Bromodeoxyuridine labeling for S-phase measurement in breast carcinoma

BACKGROUND: The S-phase fraction relates to proliferation, an important determinant of tumor behavior, and has been measured most accurately with the DNA precursor tritiated thymidine (TT). The TT labeling index (LI) is a strong stage-independent prognostic indicator for breast carcinoma. The thymidine analogue 5-bromodeoxyuridine (BrdU) is also incorporated into DNA and has the advantage over TT of immunohistochemical detectability rather than requiring autoradiography, but it is less well studied in breast carcinoma. This report demonstrates the equivalence of TT and BrdU LI and explores the relationships between LI and other biologic measurements. METHODS: The LI of 234 consecutive breast carcinomas were measured with TT as was a subsequent series of 450 cases with BrdU, both by incubation in vitro. RESULTS: The mean BrdU LI was 6.4 +/- 0.3% in comparison with 6.9 +/- 0.4% in the prior TT series. LI was unaffected by storage for 24 hours at 4 degrees C before labeling with BrdU. The BrdU and TT LI both correlated: (1) positively with tumor size, histologic type, nuclear size, the number of axillary metastases, the level of DNA ploidy, and the percent S-phase by flow cytometry and (2) negatively with the age of the patient and the levels of estrogen receptor and progesterone receptor measured either by ligand binding or by immunohistochemistry. CONCLUSIONS: BrdU labeling in vitro was an advantageous method for measuring S-phase fraction in breast carcinoma that produced results comparable to those from TT labeling. It should be equally effective for breast cancer kinetic classification and prognosis and is a suitable standard to evaluate newer methods for measuring cellular proliferation.     

Pharmacokinetics and amoebicidal activity of (+-)-(E)-3-(4- methylsulphinylstyryl)-1,2,4-oxadiazole (BTI 2286E) and its sulphone metabolite (BTI 2571E) in the golden hamster, Mesocricetus auratus

We studied, clinically and experimentally, hypertrophy of the part of the liver not embolized after portal vein embolization (PVE). The subjects of the clinical study were 29 patients with hepatocellular carcinoma (HCC) who underwent embolization of the right first portal branch; 19 patients had cirrhosis, and 10 did not. The volume of the liver was calculated from computed tomograms obtained before PVE and 2 weeks after. In all patients, the volume of the nonembolized (left) lobe increased significantly. For the experimental study, we used male Wistar rats. Normal rats were untreated, and in the other rats cirrhosis was induced with carbon tetrachloride. The portal branch that supplies 70% of the total volume of the liver was embolized. The rats underwent one of four procedures: 70% PVE, 70% portal vein ligation, 70% hepatectomy, or laparotomy only. Rats wre killed at different times after surgery, and the livers were removed and weighed. The mitotic index and DNA synthesis were measured in the nonembolized lobe (PVE group), in the lobe not supplied by the ligated branch (ligation group), or in the remaining liver (hepatectomy group). The liver weight, mitotic index, and DNA synthesis were high in the PVE, ligation, and hepatectomy groups for both normal rats and rats with cirrhosis. PVE caused cell proliferation and hypertrophy in the nonembolized part of the liver in the normal rats and even in those with cirrhosis. We concluded that PVE can extend the surgical indications for patients with HCC and underlying cirrhosis.     

Cell division and deoxyribonucleic acid (DNA) synthesis in cultures of stimulated lymphocytes

The responses of lymphocytes cultured with various stimulants were analysed with respect to DNA synthesis and cell division. Autoradiographic labelling with [3H]thymidine indicated that similar proportions of cells had incorporated this labelled precursor for DNA synthesis during both short and long periods of exposure to this specific precursor for DNA synthesis. Changes in labelling index (LI) after pulsing these cells with [3H]thymidine showed that exchange of labelled material, which could not be chased out with unlabelled thymidine, was responsible for the increases of LI seen. Failure to prevent this increase with excess unlabelled thymidine indicated that direct incorporation of [3H]thymidine did not account for this exchange. Using hydroxyurea and colcemid arrest to analyse cell cycle events in these cultures, it was shown that approximately 70 per cent of the responding cells in cultures of stimulated lymphocytes, while actively synthesizing DNA, were not in cell cycle for division. It was concluded that DNA turnover, involving synthesis and exchange of newly synthesized material, possibly DNA, was occurring in these cells.     

Partial hepatic resection for hepatocellular carcinoma

This review summarizes the efficacy of the most common therapeutic option for hepatocellular carcinoma (HCC), partial hepatic resection, taking into account not only its antitumoural effect, but also its consequences on survival. Partial hepatic resection results in 5 year survival rates as high as 45% in more favourable subgroups having: small tumours, well-differentiated tumours, unifocal tumours, a lack of vascular invasions, an absence of cirrhosis, and the fibrolamellar variant. Resection has been limited primarily by low resectability rates and recurrent disease. However, surgical resection in the form of partial hepatectomy is the preferred treatment for HCC. The early detection of tumours by screening high-risk populations is crucial. During the 12 year period between 1983 and 1994, hepatic resections were carried out in 382 patients with HCC. One hundred and fifty-three (40%) had HCC smaller than 5 cm in diameter. There were 294 male and 88 female patients, with an average age of 52.3 years. Among them, 45% had liver cirrhosis and 73% were positive for hepatitis B surface antigen. Two hundred and eighteen (57%) were positive for hepatitis C virus circulating antibodies (since 1991). Operative mortality was 3.9%. The overall survival rates at 1, 3 and 5 years were 71, 52 and 46%, respectively. Sex, cirrhosis, Child's staging, surgical procedure, blood loss, pathological pattern, presence of capsule, surgical margin and DNA ploidy appeared to be factors not related to prognosis. However, alpha-fetoprotein level, size (whether less than or greater than 5 cm), and vascular invasion were factors which significantly affect survival.     

Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma

The aim of the study was to assess the incidence of both types of liver cell dysplasia and concomitance with cirrhosis, hepatocellular carcinoma (HCC) and positive reaction for HBsAg in the autopsy material and an attempt to determine a relationship between these two types of liver cell dysplasia and hepatocellular carcinoma. Autopsy material included 102 cases of hepatocellular carcinoma, 101 cases of hepatocirrhosis without accompanying cancer and 106 control cases. Histological specimens stained with HE were analyzed for the presence of large liver cell dysplasia (LLCD) according to Anthony et al., small liver cell dysplasia (SLCD) according to Watanabe et al., the presence of macroregenerative nodules (< 8 mm) and antigen HBs (stained with orcein according to Shikata). The detected LLCD were also assessed semiquantitatively taking into account the number of dysplastic areas in a given case. Statistical significance of the results was tested with the chi square test. LLCD was most frequently detected in HCC with concomitant cirrhosis (55.3%), then in cirrhosis without HCC (40.6%), and in HCC without cirrhosis only in 12.5%. LLCD was found significantly more frequently (p < 0.05) in cirrhosis with HCC than in cirrhosis without HCC. Antigen HBs was found in 25.6% of cirrhoses and/or HCC. No significant differences in the presence of HBsAg were seen between the analyzed groups. The incidence of LLCD and HBsAg in controls was significantly lower than in other groups. A mean age at death in case of cirrhosis with HCC subdivided into that with or without LLCD was not significantly different, whereas in case with cirrhosis with LLCD age at death was 10.8 years higher (the difference statistically significant). Analysis of material with respect to gender revealed a high proportion of men in case of HCC with concomitant cirrhosis but without LLCD (13:1). A strong relationship was seen between the presence of positive reaction for HBsAg and LLCD (p < 0.001). Also the intensity of LLCD positively correlated with the presence of HBsAg. Furthermore, a positive correlation was seen between the presence of LLCD and macronodular cirrhosis (posthepatitic). The present findings suggest a closer relation between HBV infection and LLCD than between cirrhosis or HCC and LLCD. Also morphological patterns of LLCD foci do not confirm the hypothesis of some investigators about the precancerous character of these lesions. In the whole current material only seven cases of SLCD were detected. They were all present in cirrhotic livers with concomitant HCC. Both the morphological pattern of these lesions and their sometimes discerned close spatial relation with HCC foci indicate that SLCD is an alternative way of HCC development.     

Blood flow rate: an important determinant of urea clearance and delivered Kt/V

PURPOSE: To compare the magnetic resonance (MR) imaging findings of primary hepatocellular carcinoma (HCC) in cirrhotic versus noncirrhotic livers. MATERIALS AND METHODS: MR images in 36 patients with HCC (30 men and she women aged 42-84 years [mean age, 65 years]) were retrospectively reviewed. The number and size of hepatic lesions were assessed. Lesion margins were categorized as well circumscribed or ill defined. The presence of a capsule, intratumoral high signal intensity on T1-weighted MR images, and a stellate scar were determined. RESULTS: Eleven (31%) patients had MR imaging evidence of cirrhosis, and 25 (69%) did not: Lesions in cirrhotic livers differed significantly from those in noncirrhotic livers in terms of size (22 cm2 vs 99 cm2, P < .05), frequency of a solitary lesion (27% vs 72%, P < .05), and frequency of a central scar (6% vs 50%, P < .05). There was no difference between the cirrhotic and noncirrhotic livers with regard to tumor margin, intratumoral high signal intensity on T1-weighted images, or tumor capsule. CONCLUSION: Differences exist in the MR imaging appearance of HCC between patients with and those without cirrhosis, although there is overlap of imaging findings.     

Atypical cutaneous histological features of visceral leishmaniasis in acquired immunodeficiency syndrome

OBJECTIVE: A sex hormone imbalance has been reported in patients with hepatocellular carcinoma (HCC). We investigated the serum levels of eight sex hormones in patients with alcohol-related and non-alcohol-related cirrhosis and HCC. METHODS: Luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone and sex hormone binding globulin were assayed in 81 patients with cirrhosis (59 men, 22 women) and 97 with HCC and cirrhosis (82 men, 15 women). Hepatitis B or hepatitis C virus infection was present in 58% of patients with cirrhosis and 69% of patients with HCC. Alcohol abuse was the aetiopathogenetic factor in the remaining patients. RESULTS: In men, mean testosterone levels were at the lower limit of the normal range for both patients with HCC and for controls with cirrhosis. Mean estradiol levels were increased both in patients with HCC and in those with cirrhosis, but patients with alcohol-related HCC had higher estradiol levels (P = 0.0002). An index of sex hormone imbalance, the estradiol to testosterone ratio (ETR), was calculated. The ETR was significantly higher in patients with alcohol-related HCC (P = 0.0002). Multiple regression analysis showed that the ETR correlated best with patients' diagnosis (P < 0.05). In women, the ETR was significantly lower in patients with HCC than in controls with cirrhosis. CONCLUSIONS: Men with alcohol-related HCC are characterized by an oestrogen and androgen imbalance and have a higher ETR than patients with other types of liver damage. Since sex hormones modulate hepatocellular proliferation, our data suggest that a sex hormone imbalance plays a role in hepatocarcinogenesis in patients with alcohol-related cirrhosis.     

Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer

We have studied the feasibility of detecting tumor-associated aberrant p16 methylation in the circulation of patients with hepatocellular carcinoma (HCC). We extracted DNA from the tumor tissues and peripheral blood plasma or serum of 22 HCC patients. p16 methylation was found in 73% (16 of 22) of HCC tissues using methylation-specific PCR. Among the 16 cases with aberrant methylation in the tumor tissues, similar changes were also detected in the plasma/serum samples of 81% (13 of 16) of the cases. No methylated p16 sequences were detected in the peripheral plasma/serum of the six HCC cases without these changes in the tumor, in 38 patients with chronic hepatitis/cirrhosis, or in 10 healthy control subjects. These results suggest that circulating liver tumor DNA may be detected using tumor-associated DNA methylation changes. Because methylation abnormalities have been found in many other genes and tumor types, this approach may have implications for the noninvasive detection of a wide variety of cancers.     

Detection of hepatocellular carcinoma in patients with cirrhosis: MR imaging versus angiographically assisted helical CT

OBJECTIVE: The purpose of our study was to compare the combination of conventional spin-echo, phase-shift gradient-recalled echo (GRE), and triple-phasic dynamic GRE MR imaging with the combination of helical CT hepatic arteriography (CTA) and CT performed during arterial portography (CTAP) in the preoperative detection of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirty-seven patients with cirrhosis underwent MR imaging and angiographically assisted CT imaging. Paired T1- and T2-weighted spin-echo images, paired in-phase and out-of-phase GRE images, triple-phasic dynamic GRE images, the combined MR images, and the paired CTA and CTAP images were retrospectively and independently reviewed by three radiologists. Image review was done on a segment-by-segment basis. Of the 280 liver segments, 58 segments contained 79 HCCs that were 0.5-8.0 cm (mean, 2.0 cm) in diameter. The diagnostic value of each pair of images was rated by means of receiver operating characteristic curve analysis. RESULTS: The diagnostic accuracy of combined CTA and CTAP (mean area under the receiver operating characteristic curve [Az] = 0.94) was significantly better than that of spin-echo (Az = 0.86, p < .0001), phase-shift GRE (Az = 0.83, p < .0001), dynamic GRE (Az = 0.85, p < .0001), and all combined (Az = 0.91, p < .001) MR imaging. The relative sensitivity of combined CTA and CTAP (89%) was also significantly (p < .0005) better than that of the combined MR imaging (75%). CONCLUSION: Angiographically assisted helical CT imaging was superior to MR imaging combined with conventional spin-echo, phase-shift GRE, and triple-phasic dynamic GRE techniques in the detection of HCC in patients with cirrhosis. The noninvasive dedicated combined MR imaging could not obviate invasive angiographically assisted CT imaging. Combined CTA and CTAP is recommended, especially in the preoperative examination of patients with HCC.     

Complementary replication R- and G-band patterns induced by cell blocking at the R-band/G-band transition, a possible regulatory checkpoint within the S phase of the cell cycle

The characteristic band patterns of replication banding (dynamic banding) were analyzed. High-resolution (550-1,250 bands per haploid genome) G- and R-band patterns were obtained after 5-bromo-2'-deoxyuridine (BrdU) incorporation during early or late S phase. Thymidine-BrdU permutation culture methods, which arrest DNA synthesis at the R-band/G-band transition, allow complementary BrdU substitution. The RBI (R bands by BrdU using immunological staining) and GBI (G bands by BrdU using immunological staining) band patterns were complementary for all chromosomes. There was no overlapping, and every part of each chromosome was positively stained by one of the two banding procedures. Comparative analysis of RBG (R bands by BrdU using Giemsa staining) and RBI band patterns, as well as GBG (G bands by BrdU using Giemsa staining) and GBI band patterns, showed good congruency, displaying a very good band-for-band match. The congruency and complementarity found for these band patterns show that high concentrations of both thymidine and BrdU blocked S-phase progression near the R-band to G-band replication transition within the S phase. They also prove that BrdU incorporation is complementary and, therefore, demonstrate the existence of the R/G transition: a possible regulatory checkpoint within the S phase of the cell cycle.     

Diagnostic imaging and interventional therapy of hepatocellular carcinoma

Diagnostic imaging has many important roles in the management of patients with hepatocellular carcinoma (HCC). In diagnosis, lipiodol CT (LCT) has been shown to be the most sensitive imaging modality (90-97%) for all sizes of lesions; all other modalities have high sensitivities for lesions 1-3 cm but low sensitivities for lesions < 1 cm (ultrasound 33-37%, conventional CT 20-42% and digital subtraction angiography 40-55%). All imaging modalities understage HCC. Once again LCT is the most accurate method of evaluating the extent of tumour, but even this method does not identify all satellite nodules. Ultrasound has been proposed as a screening method, but this cannot be justified on the basis of its results or cost benefit analysis. Both CT and dynamic MRI play useful roles in evaluating the efficacy and follow-up of patients undergoing chemoembolization (TACE) and percutaneous ethanol injection (PEI). Although surgery remains the best treatment of HCC, it is unsuitable in most of the cases which would be better treated with interventional therapy. This article presents a review of the literature regarding the use of TACE, PEI or a combination of both procedures in the treatment of HCC. A multicentric study has shown that patients with monofocal lesions less than 5 cm in diameter are better treated with PEI, which is therefore a good alternative to the surgical treatment; patients with multifocal lesions (maximum of three lesions) show a better survival with TACE. Combined treatment with TACE and PEI proves to be effective in patients with large HCC.     

Hepatocellular carcinoma: surgical treatment

Worldwide the hepatocellular carcinoma (HCC) is one of the most common malignancies. There is a coincidence with liver cirrhosis or chronic hepatitis B/C in most cases. HCC can be suspected by ultrasound and by rise of the tumor marker (AFP). Further investigations, like biopsies, are not necessary if angiography or computed tomography in combination with patient history and elevated AFP levels are positive. The prognosis of untreated HCC is extremely poor. Live expectancy of symptomatic patients is only a couple of weeks. Radical tumor removal by liver resection or transplantation is the only treatment with curative intent. However these options are only suitable for patients with limited disease. Five year survival after curative liver resection depends on the tumor stage, ranging from 25% to 67%. The results after liver transplantation are similar for small cancer. Large, symptomatic tumors are in most cases only suitable for palliative treatment (chemoembolisation, ethanol injection, chemotherapy, immunotherapy). The strong dependence of prognosis on tumor extent underlines the importance of screening patients with elevated risk of developing an HCC. The early recognition of small tumors allows curative therapy with good results.     

Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes

In this study we have determined the incidence of hepatocellular carcinoma (HCC) development in primary biliary cirrhosis (PBC) and its effects on patient survival. Six hundred and sixty seven patients with liver histology compatible with or diagnostic of PBC were seen over a 20-year period. Two hundred and seventy three patients who had stage III or IV disease on their last biopsy and who had been followed up for at least 1 year following that biopsy (total follow-up with advanced disease 2,010 patient years) were identified (243 female, 30 male). Patients who developed HCC were identified and their confounding risk factors were excluded. Mayo risk scores were calculated for each clinic attendance and expected survival for each time point was compared with subsequent actual survival. Sixteen cases of HCC were seen in the patients with stage III or IV disease on last biopsy, providing an overall incidence of 5.9% in this group. Fourteen of these patients had died of HCC related causes, and 2 patients were alive at the census point. The incidence of HCC was significantly higher in males with stage III/IV disease than in females (20% vs. 4.1%, P < .005). Nine of one hundred and eight (8.3%) total female deaths in this group was attributable to HCC compared with 5 of 11 (45.5%, P < .05) male deaths. HCC was not seen in any of the 394 patients with stage I and II PBC followed-up over the same time period. Throughout the disease course of all PBC patients with HCC, the Mayo prognostic model over-predicted survival. Whereas it is a relatively rare complication of cirrhotic PBC in women, HCC is a relatively common cause of death in male PBC patients with cirrhosis. HCC typically develops several years after the onset of cirrhosis, and is poorly predicted by prognostic models. In view of these findings, consideration should be given to careful screening for HCC in male PBC patients with cirrhosis. The risk of HCC development may be an additional reason to consider earlier transplantation in these patients.     

The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma

BACKGROUND: Measurements of serum concentrations of des-gamma-carboxy prothrombin (DCP) are widely used for diagnosing hepatocellular carcinoma (HCC). However, the DCP is not always sensitive enough to detect small HCCs. In the current study, the authors investigated the usefulness of DCP in the early diagnosis of HCC, using a more sensitive enzyme immunoassay than is conventionally employed. METHODS: The authors examined 148 serum samples with DCP concentrations from a conventional assay of less than 100 mAU (arbitrary unit)/mL from 91 patients with HCC and 57 with cirrhosis. DCP concentrations were determined by a more sensitive enzyme immunoassay (ED-036 kit, Eisai Laboratory, Tokyo, Japan) with a minimal detection level of 10 mAU/mL. Ninety-one HCC patients had 43 solitary small HCCs (with a greatest dimension of less than 2 cm). Of these 43 HCCs, 12 were well differentiated. RESULTS: The mean serum concentration of DCP in HCC (48.3 +/- 24.3, mean +/- standard deviation [SD]) was higher than in cirrhosis (20.3 +/- 10.3); this difference was statistically significant. When the tentative cutoff level of 40 mAU/mL (almost corresponding to the mean value + 2SD in patients with cirrhosis) was used as the level of discriminating HCC from cirrhosis, 62% of patients (56 of 91) with HCC had DCP values above this level (sensitivity). However, only three patients with cirrhosis had higher DCP levels. Thus, the specificity of this test was 95% (54 of 57 patients). The total accuracy was 74% (56 + 54/91 + 57). Twenty-three of 43 solitary small HCCs (53%) had DCP values above the cutoff level. Furthermore, 7 of 12 (58%) small, well-differentiated HCCs less than 2 cm in greatest dimension had higher DCP values. CONCLUSIONS: The results of this study indicate that DCP determination by sensitive enzyme immunoassay is useful in the early diagnosis of HCC because a high specificity is maintained.     

Prognostic factors after hepatic resection for hepatocellular carcinoma associated with Child-Turcotte class B and C cirrhosis

OBJECTIVE: To evaluate prognostic factors after resection of hepatocellular carcinoma (HCC) in patients with Child-Turcotte class B and C cirrhosis. SUMMARY BACKGROUND DATA: Although hepatic resection remains the mainstay in the treatment of HCC and can be performed with low morbidity and mortality rates in patients without cirrhosis, its role is poorly defined for patients with severe cirrhosis. METHODS: From 1986 to 1996, partial hepatectomy was performed for HCC in 63 patients with Child-Turcotte class B (n = 46) and C (n = 17) cirrhosis. There were 46 men and 17 women, with an average age of 61.2 years (range 35 to 79 years). Associated conditions were diabetes mellitus in 45, esophageal varices in 32, severe hypersplenism in 26, cholelithiasis in 13, gastroduodenal ulcer in 6, and hiatal hernia, gastric lymphoma, splenic abscess, and pancreatic cyst each in 1. Concomitant surgical procedures were performed for most of these conditions. RESULTS: Major complications occurred in 17 patients (27%), six (9.5%) of whom died within 1 month after surgery. The overall in-hospital death rate was 14.3%. Liver failure and intraabdominal sepsis were mostly fatal complications. The overall and disease-free survival rates, respectively, were 70.2% and 64.5% at 1 year, 43.5% and 23.8% at 3 years, and 21.4% and 14.9% at 5 years. Multivariate analysis with the Cox regression model revealed that favorable factors for survival were Child class B, no transcatheter arterial embolization before surgery, young age, and low alanine aminotransferase (ALT) level before surgery. CONCLUSIONS: Hepatic resection can provide a favorable result in young patients with HCC complicating Child class B cirrhosis with low hepatitis activity, but transcatheter arterial embolization before surgery should be avoided in such patients.     

Membrane potential mediates H(+)-ATPase dependence of "degradative pathway" endosomal fusion

BACKGROUND: In recent years Tpot (potential doubling time) has been measured before treatment in human tumors in an attempt to estimate the proliferation taking place during a course of irradiation. Tpot is defined as Ts/LI, where Ts is the duration of DNA synthesis and LI is the labeling index (proportion of cells synthesizing DNA). Ts is more difficult to measure than LI, so the question arises whether variation introduced during the determination of Ts is compensated by the theoretically better relevance of the quotient Tpot than of LI alone. It is not clear from comparisons with clinical outcome whether Tpot is a useful indicator of proliferation or whether LI is more prognostic, as suggested by a currently ongoing multicenter analysis elsewhere. Therefore, we investigated intercomparisons between Tpot and its components LI and Ts in two in their proliferation rates contrasting types of tumor where multiple biopsies were taken from each tumor. MATERIALS AND METHODS: Sixty patients with esophageal carcinoma and 57 patients with breast cancer were included in this study. All patients were injected with IUdR 6-8 h before surgery. From each tumor three to five biopsies were taken at surgery. Using flow cytometry, LI and Ts were measured on all biopsies in order to calculate Tpot. Logarithmic transformations of the distributions were used to examine correlations. Kappa-tests were used to assess how reliable an LI value could be in predicting the corresponding Tpot. RESULTS: Ts and LI were not completely independent, based on the within-tumor coefficients of variation (CVw). The ratio of between-tumor coefficient of variation (CVb) to the CVw suggested that the discriminative power of Tpot was higher than LI for esophagus, but the reverse in breast tumors, which had a larger range. Pearson correlation coefficients were high for log Tpot versus log LI in both types of tumor, but the predictive power was low, as shown by kappa-values of only 0.3-0.41 starting with LI and trying to predict the corresponding value of Tpot. Increasing widths of a central 'gray zone' were investigated for improved discrimination between fast and slow proliferation. Multiples of the within-tumor standard deviation, equally on each side of the median, were used to vary the width of the gray zone. Without a gray zone no more than 70% successful matching was obtained in esophagus tumors, compared with 80% in breast tumors. However, by excluding about half of the esophageal tumors an 80% success rate was achieved. In breast tumors over 90% matching was obtained more easily, keeping 80% of the tumors classifiable. For both tumor types correlations between Ts and Tpot were weak, with a trend towards short Ts associated with short Tpot and also with low LI. The latter correlation was significant for esophageal tumors and resulted in Tpot values having a smaller range than the LIs. CONCLUSION: Although there were good correlation coefficients between Tpot and LI, the predictive power of either from the other was not reliable, except by excluding a significant number of tumors close to the medians. The predictive value of LI for Tpot was higher for breast tumors because the spread in cell kinetic measurements was wide. Until more clinical data become available on outcome in comparison with LI or Tpot, it is still worthwhile to measure Tpot and to assess the prognostic value of both LI and Tpot in relation to outcome.     

Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience

The objective of our work was to evaluate the long-term results of percutaneous ethanol injection (PEI) for the treatment of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. A total of 184 cirrhotic patients with HCC underwent PEI as the only anticancer treatment over an 8-year period. Patients were followed after therapy by means of clinical examinations, laboratory tests, and US and CT studies performed at regular time intervals. Survival rates were determined according to the Kaplan-Meier method. The overall survival was 67% at 3 years, 41% at 5 years, and 19% at 7 years. The 3-, 5-, and 7-year survival rates of patients with single HCC < or = 3 cm (78, 54, and 28%, respectively) were significantly higher (p < 0.01) than those of patients with single HCC of 3.1-5 cm (61, 32, and 16, respectively) or multiple HCCs (51, 21, and 0%, respectively). Survival of Child-Pugh A patients (79% at 3 years, 53% at 5 years, and 32% at 7 years) was significantly longer (p < 0.01) than that of Child-Pugh B patients (50% at 3 years, 28% at 5 years, and 8% at 7 years). A selected group of 70 patients with Child-Pugh A cirrhosis and single HCC < or = 3 cm had a 7-year survival of 42%. Long-term survival of cirrhotic patients with HCC treated with PEI is comparable to that reported in published series of matched patients submitted to surgical resection.