During the 10-year period (1980 to 1989), 76 patients with hepatocellular carcinoma (HCC) were treated by subtotal hepatic resection (HX) and 105 patients by orthotopic liver transplantation (TX) under cyclosporine-steroid therapy. Overall 1- to 5-year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2%, and 32.9%, respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6%, and 35.6%, respectively. The survival rates after HX and after TX correlated well with pTNM stages and were similar in each stage between the two groups. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly better than those after HX at each stage of pTNM classification. The tumor-recurrence rate was high both after HX (50%) and TX (43%), particularly in advanced stages of pTNM classification (60% or more). Twelve patients after HX and 13 patients after TX lived more than 5 years during this 10-year period. Fibrolamellar HCC and early stages of HCC were highly represented among the long-term survivors. Further improvement in survival rates depends on nonsurgical anti-cancer therapy before and/or after surgical removal of HCC.

ABSTRACT:The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wildtype Fc sequences.

Hepatocellular carcinoma (HCC) generally arises in a cirrhotic liver and, in most cases, is multifocal and bilobar. Although trans-hepatic artery chemoembolization (TACE) can be highly affective in shrinking tumors, it is limited by virtue of the damage that it can cause to the liver that is already damaged by chronic disease. A high priority in HCC research, after primary prevention and early detection, is to find new treatment modalities that are both effective and non-toxic to the underlying cirrhotic liver. A cohort of 65 patients with biopsy-proven unresectable HCC have been treated with hepatic arterial 90 Yttrium microspheres (Therasphere), and the interim results are reported here. Only 1 cycle of Therasphere treatment ever was performed on 46 patients, 17 patients had 2 cycles, and 2 patients had 3 cycles of therapy. The median dose delivered was 134 Gy, typically as either 5 or 10 GBq (2-4 million microspheres). Clinical toxicities include 9 episodes of abdominal pain and 2 episodes of acute cholecystitis, requiring cholecystectomy. A main lab toxicity was elevated bilirubin which increased by more than 200 % in 25 patients (30.5 %) during 6 months of therapy, although 18 of these patients had only transient elevation. A prominent finding was prolonged and profound (> 70%) lymphopenia in more than 75% of the patients, but without clinical significance. Forty-two patients (64.6%) had a substantial decrease in tumor vascularity in response to therapy, and 25 patients (38.4%) had a partial response, by computed tomography scan. Median survival for Okuda stage I patients (n ‫؍‬ 42) was 649 days (historical comparison 244) and for Okuda stage II patients (n ‫؍‬ 23) was 302 days (historical comparison 64 days). All patients were followed after therapy for a minimum of 6 months. There were 42 deaths, 21 due to liver failure, 6 from HCC progression, and 3 from metastases. Therasphere appears to be a relatively safe and effective therapy for advanced-stage unresectable HCC. (Liver Transpl 2004;10:S107-S110.)

The growth of human hepatoma Hep 3B cells is potently inhibited by TGF-fl1 (ID50 = 0.2 ng/ml, 8 pM). A mutant cell line was derived that was not inhibited in growth by TGF-fi1 at 5 ng/ml (200 pM) and that lacked TGF-18 receptor type II (TGF-,SRIII). Several other naturally occurring TGF-,3-resistant tumor cell lines that lack TGF-.BRII also lack TGF-,lRI (2,6,15), and in other cases they also lack TGF-pRIII (24), but absence of the TGF-P inhibitory effect on growth most consistently correlates with loss of TGF-,8RI and/or TGF-,lRII. These observations led to the hypothesis that TGF-,&mediated signaling involves both TGF-pRI and TGF-,lRII (19,22,23,25). Recently, a cDNA encoding the TGF-f3RII protein has been isolated by using an expression cloning strategy (26); its cytoplasmic region, when expressed in bacteria, demonstrated serine/threonine autophosphorylation activity (26). Furthermore, another, broadly expressed TGF-f3 receptor (type V) has also been reported to haveThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. kinase activity (27), but its involvement in signaling by TGF-,8 has not been established. (Invitrogen, San Diego). Recombinant plasmids, which expressed both sense and antisense TGF-,8RII genes, were purified by Qiagen-pack 500 (Qiagen, Chatsworth, CA). Plasmid DNAs (20 pg), rendered linear by the Sfi I restriction enzyme, were transfected by electroporation at 250 V and 960 uF capacitance, Abbreviations: TGF-(3, transforming growth factor P; TGF-I3RI, TGF-83RII, and TGF-,BRIII, TGF-,8 receptor types I, II, and III, respectively; Hep 3B-TS, human hepatoma cell line sensitive to

The growth rates of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLTX) were estimated by calculating the tumor doubling time (TDT) in 20 patients. The mean TDT, calculated by multiple measurement of tumor size, was 44.3 ± 11.3 days (mean ± standard error) in 12 patients with pulmonary metastasis (range, 10 to 161 days) and 37.6 ± 8.9 days (range, 7 to 65 days) in 5 patients with liver allograft recurrence. The TDT as estimated by serum alpha‐fetoprotein (AFP) levels in 6 patients was 37.3 ± 10.0 days (range, 12 to 84 days). The mean TDT obtained from 5 control subjects with HCC who were treated with liver resection (without immunosuppression) was 273.8 ± 79.1 days (range, 82 to 560 days). The disease‐free period and survival time after OLTX both correlated well with the TDT (r = 0.546 and r = 0.701, respectively). The patients with fibrolamellar HCC had a greater TDT and a longer survival time than those with nonfibrolamellar HCC. Despite a wide range of TDT in patients who received transplants, their recurrent HCC tumors grew significantly faster than those of patients with the same disease who did not receive transplants. The factors involved in this accelerated growth rate may include the use of immunosuppressive drugs and the consequent suppression of host immunity against the growth of micrometastasis. Cancer 68:2095–2100.