Non-surgical treatment of hepatocellular carcinoma

A decade ago, surgery was the only satisfactory treatment modality for hepatocellular carcinoma (HCC), but it was limited only to selected cases. For the majority of cases of HCC, systemic chemotherapy was one of the few treatment alternatives, but provided only marginal benefit. In the past 20 years, diagnostic methods have improved to an extent that small HCC less than 1 cm can be detected. Moreover, non-surgical treatment is available, of which regional therapy has been shown to prolong patients' survival, and may even replace surgical resection in some cases. Regional therapy is indicated for the treatment of HCC when there is no extrahepatic metastasis and the patient has adequate liver function reserve, thus permitting repeated therapy. Transcatheter hepatic arterial embolization (TAE) using various embolizers has been well documented to include controlled studies. However, it is not indicated for patients with thrombosed main portal veins. Its therapeutic effect is also doubtful when the tumour is infiltrative in nature or is hypovascular, too large or too small. Additional chemotherapeutic agents mixed into the embolizer with lipiodol and degraded starch microspheres or styrene-maleic acid-neocarzinostatin in which chemotherapeutic agents are embedded, are used with a better response, but the survival rate has not shown significant improvement. Ultrasound-guided local injection therapy is another new method of treatment of HCC. Of these techniques, percutaneous ethanol injection therapy (PEIT) is widely used with excellent results for small, encapsulated tumours in livers with less than three HCC. Percutaneous ethanol injection therapy can also be used in cases with portal vein thrombosis, but it is not suitable for patients having coagulopathy or ascites. Using acetic acid, OK-432, interferon or anti-cancer drugs in the injection therapy shows no further benefit over ethanol alone. Transcatheter echoguided thermotherapy or cryotherapy has been reported in small series of patients, as has target therapy with immune or radiotherapy and conformal radiotherapy. Preliminary studies show encouraging results. Systemic therapy with either single drug or multidrugs is ineffective, with a response rate of less than 20%. Immunotherapy, such as with interferon or other cytokines, is not beneficial. Hormone therapy has not been promising, except for treatment with tamoxifen, which has been reported to show some beneficial effect. Gene therapy is still in its infancy. In summary, recent progress in non-surgical treatment of HCC has resulted in a breakthrough of regional therapy looking quite promising. Moreover, a combination of different types of regional therapies may yield better outcomes in selected individuals.     

Practical considerations in the rehabilitation of the aged

Enlightened geriatric care provides assistance to the elderly for living independently as long as possible. Essential to this amenity is the high priority placed upon restoration in coordination with other forms of therapy. Medical rehabilitation too often has been associated with employment-oriented goals and with major physical achievements. Restoration of the young spinal-injured paraplegic patient has been a model for rehabilitation medicine. The aged, also, often can be restored to optimal levels of functional capacity commensurate with their lesser needs. Rehabilitative principles for the management of disability are the same in old age as at any other time of life. Certain age-related factors, however, profoundly influence programs of restoration for the elderly. These factors need full consideration when physicians plan appropriate care for their aged patients. A list of guidelines is presented.     

Current status of treatment for small hepatocellular carcinoma

In recent years ethanol injection therapy (PEI) and transcatheter hepatic arterial embolization (TAE) have come to be widely used in the treatment of small hepatocellular carcinoma, and the introduction of microwave coagulation therapy (MCT) more recently has made it possible to perform a variety of non-surgical treatments even in cases in which surgical resection has been indicated until now. There have also been reports based on survival rates that results comparable to those obtained by surgical resection can be achieved with non-surgical methods. The main issue is whether PEI or resection should be selected to treat small hepatocellular carcinomas. However, the recurrence rate after PEI is higher than after surgical resection, and according to our results, in patients with solitary lesions, especially when the tumor diameter is 2 cm or less, the level of malignancy in many cases is also low biologically, and postoperative survival rates (recurrence-free survival rates) are favorable [5 years : 85.0% (64.3%); 10 years: 67.9% (42.2%)]. After thoroughly evaluating liver function in these cases, while surgical resection should be considered first, it is also important to use a combination of various treatment methods rather than always resort to a single method.     

Successful treatment of hepatocellular carcinoma with All-trans-retinoic acid

A 44-year-old female patient was admitted to our department with diagnosis of malignant lymphoma. The abdominal USG and CT showed multiple liver lesions with partial portal vein thrombosis, moderately increased alfa-fetoprotein (AFP), ASAT, ALAT (2x normal value), serology was negative for HBV and HCV. Liver transplantation was suggested but refused because of portal vein thrombosis. ATRA (45 mg/m2/day orally) was given on the basis of the assumption that HCC and acute promyelocytic leukaemia share similar oncogenic pathway (alter the RAR alpha and beta receptors). She was gained 15 kg-s and has resumed her work as a teacher for the last 20 months. Abdominal CT showed a complete regression of the intrahepatic tumour.     

Practical considerations of immunoprophylaxis in viral hepatitis

Hepatitis virus infections belong to the major etiological factors of both acute and chronic liver diseases. During the last years--apart from the passive immunoprophylaxis through the administration of immunoglobulin--safe and efficacious hepatitis vaccines (against hepatitis A and B viruses) has also became available in Hungary. In this review the authors focus on the practical considerations of the immunoprophylaxis of hepatitis viruses. General consensus concerning the clinical use of hepatitis A vaccine has not been accepted, and human immunoglobulin is the only acceptable measure to prevent postexposure hepatitis A virus infection. Hepatitis B immunoglobulin (HBIG) is administered to prevent hepatitis B infection after exposure of HBV-contaminated body fluids and in infants born to HbsAg-positive mothers. Recombinant hepatitis B vaccine has the crucial note in the WHO's program for eradication of hepatitis B. While in the areas of high endemicity the implementation of universal hepatitis B vaccination is recommended, in the countries with low HbsAg-carrier prevalence infants' and/or adolescents' vaccination can offer alternative choices. Prevention of health-care workers against hepatitis virus infection and the vaccination of patients with chronic liver disease are also of great importance. There is also an urgent need to establish multidisciplinary professional cooperation to be able to carry out effectively the WHO's recommendations for prevention of hepatitis B infection.     

Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma

BACKGROUND: Antibody-based reagents have failed to live up to their anticipated role as highly specific targeting agents for cancer therapy. Targeting with human single-chain Fv (sFv) molecules may overcome some of the limitations of murine IgG, but are difficult to produce with conventional hybridoma technology. Alternatively, phage display of antibody gene repertoires can be used to produce human sFv. OBJECTIVES: To isolate and characterize human single chain Fvs which bind to c-erbB-2, an oncogene product overexpressed by 30-50% of breast carcinomas and other adenocarcinomas. STUDY DESIGN: A non-immune human single-chain Fv phage antibody library was selected on human c-erbB extracellular domain and sFv characterized with respect to affinity, binding kinetics, and in vivo pharmacokinetics in tumor-bearing scid mice. RESULTS: A human single-chain Fv (C6.5) was isolated which binds specifically to c-erbB-2. C6.5 is entirely human in sequence, expresses at high level as native protein in E. coli, and is easily purified in high yield in two steps. C6.5 binds to immobilized c-erbB-2 extracellular domain with a Kd of 1.6 x 10(-8) M and to c-erbB-2 on SK-OV-3 cells with a Kd of 2.0 x 10(-8) M, an affinity that is similar to sFv produced against the same antigen from hybridomas. Biodistribution studies demonstrate 1.47% injected dose/g tumor 24 h after injection of 125I-C6.5 into scid mice bearing SK-OV-3 tumors. Tumor:normal organ ratios range from 8.9:1 for kidney to 283:1 for muscle. CONCLUSIONS: These results are the first in vivo biodistribution studies using an sFv isolated from a non-immune human repertoire and confirm the specificity of sFv produced in this manner. The use of phage display to produce C6.5 mutants with higher affinity and slower k(off) would permit rigorous evaluation of the role of antibody affinity and binding kinetics in tumor targeting, and could result in the production of a therapeutically useful targeting protein for radioimmunotherapy and other applications.     

Chronic oral etoposide and tamoxifen in the treatment of far-advanced hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a chemoresistant tumor that frequently expresses a high level of p 170 glycoprotein of the multidrug-resistance (MDR) gene. Preliminary data suggested that VP-16 showed modest activity in HCC. Recently, schedule-dependent cytotoxicity of VP-16 has been demonstrated. In this study, we tested the therapeutic efficacy of chronic oral VP-16 plus tamoxifen, a potential MDR-reversing agent, in patients with far-advanced HCC. METHODS: A prospective single-arm study was conducted in the National Taiwan University Hospital. To be eligible, patients must have had unresectable and non-embolizable HCC, objectively measurable tumors, adequate hemogram with absolute granulocyte count greater than or equal to 2,000/mm3, and platelet count greater than or equal to 1x10 (5)/mm3, total serum bilirubin less than or equal to 3.0 mg/dl, age less than or equal to 75 years, and a Karnofsky performance status of greater then or equal to 50%. The treatment included VP-16 (Bristol-Myers-Squibb, Princeton, NJ), 50 mg/m2/day, orally, Days 1 to 21, and tamoxifen (Pharmachemie B.V. Haarlem, Netherlands), 40 mg/day, orally, Days 1 to 21; repeated every 5 weeks. RESULTS: Between December 1990 and December 1993, a total of 33 patients were enrolled in the study. There were 28 men and 5 women, with a median age of 51 years. They received an average of 3.2 (range: 1-10) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3 and Grade 4 leucopenia developed in 6 patients (18.2%) and 4 (12.1%) patients, respectively. Grade 3 and 4 thrombocytopenia developed in 2 patients (6.1%). Treatment-related death occurred in one patient due to sepsis. Mild gastrointestinal toxicities were common with Grade 1 and 2 nausea. Grade 1 and 2 vomiting, Grade 1 and 2 diarrhea, and Grade 1 and 2 stomatitis, developed in 13 (39.4%), 7 (21.2%), 12 (36.4%), and 16 (48.5%) patients, respectively. Grade 3 and 4 gastrointestinal toxicities were rare. Deep vein thrombosis occurred in one patient (3.0%). Eight patients (24.2%, 95% confidence interval 11%-42%) had achieved a partial remission, with a median time-to-progression of 6 months (2-11). Median survivals of the responders and non-responders were 8.0 and 3.0 months, respectively (P < 0.05). The median Karnofsky performance status of the responders improved from 70% to 80%. CONCLUSIONS: Chronic oral VP-16 and tamoxifen has modest activity and acceptable toxicity in far-advanced HCC, and is a useful palliative treatment in about a quarter of such patients.     

Etiology, screening, and treatment of hepatocellular carcinoma

The prognosis with large hepatocellular carcinomas is poor, and only palliative treatment is available. Small tumors are amenable to several modes of treatment, including liver transplantation, resection, or alcohol injection, with acceptable 5-year survival rates. Although the value of screening for hepatocellular carcinoma has yet to be shown, these data, coupled with the recognition of at-risk groups and useful diagnostic techniques, might encourage the clinician to screen at-risk patients in the clinic. New imaging techniques such as ultrasonographic angiography enhanced with CO2 microbubbles, or color Doppler ultrasound, may clarify the intratumoral blood flow of small tumors.     

Practical considerations of outpatient infusion therapy in the HIV arena

In conclusion, OPAT is a cost-effective, quality-controlled alternative setting for treating patients with HIV. The program provides a desirable situation for the patient, physician, and nurse. Continuity of care provided by the health care team in the physician's office is a unique situation that can meet the treatment modalities necessary to care for the HIV patient with dignity and pride. In short, OPAT offers an attractive alternative to long-term hospitalization for a variety of HIV-related infections. Such therapy is rapidly becoming a standard of treatment that provides both cost savings and efficacious medical care to patients with HIV-related complications.     

Biochemical modulation of doxorubicin by high-dose tamoxifen in the treatment of advanced hepatocellular carcinoma

BACKGROUND/AIMS: In vitro data have indicated that tamoxifen (> 2.5 uM) significantly enhances the cytotoxic effect of doxorubicin in hepatocellular carcinoma (HCC) cells. This clinical study was conducted to examine whether tamoxifen, at a dose sufficient to result in a plasma concentration of more than 2.5 uM, may improve the therapeutic efficacy of doxorubicin in patients with advanced HCC. METHODOLOGY: A prospective phase II study was conducted. Eligible patients had unresectable and non-embolizable HCC, objectively measurable tumors, adequate neogram with absolute granulocyte count > 2,000/mm3 and platelet count > 1 x 10/mm3, total serum bilirubin < 3.0 mg/dl, age > or = 75 year, and a Karnofsky performance status < or = 50%. The treatment included oral tamoxifen 40 mg/m2, q.i.d, Day 1 to 7, and intravenous doxorubicin 60 mg/m2, Day 4, repeated every 3 weeks. RESULTS: Between May 1994 and December 1996, a total of 38 patients were enrolled in the study. Thirty-six patients were evaluable for tumor response and treatment-related toxicities. There were 32 men and 4 women, with a median age of 49 years. They received an average of 3.8 (range:1-12) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3-4 leucopenia and Grade 3-4 thrombocytopenia developed in 27.2% and 12.5% courses given, respectively. Gastrointestinal toxicity was generally mild. Three patients developed symptomatic cardiac toxicity. Twelve patients (33.3%, 95% confidence interval 17-51%) had achieved a partial remission (PR), with a median progression-free survival of 7 months. Median survivals of the responders and non-responders were 10 and 3 months, respectively (p<0.05). The median Karnofsky performance status of the responders improved from 74.0+/-6.3% to a post-chemotherapy value of 93.2+/-4.6% (p<0.05) CONCLUSIONS: High dose tamoxifen appears to be an effective biochemical modulator of doxorubicin in the treatment of HCC. Prospective randomized phase III studies comparing doxorubicin alone versus doxorubicin plus high-dose tamoxifen are needed.     

Erythropoietin in hepatocellular carcinoma

Hemopoietic alterations may occur during tumoral diseases, determining anemia. In most cases, serum EPO levels were lower than normal values. Hepatocellular carcinoma (HCC), one of the most frequent malignancies world-wide, is often characterized by mild anemia and increased serum EPO levels. We studied 30 HCC patients and 20 healthy subjects. We found that HCC patients presented higher serum EPO levels than healthy controls. In HCC patients, there was a significant inverse correlation between serum EPO levels and red blood cell count or hemoglobin levels. We postulated that the elevated serum EPO levels observed in these patients may be due to reduced hepatic clearance of EPO, and to the influence of cytokine-mediated inflammatory factors.     

Surgical treatment of patients with mixed hepatocellular carcinoma and cholangiocarcinoma

BACKGROUND: The results of treatment of mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) remain unclear because of the rarity of this disease. METHODS: Of 218 patients with primary liver carcinoma treated from 1979 to 1995, 6 had a histologic diagnosis of mixed HCC and CC (MHC). Five had chronic liver disease. Serum carcinoembryonic antigen (CEA), CA 19-9, and alpha-fetoprotein (AFP) levels were determined and hepatic angiography was performed preoperatively. Left trisegmentectomy (with portal vein reconstruction) and extended right lobectomy were performed in one patient each, whereas selective subsegmentectomy was done in three patients, and partial resection of segment 3 in one patient. Hilar lymphadenectomy was performed in two patients. RESULTS: Mild liver dysfunction was observed in two patients. The resected tumors ranged from 2.7 to 12 cm in size and all showed intermingling of HCC and CC elements. A preoperative diagnosis of MHC was possible in one patient because of a high AFP level and hypovascularity, whereas a high CEA level and hypervascularity led to the diagnosis in another patient. High levels of AFP, CEA, and CA 19-9 were observed in three, one, and three patients, respectively. There were no metastases in the dissected lymph nodes. Although 2 patients had died by 2 years after surgery, the 5-year survival rate was 60% and there were 2 long term survivors for more than 10 years. CONCLUSIONS: A hypervascular tumor with high CEA and CA 19-9 levels or a hypovascular tumor with a high AFP level may suggest a preoperative diagnosis of MHC in patients with suspected HCC. Extensive surgery is an effective treatment for this disease, except in patients with satellite nodules. Hilar lymphadenectomy may not be necessary in selected patients.     

Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.     

Ruptured hepatocellular carcinoma: treatment strategy and prognostic factor analysis

BACKGROUND: The prognosis of ruptured hepatocellular carcinoma (HCC) is generally poor, but few studies have focused on the analysis of prognostic factors of this catastrophic event. METHODS: Eighty-four consecutive patients with ruptured HCC were included. Twenty-nine clinical and laboratory variables were correlated to prognosis by using uni- and multivariate analyses. RESULTS: Epigastralgia and/or right upper quadrant abdominal pain was the most common initial presentation (70%), followed by shock (42%), abdominal distension (27%) and others (17%). Of these 84 patients, 50 patients were treated by supportive measure, 21 by operation and 13 by transcatheter arterial embolization (TAE). The median survival was 13, 30 and 202 days in each group, respectively, and 24 days overall. TAE showed the lowest hemostatic failure rate (20%). Univariate analysis showed that active treatment (operation or TAE), group I tumor with a solitary nodule or single nodule with proliferation into surrounding area, serum creatinine (< or = 1.2 mg/ml), alkaline phosphatase (< or = 95 U/L), alanine aminotransferase (ALT, < or = 40 U/L), total bilirubin (< or = 1.6 mg/ml), initial systolic blood pressure (> or = 90 mmHg), and absence of main portal vein thrombosis were correlated with a survival longer than 90 days (p < 0.05) in univariate analysis. Active treatment, ALT level and initial systolic blood pressure were still significant in multivariate analysis (p < 0.05). CONCLUSIONS: TAE may help stop the tumor bleeding. Treatment regimen, ALT levels and initial blood pressure are correlated with the prognosis of ruptured HCC.     

Value of percutaneous ethanol injection in the treatment of hepatocellular carcinoma in a cirrhotic liver]

Over the last few decades there has been a substantially higher percentage of successful organ transplants but also a significant imbalance between the demand for and the supply of organs, creating the basis for a highly profitable black market trade in human organs. Sometimes there are reports that children have been kidnapped, only to reappear later lacking one kidney, or that they simply disappear and are subsequently killed to have all their transplantable organs removed for profit. The European Union feels that there is a need for action and that it has a duty to act in this field, especially for ethical reasons. There is now established close co-operation between the various European transplant organizations. The legal protection of children with regard to organ transplantation is not specifically mentioned in the existing conventions because this issue was not foreseen at the time of their preparation. However, the issue is covered in a broader sense by more general provisions. There are endless rumours surrounding this area. Members of various organizations who travel in the suspected countries say that the trafficking in children who are sold for transplantation is well known, but it is too difficult and very dangerous to catch the people involved. We have to conclude that it has been impossible to prove or disprove the rumours, but they are consistent and we all, especially in the health care professions, have an obligation to be keenly aware of how and where organs are obtained.     

Thoughts on termination: Practical considerations.

This article reviews the literature on planned and forced termination. An overview of topics, including criteria for termination, technique of termination, and reactions to termination due to the sudden death of a therapist, is presented. We also examine the posttermination phase, subsequent therapy, and positive effects of forced termination. The purpose of this article is to add to the existing body of knowledge in the area of termination and to provide clinicians with therapeutic guidelines that can prove very useful in addressing patients' reactions to untimely and forced termination. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Practical considerations for the use of the optical disector in estimating neuronal number

A cDNA of Trichoderma harzianum (chit42), coding for an endochitinase of 42 kDa, has been cloned using synthetic oligonucleotides corresponding to amino-acid sequences of the purified chitinase. The cDNA codes for a protein of 423 amino acids. Analysis of the N-terminal amino-acid sequence of the chitinase, and comparison with that deduced from the nucleotide sequence, revealed post-translational processing of a putative signal peptide of 22 amino acids and a second peptide of 12 amino acids. The chit42 sequence presents overall similarities with filamentous fungal and bacterial chitinases and to a lesser extent with yeast and plant chitinases. The deduced amino-acid sequence has putative catalytic, phosphorylation and glycosylation domains. Expression of chit42 mRNA is strongly induced by chitin and chitin-containing cell walls and is subjected to catabolite repression. Southern analysis shows that it is present as a single-copy gene in T. harzianum. chit42 is also detected in several tested mycoparasitic and non-mycoparasitic fungal strains.     

Therapy of hepatocellular carcinoma

The therapeutic modalities in patients with hepatocellular carcinoma (HCC) depend on the number, size and location of the lesions as well as the stage of the underlying liver disease and the physical condition of the patient. In patients with small and solitary lesions, resection, liver transplantation and in some cases percutaneous ethanol injection (PEI) can be curative. In more advanced stages of the disease with larger or multiple lesions, PEI and/or transarterial chemotherapy with or without embolization (TACE or TAC) can slow the progression of the disease. In disseminated disease, a radiotherapeutic approach can be taken in selected cases. The therapeutic strategy in patients with HCCs should be individualized, frequently involving a combination of therapeutic modalities. In contrast to the earlier dismal prognosis, for most HCC patients there is today a therapeutic strategy that results in prolongation of life and in some cases even cure.