. The renin-angiotensin system is a good candidate target for antifibrotic treatment, and angiotensin-II type-1 receptor blockers, such as sartans, are probably effective. Clinical trials are currently ongoing using marketed drugs, while new multitargeted drugs are likely to emerge from basic research.

Evaluation and improvement of a reliable diagnosis of cirrhosis by blood tests.

OBJECTIVE: To evaluate the rates of reliable diagnosis of cirrhosis by two usual blood tests. METHODS: Reliable diagnosis was mainly evaluated by comparing rates of positive (PPV) and negative (NPV) predictive values with FibroTest and FibroMeters, as either standard test or specifically designed for cirrhosis, in 1056 patients with chronic hepatitis C. RESULTS: Using the diagnostic limits provided by fibrosis stage scales, the PPV for cirrhosis was: standard FibroMeters: 68.5% versus FibroTest: 37.1%. Using 95% PPV, the cirrhosis detection rate was: specific FibroMeter: 26.1% versus FibroTest: 2.0% (P<10(-3)). The cirrhosis detection rate increased from 26 to 65% by performing liver biopsy in 8% of patients with indeterminate results on specific FibroMeter between 95% NPV and PPV. On the other hand, specific FibroMeter provided three intervals of 95% reliable diagnosis with no biopsy: less than or equal to 95% NPV: no cirrhosis (threshold: diagnosis); significant fibrosis; and greater than or equal to 95% PPV: cirrhosis. CONCLUSION: The detection rate and PPV for cirrhosis using fibrosis scales were fair for standard FibroMeter and poor for FibroTest. Around one-fourth of cases of cirrhosis are detected by the 95% PPV of specific FibroMeter, and around two-thirds by performing an additional liver biopsy in only 8% of patients. Finally, specific FibroMeter can avoid liver biopsy by classifying patients into three categories: no cirrhosis; significant fibrosis; and cirrhosis.

FibroMeters: a family of blood tests for liver fibrosis.

FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.

BACKGROUND: The composite histological endpoint comprising nonalcoholic steatohepatitis (NASH) and NAFLD activity score ≥4 and advanced fibrosis (F ≥ 2) ("fibrotic NASH") is becoming an important diagnostic target in NAFLD: it is currently used to select patients for inclusion in phase III therapeutic trials and will ultimately be used to indicate treatment in clinical practice once the new drugs are approved. AIM: To develop a new blood test specifically dedicated for this new diagnostic target of interest. METHODS: Eight Hundred and forty-six biopsy-proven NAFLD patients from three centres (Angers, Nice, Antwerp) were randomised into derivation and validation sets. RESULTS: The blood fibrosis tests BARD, NFS and FIB4 had poor accuracy for fibrotic NASH with respective AUROC: 0.566 ± 0.023, 0.654 ± 0.023, 0.732 ± 0.021. In the derivation set, fibrotic NASH was independently predicted by AST, HOMA and CK18; all three were combined in the new blood test MACK-3 (hoMa, Ast, CK18) for which 90% sensitivity and 95% specificity cut-offs were calculated. In the validation set, MACK-3 had a significantly higher AUROC (0.847 ± 0.030, P ≤ 0.002) than blood fibrosis tests. Using liver biopsy in the grey zone between the two cut-offs (36.0% of the patients), MACK-3 provided excellent accuracy for the diagnosis of fibrotic NASH with 93.3% well-classified patients, sensitivity: 90.0%, specificity: 94.2%, positive predictive value: 81.8% and negative predictive value: 97.0%. CONCLUSION: The new blood test MACK-3 accurately diagnoses fibrotic NASH. This new test will facilitate patient screening and inclusion in NAFLD therapeutic trials and will enable the identification of patients who will benefit from the treatments once approved.

Fibrinogen angers with a new deletion (gamma GVYYQ 346-350) causes hypofibrinogenemia with hepatic storage.

INTRODUCTION: This study reports a family with chronically abnormal blood liver function tests (LFT) and congenital hypofibrinogenemia. The proposita had cirrhosis initially related to alcohol abuse and chronic viral hepatitis C (HCV), but abnormal LFT persisted even when alcohol intake was stopped and despite HCV treatment was efficient based on serum RNA negative testing. RESULTS: Needle biopsy specimens of the proposita and her brother showed eosinophilic intra-cytoplasmic inclusions that reacted strongly with fibrinogen antisera on direct immunofluorescence. Electron microscopic examination showed that the rough endoplasmic reticulum was filled with inclusions that consisted of densely packed, curved tubular structures arranged in a fingerprint-like pattern. Coagulation studies revealed low functional and antigenic fibrinogen concentrations suggestive of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous deletion of the a7690 to g7704 nucleotides of the gamma chain gene in the 3'end of exon 8 (g 7690_7704del14; Genbank access M10014); this deletion encompassed the splicing site at position 7703 and predicts in a new putative consensus splicing sequence (AATGgtatgtt). RNA was extracted from a liver specimen from the proposita's brother. The cDNA obtained by reverse transcription polymerase chain reaction confirmed the usage of a newly generated donor site at position 7688 of the genomic sequence resulting in an in-frame heterozygous 5 amino acid deletion (GVYYQ 346-350; p.G372_Q376del) and that this mutation is responsible for a new splicing site at position 7688 of the genomic sequence. CONCLUSION: we suggest that the molecular defect in fibrinogen Angers results in an impaired assembly and causes defective secretion and hepatic storage of fibrinogen.

[Tumor like presentation of primitive amyloidosis: amyloidoma]. / Forme pseudotumorale d'une amylose primitive: l'amyloïdome.

INTRODUCTION: AL-amyloidosis is a rare disease due to monoclonal immunoglobulin deposits, secondary to lymphoproliferative disorder or primitive. The deposits of amyloidosis have usually a systemic repartition. We report a tumor like presentation of amyloidosis, so-called amyloidoma. EXEGESIS: A 72-year old woman lost 10 kg within 6 months, associated with epigastric and mediastinal bulks. The biopsy of the abdominal mass showed AL-amyloidosis with kappa light chains. Since no secondary etiology could be found, the final diagnosis of primary AL-amyloidosis in a tumour like presentation, or amyloidoma, was performed. Investigations showed cardiac involvement with MRI findings, as well as kidney and bone marrow involvement. Oral melphalan as monotherapy was administered. The prognosis and the treatment of this unusual disease are discussed. CONCLUSION: Amyloidoma is a rare presentation of amyloidosis which should be evocated in front of a soft tissue mass with no clear etiology.

[Intracranial ependymomas in adult patients. Diagnosis and histological prognostic factors]. / Ependymomes intracrâniens de l'adulte. Diagnostic histologique et facteurs histopronostiques.

BACKGROUND: Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined. PURPOSE: A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology. MATERIAL: Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper). METHODS: Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index. RESULTS: Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study.

We report a prospective quantitative image analysis study of C cells in 57 normal autopsy thyroid glands, serially sectioned and wholly embedded in paraffin; all slides were immunohistochemically stained for calcitonin. Computerized quantitative image analysis was performed on 47 cases to measure C cell surface area and parenchymatous surface area after immunoperoxidase staining for calcitonin. The method was time-effective, with a good reproducibility. C cells were mainly found in the middle third of each lobe. Important inter-individual variations were observed; the maximum C cell surface area in a section (Amax) ranged from 28 x 10(3) to 470 x 10(3) microns2 (mean, 167 x 10(3) microns2) among 42 adults. Of particular interest was the important difference observed between sexes; Amax was twice as high in men (mean, 201 x 10(3) microns2) as in women (mean, 91 x 10(3) microns2; P = 0.0009). Moreover, 14 (33%) adult subjects [2 women (15%) and 12 men (41%)] fulfilled C cell hyperplasia criteria, i.e. at least 3 fields at x 100 magnification containing more than 50 C cells, suggesting that a substantial part of the normal adult population could have C cell hyperplasia.

Contribution of immunohistochemistry, electron microscopy, and cell culture to the characterization of nonfunctioning pituitary adenomas: a study of 40 cases.

We studied 40 endocrinologically inactive pituitary adenomas by immunohistochemistry, electron microscopy, and cell culture in order to determine the incidence of gonadotropic adenomas and to classify nonfunctioning adenomas. Immunohistochemical studies using a large panel of monoclonal and polyclonal antibodies identified the following nonfunctioning adenomas: 20 gonadotropic adenomas, four silent corticotropic adenomas, one plurihormonal adenoma, and 15 nonsecreting adenomas. Among nonsecreting adenomas, ultrastructural study of 13 cases identified seven null cell adenomas and six oncocytomas. Silent corticotropic adenomas were classified into subtypes I, II, and III according to Kovacs and Horvath. Most often, gonadotropic adenomas displayed a varying number of oncocytic cells, characteristic secretory granules, and a prominent Golgi apparatus. Postembedding immunoelectron microscopy was performed on eight gonadotropic or nonsecreting adenomas, but this technique did not provide any additional information. Six gonadotropic adenomas and 10 so-called nonsecreting adenomas were studied in primary cell cultures. The six gonadotropic adenomas and seven of the 10 nonsecreting adenomas released gonadotropins in the culture medium. The use of in vitro results as a supplementary diagnostic criterion allowed classification of the 40 nonfunctioning adenomas as follows: 27 gonadotropic adenomas, four silent corticotropic adenomas, one plurihormonal adenoma, and eight nonsecreting adenomas. These results demonstrate a high proportion of gonadotropic adenomas among nonfunctioning adenomas (67.5%) and the usefulness of several techniques in characterizing this type of pituitary adenoma.

Stenotic intimal thickening of the external iliac artery in competition cyclists.

Twenty-three cases of an arterial disease that affects competition cyclists are reported. Patients complained of intermittent acute claudication appearing on one lower limb only at the time of a maximal strain while cycling. Doppler hemodynamic investigation on an ergometric bicycle revealed a collapse of the ankle systolic pressure. Arteriography showed a sinuous lengthening and moderate stenosis of the external iliac artery. Pathologic examination of the artery disclosed a stenotic intimal thickening due to moderately cellular loose connective tissue with a variable distribution of collagen and elastic fibers. The cells in the affected zone were readily labeled with anti-actin and anti-myosin antibodies, and electron microscopy revealed features of synthetic smooth muscle cells. The lesion observed differs from intimal fibrodysplasia and from artherosclerosis. Abnormal local hemodynamic conditions may lead to this type of lesion. Thus, stenotic intimal thickening of the external iliac artery appears to be a new arterial disease defined by clinical, arteriographic, and pathologic features.

C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (X400) and the number of low-power magnification (X100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm2. C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

Splenic lymphoma with circulating villous lymphocytes. Report of a case with immunologic and ultrastructural studies.

A case of splenic lymphoma with circulating villous lymphocytes is reported. Short surface cellular expansions were observed on blood and marrow films and by transmission electron microscopy. The immunophenotype was that of mature B cells without CD5, CD10, CD11c, or CD25 expression or tartrate-resistant acid phosphatase. Despite a basophilic plasmacytoid-like cytoplasm, this case of splenic lymphoma with circulating villous lymphocytes differed from splenic immunocytoma in that immunofluorescence and ultrastructure suggested that the neoplastic cells did not possess high levels of intracytoplasmic immunoglobulin. Treatment of cytopenia was best achieved by splenectomy and the total follow-up thus far (30 months) seems to indicate a case of low-grade malignant lymphoma.

Primary Epstein-Barr virus infection with clonal T-cell lymphoproliferation.

A case of fatal Epstein-Barr virus infection in a previously healthy girl who was first found to have severe infectious mononucleosis with spontaneous recovery is reported. Because an abnormal immune response to the virus persisted, the disease relapsed, manifesting in cutaneous and pulmonary lesions associated with hemophagocytic syndrome responsible for death. Pathologic findings were characterized by polymorphous atypical lymphoid infiltrate, prominent necrosis, and histiocytic hyperplasia. Lymphoid cells displayed CD8 phenotype and clonal T-cell receptor gene rearrangement. Viral genome was detected in lesions by Southern blot and located in nuclei of lymphoid cells by in situ hybridization. Pathologic findings suggested fatal infectious mononucleosis; however, phenotype and genotype favored a malignant diagnosis. Clonality was demonstrated to have arisen during primary infection. Virologic examination indicated that Epstein-Barr virus was a causative agent. Such a process belongs to the recently recognized spectrum of Epstein-Barr virus-related T-cell lymphoproliferative disorders that might overlap fatal infectious mononucleosis in patients who are especially vulnerable to the virus.

Primary central nervous system lymphomas in 72 immunocompetent patients: pathologic findings and clinical correlations. Groupe Ouest Est d'étude des Leucénies et Autres Maladies du Sang (GOELAMS)

We reviewed 72 primary central nervous system lymphomas occurring in immunocompetent patients. The cases were reviewed for clinical data, histology, immunophenotype, bcl-2 and p53 expression, and Epstein-Barr virus association. Follow-up was available for 40 patients included in the Groupe Ouest Est d'étude des Leucénies et Autres Maladies du Sang (GOELAMS) lymphomes cérébraux primitifs (LCP 88) trial. Each diagnosis, requiring a consensus among at least 3 pathologists, was performed according to the recent Revised European-American Lymphoma classification and equivalents in the updated Kiel classification. Tumors were predominantly classified as diffuse large B-cell lymphomas. There were 3 T-cell lymphomas and 1 Hodgkin lymphoma. The proteins bcl-2 and p53 were expressed in 35% and 16% of the tested cases, respectively. Epstein-Barr virus was not found by in situ hybridization except in the case classfied as a cerebral localization of Hodgkin disease. No significant association was found between subtypes, bcl-2 or p53 expression, and patient survival. From the standpoint of their biologic characteristics, primary central nervous system lymphomas are very similar to systemic diffuse large B-cell lymphomas. In contrast to AIDS-related primary central nervous system lymphomas, primary central nervous system lymphomas are rarely associated with Epstein-Barr virus and in immunocompetent patients they express bcl-2 at a relatively low rate.

Investigation of bound water in frozen precancerous rat liver tissue by proton NMR.

The proton NMR spin lattice relaxation times of bound water (T1b) were studied on frozen rat liver samples during the precancerous step of cancer induction by diethylnitrosamine. Two components of the T1b were found, which show a different temperature dependence of their relative magnetization. Four different steps were identified during the experimental cancer induction according to 1H NMR findings, while only three were distinguished after histological examination. The results point to the influence of cross-relaxation and corroborate previous reports on differences observed between the heat capacity of normal and tumorous tissues.

Late recurrence of a hepatic angiomyolipoma.

Angiomyolipomas are benign mesenchymal tumours, mostly of renal origin. Hepatic angiomyolipomas are rare, and radiological and pathological diagnoses may be difficult We report on the first case of hepatic angiomyolipoma recurrence known to us, 6 years after surgical treatment of the initial tumour. Moreover, this hepatic recurrence was associated with renal angiomyolipoma without any stigmata of tuberous sclerosis.

Hepatic hyper-vitaminosis A: importance of retinyl ester level determination.

We report the case of a 32-year-old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol-binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri-sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper-vitaminosis A may be normal and lead to under-estimation of liver vitamin A overload.

A case of temporal arteritis with intrahepatic arterial involvement.

We report a case of temporal arteritis associated with anicteric cholestasis. Serial sections of a transthoracic needle biopsy of the liver revealed giant-cell arteritis in medium-sized hepatic arteries and cholangitis in adjacent bile ducts. The literature reveals that similar pathologic features have only exceptionally been observed in liver biopsies. These lesions may account for liver function disturbances commonly seen in temporal arteritis or polymyalgia rheumatica.