Hepatitis B : a light microscopical and immunohistochemical study

The findings reported in this thesis provide a basis for a strategy for anti-viral treatment of chronic hepatitis B. Theoretically several approaches to the treatment of a viral infection exist. Because there is strong evidence for a direct relation between viral replication and activity of the liver disease, one therapeutic possibility may be to achieve suppression of viral replication and thus amelioriation of disease activity. For this purpose drugs that interfere with both viral RNA transcription and the production of viral proteins can be administered in order to suppress replication of the virus. At present however such drugs are. not available. Moreover the infection will not be cured: instead only the effects will mitigated. Such a drug may suppress both the immune mechanism, by diminishing protein (HBsAg) production, and the toxic effects, by reducing proliferation of the virus. Elimination of the potential of an infected cell to produce a virus is another possibile approach. To accomplish this aim, drugs can be used that eliminate ali infected hepatocytes from the liver. As shown in chapter VI, in chronic hepatitis all hepatocytes appear to be infected by the virus, as demonstrated by the diffuse cell membranebound HBsAg localization, so that such a therapy would imply elimination of all hepatocytes. If this elimination were to occur rapidly, the result would be massive liver cell necrosis and death of the patient A more realistic way to eliminate the potential of infected cells to produce virus would be to cure infection of the hepatocyte. Such a therapy may be achieved by inhibition of viral DNA synthesis. Since viral DNA formation depends on reverse transcription, drugs such as phosphonoformic acid that interfere with reverse transcriptasewould prevent the generation of cccDNA. However preliminary results with this type of drug are not hopeful. A decline in viral replication activity is followed by rapid restoration of this activity after withdrawal of the drug. Finally, another possibility is to cure the chronic infection by creating a situation in which newly formed hepatocytes are protected against reinfection by the virus. In this way, the number of infected hepatocytes will slowly decrease, as a result of regeneration of the liver, and all infected cells will eventually disappear

Morphometrically estimated variation in nuclear size - A useful tool in grading prostatic cancer

At present there are several grading systems for prostatic carcinoma. Most are difficult to reproduce. An objective method of grading seems to be necessary and could make comparisons between various groups of patients easier and grading more reliable. In the present study morphometrically estimated nuclear size and variation in nuclear size are matched with the survival rates of 207 patients who underwent total perineal prostatetomy for cancer. On the basis of morphometrically estimated variation in nuclear size the patients could be divided into two groups with significantly differing survival rates. In this way it was possible to split the group of patients with grade 2 carcinoma (Mostofi's grading system) into two groups of patients with significantly different survival rates. The survival rates in these two groups did not differ significantly from those in the patients with Grade 1 and Grade 3 tumors respectively. The results are discussed in the light of the recent literature on the subject. Morphometry seems to be a valuable tool in grading prostatic cancer

Metastatic potential of human renal cell carcinoma: experimental model using subrenal capsule implantation in athymic nude mice

The aim of this study was to determine whether subrenal capsule (SRC) implantation is a suitable model for the study of the metastatic potential of our human renal cell carcinoma (HRCC) lines and to establish new sublines with enhanced metastatic ability. NMRI athymic nude mice 7-11 weeks old received SRC implantation of our HRCC lines RC43 and RC21. These lines were not metastatic when implanted s.c. Mice were killed after 4 or 8 weeks, or when moribund. With the RC43 cell line the success rate for implantation was 69%, with 89% of these showing metastases. The average volume of the implanted tumour fragments was 0.5 mm3 (range 0.28-0.7), the average volume at the primary site at the time of death was 9087 (9-32000) mm3. Metastases were found in lymph nodes, liver, spleen, peritoneum, psoas muscle, pancreas, diaphragm and skin. The average volume of the metastases was 4139 (0.5-9000) mm3. Growing cell lines were established in vivo and in vitro from one splenic, one peritoneal, one diaphragmatic, and one hepatic metastasis. These sublines have faster in vivo and slower in vitro growth rates than the parental lines. With the RC21 cell line the success rate for implantation was 56% and the metastatic rate 78%. The average volume of the implanted tumour was 0.8 mm3 (0.28-1.2), the average volume at the primary site at the time of death was 2685 mm3 (1.4-6534) and the average volume of metastases was 7.1 mm3 (0.5-37.5). Metastases were found in lymph nodes, lung and skin. No establishment was attempted for RC21 because of the small dimensions of these metastases. SRC implantation is thus considered a useful tool for the study of the metastatic ability of our cell lines RC43 and RC21. The establishment of new sublines with a faster growth rate and an enhanced metastatic ability will be useful for further studies on the metastatic process

Ferritin accumulation and uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: A time-course study

To establish the time-sequence relationship between ferritin accumulation and uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone at 9 weeks. In the course of time, uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver

Transplacental induction of membranous nephropathy in a neonate

We report a case of renal failure in a newborn infant due to membranous glomerulonephritis. The patient was anuric in the first 3 weeks of life, after which renal function recovered. The serum of the mother contained IgG antibodies which reacted with tubular brush borders and glomeruli of adult and fetal human kidneys. Reactivity with renal epithelium from human kidneys was detected. We suggest that a transplacental, passive Heymann nephritis-like mechanism was the pathogenesis of the neonate's symptoms, although the antigen(s) involved was shown not to be gp 330 or any of the renal antigens known to be involved in experimental nephropathies

Inhibin immunoreactivity in gonadal and non-gonadal tumors

Abstract Inhibin immunoreactivity was estimated in a number of gonadal and non-gonadal tumors. Dog Sertoli cell tumors and human granulosa cell and Leydig cell tumors contained high concentrations of inhibin-like material. Levels, comparable with those in normal testes and ovaries were detected in human testicular non-seminomas and in ovarian cystadenomas, thecomas and adenofibromas. No activity was found in human testicular Sertoli/Leydig cell tumors and seminomas and in ovarian adenocarcinomas, teratomas and a dysgerminoma. Furthermore, human adrenal cortical tissue (tumor and hyperplastic adrenal) contained inhibin immunoreactivity. No activity was found in human tumors of the stomach, gut, liver, kidney, pancreas and mammary gland or in meningiomas. It is concluded that inhibin is not a good marker for specific gonadal tumors. Inhibin might have intratumor actions a growth or differentiation factor

Variation of prostate-specific antigen expression in different tumour growth patterns present in prostatectomy specimens

A series of 55 randomly chosen radical prostatectomy specimens was analyzed for expression of prostate-specific antigen (PSA) by immunohistochemical techniques. Tissue sections were selected in such a manner that in addition to glandular benign prostatic hyperplasia (BPH), one or more different prostatic tumour growth patterns were present. Four monoclonal antibodies, directed against three different PSA epitopes, and one polyclonal anti-PSA antiserum were used. Expression of PSA was compared with that of prostate-specific acid phosphatase (PAP), recognized by two different polyclonal antisera. A critical dilution aimed at a maximum of staining intensity on BPH tissue sections was chosen for all antibodies. Anti-PSA and anti-PAP antisera stained essentially all BPH samples (over 90%). Irrespective of the nature of the antibodies used, PSA expression was found to be decreased in prostatic carcinoma. A clear cut relationship was found between immunoreactivity for PSA and the degree of differentiation of the tumour area. Under the experimental conditions used the PSA monoclonal antibodies stained only 1 out of 10 undifferentiated carcinomas, whereas 50% to 70% of the well- and moderately-differentiated carcinomas showed immunoreactivity. This correlation was less pronounced with the PAP staining pattern. If the PSA antibody titer was raised the percentage of clearly staining undifferentiated carcinomas could be considerably increased (up to 60%-100%), indicating that PSA expression is not absent, but lowered in most (if not all) undifferentiated carcinomas

Prediction of long-term clinical outcome in a diverse chronic hepatitis B population: Role of the PAGE-B score

An abundance of noninvasive scores have been associated with fibrosis and hepatocellular carcinoma (HCC) development. We aimed to compare the prognostic ability of these scores in relation to liver histology in chronic hepatitis B (CHB) patients. Liver biopsies from treatment-naïve CHB patients at one tertiary care centre were scored by a single hepato-pathologist. Laboratory values at liver biopsy were used to calculate the PAGE-B, REACH-B, GAG-HCC, CU-HCC and FIB-4 scores. Any clinical event was defined as HCC development, liver failure, transplantation and mortality. HCC and mortality data were obtained from national database registries. Of 557 patients, 40 developed a clinical event within a median follow-up of 10.1 (IQR 5.7-15.9) years. The PAGE-B score predicted any clinical event (C-statistic.86, 95% CI: 0.80-0.92), HCC development (C-statistic.91) and reduced transplant-free survival (C-statistic.83) with good accuracy, also when stratified by ethnicity, antiviral therapy after biopsy or advanced fibrosis. The C-statistics (95% CI) of the REACH-B, GAG-HCC, CU-HCC and FIB-4 scores for any event were.70 (0.59-0.81),.82 (0.75-0.89),.73 (0.63-0.84) and.79 (0.69-0.89), respectively. The PAGE-B event risk assessment improved modestly when combined with the Ishak fibrosis stage (C-statistic.87, 95% CI: 0.82-0.93). The PAGE-B score showed the best performance in assessing the likelihood of developing a clinical event among a diverse CHB population over 15 years of follow-up. Additional liver histological characteristics did not appear to provide a clinically significant improvement

Interferon alfa for chronic hepatitis B infection: Increased efficacy of prolonged treatment

Interferon alfa (IFN-a) is the primary treatment for chronic hepatitis B. The standard duration of IFN-a therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-a treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in wh

Effect of neoadjuvant chemoradiotherapy on health-Related quality of life in esophageal or junctional cancer: Results from the randomized CROSS trial

Purpose To compare pre-agreed health-related quality of life (HRQOL) domains in patients with esophageal or junctional cancer who received neoadjuvant chemoradiotherapy (nCRT) followed by surgery or surgery alone. Secondary aims were to examine the effect of nCRT on HRQOL before surgery and the effect of surgery on HRQOL. Patients and Methods Patients were randomly assigned to nCRT (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) followed by surgery or surgery alone. HRQOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ-C30) and –Oesophageal Cancer Module (QLQ-OES24) questionnaires pretreatment and at 3, 6, 9, and 12 months postoperatively. The nCRT group also received preoperative questionnaires. Physical functioning (PF; QLQ-C30) and eating problems (EA; QLQ-OES24) were chosen as predefined primary end points. Predefined secondary end points were global QOL (GQOL; QLQ-C30), fatigue (FA; QLQ-C30), and emotional problems (EM; QLQ-OES24). Results A total of 363 patients were analyzed. No statistically significant differences in postoperative HRQOL were found between treatment groups. In the nCRT group, PF, EA, GQOL, FA, and EM scores deteriorated 1 week after nCRT (Cohen’s d: 20.93, P, .001; 0.47, P, .001; 20.84, P, .001; 1.45, P, .001; and 0.32, P = .001, respectively). In both treatment groups, all end points declined 3 months postoperatively compared with baseline (Cohen’s d: 21.00, 0.33, 20.47, 20.34, and 0.33, respectively; all P, .001), followed by a continuous gradual improvement. EA, GQOL, and EM were restored to baseline levels during follow-up, whereas PF and FA remained impaired 1 year postoperatively (Cohen’s d: 0.52 and 20.53, respectively; both P, .001). Conclusion Although HRQOL declined during nCRT, no effect of nCRT was apparent on postoperative HRQOL compared with surgery alone. In addition to the improvement in survival, these findings support the view that nCRT according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study–regimen can be regarded as a standard of care