Guido Alberto Massimo Tiberio

Early and Late Recurrence After Liver Resection for Hepatocellular Carcinoma: Prognostic and Therapeutic Implications

Objective:To evaluate the predictive factors, the therapy, and the prognosis of intrahepatic recurrence (IR) after surgery for hepatocellular carcinoma (HCC). Summary Background Data:The predictive factors of IR are debated. To class the recurrence according to the modality of presentation may help to find a correlation and to select the right therapy for the recurrence. Methods:A total of 213 patients were evaluated. Risk factors for recurrence were related to time (<2 years and >2 years) and type of presentation (marginal, nodular, and diffuse). Prognosis and therapy for the recurrence were studied in each group of patients. Results:IR was observed in 143 patients; 109 were early (group 1) and 34 late recurrences (group 2). Cirrhosis, chronic active hepatitis (CAH) and HCV positivity were independently related to the risk of recurrence with a cumulative effect (92.5% of recurrences in patients with 3 prognostic factors). For group 1, the neoplastic vascular infiltration together with cirrhosis, HCV positivity, CAH, and transaminases were significant; all the 11 patients with 5 negative prognostic factors showed an early recurrence. On the contrary, only cirrhosis was related to a late recurrence. Survival rate was significantly better in late than in early recurrence (61.9%, 27.1% and 25.7%, 4.5% at 3–5 years); a curative procedure was performed in 67.6% in group 1 and 29.3% in group 2. After a radical treatment of IR, the survival was comparable with the group of patients without recurrence. Conclusions:Early and late recurrences are linked to different predictive factors. The modality of presentation of the recurrence together with the feasibility of a radical treatment are the best determinants for the prognosis.

Vascular Remodeling and Duration of Hypertension Predict Outcome of Adrenalectomy in Primary Aldosteronism Patients

Remodeling of the resistance arteries is a hallmark of arterial hypertension and predicts cardiovascular events, but it was unknown whether it could also predict the blood pressure response to adrenalectomy of patients with an aldosterone-producing adenoma. Therefore, we investigated the outcome of adrenalectomy as a function of vascular remodeling in the context of the preoperative features of aldosterone-producing adenoma patients. At 2 referral centers for hypertension, we prospectively measured the media:lumen ratio of small arteries from fat tissue of 50 consecutive aldosterone-producing adenoma patients treated with adrenalectomy. The blood pressure response to adrenalectomy was assessed by considering the blood pressure values and the number and dosages of antihypertensive medications. Adrenalectomy significantly (P<0.001) lowered plasma aldosterone (from 27.3±4.9 ng/dL to 8.3±11.2 ng/dL), the aldosterone:renin ratio (from 117±35 to 11±2), and blood pressure (from 163±22/98±2 mm Hg to 133±2/84±1 mm Hg), even despite a reduction (from 141±14 to 100±15; P=0.02) of the score of antihypertensive treatment. It provided cure of hypertension in 30% of the aldosterone-producing adenoma patients, normotension with less antihypertensive therapy in 52%, and improved blood pressure control in the rest. The media:lumen ratio and the known duration of hypertension significantly predicted the blood pressure response to adrenalectomy at univariate and multivariate analyses. Because a long duration of hypertension and/or the presence of vascular remodeling imply lower chances of blood pressure normalization at long-term follow-up postadrenalectomy, these findings emphasize the importance of an early diagnosis of aldosterone-producing adenoma.

Endothelial dysfunction in small resistance arteries of patients with non-insulin-dependent diabetes mellitus

Objective Arterial hypertension is frequently associated with the presence of endothelial dysfunction in human subcutaneous small resistance arteries, as evaluated by responses to acetylcholine or bradykinin; however it is not known whether patients with diabetes mellitus show similar alterations. Therefore, we have investigated endothelial function in subcutaneous arteries of normotensive subjects (NT), of patients with essential hypertension (EH), of patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as of patients with both essential hypertension and non-insulin-dependent diabetes mellitus (NIDDM + EH). Patients and methods All subjects were submitted to a biopsy of the subcutaneous fat. Small arteries were dissected and mounted on a micromyograph. The media to lumen ratio (M/L) was calculated. A concentration-response curve to acetylcholine, to bradykinin as well as to the endothelium-independent vasodilator sodium nitroprusside were performed. We also evaluated the contractile response to endothelin-1. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) plasma levels were also measured. Results The vasodilatation to acetylcholine and bradykinin (but not to sodium nitroprusside) was significantly and similarly reduced in EH, in NIDDM, and in NIDDM + EH compared with NT. The contractile response to endothelin-1 was similarly reduced in EH, in NIDDM and in NIDDM + EH. Plasma ICAM-1 and VCAM-1 concentrations were higher in EH, NIDDM and NIDDM + EH than in NT. Conclusions An evident endothelial dysfunction was detected in patients with NIDDM, and the simultaneous presence of EH did not seem to exert an additive effect. The contractile responses to endothelin-1 were reduced possibly as a consequence of ETA receptor down-regulation.

Relationship between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry.

Background: Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, are frequently present in hypertensive and/or diabetic patients, and may represent the earliest alteration observed. Furthermore, media-to-lumen ratio of small arteries evaluated by micromyography has a strong prognostic significance; however, its extensive evaluation is limited by the invasivity of the assessment, since a biopsy of subcutaneous fat is needed. Noninvasive measurement of wall-to-lumen of retinal arterioles using scanning laser Doppler flowmetry (SLDF) has recently been introduced. However, this new technique has not yet been compared to micromyographic measurement, generally considered the gold standard approach. Methods and results: We investigated 40 individuals and patients, 24 of them were hypertensive patients and 16 normotensive individuals. All patients underwent a biopsy of subcutaneous fat during an elective surgical intervention. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and media-to-lumen ratio was measured. In addition, an evaluation of wall-to-lumen ratio of retinal arterioles by SLDF was performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). A close correlation was observed between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles (r = 0.76, P < 0.001; P < 0.001, r2 = 0.57). Conclusion: A noninvasive and easily repeatable procedure (intraobserver and interobserver variation coefficient <13%) such as an evaluation of the arterioles in the fundus oculi by SLDF may provide similar information regarding microvascular morphology compared with an invasive, accurate and prognostically relevant micromyographic measurement of media-to-lumen ratio of subcutaneous small arteries.

Heterogeneous expression of toll-like receptors in lymphatic endothelial cells derived from different tissues

As lymphatic endothelial cells (LECs) express different lymphatic and vascular markers depending on the organ they are derived from, we analysed whether they also show a heterogeneity of response against pathogens. To this end we analysed, for the presence of mRNA encoding for all human toll‐like receptor (TLR), LECs isolated from lymph nodes and thymuses. RNA for TLR1–6 and 9 was identified in thymus‐derived cells, whereas cells derived from lymph nodes contained mRNA for TLR1–4, 6 and 9, but failed to express mRNA specific for TLR5. The differential expression of TLRs was confirmed by the phosphorylation of nuclear factor‐κB p65 only when the two types of LECs were incubated with the appropriate TLR agonists. The stimulation with specific agonists gives rise to a heterogeneous pattern of cytokine and chemokine secretion: thymus‐derived LECs produced preferentially interleukin‐6, interferon‐inducible protein (IP)‐10 and tumour necrosis factor‐α, whereas cells prepared from lymph nodes mainly released interleukin‐8, monocyte chemotactic protein‐1, RANTES and (IP)‐10. Finally, cells purified from lymph nodes expressed a higher level of intercellular adhesion molecule‐1 than did cells prepared from the thymus when stimulated with several TLR agonists. The expression of a large set of TLRs and the responsiveness to specific agonists suggest that LECs are able to respond to pathogens, and the observed differences reflect specialized functions, redundancy and/or roles of LECs of different origin.

IL-6 Promotes compensatory liver regeneration in cirrhotic rat after partial hepatectomy

Major hepatic resection in cirrhotic patients is associated with impaired liver regeneration and failure, leading to high peri-operative mortality. In this work, the causes of defective regeneration in cirrhotic liver and the utility of IL-6 treatment were investigated in an experimental model combining cirrhosis and partial hepatectomy in the rat. Relative to normal controls, decompensated cirrhotic animals showed decreased survival, while compensated cirrhotic animals showed similar survival but reduced hepatic DNA synthesis and newly regenerated liver mass amount. Defective liver regeneration was associated with a decrease in STAT3 and NF-kB activation, consistent with an increased accumulation of their respective inhibitors PIAS3 and IkBalpha, and with a decreased induction of Bcl-xL. Treatment with recombinant IL-6 enhanced survival of decompensated cirrhotic animals, while it did not affect survival of compensated cirrhotic animals but sustained liver regeneration, by restoring STAT3 and NF-kB activation and Bcl-xL induction to the levels found in normal controls. The pro-growth effects exerted by IL-6 treatment in cirrhotic liver were attained also at low, pharmacologically acceptable doses. In conclusion, our results suggest that IL-6 treatment may be therapeutic in major resection of cirrhotic liver.

Is mild vascular cognitive impairment reversible? Evidence from a study on the effect of carotid endarterectomy

Abstract Mild vascular cognitive impairment (mVCI) is a broader term that is intended to detect cognitive loss before the development of dementia. The identification of preventable risk factors as well as therapeutic strategies of intervention is still unclear. It has been suggested that carotid endarterectomy (CEA) improves cognitive functions, beyond the well-known preventive effect upon future stroke events. In the present study, we evaluated the beneficial effect of CEA in restoring mVCI. Among a large sample of subjects, who underwent CEA for severe carotid stenosis, two groups were identified according to the absence (CON) or the presence of cognitive impairment (mVCI). A multidimensional neuropsychological and behavioural assessment was performed in the week prior, and at a 3-month follow-up after CEA. The incidence of mVCI in this sample was 38%. Seventy-eight patients completed the follow-up (48 CON, 30 mVCI). Both groups showed a clinical improvement after CEA, although the effect was significantly higher in the mVCI group in regard to verbal memory (short story, p < 0.05), and attention (digit span, p < 0.05) scores. At follow-up, 60% of mVCI subjects were classified as having normal cognitive functions. Index of disease severity and peripheral arterial disease were found to be the predictors of improvement. These findings support that mVCI represents a heterogeneous, in some cases reversible condition. CEA might be considered a therapeutic option to treat and prevent cognitive decline in mVCI patients.

Laparoscopic Versus Open Surgery for Gastric Gastrointestinal Stromal Tumors: What Is the Impact on Postoperative Outcome and Oncologic Results?

OBJECTIVES The aim of the study was to compare the postoperative and oncologic outcomes of laparoscopic versus open surgery for gastric gastrointestinal stromal tumors (gGISTs). BACKGROUND The feasibility of the laparoscopic approach for gGIST resection has been demonstrated; however, its impact on outcomes, particularly its oncologic safety for tumors greater than 5 cm, remains unknown. METHODS Among 1413 patients treated for a GIST in 61 European centers between 2001 and 2013, patients who underwent primary resection for a gGIST smaller than 20 cm (N = 666), by either laparoscopy (group L, n = 282) or open surgery (group O, n = 384), were compared. Multivariable analyses and propensity score matching were used to compensate for differences in baseline characteristics. RESULTS In-hospital mortality and morbidity rates in groups L and O were 0.4% versus 2.1% (P = 0.086) and 11.3% vs 19.5% (P = 0.004), respectively. Laparoscopic resection was independently protective against in-hospital morbidity (odds ratio 0.54, P = 0.014). The rate of R0 resection was 95.7% in group L and 92.7% in group O (P = 0.103). After 1:1 propensity score matching (n = 224), the groups were comparable according to age, sex, tumor location and size, mitotic index, American Society of Anesthesiology score, and the extent of surgical resection. After adjustment for BMI, overall morbidity (10.3% vs 19.6%; P = 0.005), surgical morbidity (4.9% vs 9.8%; P = 0.048), and medical morbidity (6.2% vs 13.4%; P = 0.01) were significantly lower in group L. Five-year recurrence-free survival was significantly better in group L (91.7% vs 85.2%; P = 0.011). In tumors greater than 5 cm, in-hospital morbidity and 5-year recurrence-free survival were similar between the groups (P = 0.255 and P = 0.423, respectively). CONCLUSIONS Laparoscopic resection for gGISTs is associated with favorable short-term outcomes without compromising oncologic results.

Distant nodal metastasis: is it always an unresectable disease?

This article aims at analyzing the published literature concerning the treatment of patients with gastric cancer and distant nodal metastases, actually considered metastatic disease. A systematic search was undertaken using Medline, Embase, Cochrane and Web-of-Science libraries. No specific restriction on year of publication was used; preference was given to English papers. Both clinical series and literature reviews were selected. Only 11 papers address the issue of surgery for nodal basins outside the D2 dissection area. From these papers, in selected cases extended surgery may prove useful in prolonging survival, when a comprehensive therapeutic pathway including chemotherapy is scheduled. In conclusion, in presence of nodal metastases outside the loco-regional nodes, surgery may be considered for metastatic nodes in stations 13 and 16, in selected cases.