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Partial hepatectomy with or without endotoxin does not promote apoptosis in the rat liver.

BACKGROUND: Liver insufficiency and failure has been described following subtotal hepatectomy. The cause is poorly understood but may be because of attrition of hepatocytes through enhanced cell death pathways such as apoptosis. The trigger for this could be reduction beyond a critical mass of liver tissue or the influence of endotoxin (LPS) on cytokine activation. The experiment was designed to answer these questions. MATERIALS AND METHODS: Rats were subjected to either 30% or 70% hepatectomy. Sacrifice occurred on either postoperative day 2 or 4. At sacrifice remnant livers were examined for apoptosis through the direct Tunel immunoperoxidase method (apoptotic index) and soluble histone ELISA. A second group of rats underwent 30% or 70% hepatectomy and were given either saline or endotoxin (LPS). Sacrifice occurred on postoperative day 1, 2, or 4. Liver samples were analyzed for apoptosis by Tunel immunoperoxidase, histone-associated DNA, TNF-alpha, and caspase-3. Mitotic activity and evidence of hepatocellular necrosis were also determined. RESULTS: By comparison to prehepatectomy values, rats subjected to hepatectomy alone failed to disclose any effect of resection on apoptotic activity. By comparison to sham operated controls there was a modest but significant increase in apoptotic activity at day 4 in the 30% and 70% hepatectomized rates by apoptotic index but not the soluble histone ELISA. Injection of LPS without hepatectomy produced an increase in apoptotic activity by apoptotic index and soluble histone ELISA methods on day 1 and 2. The addition of 30% or 70% hepatectomy produced a sporadic, but not sustained, increase in apoptotic activity which may have been because of LPS injection alone. Tissue TNF-alpha levels increased with LPS but changed little with addition of hepatectomy. Mitotic activity remained essentially unchanged with or without LPS injection. No evidence of hepatocellular necrosis was detected with LPS and extended hepatectomy. CONCLUSIONS: Apoptosis does not appear to be a prominent feature in the posthepatectomy liver, with or without addition of LPS. Even with accelerated TNF-alpha production from LPS, the mitotic pathways continue to take precedent. Apoptosis, except for occasional sporadic bursts, is effectively suppressed. It is not likely that apoptosis contributes to depletion of functional hepatocytes and liver insufficiency.

Animals↗

Mutant frequency of lacI in transgenic mice following benzo[a]pyrene treatment and partial hepatectomy.

The Big Blue, transgenic mouse provides an in vivo mutation system that permits the study of pharmacodynamic parameters on mutant frequency (MF) following xenobiotic exposure. We have studied the effects of cellular proliferation on the frequency of mutations in the lacl transgene by evaluating the MF in the liver of male C57B1/6 Big Blue mice following treatment with benzo[a]pyrene (B[a]P) and a partial hepatectomy. Mice received either 40 mg/kg of B[a]P in corn oil or corn oil alone by i.p. injection on three consecutive days, followed by a partial hepatectomy on the fourth day. Three days later (i.e., 7 days following the initial B[a]P injection), the animals were sacrificed and the MF in the liver was compared to the MF observed in the liver of the same mouse at the time of hepatectomy. Induction of cytochrome P-450 1A (CYP1A) following B[a]P treatment was evident by Western blot analysis. The MF in untreated control animals was not significantly different at hepatectomy (4.7 +/- 0.8 x 10(-5)) and 3 days later, at sacrifice (3.0 +/- 0.4 x 10(-5)). Neither was the MF observed in the B[a]P-treated mice at the time of sacrifice (12.0 +/- 2.1 x 10(-5)) significantly different from the MF observed at the time of hepatectomy (10.6 +/- 5.3 x 10(-5)). However, B[a]P-treatment resulted in a 4.0-fold increase in MF at sacrifice which was significantly different (p < 0.05), when compared to the untreated controls. The B[a]P-treated mice at hepatectomy showed a modest 2.2-fold increase in MF which was not statistically significantly different from the untreated controls. In addition, both control and B[a]P-treated tissues gave sectored mutant plaques. The sectored plaque frequency (SPF) was significantly elevated (p < 0.05) in the B[a]P-treated mice at hepatectomy (4.2 +/- 1.0 x 10(-5)) and sacrifice (7.3 +/- 2.4 x 10(-5)) as compared to the respective frequency in the control mice at hepatectomy (1.9 +/- 0.7 x 10(-5)) and sacrifice (1.4 +/- 0.2 x 10(-5)). One explanation for this data is the persistence of the B[a]P adducts in the mouse genomic DNA that was packaged into the lambda phage, and ultimately fixed as mutations in Escherichia coli.

Animals↗

Functional capacity of the liver after two-thirds partial hepatectomy in the rat.

BACKGROUND: Liver cell proliferation after partial hepatectomy in rats has been thoroughly investigated. Although DNA synthesis and morphologic restoration have been studied in this rat model, the functional capacity of the remnant liver during regeneration has not been elucidated. METHODS: We measured the indocyanine green disappearance rate (ICG-k) and serum aminopyrine (CLamp) in rats at various intervals after two-thirds hepatectomy. Morphologic restoration of the liver after hepatectomy was evaluated on the basis of remnant liver weight, proliferating cell nuclear antigen labeling index, and the DNA content of the regenerating liver. Serial changes in ICG-k and CLamp after two-thirds hepatectomy were compared with the degree of morphologic restoration. RESULTS: ICG-k and CLamp were reduced by one third in rats after two-thirds hepatectomy. Although the rate of restoration of remnant liver weight was steady after hepatectomy, ICG-k and CLamp were lowest about 36 hours after hepatectomy. The restoration of ICG-k was comparable to that of liver weight, but the restoration of CLamp was delayed. CONCLUSIONS: Functional liver capacity was minimal during parenchymal cell mitosis in the regenerating liver. Functional restoration after two-thirds hepatectomy was delayed in comparison with morphologic restoration in rat.

Aminopyrine↗

High plasma levels of arginine and liver arginase in Kupffer-cell-depleted rats after partial hepatectomy.

BACKGROUND/AIMS: The remnant liver after partial hepatectomy releases arginase into the plasma, which is a reliable indicator of hepatocellular damage. Little information is available on how this release affects arginine plasma levels. We hypothesized that Kupffer cells after partial hepatectomy may prevent further hepatocellular damage, contributing to lower arginase release. The aim of the study was to evaluate the role of Kupffer cells in plasma arginase activity and arginine plasma levels after partial hepatectomy. METHODS: Wag/Rij rats (n=72, 250-275 g) were randomly assigned to receive 1 ml liposome-encapsulated dichloromethylene-diphosphonate in order to eliminate Kupffer cells (DMDP, n=24), 1 ml liposome encapsulated-phosphate buffered saline (PBS, n=24) or 1 ml NaCl 0.9% (NaCl, n=24) intravenously. Forty-eight hours later, all rats had a two-third liver resection. Rats were killed at 0, 24, 48 and 96 h after partial hepatectomy. RESULTS: Arginase plasma activity was higher in the DMDP-treated group compared to NaCl and PBS (both p<0.01, p<0.05, p<0.01 and p<0.05 for 0, 24, 48 and 96 h after partial hepatectomy respectively). Arginine plasma levels increased, but were lower in the DMDP group compared to NaCl and PBS (both p<0.05, 24 h after hepatectomy). CONCLUSION: The study showed that Kupffer cell depletion results in a higher arginase release from the remnant liver after partial hepatectomy, indicating a hepatocellular protective function of Kupffer cells. Despite this arginase release, arginine plasma levels were increased after partial hepatectomy.

Amino Acids↗

Liver regeneration in response to partial hepatectomy in rats treated with retrorsine: a kinetic study.

BACKGROUND/AIM: We have designed an experimental model in which transplantation of normal hepatocytes into rats previously treated with retrorsine (a naturally-occurring pyrrolizidine alkaloid) results in near-complete replacement of the recipient liver by donor-derived cells. Two/thirds partial hepatectomy was found to be essential for this process to occur. To probe this finding, in the present study we describe the kinetics of liver regeneration in response to partial hepatectomy in rats given retrorsine. METHODS: Six-weeks-old male Fisher 344 rats received retrorsine (2 injections of 30 mg/kg each, i.p., 2 weeks apart), or the vehicle. Four weeks after the last injection, partial hepatectomy was performed and rats were killed at 1, 2, 3, 6, and 15 days thereafter. RESULTS: At time zero, i.e. prior to partial hepatectomy, liver weight and total liver DNA content were significantly lower in retrorsine-treated animals compared to controls (DNA content: 19.2+/-1.7 vs. 25.7+/-1.1 mg/liver). Diffuse megalocytosis (enlarged hepatocytes) was present in the group exposed to retrorsine. By day 3 post-partial hepatectomy liver DNA content in control animals had more than doubled compared to day 1 values (20.2+/-1.5 vs. 8.8+/-1.2), while very little increase was seen in retrorsine-treated rats at the same time points (7.6+/-0.4 vs. 6.1+/-0.2). At 2 weeks after partial hepatectomy, total DNA content returned close to normal levels in the control group (26.9+/-1.0 mg/liver); however, the value was still very low in animals receiving retrorsine (9.1+/-0.7). Data on BrdU labeling were consistent with this pattern and indicated that DNA synthesis following partial hepatectomy was largely inhibited in the retrorsine group. Similarly, no mitotic response was observed in hepatocytes following partial hepatectomy in animals exposed to retrorsine. CONCLUSIONS: These results clearly indicate that retrorsine exerts a strong and persistent cell cycle block on hepatocyte proliferation. Further, these results are in agreement with the hypothesis that selective proliferation of transplanted hepatocytes in retrorsine-treated animals is dependent, at least in part, on the persistent cell cycle block imposed by the alkaloid on endogenous parenchymal cells.

Animals↗

Surgical treatment of hilar bile duct carcinoma: experience with 25 consecutive hepatectomies.

To evaluate our recent surgical policy regarding hilar bile duct carcinoma, we evaluated 62 cases treated between 1976 and 1993, and 25 cases treated between 1994 and 2000. In the late period we used percutaneous transhepatic portal vein embolization (PTPE) before extended right hepatectomy; S4a + S5 + S1 hepatectomy for elderly patients and those with poor liver function; and routine total caudate lobectomy including the paracaval portion and resection of the inferior portion of the medial segment (S4a). Sixty-five (74.7%) of the 87 patients underwent hepatectomy: 40 in the early period and 25 in the late period. Bile duct resection alone was performed in 22 patients, all in the early period. Resection was curative in 54.8% in the early period and 88.0% in the late period. The 3- and 5-year survival rates in the early period were 27.1% and 20.2%, respectively, as compared to 59.9% and 49.9% in the late period. Analysis of the 25 hepatectomies in the late period revealed improved survival times compared to patients treated by PTPE with extended right hepatectomy. No complications occurred after extended left hepatectomy or S4a + S5 + S1 hepatectomy, but four patients (16%) who underwent extended right hepatectomy plus PTPE died postoperatively. Our policy has resulted in improved outcome in patients with hilar bile duct carcinoma.

Adult↗

Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy.

BACKGROUND: Radiofrequency (RF) current, converted into heat through ion agitation and friction, can destroy liver tumours by means of coagulation necrosis. This study assessed whether percutaneous RF ablation is a useful and safe technique for the treatment of liver tumour recurrence after hepatectomy. METHODS: Forty-seven patients presenting with local recurrence after hepatectomy for malignant tumours (29 with colorectal secondaries) were treated with percutaneous RF ablation instead of repeat hepatectomy. RF thermal ablation was performed under image guidance for 12-15 min. This group represented 63 per cent of 75 patients treated with curative intent for liver recurrence in the same time interval. The other 28 patients underwent repeat hepatectomy. RESULTS: The mean(s.d.) number of liver metastases destroyed was 1.4(0.7) (range 1-3) and their diameter was 21(8) (range 9-35) mm. Twenty-six patients presented with liver recurrence at least once but up to three times after the initial RF application. Incomplete local RF treatment was observed in six of 47 patients. Fifteen patients developed extrahepatic recurrence. The mean(s.d.) interval between RF ablation and the last follow-up visit was 14.4(10.1) (range 5.5-40) months. One death and three major complications occurred. Survival rates at 1 and 2 years were 88 and 55 per cent respectively. A retrospective study of the authors' database over two similar consecutive periods showed that RF ablation increased the percentage of curative local treatments for liver recurrence after hepatectomy from 17 to 26 per cent and decreased the proportion of repeat hepatectomies from 100 to to 39 per cent. CONCLUSION: Percutaneous RF treatment increases the number of patients eligible for curative treatment. It should be preferred to repeat hepatectomy when feasible and safe because it is less invasive. Repeat hepatectomy is indicated only when percutaneous RF ablation is contraindicated or fails.

Adolescent↗

Energy metabolism and regeneration in transgenic mouse liver expressing creatine kinase after major hepatectomy.

BACKGROUND & AIMS: The catalysis of a creatinine/phosphocreatine system by creatine kinase is not expressed in the liver. The aim of this study was to examine the energy energy metabolism and regeneration after hepatectomy using transgenic mouse liver expressing creatine kinase to clarify the effects of phosphocreatine on liver regeneration. METHODS: Transgenic mice were divided into two groups: group 1 was fed normal chow, and group 2 was fed 10% creatine chow for 5 days. Hepatic energy metabolism was evaluated before and after hepatectomies. Changes in remnant liver weight gain and bromodeoxyuridine labeling index were measured after 70% and 80% hepatectomies. RESULTS: Hepatic adenosine triphosphate level 24 hours after 70% hepatectomy was significantly higher in group 2 than group 1 (P<0.05). In group 2, mitochondrial adenosine triphosphate synthesis was enhanced because of elevated intramitochondrial adenine nucleotide content before hepatectomy, leading to sufficient adenosine triphosphate synthesis after a 70% hepatectomy. Bromodeoxyuridine DNA labeling index 24 hours after a 70% hepatectomy was significantly higher in group 2 than group 1. Rapid liver weight gain was observed in group 2 after a 70% hepatectomy. CONCLUSIONS: Abundant phosphocreatine promotes liver regeneration by reinforced hepatic energy metabolism. Gene transfer of creatine kinase to the liver may be a potential method in liver surgery.

Adenine Nucleotides↗

Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy.

BACKGROUND & AIMS: Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is synthesized in the form of a membrane-anchored precursor (proHB-EGF), which subsequently is processed proteolytically to mature HB-EGF. This study describes the effects of HB-EGF on liver regeneration after 70% partial hepatectomy in proHB-EGF transgenic mice with liver-specific expression. METHODS & RESULTS: No significant differences in liver/body weight ratios and in bromodeoxyuridine (BrdU)-labeling index (the ratios of BrdU-positive hepatocyte nuclei) were found between adult transgenic and wild-type mice. However, in regenerating liver after partial hepatectomy, transgenic mice had higher liver/body weight ratios than wild-type mice and at 120 hours reached a level equal to that before partial hepatectomy. The BrdU-labeling index was about 5 times higher in the livers of transgenic mice compared with the wild type (51.5% vs. 10.2%, respectively; P < 0.01) at 48 hours after partial hepatectomy. Activation of microtubule-associated protein kinase after partial hepatectomy was higher and earlier in the transgenic mice as compared with the wild-type mice. Soluble HB-EGF was increased in the liver (at 8 min) after partial hepatectomy, indicating that the shedding of proHB-EGF occurred after partial hepatectomy. CONCLUSIONS: The transgenic expression of HB-EGF accelerates the proliferation of hepatocytes after partial hepatectomy, suggesting that HB-EGF functions as a hepatotrophic factor in vivo.

Animals↗

Partial hepatectomy is a promoter of hepatocarcinogenesis in C57BL/6J male mice but not in C3H/HeJ male mice.

We have shown previously that the difference between C57BL/6J and C3H/HeJ male mice in their susceptibilities to chemically-induced liver tumors results predominantly from an allelic difference at the Hepatocarcinogen sensitivity (Hcs) locus. This locus modulates the rate of growth of preneoplastic liver lesions and may also play a role in the turnover of normal hepatocytes in the adult liver. To define further the growth regulatory pathway of which the Hcs gene is a component, we asked whether the expression of the Hcs gene would modulate the response of preneoplastic liver lesions to the physiologic growth stimulus generated by a two-thirds hepatectomy. Twelve-day-old male and female C57BL/6J and C3H/HeJ mice were injected with 0.5 mumols N-ethyl-N-nitrosourea/g body weight. At six weeks of age half the animals received a two-thirds hepatectomy. Groups of animals were killed between 14 and 44 weeks of age for analysis of glucose-6-phosphatase (G6Pase)-deficient foci and hepatic tumors. The partial hepatectomy induced a regenerative response that caused both the G6Pase-deficient foci and the surrounding, histochemically normal hepatocytes to undergo several rapid rounds of division. As a result, the G6Pase-deficient foci were larger in the hepatectomized animals than in the sham operated controls. The foci in the non-hepatectomized C57BL/6J male mice grew more slowly than in the C3H/HeJ male mice [volume doubling time (Td) = 2.9 +/- 0.1 weeks and 2.0 +/- 0.6 weeks, respectively]. Following partial hepatectomy, the G6Pase-deficient foci in the C57BL/6J male mice maintained a significantly higher growth rate (Td = 2.2 +/- 0.3 weeks) than the foci in the sham operated C57BL/6J male mice. The partial hepatectomy did not have any long term effect on the growth rate of the G6Pase-deficient foci in the C3H/HeJ male mice nor in female mice of either strain. At 32 weeks of age, the mean liver tumor multiplicity for hepatectomized C57BL/6J male mice was approximately 5.3-fold greater than that for sham operated animals. In contrast, a two-thirds hepatectomy resulted in a 60% reduction in the number of liver tumors in C3H/HeJ male mice relative to sham operated mice. These data demonstrate that partial hepatectomy can act as a promoter of hepatocarcinogenesis in C57BL/6J male mice but not C3H/HeJ male mice. We propose that the Hcs gene and partial hepatectomy may promote hepatocarcinogenesis through the same pathway of growth regulation.

Animals↗

Repeated hepatectomy for recurrent intrahepatic cholangiocarcinoma: report of two cases.

Repeated hepatectomy for remnant liver recurrence of primary intrahepatic cholangiocarcinoma (ICC) is a seldom-encountered surgical technique because of its poor prognosis. Here, we present two long-term survivors of recurrent ICC by repeated hepatectomy. One patient underwent five hepatectomies in 6 years; first, extended left hepatectomy for a primary mass-forming-type ICC and then four partial hepatectomies for independent recurrent tumors all developing in segment V. The other patient underwent re-hepatectomy for a very large recurrent tumor 7 years after the first left hepatectomy for a primary periductal-infiltrating-type ICC; and has survived for approximately 2 years from the second operation under hepatic arterial infusion chemotherapy. The recurrent tumor in the latter case arose in the segment IV remnant corresponding to the cut margin of the liver after the first inappropriate left hepatectomy. The mode of hepatic recurrence seemed closely related to the portal segmentation: in the first case, intrahepatic metastases via portal tributaries; and in the second, the occult residual cancer spreading widely through bile ductules.

Aged↗

Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: analysis of prognostic factors for 763 cases recorded at 18 institutions.

PURPOSE: Factors affecting treatment prognosis and therapeutic results for hepatic metastasis of colorectal cancer were investigated. METHODS: Therapeutic results, especially of hepatectomy, were investigated for hepatic metastasis of colorectal cancer in 763 patients (585 underwent hepatectomy) treated between 1992 and 1996 at 18 institutions that participated in the "Study for establishing treatments for hepatic and pulmonary metastasis of colorectal cancer" sponsored by a Grant-in-Aid (10-11) for Cancer Research from the Ministry of Health, Welfare and Labor of Japan. RESULTS: The five-year survival rate for those treated by hepatectomy was significantly higher (32.9 percent) than for those not undergoing hepatectomy (3.4 percent). After hepatectomy for hepatic metastasis, the most prevalent form of recurrence was in the remnant liver (41.4 percent), followed by recurrence of pulmonary metastasis (19.2 percent), and other (7.2 percent). Factors of the primary tumor adversely affecting prognosis after hepatectomy for hepatic metastasis included poorly differentiated adenocarcinoma or mucinous carcinoma, depth of invasion of si/ai, lymph-node metastasis of Stage n3 and n4 by the Japanese classification of colorectal carcinoma, number of metastatic lymph nodes of more than four, and Dukes Stage D. Factors at the time of hepatectomy adversely affecting prognosis after surgery for hepatic metastasis included residual tumor, extrahepatic metastasis, hepatic metastasis of degree H3 stipulated by the Japanese classification of colorectal carcinoma, number of metastases of four or more, pathology of hepatic metastasis of poorly differentiated adenocarcinoma, resection margin of <10 mm, and carcinoembryonic antigen value higher than normal preoperative and one month postoperative. CONCLUSIONS: Among therapies for hepatic metastasis of colorectal cancer, the present study clearly revealed that hepatectomy is the treatment of choice whenever feasible. Postoperative recurrence often is localized in the remnant liver, or there may be a systemic recurrence of pulmonary metastasis. Thus, methods of prevention will be a future theme.

Colorectal Neoplasms↗

Is extended hepatectomy for hepatobiliary malignancy justified?

BACKGROUND: Extended hepatectomy may be required to provide the best chance for cure of hepatobiliary malignancies. However, the procedure may be associated with significant morbidity and mortality. METHODS: We analyzed the outcome of 127 consecutive patients who underwent extended hepatectomy (resection of > or = 5 liver segments) for hepatobiliary malignancies. RESULTS: The patients underwent extended hepatectomy for colorectal metastases (n = 86; 67.7%), hepatocellular carcinoma (n =12; 9.4%), cholangiocarcinoma (n =14; 11.0%), and other malignant diseases (n =15; 11.5%). Thirty-two left and ninety-five right extended hepatectomies were performed. Eight patients also underwent caudate lobe resection, and 40 patients underwent a synchronous intraabdominal procedure. Twenty patients underwent radiofrequency ablation, and 31 underwent preoperative portal vein embolization. The median blood loss was 300 mL for right hepatectomy and 600 mL for left hepatectomy (P = 0.02). Thirty-six patients (28.3%) received a blood transfusion. The overall complication rate was 30.7% (n = 39), and the operative mortality rate was 0.8% (n = 1). Significant liver insufficiency (total bilirubin level > 10 mg/dL or international normalized ratio > 2) occurred in 6 patients (4.7%). Multivariate analysis showed that a synchronous intraabdominal procedure was the only factor associated with an increased risk of morbidity (hazard ratio [HR], 4.9; P = 0.02). The median survival was 41.9 months. The overall 5-year survival rate was 25.5%. CONCLUSIONS: Extended hepatectomy can be performed with a near-zero operative mortality rate and is associated with long-term survival in a subset of patients with malignant hepatobiliary disease. Combining extended hepatectomy with another intraabdominal procedure increases the risk of postoperative morbidity.

Adult↗

A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases.

OBJECTIVE: To assess outcome after a 2-stage hepatectomy procedure (TSHP) combined with portal vein embolization (PVE) in the treatment of patients with unresectable multiple and bilobar colorectal liver metastases (MBCLM). BACKGROUND: Patients with MBCLM are often considered for palliative chemotherapy only, due to too small future remnant liver (FRL). Recently, right hepatectomy with simultaneous left liver wedge resections after previous right PVE has been reported in a curative intent. However, the growth of metastatic nodules in FRL after PVE can be more rapid than that of the nontumoral remnant hepatic parenchyma. Therefore, metastases located in the FRL should be ideally resected before PVE. Then, a right (or extended right) hepatectomy can be safely performed during a second-stage hepatectomy. Therefore, we analyzed our experience with the use of TSHP combined with PVE in treatment of MBCLM. PATIENTS AND METHODS: Between December 1996 and April 2003, 33 patients with unresectable MBCLM were selected for a TSHP. A right or an extended right hepatectomy was planned after treatment of left FRL metastases to achieve a curative resection. The first-stage hepatectomy consisted in a clearance of the left hemiliver by resection or radiofrequency destruction of metastases of the left FRL. Subsequently, a right PVE was performed to induce atrophy of the right hemiliver and hypertrophy of the left hemiliver. Finally, a second-stage hepatectomy was planned to resect the right liver metastases. RESULTS: There was no operative mortality. Post-PVE morbidity was 18.1%; postoperative morbidity was 15.1% and 56.0% after first- and second-stage hepatectomy, respectively. TSHP could be achieved in 25 of 33 patients (75.7%). The 1- and 3-year survival rates were 70.0% and 54.4%, respectively, in the 25 patients in whom the TSHP was completed. CONCLUSIONS: In selected patients with initially unresectable MBCLM, a TSHP combined with PVE can be achieved safely with long-term survival similar to that observed in patients with initially resectable liver metastases.

Antineoplastic Combined Chemotherapy Protocols↗

Hepatectomy for metastatic noncolorectal gastrointestinal, breast and testicular tumours.

BACKGROUND: The indications for hepatectomy for colorectal or neuroendocrine metastases are becoming clear with increasing experience reported. For other primary diseases, however, the overall number of cases is relatively small, and it is more difficult to derive clear guidelines. This paper reviews the reported experience of hepatectomy for metastases from non-colorectal gastrointestinal primary cancers, breast cancer and testicular teratoma. The aim is to determine for each whether and under what circumstances hepatectomy is indicated. METHODS: A Medline search was used to identify papers reporting hepatectomy for metastases from non-colorectal gastrointestinal carcinomas, breast carcinomas and testicular teratomas. The data collected included the primary disease, the number of cases reported, the survival post-hepatectomy and any prognostic factors associated with outcome. RESULTS: Of the gastrointestinal malignancies, hepatectomy for gastric metastases yields a 5-year survival, roughly half that reported for colorectal disease, and further elucidation of prognostic factors would be desirable. Results were poor for other gastrointestinal malignancies. Good results were reported for breast and testicular teratoma. CONCLUSION: Of the non-colorectal gastrointestinal primaries, at present only hepatectomy for gastric metastases can be cautiously recommended. For nongastrointestinal primaries, hepatic metastases probably represent widespread dissemination even if occult, and therefore, hepatectomy may only be of use when effective adjuvant treatments are available.

Adult↗

Effect of serotonin receptor 2 blockage on liver regeneration after partial hepatectomy in the rat liver.

UNLABELLED: The effect of serotonin receptor 2 blockade (5-HT(2)) on liver regeneration after 30-34% and 60-70% partial hepatectomy in the rat liver was investigated. MATERIALS AND METHODS: Male Wistar rats were subjected to 60-70% (group I) and 30-34% (group II) partial hepatectomy. Serotonin receptor 2 blockade was exerted by intraperitoneal administration of ketanserin at different doses and time points after partial hepatectomy. The rats of all groups were killed at different time points until 96 h after partial hepatectomy. The rate of liver regeneration was evaluated by the mitotic index in hematoxylin and eosin sections, the immunochemical detection of Ki67 and proliferating cell nuclear antigens, the rate of [(3)H]-thymidine incorporation into hepatic DNA and liver thymidine kinase enzymatic activity. RESULTS: Liver regeneration peaked at 24 and 32 h after partial hepatectomy in 60-70% hepatectomized rats. In 30-34% hepatectomized rats liver regeneration peaked at 60 h, whereas low rates of regenerative activity were observed between 24 and 72 h after partial hepatectomy. Ketanserin administration arrested liver regeneration only when administered at 16 h after 60-70% partial hepatectomy. Ketanserin also abrogated the observed peak of regenerative activity at 60 h in 30-34% hepatectomized rats when administered at 52 h after partial hepatectomy. All indices of liver regeneration were affected by ketanserin administration. CONCLUSIONS: Serotonin receptor 2 blockade can arrest liver regeneration only when administered close to G1/S transition point, and that while serotonin may be a cofactor for DNA synthesis, it does not play a role in initiation of liver regeneration.

Animals↗

Transforming growth factor alpha (TGF-alpha) expression correlates with DNA replication in regenerating rat liver whatever the hepatectomy extent.

Liver regeneration is a physiological mechanism that leads to restoration of the hepatic parenchyma following hepatectomy or toxic injury. As a two-third hepatectomy is the usual model to analyse this phenomenon, few studies have compared liver regeneration after minor vs major hepatectomy. We have used a quantitative RT-PCR technique to study the hepatic transcription of the TGF-alpha gene in rats submitted to 30% or 80% hepatectomy and we have correlated this transcription with the regenerative response assessed by flow cytometry and Ki-67 expression. The level of TGF-alpha expression and the regenerative response were different, according to the volume of liver removed, and were statistically correlated (r = 0.679, p = 0.002). TGF-alpha expression and phase S peaked at day 2 vs 6 in the 80% vs 30% hepatectomized rat groups, respectively. Ki-67 expression occurred at 2 h post-hepatectomy in the two groups of rats and was observed until day 14 mainly in the 80% hepatectomy group. Our results indicate that TGF-alpha expression in regenerating liver is strongly correlated with hepatocyte mitosis, that a delayed regenerative response occurs following 30% hepatectomy and that the course of regeneration differs between minor vs major hepatectomy.

Animals↗

FK506 with portal decompression exerts beneficial effects following extended hepatectomy in dogs.

The present study was designed to elucidate the effectiveness of portal decompression and FK506 (FK) pretreatment in extended hepatectomy in dogs. In the first set of experiment the effect of portal decompression was evaluated in two groups of dogs which underwent extended hepatectomies (80%) with or without (control) a side-to-side portacaval shunt. The presence of the shunt significantly (p < 0.05) improved the 7-day survival of the animals (57.1%) when compared with those of the control group (28.6%) and eventually the portal pressure was significantly lower and mean arterial pressure was significantly higher in the shunt group (p < 0. 05). Moreover, the animals with lower portal pressure (</=220 mm of saline) had a significantly improved 7-day survival rate than those with higher portal pressure (p < 0.001). To evaluate the role of FK pretreatment in extended hepatectomy, a more severe model of 90% hepatectomy was used in four different groups: portacaval shunt, shunt and FK pretreatment, FK pretreatment, and hepatectomy only (control). Although the shunt improved the survival rate in the 80% hepatectomy model, neither shunt (8.3%) nor FK pretreatment (0%) independently improved the survival of the animals when the hepatectomy was extended to 90%. FK pretreatment significantly improved the survival (33.3%, p < 0.05) and hepatic functions of the animals only in the presence of a shunt. Also hepatic microcirculation measured with a laser Doppler flowmeter was significantly better in the remnant liver of all treated groups than in the control group (p < 0.01). In conclusion, extended hepatectomy (90%) could be performed in otherwise normal liver after FK pretreatment and a side-to-side portacaval shunt, which improve the regenerative response in a stable hemodynamic animal.

Animals↗