Paraoxonase activity and expression is modulated by therapeutics in experimental rat nonalcoholic Fatty liver disease.

Objective. The objective of the present study is to investigate the effect of rosiglitazone, metformin, ezetimibe, and valsartan (alone or in combinations) on paraoxonase (PON) activity and PON-mRNA expression in nonalcoholic fatty liver disease (NAFLD). Methods. 54 Male Sprague-Dawley rats were divided to 9 groups: chow diet group (15 weeks); methionine-choline-deficient diet (MCDD) group (15 weeks); MCDD-treated groups for the last 6 weeks with either metformin (M), rosiglitazone (R), metformin plus rosiglitazone (M+R), ezetimibe (E), valsartan (V), or a combination of R+M+V or of R+M+V+E for a total period of 15 weeks. Results. PON activities in serum and liver were decreased in MCDD rats. PON activity in serum increased significantly in all treatment groups. PON activity in liver was also increased significantly, except only in groups R, E, V, R+M+V, and R+M+V+E. Liver PON3 mRNA expression increased significantly in groups R+M, E, V, R+M+V, and R+M+V+E whereas liver PON2 mRNA expression increased significantly in MCDD, R+M, E, V, R+M+V, and R+M+V+E. Conclusions. PON activities in serum and liver were decreased in NAFLD. Treatment with insulin sensitizers, ezetimibe, and valsartan increased PON activity and reduced oxidative stress both in serum and liver.

Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease.

HER-2 overexpression, a predictive marker of tumour aggressiveness and responsiveness to therapy, occurs in 20-30% of breast cancer. Although breast cancer is a heterogeneous disease, HER-2 measurement is carried out in primary tumour. This study aims to evaluate HER-2 overexpression in primary and metastases and its effect on treatment decisions. Biopsies from primary breast cancer and corresponding metastases from 58 patients were studied. HER-2 overexpression was evaluated immunohistochemically in all primary and metastatic sites. Positive overexpression in primary and/or metastases was confirmed by fluorescence in situ hybridisation (FISH). Discordance in HER-2 overexpression between primary and metastatic sites was 14% (eight of 58 patients). Concordance was found in 50 (86%) of patients (95% CI: 77-95). In one patient (2%), HER-2 was negative in metastasis but positive in primary. In seven (12%) patients, HER-2 was positive in metastases and negative in primary (95% CI: 3.7-20), and three of them responded to trastuzumab. Gene amplification by FISH was found in all cases with HER-2 positive (+2 and +3) by immunohistochemistry. Our data suggest that a possible discordance of HER-2 overexpression between primary and metastases should be considered when making treatment decisions in patients with primary HER-2-negative tumours.

The I1307K APC mutation in a high-risk clinic setting: a follow-up study.

While the I1307K APC mutation clearly confers an increased lifetime risk for colorectal cancer, there is a paucity of data on the natural history of colonic neoplasia in symptomatic and asymptomatic mutation carriers. In this study, 51 Jewish I1307K APC mutation carriers were identified in a high-risk familial cancer clinic over a 4-year period, of whom 29 (56.8%) (four males and 25 females) were successfully telephone interviewed for 0.5-5 years (mean 2.4 +/- 1.4) after initial genetic testing. Of these 29 cases, one individual was diagnosed with colon cancer at the age of 45 years, five had adenomatous polyps (mean number of polyps = 1.8), 11 had breast cancer (mean age at diagnosis 49.5 +/- 10.5 years), and 12 were asymptomatic, at the time of the testing. During the follow-up period, new colonic polyps were diagnosed in three mutation carriers, two with previously diagnosed colon cancer and polyps and only one of the asymptomatic mutation carriers, and two additional previously affected patients had new cancer diagnoses: gastric cancer and melanoma. From this descriptive study, it seems that the short-term risk for colonic polyps in I1307K APC mutation is low, primarily affecting patients with previously diagnosed colon tumors.

Primary lymphoma of the liver: clinical features and outcome of 9 patients.

PURPOSE: Primary liver lymphoma (PLL) is a rare lymphoproliferative disorder of unknown etiology. The prognosis in affected patients is poor, consisting of brief remissions, rapidly developing resistance to chemotherapy, early recurrence, and short survival. Most studies related to PLL are based on case reports. The aim of this retrospective study was to review our experience with PLL. PATIENTS AND METHODS: From 1985 to 2000, 9 patients who fulfilled the diagnostic criteria for PLL were treated at our hospital. All patients underwent a thorough work-up and were staged accordingly. RESULTS: The disease occured in middle and higher-aged patients (median age 63 years). Primary presenting complaints were abdominal pain, mainly in the right upper quadrant, and hepatomegaly. Liver function tests and lactate dehydrogenase (LDH) levels were elevated. Liver imaging (computed tomography-CT) and isotopic methods (gallium scan) demonstrated liver involvement either as solitary or multiple space-occupying lesions. Pathologic examination demonstrated diffuse, large cell (DLCL), B-type lymphoma in 7/9 (78%) patients. Doxorubicin-based chemotherapy was the mainstay of treatment. Good partial or complete remission rates were achieved in 7 patients, albeit for a brief period of time. CONCLUSION: Most patients with PLL succumb to their illness, despite its being relatively chemotherapy-sensitive. The introduction of intensive chemotherapy, plus/minus radiotherapy, and/or surgery has been considered in some studies.

Primary lymphoma of bone--a retrospective study. Experience at the Northern Israel Oncology Center (1979-2000).

OBJECTIVE: This retrospective study describes our experience with the diagnosis, treatment, results and long-term follow-up of primary bone lymphoma (PBL). PATIENTS AND METHODS: Nineteen patients diagnosed with PBL were reviewed. Seven patients presented with stage I(E) disease, four with stage II(E) (regional lymphadenopathy), and eight with stage IV disease (disseminated bone involvement). Only one stage IV patient exhibited 'B' symptoms. The majority (72%) demonstrated diffuse, large cell, B-type lymphoma. All patients were treated with adriamycin-based chemotherapy and consolidation radiotherapy to the primary site (8 patients: early PBL) or the most bulky area (3 patients: stage IV PBL). RESULTS: Ten stage I(E)/II(E) patients are alive with no evidence of disease (NED) and only one died due to metastatic secondary lung cancer while with NED from his PBL. Eight stage IV patients are alive with NED. Median follow-up for all living patients: 77 months. Side effects were mild and did not necessitate delay in treatment. CONCLUSIONS: Our departmental policy of treating PBL patients with an anthracycline-based regimen and involved field radiotherapy proved to be successful in achieving excellent long-term, disease-free survival. Phase III randomized, controlled, clinical trials will determine the true role of consolidation radiotherapy in PBL, when considering severe late side effects, including radiation-induced bone tumors.

An approach for high sensitivity detection of breast cancer by analysis of changes in structure of the cytoplasmic matrix of lymphocytes specifically induced by a specific breast tumour antigen (MUC-l/SEC).

An alternative procedure for detection breast cancer was examined based on the observation that lymphocytes re-exposed in vitro to antigenic stimulation will change their intracellular structuredness as measured by polarization of fluorescent light emitted by fluorescein labeled cells (SCM test). The specific antigen MUC-l/SEC was used to elicit such response in lymphocytes of patients with and without breast cancer. Eighty-five samples with breast cancer were tested, of which 72 were correctly diagnosed. Of the 41 controls, 35 were correctly identified as healthy subjects. The sensitivity of the test was 85% and the specificity was 81%. These results suggest a possible valuable method for screening and early detection of breast cancer. The clinical importance of this procedure lies in the ability to screen high-risk populations with higher specificity and sensitivity than any combinations of currently available procedures for breast cancer detection.

Early detection of malignant process in benign lesions of breast tumor by measurements of changes in structuredness of cytoplasmic matrix in circulating lymphocytes (SCM test) reinduced in vitro by specific tumor antigen.

Early detection is crucial for successful treatment of all types of cancer. The specificity and sensitivity of the current methods vary from 50% to 80%. The use of specific tumor antigens and cytometric technology has resulted in the development of a new procedure for the early detection of breast tumors. This new method is reported. The test utilizes static cytometry, which records polarization and intensity changes in fluorescent light emitted from each individual lymphocyte obtained from tumor-bearing patients stimulated by the relevant specific tumor antigen. Using MUC-1/SEC as the specific antigen, we detected breast tumors with 85% specificity and 81% sensitivity in 137 breast tumor-bearing women. A significant linear correlation was found between the SCM test and the conventional classification of relative risk for breast cancer in benign lesions, suggesting that this is a precise method that could be used in mass screening for early detection of breast cancer.

Diagnosis and treatment of primary non-Hodgkin's lymphoma of the parotid gland: a retrospective study - Experience at the Northern Israel Oncology Center (1977-1999).

PURPOSE: The treatment and outcome of primary parotid gland non-Hodgkin's lymphoma (PGL) has rarely been described. This retrospective study documents the clinicopathologic features and treatment results in this relatively rare entity. PATIENTS AND METHODS: This study was conducted on 11 patients diagnosed and treated for primary PGL over a period of 22 years. RESULTS: Of the 4 male and 7 female patients, only one presented with the classic pattern of Sjögren's syndrome (SS) simultaneous with PGL, and only 4 patients demonstrated a low-grade Maltoma type. None of the patients had evidence of disease at the end of the primary treatment; 4 patients are alive and well from 6 months to 10 years after the end of treatment. Four patients relapsed and died due to therapy-resistant disease and 3 patients died of nonmalignant causes while in complete remission. CONCLUSION: The majority of patients with primary non- Hodgkin's lymphoma of the parotid gland present with early- stage disease. Accurate staging is mandatory. Low-grade, localized PGL can be treated successfully with primary radiotherapy alone. The aggressive type of PGL should be treated with combined chemoradiotherapy-based regimens.

[Stromal tumors of gastrointestinal tract: clinical and pathological features].

During the period 1991 till 1999, ten patients with primary stromal tumors of the gastrointestinal tract (stomach, duodenum, jejunum, ileum and rectum) were treated. Nine patients underwent radical resection and one patient had non-complete resection of the tumor. The median age of the group was 63 years for 7 male and 3 female patients. The median follow-up period was 58 months. The tumor size was 4.5-17 cm. (median 10 cm.) The median survival was 43 months. Five patients remained alive without the disease (median survival 87 months). One patient died with no evidence of the disease after 12 months. One patient remains alive with liver metastases for 13 months and 4 patients died of metastatic disease (median survival 10 months). Features associated with decreased survival included tumor size > 5-8 cm., mitotic counts > 5 mitotic figures per 50 high-power microscopic fields and high cellularity.

Treatment of Kaposi's sarcoma with vinblastine in patients with disseminated dermal disease.

BACKGROUND: Classic Kaposi's sarcoma is a rare tumor with an indolent behavior. Local therapy is not applicable in disseminated cutaneous disease. Patients with advanced disease are usually treated with systemic chemotherapy. OBJECTIVES: To assess the effectiveness and toxicity of single-agent vinblastine in the treatment of disseminated and recurrent Kaposi's sarcoma. METHODS: Ten patients with wide cutaneous spread of classic Kaposi's sarcoma were treated with single-agent vinblastine, 6 mg/m2 intravenously once every 2 weeks. Vinblastine was continued for 2 months after achieving a maximal response. RESULTS: The male:female ratio was 2.3:1, and median age 64 years (range 50-79 years). The median number of involved nodules in the skin was 34. The overall response rate was 90%, 5 with complete response (50%) and 4 with partial response (40%). Complete responders had a longer duration of response than partial responders: 41.2 vs. 14.8 months. The median survival of all patients was 33 months. Side effects were minimal and tolerable. CONCLUSIONS: Vinblastine is very effective in the treatment of extensive classic 'Kaposi's sarcoma, and results in a high response rate, long survival and disease-free survival with tolerable toxicity.

Octreotide in the treatment of severe chemotherapy-induced diarrhea.

BACKGROUND: Chemotherapy-induced diarrhea (CID) is a common side effect of a number of chemotherapeutic agents. Conventional therapy for severe CID with opioids or loperamide is moderately effective. A prospective trial was conducted using octreotide acetate for treatment of severe CID refractory to loperamide. PATIENTS AND METHODS: Thirty-two patients with grade 2 and 3 CID refractory to loperamide were treated with octreotide at a dosage of 100 microg subcutaneously 3x/day for three days followed by 50 microg 3x/day for three days. Previous chemotherapy consisted of regimens containing fluorouracil, leucovorin, CPT-11, cyclophosphamide, methotrexate and cisplatin. Primary tumors were colorectal (n = 23), gastric (n = 3), and other cancers (n = 6). RESULTS: Complete resolution of diarrhea was obtained in 30 of 32 patients (94%); 5 within 24 hours, 14 within 48 hours, and 11 within 72 hours of treatment. Nineteen patients were treated as outpatients. Thirteen were hospitalized for a median of three days. Response was unaffected by age, gender, performance status, previous chemotherapy or primary tumor site. No side effects related to octreotide were observed. CONCLUSIONS: Octreotide 100 microg subcutaneously 3x/day for three days is an effective, safe treatment for CID given primarily or as a second-line therapy after loperamide failure.

Primary malignant lymphoma of the parotid gland report of three cases.

AIMS AND BACKGROUND: To document the clinicopathologic features and treatment modalities of primary malignant parotid gland lymphoma, based on three cases diagnosed and treated at Oldchurch Hospital, Romford, UK. METHODS: Three patients, two with stage II and one with stage IV disease, received primary treatment consisting of chemotherapy following surgical biopsy. RESULTS: All three patients obtained rapid complete remission during their scheduled chemotherapy. One patient is alive without evidence of disease 12 months from the end of treatment. One patient, a frail, elderly gentleman, died due to massive pneumonia while in complete remission for two months. The third patient, who developed local recurrences in both parotid glands without transformation of his low-grade histology, achieved a second complete remission following chemo- and radiotherapy. All side effects were of a mild nature. CONCLUSION: Malignant lymphoma of the parotid gland is a chemo- and radiosensitive disease.

[Preservation of the larynx in advanced cancer--experiences at the Oncology Department, Rambam Medical Center, Haifa].

The effectiveness of sequential chemo-radiotherapy in preserving the larynx in advanced laryngeal carcinoma was assessed. 4 unselected patients (19 men and 2 women, mean age 60 years) with advanced squamous cell carcinoma of the larynx (T3-4/N0-3) received induction chemotherapy consisting of 2-3 cycles of cisplatin (100 mg/m2) and 5-fluorouracil (1000 mg/m2/day) as a continuous infusion on days 1-5, followed by definitive radiotherapy: 50 Gy to the whole neck, 70 Gy to the larynx and clinically involved nodes, using a combination of 6 MV photons and 9-12 MeV electrons. 19 of the 21 patients responded to combined therapy but there was no response to induction therapy in 2 (10%) and 2 did not complete therapy due to severe toxicity. At a mean follow-up of 40 months, 7 had undergone total laryngectomy (33%), for an overall 5-year laryngeal preservation rate of 66%. Reasons for total laryngectomy in 2 patients were no response, and in 5 tumor recurrence. Mean survival was 39 months (range 11-46 months); at last follow-up, 17 of 21 were alive and disease-free, 11 of whom had a functional larynx (65% of survivors). 2 had died due to disease progression and due to a cardiovascular event. Sequential chemo-radiation allows laryngeal preservation in about 2/3 of surviving patients without compromising survival.

Pediatric thyroid carcinoma: 22 years of experience at the Northern Israel Oncology Center (1973-1995).

Over the past 22 years, 16 children with thyroid carcinoma were referred to the Northern Israel Oncology Center. All patients had undergone surgical procedures, either total or subtotal thyroidectomy, and 7 patients had undergone cervical lymph node dissections. Postoperatively, 5 patients underwent thyroid ablation with radioactive 131I as first treatment. Two patients received postoperative external radiation therapy to a field encompassing the cervical region, superior mediastinum, and both supraclavicular grooves. After a median follow-up of 60 months (range, 5-169 months), all patients are alive with no evidence of recurrent disease. Two patients who had recurrences, one in the submaxillary lymph nodes and one in the lungs, were salvaged successfully with retreatment with 131I therapy. No severe acute or long-term side effects were exhibited. The long-term results of treatment of pediatric thyroid carcinoma are excellent, but there remains disagreement over the extent of surgical and postsurgical treatment required.

Follicular carcinoma of the thyroid gland: prognostic factors, treatment, and survival.

Prognostic variables and treatment outcomes of 82 patients treated at the Northern Israel Oncology Center were reviewed. There were 59 women and 23 men in this series. The female/male ratio was 2.6/1. Median age was 46 years. Median follow-up was 11.4 (range: 3.8-24 years). Median tumor size was 3.6 cm. When first seen, 4 patients had lymph node involvement and 11 (13%) had distant metastases. Surgical treatment was total thyroidectomy in 37 patients (45%), subtotal thyroidectomy in 38 (46%), and lesser procedures in 7 (9%). Sixty-six patients (80%) were treated after surgery with 131I to ablate thyroid remnants. Doses ranged between 30 and 80 mCi. The 20-year overall actuarial survival rate was 65%. The actuarial survival rate of patients <40 years of age was 96% versus 33% in patients >50 years of age (p = 0.0008). Patients with distant metastases at presentation had inferior survival compared with patients without metastases. In conclusion, we found subtotal thyroidectomy followed by 131I and hormone therapy to provide survival similar to that with total thyroidectomy, with less morbidity. Risk factors include: age > or =40 at the time of diagnosis, presence of distant metastases, capsular invasion, tumor size > or =2 cm, and male gender.

An approach for high sensitivity detection of prostate cancer by analysis of changes in structuredness of the cytoplasmic matrix of lymphocytes specifically induced by PSA-ACT.

PURPOSE: An alternative procedure for detection of prostate cancer was examined based on the observation that cells reexposed in vitro to antigenic or mitogenic stimulation will change their intracellular structuredness as measured by polarization of fluorescent light emitted by labeled cells (SCM test). MATERIALS AND METHODS: Lymphocytes derived from patients bearing a nonmalignant prostate tumor and healthy individuals were exposed to PSA-ACT, PHA, and MUC-1. RESULTS: Of sixty-five patients with prostate carcinoma (CaP), sixty-two were correctly diagnosed by the test. Of the eighty males in the control group, five were incorrectly diagnosed as having the disease and seventy-five were correctly diagnosed as healthy subjects. The sensitivity of the test was 96.8%. The specificity was 91.1%. The BPH (Benign Prostatic Hyperplasia) control group exhibited a sensitivity of 9.38%, but the specificity was 91.1%. Similar percentages for specificity and sensitivity were observed in the NRT (Non-Relevant Tumor) control group. CONCLUSIONS: The results shown here indicate the possibility of a different use of PSA-ACT for detection of prostate cancer with high specificity and sensitivity.

Effect of adjuvant tamoxifen therapy on thyroid function in postmenopausal women with breast cancer.

Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and total tri-iodothyronine (TT3) concentrations were measured in 45 postmenopausal breast cancer patients before adjuvant treatment with tamoxifen and at 3- and 6-month intervals. A significant increase in TSH (p = 0.002) at the end of 3 months and a subsequent decrease at the end of 6 months was noted. There were no significant changes in TT3 and FT4. We concluded that tamoxifen therapy in postmenopausal women may result in a reversible increase in TSH after 3 months.