Novel strategy for a bispecific antibody: induction of dual target internalization and degradation.

Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.

Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma.

BACKGROUND: Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC). AIM: To determine the maximum tolerated dose (MTD) of the oral mTOR inhibitor everolimus in advanced HCC patients. METHODS: Patients with locally advanced or metastatic HCC (Child-Pugh class A or B) were enrolled in an open-label phase 1 study and randomly assigned to daily (2.5-10 mg) or weekly (20-70 mg) everolimus in a standard 3 + 3 dose-escalation design. MTD was based on the rate of dose-limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified. RESULTS: Thirty-nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)-seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg-seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively. CONCLUSIONS: The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti-viral therapy should be mandatory for HBsAg-seropositive patients (ClinicalTrials.gov NCT00390195).

Intravenous iron attenuates postvaccination anti-HBsAg titres after quadruple hepatitis B vaccination in dialysis patients with erythropoietin therapy.

BACKGROUND: Anaemia in patients with end-stage renal disease (ESRD) is commonly treated with recombinant human erythropoietin (rHuEPO), often in combination with an adjuvant iron supplement. There is much evidence that rHuEPO can influence the immune response by its effect on lymphocytes. Also, iron catalyses the formation of radicals and increases the risk of major infections by negatively affecting the immune system. The relationship between antibodies to hepatitis B surface antigen (anti-HBsAg) responsiveness after hepatitis B vaccination and rHuEPO/adjuvant iron supplementation has not been reported before. AIM: To determine the effects of subcutaneous erythropoietin and intravenous (i.v.) iron therapy on the responsiveness of anti-HBsAg after quadruple hepatitis B vaccination among ESRD patients. METHODS: Retrospective medical records were reviewed in a hospital with a tertiary teaching facility. Eighty-three ESRD patients, including 51 who underwent haemodialysis and 32 who underwent peritoneal dialysis therapy, received a quadruple recombinant hepatitis B vaccine. We investigated anti-HBsAg titres in those patients who either received rHuEPO alone (n = 50) or rHuEPO in combination with i.v. iron (n = 33). RESULTS: We found that the postvaccination anti-HBsAg titre was significantly lower in the rHuEPO plus i.v. iron group when compared with the group with rHuEPO alone (p < 0.05). The increment of anti-HBsAg between the initial month and the seventh month was positively correlated with therapeutic rHuEPO dosages in the group with rHuEPO alone (r = 0.303, p = 0.033). This relationship was not present in the rHuEPO with i.v. iron group (r = -0.289, p = 0.229). CONCLUSIONS: The levels of anti-HBsAg after hepatitis B vaccination are positively correlated with the dose of rHuEPO treatment during the vaccinated period among ESRD patients without i.v. iron supplementation. Also, i.v. iron negatively impacts the responsiveness of anti-HBsAg titre after hepatitis B vaccination in ESRD patients who have undergone rHuEPO therapy.

Quantitative profile of estrogen receptor variants/isoforms in Taiwanese women with breast cancer.

AIM: To quantify ER variants/isoforms for women with breast cancer in Taiwan, an area with remarkably low breast cancer rates, but with an early onset and poor prognosis. METHODS: Real-time PCR technology was exploited to quantify mRNAs of ERalpha, ERalphaE3Delta, ERalphaE5Delta, ERalphaE7Delta and ERbeta, in 49 breast cancer and paired adjacent normal tissues. Clinical parameters were assembled and tested for assocation with the ER expression. RESULTS: Comparison of cancer and matched normal samples showed significantly decreased ERbeta (p < 0.001) in cancer tissues, and constant amounts of ERalpha and their variants. The results revealed significantly lower ERalphaE7Delta/ERalpha (p = 0.030) and ERbeta/ERalpha (p = 0.035) ratios in patients with lymph node (LN) metastasis than in those without LN metastasis. CONCLUSION: Our data suggests that ERalphaE7Delta and ERbeta may regulate ERalpha in normal human breast tissue.

Fully automated large-scale assessment of visceral and subcutaneous abdominal adipose tissue by magnetic resonance imaging.

OBJECTIVE: To describe and evaluate a fully automated method for characterizing abdominal adipose tissue from magnetic resonance (MR) transverse body scans. METHODS: Four MR pulse sequences were applied: SE, FLAIR, STIR, and FRFSE. On 39 subjects, each abdomen was traversed by 15 contiguous transaxial images. The total abdominal adipose tissue (TAAT) was calculated from thresholds obtained by slice histogram analysis. The same thresholds were also used in the manual volume calculation of TAAT, subcutaneous abdominal adipose tissue (SAAT) and visceral abdominal adipose tissue (VAAT). Image segmentation methods, including edge detection, mathematical morphology, and knowledge-based curve fitting, were used to automatically separate SAAT from VAAT in various 'nonstandard' cases such as those with heterogeneous magnetic fields and movement artefacts. RESULTS: The percentage root mean squared errors of the method for SAAT and VAAT ranged from 1.0 to 2.7% for the four sequences. It took approximately 7 and 15 min to complete the 15-slice volume estimation of the three adipose tissue classes using automated and manual methods, respectively. CONCLUSION: The results demonstrate that the proposed method is robust and accurate. Although the separation of SAAT and VAAT is not always perfect, this method could be especially helpful in dealing with large amounts of data such as in epidemiological studies.

Infrared thermography to mass-screen suspected SARS patients with fever.

Fever greater than 38 degrees C is a cardinal sign of patients with the severe acute respiratory syndromes (SARS). To reduce the risk of nosocomial cross infections, screening all patients and visitors who visit hospitals and clinics for fever at the entrance of every hospital building has become a standard protocol in Taiwan during the SARS epidemic from mid-April to mid-June 2003. We used a digital infrared thermal imaging (DITI) system (Telesis Spectrum 9000 MB) to conduct mass screening of patients and visitors who entered the hospital to identify those with fever. The DITI system has two components: a sensor head and a PC imaging workstation. The sensor head is an optic-mechanical device which consists of imagining optics for focusing the infrared source information on the infrared detector. The infrared images are further converted into electrical signals, which are then processed for real-time display on the monitor. During the period from April 13 to May 12 2003, 72,327 outpatients and visitors entered Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan. A total of 305 febrile patients (0.42%) was detected by infrared thermography. Among them, three probable SARS patients were identified after thorough studies including contact history, laboratory tests and radiology examinations. The findings suggests that infrared thermography was an effective and reliable tool ideal for mass-screening patients with fever in the initial phase of screening for SARS patients at a busy hospital which sees approximately 3,000 outpatients every weekday during the SARS epidemic.

The role of transcatheter arterial embolization for patients with unresectable hepatocellular carcinoma: a nationwide, multicentre study evaluated by cancer stage.

BACKGROUND: Transcatheter arterial embolization is a major palliative treatment for unresectable hepatocellular carcinoma, but the survival benefit of transcatheter arterial embolization is controversial. AIM: To evaluate the role of transcatheter arterial embolization in different stage of unresectable hepatocellular carcinoma and to select patients who can get the best benefit from the treatment. METHODS: From 1991 to 1995, 476 patients who had unresectable hepatocellular carcinoma from four medical centres in Taiwan were enrolled. Among them, 425 underwent transcatheter arterial embolization, and 51 received supportive treatment alone. The survivals between the two groups were compared. RESULTS: Among the 476 patients, transcatheter arterial embolization can significantly prolong survival. The 1-, 2-, and 5-year survival rates for patients who underwent transcatheter arterial embolization were 60.2%, 39.3%, and 11.5%; and the rates for patients who underwent supportive treatment were 37.3%, 17.6%, and 2%, respectively (P = 0.0002). The survival benefit of transcatheter arterial embolization was observed in patients between Cancer and the Liver Italian Program 0 and Cancer and the Liver Italian Program 4. In multivariate analysis, transcatheter arterial embolization, tumour size <5 cm and earlier Cancer and the Liver Italian Program stage were independent factors associated with a better survival. CONCLUSIONS: For patients who fulfilled the criteria of transcatheter arterial embolization, embolization can serve as a primary treatment for patients with unresectable hepatocellular carcinoma. The survival benefit of transcatheter arterial embolization is regardless of tumour stages.

Significance of intraoperative peritoneal culture of fungus in perforated peptic ulcer.

BACKGROUND: The incidence of postoperative fungal infection is increasing and the gastrointestinal tract is the major source, but antifungal therapy in perforated peptic ulcer (PPU) is still controversial. The aim of this study was to determine the significance of intraoperative peritoneal fluid culture of fungus and establish the indications for treatment. METHODS: Between July 1997 and September 2001, all patients admitted with a PPU were studied. Clinical data and peritoneal fluid for culture were collected. Risk factors for a positive peritoneal fluid culture of fungus and outcome were evaluated, and related to the development of surgical site infection, duration of hospital stay and mortality rate. RESULTS: One hundred and forty-five patients with a PPU were included; 63 (43.4 per cent) had positive peritoneal fluid fungal culture. Age, preoperative organ failure, delay in operation, high Mannheim Peritonitis Index (MPI) and Acute Physiology And Chronic Health Evaluation (APACHE) II scores, and preoperative antibiotic therapy were risk factors for a positive fungal culture. Sex and an MPI score of 20 or more remained significant in multivariate analysis (P < 0.001). Patients with a positive fungal culture had a higher incidence of surgical site infection, a longer hospital stay and a significantly higher mortality rate, especially when this was combined with a high MPI score. CONCLUSION: Positive peritoneal fungal culture was common and was a significant risk factor for adverse outcome in patients with a PPU. A high MPI score could be used as an indicator for prophylactic antifungal therapy.

Clinicopathologic correlation of serum tissue polypeptide specific antigen in hepatocellular carcinoma.

OBJECTIVE: Recently, tissue polypeptide specific antigen (TPS) has been introduced as a cell proliferation marker. Little is known about its clinical significance in hepatocellular carcinoma (HCC). This study aimed to clarify serum TPS levels and tumor invasiveness of HCC. METHODS: Serum TPS levels were determined with a monoclonal TPS IRMA assay in 69 patients with HCC. A correlation between serum TPS levels and clinical, biochemical, and pathological features was sought and compared with that of alpha-fetoprotein (AFP). In 57 healthy subjects, 56 patients with biopsy-proven chronic hepatitis and in 49 patients with liver cirrhosis, serum TPS levels were assayed and compared. RESULTS: Serum TPS levels were significantly correlated with glutamic oxalacetic transaminase (p < 0.0001), glutamic pyruvic transaminase (p < 0.001), and lactate dehydrogenase (p = 0.027). There tended to be a positive relationship between serum TPS levels and tumor size, histological differentiation, capsular invasion, portal invasion, and clinical staging, although it did not reach statistical significance. A significant correlation, however, was observed between AFP and tumor size (p = 0.01), number (p = 0.042), histological grading (p = 0.028), portal invasion (p = 0.009), and clinical staging (p = 0.03). Patients with HCC had significantly higher TPS than healthy subjects (p < 0.001). However, there was substantial overlap between patients with HCC, chronic hepatitis, and liver cirrhosis. CONCLUSIONS: Our data suggest that serum TPS is not significantly related to tumor invasiveness in patients with HCC. Serum TPS levels are affected by the proliferative activity of the underlying chronic liver disease, which is frequently associated with HCC in Chinese patients. As a cell proliferation marker, serum TPS should be interpreted cautiously in the presence of chronic liver disease.

Identification of a pre-S2 mutant in hepatocytes expressing a novel marginal pattern of surface antigen in advanced diseases of chronic hepatitis B virus infection.

BACKGROUND AND AIMS: The expression of hepatitis B viral (HBV) antigens in liver tissue reflects the replicative status of chronic HBV infection. We have previously recognized a novel marginal pattern of hepatitis B surface antigen (HBsAg) in hepatocytes, which usually clusters in groups and emerges at the late non-replicative phase. This study was designed to investigate whether the marginal-type HBsAg represented the gene product of a specific HBV-surface mutant. METHODS: Microdissection of cirrhotic nodules homogeneously expressing marginal HBsAg was performed on two of 12 resected livers from HBsAg-seropositive patients with hepatocellular carcinoma. The gene presumably encoding marginal HBsAg was polymerase chain reaction (PCR)-cloned, sequenced and analysed. In vitro transfection and expression of the cloned surface mutant plasmids were performed on the Huh7 cell line to illustrate intrahepatic HBsAg expression. RESULTS: Immunohistochemical staining revealed that the marginal HBsAg was positive for pre-S1 and thus contained large surface proteins. The PCR cloning and sequencing of the genes presumably encoding marginal-type HBsAg in both cases revealed the same deletion at the 5' terminus (nt 2-55) of pre-S2. A point mutation on the small-surface (S) antigen was also found in one case. The pre-S2 deletion sequence and the mutation sites of the S gene coincide with human lymphocyte antigen-restricted T- and/or B-cell epitopes. In vitro transfection of the mutant plasmid revealed a blot-like retention or accumulation of HBsAg in the cytoplasm or at the periphery of hepatocytes, accompanied by a decreased secretion of HBsAg in the culture supernatant, mimicking intrahepatic expression. CONCLUSION: A natural pre-S2 deletion mutant was identified in hepatocytes expressing a novel marginal pattern of HBsAg, which probably contains mutant, large, surface proteins. The biological significance of the pre-S2 deletion mutant should be interesting in view of the clustering proliferation of hepatocytes expressing marginal HBsAg.

Carbon urea breath test is not as accurate as endoscopy to detect Helicobacter pylori after gastrectomy.

BACKGROUND: This study was conducted to determine (1) whether Helicobacter pylori infection decreases in conjunction with time elapsed after gastrectomy and (2) the diagnostic efficacy of (13)C urea breath test (UBT) for H pylori in patients after gastrectomy. METHODS: From January 1997 to June 1998, 86 patients who had undergone gastrectomy and 180 patients with dyspepsia without gastrectomy were enrolled. A UBT for the analysis of excess (13)CO(2)/(12)CO(2) ratio (ECR) was obtained for each patient. Each patient also underwent endoscopy to obtain gastric biopsies for histology and H pylori culture. The presence of H pylori by either histology or culture served as the standard to test the efficacy of UBT. The 86 patients with a prior gastrectomy were categorized into 3 subgroups (I, less than 1 year; II, 1 to 3 years; III, greater than 3 years), according to the interval between surgery and UBT. The initial H pylori status of these 86 patients was determined by histologic evaluation of the resected stomach. RESULTS: At trial initiation, the postgastrectomy group had a lower H pylori infection rate (52.3%) as compared with the dyspeptic control group (80%). The initial H pylori status among subgroups I, II, and III was similar. There was a trend for the presence of H pylori in the stomach to decrease with increasing time elapsed after surgery (I to III: 68.8%, 48.3%, 36%, respectively; p < 0.05). The maximum UBT sensitivity and specificity achieved were 82.2% and 87.8% in the gastrectomy group and 97.2% and 96.3% in the dyspeptic group, with cutoff points of 2.5 and 4.0, respectively. CONCLUSION: The prevalence of H pylori diminishes with time elapsed after gastrectomy. UBT for detection of H pylori is more effective in patients without prior gastrectomy than in patients who have undergone gastrectomy and is less effective than endoscopy for patients who have had a gastrectomy.

Incisional hernia after laparotomy: prospective randomized comparison between early-absorbable and late-absorbable suture materials.

Incisional hernia is a serious postoperative complication of laparotomy. Selecting an appropriate suture material may lessen such morbidity. This study undertook a prospective, randomized comparison of early-absorbable polyglactin 910 suture versus late-absorbable polydioxanone loop suture for fascial closure after abdominal surgery. A series of 340 consecutive patients undergoing elective laparotomy were randomized to have fascial closure with either polyglactin 910 suture or polydioxanone loop suture between October 1993 and August 1996. A 2-year follow-up revealed that 23 patients had died, and the overall mortality rate was 6.8% (23/340). Ten (10/340, 2.9%) patients, including seven with polyglactin 910 suture and three with polydioxanone loop suture, developed incisional hernias. The early postoperative evaluation revealed an incidence of wound infection of 4.1% (14/340). The development of incisional hernia was not secondary to postoperative wound infection in this study. Among these 340 patients, 192 had malignant diseases and 148 had nonmalignant ones. Fascial closure with polyglactin 910 suture was associated with more incisional hernias than that with polydioxanone loop suture, with marginal significance for patients in the malignant group (4.7% versus 0%, p = 0.07) but not in the nonmalignant group (2.6% versus 4.2%, p = 0.67). In conclusion, abdominal closure with a late-absorbable polydioxanone loop suture may be beneficial to patients with a malignant disease for preventing incisional hernia.

Successful birth after intracytoplasmic sperm injection for severe male factor infertility in a woman with poor response to controlled ovarian hyperstimulation.

Poor responders to controlled ovarian hyperstimulation (COH) present a clinical challenge for in vitro fertilization (IVF) and embryo transfer. The failure of IVF for the treatment of severe male-factor infertility can now be overcome by intracytoplasmic sperm injection (ICSI). The infertile couple documented in this case report came to our hospital because of bilateral tubal occlusion and severe oligoasthenospermia. After three poor-response cycles to COH, one mature oocyte was retrieved and was fertilized using ICSI. Normal fertilization ensued and one good-quality, eight-celled embryo was transferred into the woman's uterus. A single gestation was confirmed by ultrasound seven weeks after transfer. Amniocentesis was performed at 16 weeks and demonstrated a normal male fetus with a karyotype of 46,XY. The patient had a spontaneous, normal, vaginal delivery of a 2,650 g healthy male infant.

Hepatofugal flow on computed tomography of arterial portography: its correlation with esophageal varices bleeding.

BACKGROUND/AIMS: To study the portal flow patterns from CTAP (computed tomography of arterial portography), then to predict the existence of esophageal varices bleeding clinically. METHODOLOGY: 192 patients who underwent CTAP from superior mesenteric artery infusion were recruited in this study. The obtained images were classified according to our proposed criteria. Stage 0: hepatopetal flow, when all the contrast medium from the superior mesenteric vein entered the portal vein. Stage 1: when the contrast medium opacified the splenic vein or the other collateral vessels. Stage II: when the contrast medium opacified the paraesophageal vessels without entering the inner wall of the esophagus. Stage III: when the contrast medium opacified the collaterals up to the inner wall of the esophagus. RESULTS: The incidence of bleeding esophageal varices was correlated to the different stages of collateral flows pattern obtained. The esophageal varices bleeding rates were 0/137, 1/16, 1/14, 16/25 for stage 0, I, II and III, respectively. The incidence of bleeding esophageal varices was significantly higher in stage III group than in the other groups (P < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of stage III patients in regard to the occurrence of bleeding esophageal varices were estimated as 80.0%, 98.8%, 88.9%, 94.8%, and 94.3%, respectively. CONCLUSIONS: Our results show that CTAP demonstrates the portal flow patterns and collateral veins clearly, which can serve as an excellent imaging modality to predict the risk of esophageal varices bleeding.

Prospective randomized comparison between pylorus-preserving and standard pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy, with either gastrectomy (Whipple procedure) or pylorus-preserving pancreaticoduodenectomy (PPPD), is a complex procedure. Technical diversity, variation and sampling bias exist among surgeons. Previous reports comparing these two procedures are retrospective and not randomized. These factors should be considered seriously and eliminated in comparisons between the two procedures. METHODS: From August 1994 to August 1997, a prospective randomized comparison was conducted between the Whipple procedure and PPPD performed by the same surgeon with the same approach and same anastomotic fashion for periampullary cancer. After exclusion of seven patients, 31 patients were eligible for the study, 16 receiving PPPD and 15 a Whipple procedure. No significant difference in the age, sex distribution, tumour localization or staging was noted between the two groups. RESULTS: One operative death after PPPD and no operative death after the Whipple procedure resulted in a 3 per cent mortality rate in the 31 patients. Median duration of the Whipple operation was 235 (range 195-305) min, with a median blood loss of 500 (range 230-3100) ml and a median blood transfusion of 0 (range 0-10) units. In the patients who had PPPD, median operating time was 230 (range 170-275) min, median blood loss was 350 (range 100-1200) ml and median blood transfusion was 0 (range 0-4) units. There were two minor leaks from the pancreaticojejunostomy after the Whipple procedure and no leakage after PPPD, resulting in 6 per cent minor leakage in 31 patients. These outcomes were not significantly different. Delayed gastric emptying was observed more frequently after PPPD (six of 16 patients) than after the Whipple procedure (one of 15 patients), with marginal significance (P = 0.08, two-sided Fisher's exact test). CONCLUSION: In this prospective randomized study, both PPPD and the Whipple procedure were associated with low mortality and operative morbidity rates. There was no significant difference between PPPD and Whipple resection in terms of operative mortality and morbidity, operating time, blood loss and blood transfusion. PPPD was associated with more frequent delayed gastric emptying, although study of more patients is needed to confirm this.

Immunolocalization of BRCA1 protein in normal breast tissue and sporadic invasive ductal carcinomas: a correlation with other biological parameters.

AIM: BRCA1, a nuclear phosphoprotein, normally functions as a negative regulator of the cell cycle and may be an active inhibitor of neoplastic progression. Mutation of the BRCA1 gene has been demonstrated in 80% of familial breast cancer. Decreased mRNA levels or aberrant subcellular locations of BRCA1 have been identified in breast cancer lines and in sporadic cases of breast cancer tissues. The expression of BRCA1 in large series of variously differentiated breast carcinomas with correlation with other biological parameters has not been clarified. METHODS AND RESULTS: The BRCA1 expression in normal breast tissue (n = 15) and in sporadic cases of invasive ductal carcinoma (n=108) was determined using immunohistochemistry. BRCA1 expression was correlated with other prognostic parameters including p53, c-erbB-2, bcl-2, oestrogen receptor (ER), histological grade, tumour size, axillary lymph node status and age. BRCA1 was exclusively (100%) localized in the nuclei of normal ductal and lobular epithelia. However, this nuclear expression pattern was variable in breast carcinoma (76.8%). Loss of nuclear BRCA1 expression (22 of 108 cases, 20.4%) correlated well with high histological grade (P<0.025) and bcl-2-negative tumours (P<0.05) and frequently in ER-negative tumours. CONCLUSION: BRCA1 nuclear expression could be considered to represent the normal or physiological phenotype. Complete loss of BRCA1 nuclear expression in breast cancer and its correlation with other poor prognostic markers suggest that BRCA1 expression may play an important role in the pathogenesis and prognosis of sporadic breast carcinoma. Altered BRCA1 phenotype may therefore provide an additional prognostic parameter for breast cancer.

Inflammatory pseudotumor of the liver in a patient with human immunodeficiency virus infection.

A 31 year-old male was admitted for investigation of a hepatic tumor, which was incidentally found during abdominal sonography. Abdominal ultrasound revealed a large heterogeneous hyperechoic mass, 4x6x5cm in size, located at the inferior portion of the medial segment of the liver. Abdominal computed tomography without enhancement showed a hepatic tumor, 6 cm in size, in the medial segment of the liver. Malignancy was suspected in the light of radiological presentation. Therefore, wedge resection of the hepatic tumor was performed. The pathological findings revealed that the hepatic tumor was composed of dense fibrous tissue, plump spindle cells, foamy histiocytes, abundant lymphocytes, plasma cells and macrophages which led to the diagnosis of inflammatory tumor of the liver. The post-operative course was uneventful, and the patient was discharged two weeks after operation. Unfortunately, high fever and persisting headache were noted one week after discharge, thus the patient was re-admitted. The infectious focus was investigated during the second admission. Serological test for anti-human immunodeficiency virus was positive. Computed tomography of the brain revealed inflammatory changes over the territory of right middle cerebral artery. The patient died two weeks after the onset of encephalitis. We believe this to be the first case of inflammatory pseudotumor of the liver associated with human immunodeficiency virus infection.