Propensity score analysis of outcomes following laparoscopic or open liver resection for hepatocellular carcinoma.

BACKGROUND: Liver resection is a potentially curative approach for hepatocellular carcinoma (HCC). Laparoscopic liver resections may reduce complication rates, especially in patients with cirrhosis. The aim of this study was to compare the results of laparoscopic liver resection with those of open liver resection for HCC. METHODS: Patients with cirrhosis who underwent minor liver resections for HCC from 2006 to 2013 were identified retrospectively from a prospective database according to the technique adopted (laparoscopic or open). Short- and long-term outcomes were compared between the two groups before and after 1 : 1 propensity score matching. RESULTS: A total of 269 patients were considered: 226 who underwent open liver resection and 43 who had a laparoscopic procedure. The two groups differed at baseline in terms of median age, sex, performance status, tumour location and type of resection. After propensity score matching, two comparable groups of 43 patients each were obtained. Intraoperative bleeding, margin clearance and operative mortality were similar in the two groups, whereas complication rates were lower (49 versus 19 per cent in open versus laparoscopic groups respectively; P = 0·004) and median hospital stay was shorter (8 versus 5 days; P < 0·001) in the laparoscopic group. On multivariable logistic regression analysis, the only independent factor that reduced the risk of postoperative complications was the use of laparoscopy (odds ratio 0·12, 95 per cent c.i. 0·03 to 0·55; P = 0·006). Median overall survival was 57·8 months in the open group and 48·8 months in the laparoscopic group (P = 0·802). Median disease-free survival was 31·7 and 25·5 months respectively (P = 0·990). CONCLUSION: In comparison with the open approach, laparoscopic minor liver resections for HCC improved short-term outcomes, with similar survival results.

Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology.

PURPOSE: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. METHODS: We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50% and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. RESULTS: MAA and (90)Y biodistributions were not different (71% of cases), different in 23% and uncertain in 6%. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50%) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14%, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy. CONCLUSION: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.

A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres.

AIM: Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues. METHODS: Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere® prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed. RESULTS: Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70-105] Gy, [105-140] Gy. DISCUSSION: A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose). CONCLUSION: As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions.

Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with (90)Y microspheres: the experience of the National Tumor Institute of Milan.

In most centres, the choice of the optimal activity to be administered in selective intra-arterial radioembolization with microspheres is nowadays based on empirical models which do not take into account the evaluation of tumour and non tumour individual absorbed dose, despite plenty of published data which showed that local efficacy is correlated to tumour absorbed dose, and that the mean absorbed dose is a toxicity risk factor. A pitfall of the crudest, empirical tumour involvement method are 20 deaths in a single centre which adopted it to administer the whole liver, or the need of systematic 25% subjective reduction of activity prescribed with body surface area method. In order to develop a possibly safer and more effective strategy based on real individual dosimetry, we examine first external beam liver radiation therapy results. The half century experience has something to be borrowed: the volume effect, according to which the smaller the fraction of the irradiated liver volume, the higher the tolerated dose. Different tolerance for different underlying disease or previous non radiation treatment is to be expected. Radiobiological models experience also has to be inherited, but not their dose reference values. Then we report the published dosimetric experience about (90)Y microsphere radioembolization of primary and metastatic liver tumours. In addition we also present original data from our growing preliminary experience of more refined (99m)Tc MAA SPECT based calculations in hepatocarcinoma patients. This overcame the mean dose approach in favour of the evaluation of dose distribution at voxel level. An insight into dosimetry issues at microscopic level (lobule level) is also provided, from which the different radiobiological behaviour between resin and glass spheres can be understood. For tumour treatment, an attenuation corrected (99m)Tc- SPECT based treatment planning strategy can be proposed, although quantitative efficacy thresholds should be differentiated according to the kind of pathology and previous treatment. For non tumour liver parenchyma, data in favour of a relationship between absorbed dose and dangerous effects are encouraging. Unfortunately in hepato-cellular carcinoma, some confounding factors may hamper the adequate estimation of the risk of toxicity. First there is a lack of consensus about the exact definition of toxicity after (90)Y microsphere radioembolization. Second, for HCC patients, progression of both cancer and cirrhosis can simulate a radioinduced toxicity, making the analysis more complex.

Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: effect of liver transplantation.

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the beta-cell function and an insulin clamp combined with [3-(3)H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P <.05) and insulin deficiency during the OGTT (P <.05). Liver transplantation normalized endogenous glucose production and insulin sensitivity but failed to cure diabetes in 8 of the 24 patients because a markedly low insulin response during the OGTT. Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesis of cirrhosis did not predict in whom liver transplant was going to cure diabetes. On the contrary, a reduced secretory response characterized the patients in whom the transplant would not be curative. In summary, insulin resistance was a primary event complicating cirrhosis but additional beta-cell secretory defects were crucial for development of diabetes. Liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless 33% were still diabetics because the persistence of a reduced beta-cell function, which makes these patients eventually eligible for combined islet transplantation.

Early administration of enteral nutrients in critically ill patients.

Aggressive nutrition intervention has become an essential component in the therapy of critically ill patients. Early provision of enteral nutrients within 24 hours of injury or surgery appears optimal and is associated with benefits such as a reduction in septic complications, a decrease in the hypermetabolic response to severe burn injury, and improved wound healing. Early enteral nutrient administration has a significant impact on preserving gastrointestinal integrity and barrier function and maintaining intestinal immunologic defenses, which may have a role in decreasing infectious outcomes in critically ill patients. Establishing an enteral access becomes a priority with early feeding. Small intestine feeding usually is preferred to gastric nutrient administration, yet some declare biologic superiority with intragastric feedings. The optimal enteral product for use in critically ill patients remains unknown. Key nutrients, such as glutamine, arginine, fiber, and alternative lipids, may have potential benefits and need to be considered when formulating an enteral regimen in this patient population.

Characterization of human parainfluenza virus type 2 RNAs in infected cells and by in vitro synthesis.

The RNA species synthesized in HPIV-2 infected CV-1 cells were identified and characterized. The largest RNA of approximately 5.5 x 10(6) in molecular weight (MW) based on electrophoretic mobility, was identified as the genomic RNA. The other small RNA species of MWs 2.4 x 10(6), 1.1 x 10(6), 0.77 x 10(6), 0.68 x 10(6) and 0.5 x 10(6) were identified as mRNAs. The five smallest RNAs were also synthesized in vitro and comigrated with RNAs synthesized in virus-infected cells. mRNAs synthesized both in vitro and in virus-infected cells were translated in vitro. NP, P, M and V proteins synthesized in vitro comigrated, when analyzed by SDS-PAGE, with the authentic proteins synthesized in virus-infected cells. Additionally, peptide mapping showed that the NP, P and M proteins synthesized in vitro were indistinguishable from their counterparts synthesized in infected cells. Analysis of the proteins from virions identified L, HN, NP, F (F1, F2), P, M and V proteins as virion structural proteins. Electrophoretic mobility of reduced and nonreduced F proteins was found to be different due to the conformational changes conferred by disulfide bonds.

Characterization of the in vitro system for the synthesis of mRNA from human respiratory syncytial virus.

An in vitro transcription system for human respiratory syncytial virus (RSV) is described. Purified viral nucleocapsid (RNP) isolated from virus-infected cells was shown to support transcription of all 10 genes encoded by the virus as determined by Northern blot hybridization. The mRNAs synthesized were polyadenylated and comigrated with the corresponding mRNAs synthesized in virus-infected cells when analyzed in agarose-urea gel electrophoresis. The in vitro-synthesized mRNAs are functional as determined by their capacity to synthesize protein in vitro. The transcriptional reaction was significantly stimulated by the uninfected host cell lysate, indicating a requirement of host factor(s) in mRNA synthesis. Preliminary results suggest that cellular actin is involved in this process.

Interaction of Leishmania donovani promastigotes with human phagocytes.

Leishmania donovani is an important intracellular protozoal pathogen of humans, which resides solely within mononuclear phagocytes. Phase-contrast microscopy and cinemicroscopy were used to examine the interaction of L. donovani promastigotes with human phagocytes to characterize and quantitate the sequence of events that results in leishmanial infection.

Interaction of Leishmania donovani promastigotes with human monocyte-derived macrophages: parasite entry, intracellular survival, and multiplication.

Leishmania donovani promastigotes were incubated with human monocyte-derived macrophages in vitro to assess the role of macrophages in the early stage of visceral leishmaniasis. Adherent mononuclear cells, obtained from nonimmune human donors, were cultivated on glass cover slips for 5 days and then incubated with axenically grown promastigotes in the presence of heat-inactivated autologous serum. Promastigotes attached to macrophages with either their flagellar or aflagellar ends, and macrophage pseudopodia formed around them. Intracellular parasites were identified within phagocytic vacuoles by electron microscopy, and the parasites assumed a form similar to that of amastigotes obtained from infected hamster spleens. Initially, 67 +/- 5% of the macrophages were infected with a mean of 4.2 +/- 0.7 parasites per infected cell. After 6 days of incubation, 79 +/- 7% of the macrophages were infected with 15.9 +/- 3.2 parasites per infected cell. The total number of parasites per monolayer increased from 4.8 +/- 0.8 x 10(5) to 1.8 +/- 0.4 x 10(6) (P less than 0.05). Dividing parasites were identified in macrophage vacuoles by electron microscopy. Human monocyte-derived macrophage vacuoles by electron microscopy. Human monocyte-derived macrophages can phagocytize promastigotes, allow the conversion of promastigotes to an amastigote-like state, and support intracellular multiplication.