Carmine Tinelli

Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?

If liver transplantation is not feasible, partial resection is considered the treatment of choice for hepatocellular carcinoma (HCC) in patients with cirrhosis. However, in some centers the first‐line treatment for small, single, operable HCC is now radiofrequency ablation (RFA). In the current study, 218 patients with single HCC ≤ 2.0 cm (very early or T1 stage) underwent RFA. We assessed 2 primary end points that could be easily compared with those reported for resective surgery: (1) the rate of sustained, local, complete response and (2) the rate of treatment‐related complications. The secondary end point was 5‐year survival in the 100 patients whose tumors had been considered potentially operable. After a median follow‐up of 31 months, sustained complete response was observed in 216 patients (97.2%). In the remaining 6, percutaneous ethanol injection, selective intraarterial chemoembolization, or resection were used as salvage therapy. Perioperative mortality, major complication, and 5‐year survival rates were 0%, 1.8%, and 68.5%, respectively. Conclusion: Compared with resection, RFA is less invasive and associated with lower complication rate and lower costs. RFA is also just as effective for ensuring local control of stage T1 HCC, and it is associated with similar survival rates (as recently demonstrated by 2 randomized trials). These data indicate that RFA can be considered the treatment of choice for patients with single HCC ≤ 2.0 cm, even when surgical resection is possible. Other approaches can be used as salvage therapy for the few cases in which RFA is unsuccessful or unfeasible. (HEPATOLOGY 2007.)

Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: A pilot study

Real‐time shear wave elastography (SWE) is a novel, noninvasive method to assess liver fibrosis by measuring liver stiffness. This single‐center study was conducted to assess the accuracy of SWE in patients with chronic hepatitis C (CHC), in comparison with transient elastography (TE), by using liver biopsy (LB) as the reference standard. Consecutive patients with CHC scheduled for LB by referring physicians were studied. One hundred and twenty‐one patients met inclusion criteria. On the same day, real‐time SWE using the ultrasound (US) system, Aixplorer (SuperSonic Imagine S.A., Aix‐en‐Provence, France), TE using FibroScan (Echosens, Paris, France), and US‐assisted LB were consecutively performed. Fibrosis was staged according to the METAVIR scoring system. Analyses of receiver operating characteristic (ROC) curve were performed to calculate optimal area under the ROC curve (AUROC) for F0‐F1 versus F2‐F4, F0‐ F2 versus F3‐F4, and F0‐F3 versus F4 for both real‐time SWE and TE. Liver stiffness values increased in parallel with degree of liver fibrosis, both with SWE and TE. AUROCs were 0.92 (95% confidence interval [CI]: 0.85‐0.96) for SWE and 0.84 (95% CI: 0.76‐0.90) for TE (P = 0.002), 0.98 (95% CI: 0.94‐1.00) for SWE and 0.96 (95% CI: 0.90‐0.99) for TE (P = 0.14), and 0.98 (95% CI: 0.93‐1.00) for SWE and 0.96 (95% CI: 0.91‐0.99) for TE (P = 0.48), when comparing F0‐F1 versus F2‐ F4, F0‐ F2 versus F3‐F4, and F0 ‐F3 versus F4, respectively. Conclusion: The results of this study show that real‐time SWE is more accurate than TE in assessing significant fibrosis (≥F2). With respect to TE, SWE has the advantage of imaging liver stiffness in real time while guided by a B‐mode image. Thus, the region of measurement can be guided with both anatomical and tissue stiffness information. (HEPATOLOGY 2012;56:2125–2133)

Central diabetes insipidus in children and young adults

BACKGROUND Central diabetes insipidus is rare in children and young adults, and up to 50 percent of cases are idiopathic. The clinical presentation and the long-term course of this disorder are largely undefined. METHODS We studied all 79 patients with central diabetes insipidus who were seen at four pediatric endocrinology units between 1970 and 1996. There were 37 male and 42 female patients whose median age at diagnosis was 7.0 years (range, 0.1 to 24.8). All patients underwent magnetic resonance imaging (MRI) and periodic studies of anterior pituitary function. The median duration of follow-up was 7.6 years (range, 1.6 to 26.2). RESULTS The causes of the central diabetes insipidus were Langerhans-cell histiocytosis in 12 patients, an intracranial tumor in 18 patients, a skull fracture in 2 patients, and autoimmune polyendocrinopathy in 1 patient; 5 patients had familial disease. The cause was considered to be idiopathic in 41 patients (52 percent). In 74 patients (94 percent) the posterior pituitary was not hyperintense on the first MRI scan obtained, and 29 patients (37 percent) had thickening of the pituitary stalk. Eighteen patients had changes in the thickness of the pituitary stalk over time, ranging from normalization (six patients) or a decrease in thickness (one patient) to further thickening (seven patients) or thickening of a previously normal stalk (four patients). Anterior pituitary hormone deficiencies, primarily growth hormone deficiency, were documented in 48 patients (61 percent) a median of 0.6 year (range, 0.1 to 18.0) after the onset of central diabetes insipidus. CONCLUSIONS Most children and young adults with acquired central diabetes insipidus have abnormal findings on MRI scans of the head, which may change over time, and at least half have anterior pituitary hormone deficiencies during follow-up.

Predictors of Long-Term Survival After Liver Transplantation for Hepatocellular Carcinoma

AIMS:The aim of this study was to identify predictors of both survival and tumor-free survival of a cohort of 155 patients, with hepatocellular carcinoma (HCC) and cirrhosis, who were treated by orthotopic liver transplantation (OLT).METHODS:From January 1989 to December 2002, 603 OLTs were performed in 549 patients. HCC was diagnosed in 116 patients before OLT and in 39 at histological examination of the explanted livers. Eighty-four percent of the patients met “Milan” criteria at histology. Ninety-four patients received anticancer therapies preoperatively.RESULTS:The median follow-up was 49 months (range, 0–178). Overall, 1-, 3-, 5-, and 10-yr survival were 84%, 75%, 72%, and 62%, respectively. Survival was not affected by the patients age or sex, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number, total tumor burden, bilobar tumor, and pathologic Tumor, Nodes, Metastasis (pTNM) stages. There was no statistically significant difference in survival when patients were grouped according to the recently proposed simplified pTNM staging (5-yr survival, 80% in stage I, 69% in stage II, 50% in stage III, p = 0.3) or the United Network for Organ Sharing (UNOS) staging system for HCC. Encapsulation of the tumor and α-fetoprotein levels significantly affect patient survival. Five-year survival of patients with poorly differentiated (G3) HCC was significantly worse than that of patients with moderately (G2) or well-differentiated (G1) HCC (respectively, G3 44%, G2 67%, and G1 97%, p = 0.0015). Patients with micro- or macro-vascular invasion had a worse 5-yr survival than patients without vascular invasion (49% vs 77%, p = 0.04). Multivariate analysis showed that histological grade of differentiation and macroscopic vascular invasion are independent predictors of survival (HR 2.4, 95% CI 1.4–4.1, p = 0.0009 and HR 2.8, 95% CI 1.2–6.8, p = 0.022).CONCLUSION:Histological grade of differentiation and macroscopic vascular invasion, as assessed on the explanted livers, are strong predictors of both survival and tumor recurrence in patients with cirrhosis who received transplants for HCC.

Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity.

OBJECTIVE To evaluate the reproducibility of real-time shear wave elastography in assessing liver elasticity in healthy volunteers. METHODS Forty-two volunteers were studied in day 1. Shear wave elastography studies were performed by using the ultrasound system Aixplorer™ (SuperSonic Imagine S.A., Aix-en-Provence, France) with a convex broadband probe. Measurements were carried by two operators, an expert (operator 1) and a novice (operator 2). Examinations were performed on the right lobe of the liver. Each operator performed 10 consecutive measurements in each volunteer. In a subset of volunteers (n=18) measurements were performed twice on two different days (day 1 and day 2). Intraobserver and interobserver agreement were assessed by intraclass correlation coefficient. RESULTS Intraobserver agreement between measurements performed in the same subject in the same day (day 1 or day 2) showed intraclass correlation coefficient values of 0.95 (95% confidence interval, 0.93-0.98) and 0.93 (95% confidence interval, 0.90-0.96) for operator 1 and operator 2, respectively. Intraobserver agreement between measurements performed in the same subject in different days showed intraclass correlation coefficient values of 0.84 (95% confidence interval, 0.69-0.98) and 0.65 (95% confidence interval, 0.39-0.91) for operator 1 and operator 2, respectively. Interobserver agreement was 0.88 (95% confidence interval, 0.82-0.94). CONCLUSIONS The results of this study show that shear wave elastography is a reliable and reproducible noninvasive method for the assessment of liver elasticity. Expert operator had higher reproducibility of measurements over time than novice operator.

Matrix Metalloproteinase-2, -9, and Tissue Inhibitor of Metalloproteinase-1 in Patients with Hypertension

There are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase (MMP) system and their inhibitors (TIMPs) in human hypertension. The authors hypothesized that MMP-2, MMP-9, and TIMP-1 would be abnormal in hypertension, reflecting alterations in extracellular matrix (ECM) turnover. The authors measured plasma levels and activities of MMP-2, MMP-9, and TIMP-1 in 44 hypertensive patients and 44 controls. MMP-2 levels and activity were significantly higher in hypertensive group (p < .0001). Significant increase was also observed for MMP-9 level and activity (p < .0001) and for TIMP-1 (p < .0001) in hypertensive patients. Plasma levels and activities of MMP-2, MMP-9, and TIMP-1 are increased in hypertensive patients, which may reflect abnormal ECM metabolism.

Altered intercellular glycoconjugates and dilated intercellular spaces of esophageal epithelium in reflux disease

Abstract Background and aims: The usefulness of histological diagnosis of gastroesophageal reflux disease (GERD) is limited by poor specificity or sensitivity of available diagnostic tools. Recently, ultrastructural morphometry showed interstitial space dilation (ISD) to be a reliable sign of reflux disease. Aims of this study were to (a) search for a light microscopy equivalent of ISD, (b) test its diagnostic value, and (c) look for a possible role of intercellular glycoconjugates in its genesis. Methods: Esophageal grasp biopsies were taken during endoscopy, 2–3 cm and 6–7 cm above the squamo- columnar junction, from patients under investigation for GERD symptoms. The biopsies were fixed in aldehyde solutions and embedded in resin for electron microscopy or in paraffin for routine histology, and the glycoconjugates underwent immunohistochemistry using 3-fucosyl-N-acetylactosamine antibodies. Results: Irregular intercellular space dilation was detected in the basal and prickle layers using both light and electron microscopy. Hematoxylin–eosin preparations showed ISD in 20 of 22 (90%) erosive esophagitis cases, 30 of 44 (68%) endoscopy negative GERD cases, and 1 of 12 (8%) controls, with good interobserver (K=0.75) and bioptic site reproducibility. ISD correlated with loss or rearrangement of intercellular glycoconjugates of the overlying layers and with granulocyte (eosinophil and/or neutrophil) infiltration. Conclusions: Light microscopy ISD is a suitable index of GERD. Alterations of intercellular glycoconjugates are likely to have a role in the genesis of ISD and GERD.

Contrast-Enhanced Versus Conventional and Color Doppler Sonography for the Detection of Thrombosis of the Portal and Hepatic Venous Systems

OBJECTIVE We conducted a prospective study to compare sonography, color Doppler sonography, and contrast-enhanced sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancies. SUBJECTS AND METHODS Three hundred sixteen patients with biopsy-proved hepatic tumors were studied at baseline and 3 months later with sonography, color Doppler sonography, and contrast-enhanced sonography. Thrombosis was defined as the presence of intraluminal echogenic material at sonography, absence of intraluminal color signals at color Doppler sonography, and presence of nonenhancing intraluminal area at contrast-enhanced sonography. Thrombi were considered malignant if they displayed continuity with tumor tissue at sonography, intrathrombus color signals at color Doppler sonography, and enhancing signals at contrast-enhanced sonography, both having arterial waveforms at Doppler spectral examination. Definitive diagnoses were obtained by sonographically guided biopsy except for thrombi displaying at conventional sonography unequivocal continuity with tumor tissue. RESULTS Thrombosis was detected in 79 (25.0%) of 316 patients at baseline and in 83 (26.3%) of 316 patients after 3 months. Eighty-one (97.6%) of the 83 thrombi were malignant. Definitive diagnosis was performed by imaging in 60 (72.3%) of the 83 cases and by biopsy in 23 cases (27.7%). For thrombus detection, contrast-enhanced sonography displayed significantly higher sensitivity than color Doppler sonography (p = 0.004) and borderline superiority over sonography (p = 0.058). For thrombus characterization, contrast-enhanced sonography was significantly more sensitive than color Doppler sonography (p < 0.0005) and conventional sonography (p = 0.02). CONCLUSION Contrast-enhanced sonography is superior to sonography and color Doppler sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancies.

Etiology and age incidence of precocious puberty in girls: a multicentric study.

We review the etiology and age incidence of precocious puberty in 438 girls examined between 1988-1998; 428 (97.7%) had central precocious puberty (CPP), the remaining 10 (2.3%) gonadotropin-independent precocious puberty (GIPP) of ovarian origin. The majority of CPP girls (59.6%) were aged between 7-7.9 yr, 22.4% were 6 year olds, and only 18% were under 6 years old. Cranial CT and/or MRI performed in 304/428 girls, showed neurogenic abnormalities in 56/304 (18.4%) CPP girls; 30 (9.9%) were due to previously diagnosed intracranial abnormalities and the remaining 26 (8.5%) were detected at the diagnosis of CPP. The frequency of neurogenic CPP tended to be higher in girls under 4 years of age while the frequency of idiopathic CPP tended to be higher in girls aged between 7-7.9 years, but no statistically significant differences were found. Interestingly, some CNS anomalies either of tumoral or congenital origin were detected at presentation in 7% of the girls aged over 7 years. Other related or coincidental clinical anomalies, mainly due to genetic diseases, were observed in 22/304 (7.2%) patients. History of precocious maternal menarche was found in 12/304 (4%) girls. In conclusion, idiopathic CPP was observed in 74% of the girls in this study. Neurogenic anomalies or other coincidental or related clinical findings were observed in the remaining 26%. The increased frequency of idiopathic CPP in girls aged over 7 years may suggest an early, but otherwise normal onset of puberty in many of these girls as a consequence of the trend towards earlier maturation. Nonetheless, the finding of CNS anomalies also in the older patients, raises the question of whether these patients should undergo a complete diagnostic work-up.

Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: A long‐term cohort study

In most patients with cirrhosis, successful percutaneous ablation or surgical resection of hepatocellular carcinoma (HCC) is followed by recurrence. Radiofrequency ablation (RFA) has proven effective for treating HCC nodules, but its repeatability in managing recurrences and the impact of this approach on survival has not been evaluated. To this end, we retrospectively analyzed a prospective series of 706 patients with cirrhosis (Child‐Pugh class ≤B7) who underwent RFA for 859 HCC ≤35 mm in diameter (1‐2 per patient). The results of RFA were classified as complete responses (CRs) or treatment failures. CRs were obtained in 849 nodules (98.8%) and 696 patients (98.5%). During follow‐up (median, 29 months), 465 (66.8%) of the 696 patients with CRs experienced a first recurrence at an incidence rate of 41 per 100 person‐years (local recurrence 6.2; nonlocal 35). Cumulative incidences of first recurrence at 3 and 5 years were 70.8% and 81.7%, respectively. RFA was repeated in 323 (69.4%) of the 465 patients with first recurrence, restoring disease‐free status in 318 (98.4%) cases. Subsequently, RFA was repeated in 147 (65.9%) of the 223 patients who developed a second recurrence after CR of the first, restoring disease‐free status in 145 (98.6%) cases. Overall, there were 877 episodes of recurrence (1‐8 per patient); 577 (65.8%) of these underwent RFA that achieved CRs in 557 (96.5%) cases. No procedure‐related deaths occurred in 1,921 RFA sessions. Estimated 3‐ and 5‐year overall and disease‐free (after repeated RFAs) survival rates were 67.0% and 40.1% and 68.0 and 38.0%, respectively. Conclusion: RFA is safe and effective for managing HCC in patients with cirrhosis, and its high repeatability makes it particularly valuable for controlling intrahepatic recurrences. (HEPATOLOGY 2011)