Marked Reduction In Tumor Size Research Articles

Oral Dosing of the Novel Proteasome Inhibitor CEP-18770 Shows Marked Anti-Myeloma Effects in SCID-Hu Models of Multiple Myeloma.

Abstract 1840Poster Board I-866Introduction: Currently, there is no orally administered proteasome inhibitor (PI) which has been FDA approved for the treatment of any cancer. The first PI in clinical development, bortezomib, was approved in 2003 following two successful single-agent phase II trials in relapsed multiple myeloma (MM). In contrast to bortezomib which is administered by intravenous bolus, CEP-18770 is a PI that is active as an oral formulation. Furthermore, the efficacy of orally administered CEP-18770 in multiple MM models has not been reported. In this study, we determined the effects of orally administered CEP-18770 therapy at escalating doses either daily or twice weekly in severe combined immunodeficient (SCID) mice bearing human MM that has been serially passaged in SCID mice from bone marrow derived from a MM patient before (LAGκ-1A) and after resistance (LAGκ-1B) to bortezomib developed. Materials and Methods: Each naïve SCID mouse received a 20 — 40 mm3 MM tumor piece which was surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and animals were randomized into treatment groups. CEP-18770 was administered via oral gavage either daily at 5 mg/kg or twice weekly at 10 mg/kg (M, W) throughout the study. Each week, mice were bled for hIgG levels (where applicable) and tumors were measured using standard calipers. Data graphed is the mean ± SEM with n = 15 mice/group. Results: Single-agent CEP-18770 administered orally significantly inhibited tumor growth in bortezomib-sensitive LAGκ-1A-bearing mice. A significant inhibition of both human paraprotein secretion and reduction of tumor volume was observed as soon as three weeks following initiation of treatment with CEP-18770 at 10 mg/kg twice weekly (hIgG: P = 0.0011 and tumor volume: P = 0.001). Furthermore, tumor volume growth to 700 mm3 was delayed by 94% (day 32.5 for control compared to day 63) among animals receiving this treatment regimen when compared to animals receiving no treatment. At day 35, daily administration of the PI at 5 mg/kg also resulted in significant tumor inhibition (hIgG: P < 0.0001 and tumor volume: P < 0.0001). Reductions of tumor growth by 75%, 95%, 97% and 98% on days 28, 35, 42 and 49 respectively, were observed when compared to the control group. The effect of single-agent CEP-18770 dosed orally in SCID mice bearing nonsecretory bortezomib-resistant LAGκ-1B tumors was also evaluated. Four weeks following initiation of treatment, 5 mg/kg administered daily or 10 mg/kg twice weekly, resulted in a significant reduction in tumor volume (P = 0.0327 and P = 0.0018 respectively). Tumor volume growth to 300 mm3 was delayed by 36% (day 31 for control compared to day 42 for CEP-18770-treated group) in animals receiving 5 mg/kg daily compared to animals receiving no treatment. Tumor volume at 220 mm3 was delayed by 50% (day 28 for control compared to day 42 for CEP-18770-treated mice) among animals receiving 10 mg/kg twice weekly when compared to the untreated control group. Reductions of tumor growth by 78%, 73%, 74% and 70% on days 35, 42, 49 and 56 respectively, were observed when compared to the control group. Moreover, body weights measured at treatment cessation were not significantly different between pre- and post-treatment levels for both treatment groups and MM tumor types. Conclusions: The results of these studies show a marked reduction of tumor size and delay of tumor growth, when compared to the control group, following oral administration of CEP-18770 in LAGκ-1A and LAGκ-1B-bearing mice. The potential availability of an oral PI will greatly enhance the convenience of administration of drugs in this class as bortezomib has only shown efficacy when given intravenously. Other PIs that are bioavailable and active orally in preclinical studies in the treatment of MM are now in early clinical development. The data presented in our study provide further support for clinical development of CEP-18770 as an oral formulation for the treatment of MM. Disclosures:Berenson:Cephalon, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Direct discovery and validation of a peptide/MHC epitope expressed in primary human breast cancer cells using a TCRm monoclonal antibody with profound antitumor properties.

The identification and validation of new cancer-specific T cell epitopes continues to be a major area of research interest. Nevertheless, challenges remain to develop strategies that can easily discover and validate epitopes expressed in primary cancer cells. Regarded as targets for T cells, peptides presented in the context of the major histocompatibility complex (MHC) are recognized by monoclonal antibodies (mAbs). These mAbs are of special importance as they lend themselves to the detection of epitopes expressed in primary tumor cells. Here, we use an approach that has been successfully utilized in two different infectious disease applications (WNV and influenza). A direct peptide-epitope discovery strategy involving mass spectrometric analysis led to the identification of peptide YLLPAIVHI in the context of MHC A*02 allele (YLL/A2) from human breast carcinoma cell lines. We then generated and characterized an anti-YLL/A2 mAb designated as RL6A TCRm. Subsequently, the TCRm mAb was used to directly validate YLL/A2 epitope expression in human breast cancer tissue, but not in normal control breast tissue. Moreover, mice implanted with human breast cancer cells grew tumors, yet when treated with RL6A TCRm showed a marked reduction in tumor size. These data demonstrate for the first time a coordinated direct discovery and validation strategy that identified a peptide/MHC complex on primary tumor cells for antibody targeting and provide a novel approach to cancer immunotherapy.

Preoperative Transcatheter Selective Arterial Chemoembolization in Treatment of Unresectable Hepatoblastoma in Infants and Children

The purpose of this study was to evaluate the clinical feasibility and efficacy of transcatheter selective arterial chemoembolization (TACE) for unresectable hepatoblastoma in infants and children. The study was performed with the approval of our institutional review board. Sixteen patients (13 boys, 3 girls) with unresectable hepatoblastoma were treated one to three times with preoperative TACE in an effort to improve the surgical and clinical outcome. Their ages ranged from 50 days to 60 months, with a mean age of 20.4 months. All cases were pathologically proved hepatoblastoma by fine-needle biopsy. After an intra-arterial catheter was selectively inserted into the main feeding artery of the tumor, cycles of cisplatin (40 to 50 mg/m(2)) and adriamycin (20 to 30 mg/m(2)) mixed with lipiodol were given, followed by gelatin foam particles or stainless-steel coils. Tumor response was evaluated according to tumor shrinkage, alpha-fetoprotein (AFP) levels, and pathological findings. TACE procedure was performed one to three times, depending on the patient's response. Surgical resection was carried out when the tumor volume appeared sufficiently reduced to allow safe resection by either lobectomy or extended lobectomy. A marked reduction in tumor size associated with decreased AFP level occurred after treatment. According to paired-samples test, tumor shrinkage ranged from 19.0% to 82.0%, with a mean value of 59.2%. AFP levels decreased 99.0% to 29.0% from initial levels, with a mean decrease of 60.0%. TACE allowed subsequent complete surgical resection in 13 cases and the other 3 cases underwent partial resection. One patient underwent successful orthotopic liver transplantation after receiving TACE therapy. Pathological examination showed that the mean percentage of necrotic area in the surgical specimens was 87%. Overall survival rate at 1, 3, and 5 years was 87.5%, 68.7%, and 50%, respectively. Correspondingly, event-free survival rate was 75%, 62.5%, and 43.7%, respectively. In addition, there was no marked chemotherapeutic agent-induced toxicity noted during the observation period. We conclude that TACE is feasible, well tolerated, and effective in inducing surgical resectability of hepatoblastoma in pediatric patients, which has become an independent palliative or curative therapeutic option, especially for patients without distant metastasis.

Anterior mediastinal nonseminomatous germ cell tumor with malignant transformation: A case report

We report a case of a 21-year-old man who presented with the unusual symptoms of heart failure and was found to have an anterior mediastinal yolk sac tumor. A review of the literature using the Ovid search engine was performed. The patient was treated with the current standard of neoadjuvant chemotherapy: bleomycin, etoposide, and cisplatin (BEP) with marked reduction in tumor size, followed by en bloc surgical resection. The final pathology revealed teratoma with malignant change: chondrosarcoma, adenocarcinoma, and poorly differentiated sarcoma. This is a rare initial presentation of an anterior mediastinal germ-cell tumor with treatment consisting of neoadjuvant therapy and surgical resection. In addition, we present the adverse and extremely rare malignant degeneration of this tumor.

Identification of the apoptosis activation cascade induced in mammary carcinomas by energy restriction.

Energy restriction (ER) inhibits mammary carcinogenesis and results in a marked reduction in tumor size, effects likely to be explained by ER-mediated induction of apoptosis. The goal of this study was to investigate the molecular mechanism(s) accounting for apoptosis induction. To do this, chemically induced mammary carcinomas were evaluated from rats that were ad libitum fed (control), 40% ER, or 40% ER but energy repleted for 7 days before study termination (ER-REP); the ER-REP group permitted the determination of the reversibility of ER-mediated effects. Cleaved products of poly(ADP-ribose) polymerase 1 were elevated by ER (P < 0.025) providing biochemical evidence of apoptosis induction. cDNA microarray analysis identified the Bcl-2, CARD, and IAP functional gene groupings as being involved in apoptosis induction. Consistent with the microarray data, the activities of caspases 9 and 3 were observed to be approximately 2-fold higher in carcinomas from ER rats (P < or =0.01), whereas caspase 8 activity was similar in carcinomas from all three of the groups. This evidence that ER-induced apoptosis mediated by the mitochondrial pathway was additionally supported by the finding that levels of Bcl-2, Bcl-xl, and XIAP protein were significantly lower (P < 0.01), and levels of Bax and Apaf-1 were elevated (P < 0.02) in ER carcinomas versus those carcinomas from control or ER-REP rats. Additional studies revealed that Akt phosphorylation (activation) was reduced in mammary carcinomas from ER rats. Thus, it appears that ER induces apoptosis in mammary carcinomas via a cell survival factor-dependent pathway.

Radioimmunotherapy in patients with head and neck squamous cell carcinoma: initial experience.

Despite improvements in locoregional treatment of stages III/IV squamous cell carcinoma of the head and neck (HNSCC), local and distant failure rates remain high. An effective adjuvant therapy is required for these patients. Among novel approaches is radioimmunotherapy, in which monoclonal antibodies (MAbs) are used for selective delivery of radiation to tumor cells. The suitability of 186Re-labeled chimeric MAb U36 (186Re-cMAb U36) for radioimmunotherapy was evaluated in a phase I study, with radiation dose escalating steps of 11, 27, and 41 mCi/m2. Tumor targeting was monitored with a gamma camera, and the maximum tolerated dose was established in 13 patients with recurrent or metastatic disease. Administrations were well tolerated, and excellent targeting of tumor lesions was seen. Myelotoxicity was the only toxicity observed, resulting in dose-limiting toxicity in two patients treated with 41 mCi/m2. The MTD was established at 27 mCi/m2. A marked reduction in tumor size was observed in two patients, another showed stable disease for 6 months. Radioimmunotherapy with 186Re-cMAb U36 seems to be well tolerated, with bone marrow being the dose-limiting organ. The observation of antitumor effects is encouraging for further development of radioimmunotherapy for HNSCC.

Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence.

It is estimated that there will be >184,500 new cases of prostate cancer and 42,000 prostate cancer deaths in the United States this year. In the majority of patients diagnosed with prostate cancer, the disease will be too advanced for cure with standard medical treatment. New therapeutic strategies against advanced prostate cancer are desperately needed. As alterations in tumor-suppressor gene p16 are common in prostate cancer, one novel approach is gene therapy using a replication-deficient, E1/E3-deleted adenovirus type 5 containing a p16 under the control of a truncated Rous sarcoma virus promoter (AdRSVp16). In vitro, PC-3 cells that had been stably transfected with p16 expression vector under the control of an inducible promoter had a 70% reduction in cell number compared with the parental and control vector-transfected PC-3 cells. Similarly, AdRSVp16 significantly inhibited the growth of PPC-1 and PC-3 prostate cancer cells in culture. Furthermore, PPC-1 tumors grown in nude mice treated by a single injection of AdRSVp16 had a marked reduction in tumor size compared with untreated control-treated or viral control-treated PPC-1 tumors. Animals bearing tumors treated with AdRSVp16 also had longer survival. Adenovirally mediated expression of transgene was detected in xenograft tumors for at least 2 weeks. Taken together, these results suggest that AdRSVp16 should be considered for prostate cancer gene therapy in human clinical trials.

Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle.

Described herein is the discovery of a novel series of antitumor sulfonamides targeting G1 phase of the cell cycle. Cell cycle control in G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). We previously reported our first antitumor sulfonamide E7010 as a novel tubulin polymerization inhibitor. Interestingly enough, continuous research on structurally related compounds led us to the finding of another class of antitumor sulfonamides that block cell cycle progression of P388 murine leukemia cells in G1 phase, but not in M phase. Of the compounds examined, N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) showed significant antitumor activity against HCT116 human colon carcinoma both in vitro (IC(50) 0.11 microg/mL in cell proliferation assay) and in vivo (not only growth suppression but also a marked reduction of tumor size in nude mice). Because of its promising efficacy against human tumor xenografts and its unique mode of action, E7070 is currently undergoing phase I clinical trials in European countries.

Transcatheter arterial chemoembolization in the treatment of hepatoblastoma

Background: The prognosis of hepatoblastoma is poor unless the tumor is completely resected. Various types of chemotherapy have been developed to increase its resectability. Recently, transcatheter arterial chemoembolization (TACE) has been developed for the treatment of unresectable adult hepatoma with favorable results. The authors applied this procedure to hepatoblastoma in infants and children. Methods: TACE was performed in eight hepatoblastoma cases. After an intraarterial catheter was inserted into the main feeding artery of the tumor, injection of adriamycin or THP-adriamycin (20 to 30 mg/m 2) dispersed in lipiodol and cisplatin (40 to 60 mg/m 2) followed by embolization using Gelfoam pieces was performed. Effects of TACE were evaluated according to shrinkage of tumor mass on imaging examinations, alpha-fetoprotein (AFP) levels, and pathological findings of the surgical specimens 4 weeks after TACE. Results: A marked reduction in tumor size associated with a decrease in AFP level occurred 1 month after the treatment. Tumor shirinkage ranged from 0.9% to 45.0% with a mean value of 25.8%. AFP levels decreased by 0.2% to 11.9% with a mean level of 4.6% from initial levels. In addition, there was no marked chemotherapeutic agent-induced toxicity noted during the observation period. Resection of the tumors was performed safely after TACE in all cases. Pathological examination showed massive necrosis in the surgical specimens, and the mean percentage of necrotic area within the tumor was 71.1%. Two patients died of extensive lung metastasis 2 months and 3 years after the operation, respectively. The remaining six were doing well and free of disease at a mean follow-up period of 50 months. Conclusion: TACE is an effective, safe, and useful method for the initial treatment of hepatoblastoma.

Potent antitumor activity of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine in choriocarcinoma-bearing rats.

The acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective antiretroviral agent which is currently evaluated in its oral prodrug form, bis(POM)PMEA (adefovir dipivoxil), in phase II and III clinical trials in human hepatitis B virus (HBV)- and human immunodeficiency virus (HIV)-infected individuals, respectively. We have now found that PMEA is also a potent inhibitor of growth of the highly aggressive choriocarcinoma tumor arising from rat choriocarcinoma RCHO cells grafted under the kidney capsule of syngeneic WKA/H rats. In untreated rats, massive invasive RCHO tumors, covering the whole surface of the kidney and resulting in a marked enlargement of the kidney, were observed at day 10 after tumor cell grafting. Daily treatment with PMEA at 25 mg/kg/day afforded a marked reduction in tumor size (i.e., smaller tumors and slight, if any, enlargement of the kidney). Increasing the PMEA dose to 50, 100 or 250 mg/kglday resulted in a gradual increase of the antitumor effect of the compound. At the highest dose tested, i.e., 250 mg/kg/day, PMEA completely suppressed tumor growth. The antitumor activity of PMEA persisted for at least 10 days after termination of drug treatment. In addition, delayed treatment with PMEA at a dose of 200 mg/kg/day, started at a time point where choriocarcinoma tumors had already developed, stopped further growth and even induced regression of the tumors. PMPA, a closely related structural analogue of PMEA, failed to inhibit choriocarcinoma tumor growth. This observation points to the specificity of PMEA as an antitumor agent. In view of our findings, the therapeutic potential of PMEA for the treatment of neoplastic diseases appears to merit further investigation.

New development of transarterial immunoembolization (TIE) for therapy of hepatocellular carcinoma with intrahepatic metastases.

The prognosis of patients with multiple hepatocellular carcinoma (HCC) remains disappointing. In this study, we devised a new therapeutic modality for HCC consisting of transarterial immunoembolization (TIE) using OK-432 and fibrinogen and then analyzed the preliminary results. In the first series, we applied the treatment to 19 patients with advanced HCC who had proved to be insensitive to several previous conventional treatments. In all, 14 patients (74%) with unresected HCC have currently survived for between 2 and 16 months after TIE. The remaining 5 patients died at 17, 14, 8, 7, and 4 months after TIE. The serum levels of tumor markers decreased in all of the patients, and a marked reduction in tumor size was observed in six patients after TIE. A high fever occurred in all cases, and abdominal pain and loss of appetite were also observed after TIE. However, deterioration of liver function was negligible. After confirmation of the safety of this method, we started a second study series in which this TIE treatment was selected as the first choice. Six patients have been treated to date. All patients in this group underwent hepatic resection at 6-48 days following TIE. Histological examination of the resected specimens following TIE showed massive infiltration of mononuclear cells around tumor cell nests and lytic necrosis as well as coagulation necrosis of the main tumor and the intrahepatic metastases. In conclusion, our results indicate that TIE may be a safe and promising therapy for patients with HCC.

Short-term morphologic and functional effects of bromocriptine on pituitary prolactin cell adenomas in vitro.

Bromocriptine, a dopamine agonist, rapidly reduces profactin (PRL) blood levels in vivo; it also causes a marked reduction in tumor size in patients with lactotroph adenomas within 2 weeks of initiation of therapy. The effects are direct, as shown in vitro, and are thought to be due to inhibition of gene transcription that causes alteration in tumor cell morphology. However, the morphologic changes that account for a functional response within hours of administration have not been elucidated. We report the functional and morphologic changes in 7 pituitary lactotroph adenomas studied in vitro after 2, 24, and 48 hours of incubation with bromocriptine. In 2-hour incubations, PRL release rapidly fell to 46% to 74% of control; morphologic analysis revealed an increase in the cytoplasmic volume density (CVD) of secretory granules. After 24 hours of treatment, PRL release was maximally suppressed at 18% to 32 % of control; at 24 hours, the CVDs of secretory granules and lysosomes were increased, and they remained higher than in control cells at 48 hours. The CVD of rough endoplasmic reticulum was reduced at 2 hours in some tumors, but that of Golgi complexes was reduced only at 48 hours. Cell size was altered only to slightly below 80% of control and only after 48 hours of exposure in 2 or 3 tumors. This study indicates that inhibition of PRL secretion occurs within 2 hours of exposure to bromocriptine; the initial morphologic correlates are an increase in the CVD of secretory granules, suggesting inhibition of hormone release, and a decrease in rough endoplasmic reticulum, suggesting reduction of hormone synthesis. Lysosomal accumulation occurs within 24 hours, most likely reflecting degradation of the stored hormone. Subsequently, Golgi complexes involute as the next step in reduced hormone synthesis occurs, and cell shrinkage occurs relatively later. These findings correlate well with the rapid reduction in PRL blood levels and the slower tumor shrinkage documented clinically in patients with PRL cell adenomas.

Chronic somatostatin analog administration in patients with alpha-subunit-secreting pituitary tumors.

Glycoprotein hormone-producing (GPH) pituitary adenomas represent approximately 25% of all pituitary tumors. Elevated serum levels of intact GPHs or their free alpha- and beta-subunits have been demonstrated in patients with such tumors, and isolated hypersecretion of alpha-subunit has been reported to occur in 7% of patients. Somatostatin has been shown to decrease GPH subunit levels in cultured adenoma cells in vitro, and somatostatin receptors have been identified on the cell membranes of these tumors. We, therefore, investigated the effect of chronic somatostatin analog administration on hormone production and tumor size in six patients with GPH-producing macroadenomas and elevated serum alpha-subunit levels. Patients initially received native somatostatin as an iv 250-micrograms bolus at 0800 h, followed by a constant infusion of 2 mg over 4 h, and serum alpha-subunit concentrations were measured at 30-min intervals after baseline sampling for a total of 9 h. Patients then received a somatostatin analog, octreotide (100 micrograms, twice daily, sc) for 8 weeks. Serum alpha-subunit levels were determined weekly at 30-min intervals before and for 4 h after the 0800 h octreotide dose. Pituitary magnetic resonance imaging scans and visual field testing were assessed before and after the study. During the 4-h somatostatin infusion, four patients had a significant decrease in alpha-subunit levels (P < 0.05). During the 8-week chronic octreotide administration period, two patients had significant decreases in alpha-subunit levels of 34.6% and 26.7% (P = 0.03 and 0.01, respectively). One of these two patients had a small reduction in tumor size. Two patients whose serum alpha-subunit level did not significantly change while receiving octreotide had a reduction in tumor size or definite improvement in visual field abnormalities. Three patients received a maximum octreotide dose of 250 micrograms, three times daily. In one patient, there was a significant decrease in alpha-subunit levels by 45% (P = 0.0001) in association with a marked improvement in visual field abnormalities. In another such patient, continued administration of octreotide to a maximum dose of 250 micrograms, three times daily, was associated with a marked reduction in tumor size. Of the four patients who demonstrated significant decreases in alpha-subunit concentrations during the initial somatostatin infusion, three patients had a significant reduction in alpha-subunit levels while receiving octreotide. One patient who did not have a decrease in alpha-subunit levels during the somatostatin infusion demonstrated a small decrease in tumor size during higher dose octreotide treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Prolonged Partial Remission of Malignant Fibrous Histiocytoma in Posterior Mediastinum by Immunotherapy

The case of a 16-year-old female patient with the giant cell type of malignant fibrous histiocytoma (MFH) in the left posterior mediastinum is reported. This is a very unusual site for MFH. Immunotherapy induced a prolonged partial remission lasting 15 months with a marked reduction in tumor size. The usefulness of immunotherapy for MFH needs to be evaluated.

Hepatic arterial chemoembolization as an initial treatment for hepatoblastoma

Hepatic arterial chemoembolization using Lipiodol Ultra-fluid (Laboratoire Guerbet), doxorubicin HCl, and Gelfoam (Upjohn)(L-TAE) produced good results in an infant with a hepatoblastoma initially considered to be difficult to resect. Lipiodol selectively accumulated in the tumor, and a marked reduction in tumor size with decrease of alpha-fetoprotein was observed. One month after L-TAE, left hepatectomy was performed uneventfully with a good postoperative course. L-TAE appears to be a useful treatment for hepatoblastoma.

Conversion of surgically verified unresectable to resectable hepatocellular carcinoma

During the period 1978–1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were determined by laparotomy to be unresectable, 155 (60.8%) out of them had their tumor mainly confined in right or left lobe and considered to be potentially resectable if remarkable tumor shrinkage appears after treatment. Second look operation was performed in 26 (16.8%) out of the 155 patients after marked reduction of tumor size, resection was done in all of these 26 patients. Triple or quadruple combination treatment with hepatic artery ligation (HAL), hepatic artery infusion (HAI) with chemotherapy, radiotherapy using linear accelerator, and radioimmunotherapy using 131-I antihuman HCC ferritin antibody yielded the highest conversion rate (29.8%, 14/47) as compared to double combination treatment with HAL+HAI, or cryosurgery+HAL (16.9%, 12/71) and single treatment with HAL or HAI or HAE (embolization) (0%, 0/37). The median tumor size of these 26 patients was reduced from 9.5 cm to 5.0 cm after combination treatment. The median interval between the first laparotomy and the subsequent resection was 5.0 (2–16) months. The survival rates calculated by life table method were: 1-year 86.5%, 2-year 74.3% and 3-year 74.3%. Nine cases have survival more than 3 years. Thus, multimodality combination treatment with subsequent resection might prolong survival significantly for some patients with unresectable HCC particularly confined in right lobe of a cirrhotic liver.

Antitumor effect of a specific aromatase inhibitor, 1 -methyl-androsta-1,4-diene-3,17-dione (Atamestane), in female rats bearing DMBA-induced mammary tumors

Atamestane is a potent competitive inhibitor of estrogen biosynthesis (aromatase) in several species, in vitro and in vivo, and has no endocrine side effects. In this study, the efficacy of atamestane in suppressing tumor growth was evaluated in comparing with that of a non-steroidal aromatase inhibitor (CGS 16949A, Ciba-Geigy) and ovariectomy. Female Sprague-Dawley rats bearing DMBA-tumors were treated s.c. once daily either with 30 or 150 mg/kg atamestane or with 0.1 or 0.5 mg/kg CGS 16949A for 4 weeks. At these biologically equivalent doses both aromatase inhibitors effectively inhibited tumor growth: at the end of treatment they caused a marked reduction in tumor size (up to 70%), while ovariectomy led to a complete remission of tumor growth. The histo-morphological pictures of the mammary tumors from treated animals were qualitatively almost similar to those of the control. In hosts, neither compound exerted any influence on the weight of genital organs (ovary, uterus and vagina), although the peripheral LH levels were significantly elevated by the higher dose of the aromatase inhibitors. This effect on LH levels is probably due to the elimination of the negative feed-back effect of estrogens on gonadotropin secretion (counter regulation). The serum prolactin levels were decreased by the aromatase inhibitors, indicating a diminution of estrogen levels in the treated animals. The present results clearly demonstrate that, in spite of the counter regulation, a pure aromatase inhibitor such as atamestane in sufficiently high doses is able to inhibit the growth of DMBA-induced mammary tumors in intact female rats.

Pregnancy After Bromocriptine-Induced Reduction of an Extrasellar Prolactin-Secreting Pituitary Macroadenoma

In patients with a large prolactin-secreting pituitary adenoma, a marked reduction in tumor size may be achieved with bromocriptine therapy. However, before consideration of pregnancy, surgical removal of the lesion usually is advised. A 36-year-old woman with a large extrasellar pituitary macroadenoma was treated with bromocriptine, 10 mg/day, which resulted in dramatic reduction of the tumor mass. Subsequently, she became pregnant and drug therapy was maintained throughout gestation. This case illustrates the use of bromocriptine in the management of large prolactin-secreting pituitary tumors and the necessity for adequate radiologic follow-up.

Inflammatory pseudotumor of the liver

The clinicopathologic features of a rare case of hepatic "inflammatory pseudotumor" are described and compared with those of three similar cases reported in the literature. In all four cases symptoms were systemic. The marked reduction in tumor size and the changing cellular composition, from a predominance of fibroblasts to a predominance of histiocytes, confirmed the reactive nature of the lesion in the present case. The etiology is obscure, and the significance of the associated occlusive phlebitis remains to be determined.

Effects of long-term treatment with bromocriptine on pituitary prolactinoma in a male

Poor surgical results are obtained when operating on large prolactinomas, especially when an extrasellar growth is demonstrated. Several groups have reported tumor regression following bromocriptine treatment. A case report is presented of a young hyperprolactinemic man with a large pituitary adenoma with suprasellar extension, normal visual fields, decreased libido, impotence, hypogonadism and azoospermia. This man was treated with high doses of bromocriptine for a period of 5 months. A significant improvement of potency libido and sperm concentration associated with radiological evidence of a marked reduction of tumor size was noted following suppressive treatment with this ergot alkaloid.