Total Skin Electron Irradiation and Sequential Malignancies in Mycosis Fungoides Patients: Longitudinal Study.

AIMS: To determine the role of total skin electron irradiation (TSEI) as a cause of second malignancies in mycosis fungoides patients. MATERIALS AND METHODS: Mycosis fungoides patients referred to TSEI were followed in a longitudinal study. Other diagnosed malignancies were obtained after cross-matching with the Israel National Cancer Registry database. RESULTS: Between 1974 and 2010, 197 patients were treated: 134 (68%) men, 63 (32%) women; mean age 58 ± 17years. Topical/systemic treatment was given to 134 (68%) patients. TSEI was given to 104 (68.9%) patients. Seven (4.6%) received sub-TSEI and 40 (26.5%) received focal electron irradiation fields. Forty-six (23%) patients did not receive radiotherapy. The second primaries rate was 6.7 times higher in male mycosis fungoides patients and 13.1 times higher in female mycosis fungoides patients than in the general Israeli population. Malignant melanoma developed in eight patients after radiotherapy, in one patient without irradiation. The skin-related cancer rate after irradiation versus no irradiation was higher (P = 0.018). Combination radiotherapy with psoralen + ultraviolet A and/or nitrogen mustard yielded 11 cases of skin cancer versus no cases without irradiation. CONCLUSIONS: Mycosis fungoides patients have a high incidence of sequential malignancies. TSEI is associated with higher 'skin-related cancer' rates. Close longitudinal follow-up of mycosis fungoides patients is obligatory.

Primary signet-ring cell adenocarcinoma of the uterine cervix: case report and review of the literature.

Signet-ring cell adenocarcinoma is a rare subtype of the uterine cervix; thus there are no guidelines and the prognosis is unknown. There seems to be a significant role for reporting the treatment and outcome of this rare disease in order to establish guidelines and to assist in decision-making. However, treatment should be tailored to each patient according to clinical status and disease stage. Excluding extra-genital origin is mandatory, as it will change treatment management considerably.

Malarial infections in sedentary and migratory passerine birds in Israel: description of new species.

Our objective was to investigate the diversity of Plasmodium species in birds of the Rift Valley section in Israel. Plasmodium merulae Corradetti & Scanga, 1973 was previously reported in blackbirds (Turdus merula Linnaeus, 1758), that are resident. We also report and describe three other species and seven new species of Plasmodium from migratory birds in the north, and from Eilat at the southernmost tip of the Jordan Valley. New species are: Plasmodium lusciniae sp. n., Plasmodium alloreticulatus sp. n. and Plasmodium paranuclearis sp. n. from Luscinia svecica (Linnaeus, 1758), Plasmodium phoenicuri sp. n., Plasmodium reticulatus sp. n. and Plasmodium synnuclearis sp. n. from Phoenicurus phoenicurus (Linnaeus, 1758), and Plasmodium bilobatus sp. n. from Acrocephalus schoenobaenus (Linnaeus, 1758). The morphological affinities among the new described species and between P merulae and Plasmodium vaughani Novy & MacNeal, 1904 are highlighted and discussed. The host birds belong to two families: Muscicapidae (Turdus merula, Luscinia svecica and Phoenicurus phoenicurus) and Sylviidae (Acrocephalus schoenobaenus). All the parasites species are affiliated to the so-called "vaughani complex" (Corradetti & Scanga 1973) which are small parasites that possess a characteristic refractile globule in their cytoplasm.

Effect of Chinese herbal therapy on breast cancer adenocarcinoma cell lines.

Despite the widespread use of medicinal herbs to prevent and treat many diseases, including cancer, there are insufficient scientific data on the safety and efficacy of the majority of herbal therapies. The aim of this study was to assess the effect of a unique Chinese herbal therapy (CHT) from controlled manufactured concentrated powders, on an in vitro model of breast cancer. Three breast adenocarcinoma cell lines (MDA-231, MDA-453, T47D) were exposed to CHT for 72 h. Cell viability was assessed by XTT (sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetra zolium]-bis(4-methoxy-6-nitro) benzene sulphonic acid hydrate) assay. Apoptosis and cell cycle stage were determined by fluorescence-activated cell sorting (FACS) analysis. CHT decreased cell survival in a dose-dependent manner in all tested cell lines. FACS analysis of treated and non-treated T47D cells demonstrated that the inhibitory effect of CHT was associated with an increase in apoptosis. A randomized clinical trial is currently underway to investigate CHT as supplementary therapy for breast cancer patients receiving chemotherapy.

Nuclear and cytoplasmic expression of ErbB-4 in prostate cancer.

PURPOSE: To evaluate cytoplasmic and nuclear ErbB-4 expression in prostate cancer specimens and its association with outcome. BASIC PROCEDURES: Specimens of 50 prostate cancer patients were investigated for ErbB-4 overexpression using Immunohistochemistry staining. Cytoplasmic and nuclear staining was graded as 0-3 according to its intensity. The prognostic parameters were tumor stage, PSA level, Gleason score, probability of positive lymph nodes (Partin's tables and Roach equation), and 5-year disease free survival (Kattan nomogram). MAIN FINDINGS: Overexpression of ErbB-4 (> or = 1) was detected in 30 (60%) patients and overexpression using cytoplasmic and nuclear staining was > or = 2 in 19 (38%) and 17 (34%) patients, respectively. In only one third of the specimens was there any similarity between the 2 types of staining. Advanced tumor stage, high pretreatment PSA levels and high Gleason scores were evenly distributed among the patients with low (< or = 1) and intermediate/high (> or = 2) ErbB-4 expression. The probability of lymph node involvement and 5-year disease free survival were similar in both types of staining. PRINCIPAL CONCLUSIONS: ErbB-4 was overexpressed (cytoplasmic and nuclear staining) in approximately one third of prostate cancer patients. The rate of similarity between the 2 staining types was only 33%: overexpression was evenly distributed among intermediate/high and low risk prostate cancer patients with both staining methods.

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

Plasmodium spp. in raptors on the Eurasian-African migration route.

Examination of blood smears obtained from raptors trapped while on migration at Eilat, Israel, demonstrated Plasmodium infection in Accipiter brevipes and Buteo buteo. The following species are described, from A. brevipes: Plasmodium alloelongatum n. sp., P. accipiteris n. sp. and from B. buteo: P. buteonis n. sp. and Plasmodium sp. for which we lack sufficient data for adequate species description. Overall prevalence of infection with Plasmodium spp. was very low: among 38 examined A. brevipes 5% and among 56 B. buteo 3.6%.

Establishment and characterization of a pancreatic carcinoma cell line derived from malignant pleural effusion.

BACKGROUND/AIMS: A novel cell line, designated p34, was developed from the malignant pleural effusion of a patient with carcinoma of pancreas. The objective of this work was to characterize this cell line. METHOD: The in vitro studies included karyotype analysis, immunohistochemistry, XTT cell proliferation assay, analysis of the cell cycle by FACS and cell sensitivity to chemotherapeutic drugs and irradiation. Subcutaneous and intra-spleen inoculations into nude mice were carried out to study the tumorigenicity and the metastatic tendency of this cell line. RESULTS: The p34 cell line showed typical morphological characteristics of epithelial pancreatic tumor cells. The cells were hyperdiploid with a modal number of 48, and had two markers, deletion in the short arm of chromosome 2 and duplication of the short arm of chromosome 8. The doubling time was 16 h. Subcutaneous inoculation of the cells into nude mice yielded 100% tumorigenicity, and intra-spleen inoculation resulted in extensive intra-abdominal spread. The antiproliferative effect of chemotherapy (gemcitabine, cisplatin, taxol and vinorelbine), chemopreventive agents (celecoxib and curcumin) and radiotherapy showed dose-dependent cytotoxicity. CONCLUSIONS: This p34 cell line can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells.

BACKGROUND AND AIM: Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells. METHODS: P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis. RESULTS: In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy. CONCLUSION: Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.

Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma.

BACKGROUND: Doxil (ALZA Corp., Mountain View, CA) is a formulation of doxorubicin in polyethylene-glycol coated liposomes with a prolonged circulation time and unique toxicity profile. As yet, the effect of the dose schedule on toxicity and the correlation of toxicity with pharmacokinetics have not been directly addressed. METHODS: The objectives of this study were to examine the toxicity profile and pharmacokinetics of various dose schedules of Doxil in a group of patients with metastatic breast carcinoma (MBC) previously treated with chemotherapy. Forty-five patients received a total of 268 courses of Doxil (median per patient, 5; range, 1-19). Six dose schedules were investigated: 35 mg/m2 every 3 weeks (11 patients), 45 mg/m(2) every 3 weeks (5 patients), 50 mg/m(2) every 4 weeks (5 patients), 60 mg/m(2) every 4 weeks (6 patients), 65 mg/m(2) every 5 weeks (6 patients), and 70 mg/m(2) every 6 weeks (12 patients). Doxil pharmacokinetics was examined in 24 of these patients at the dose levels of 35, 45, 60, and 70 mg/m(2). RESULTS: Stomatitis was dose related, with higher incidence and severity at doses of 60-70 mg/m(2). Skin toxicity in the form of palmar-plantar erythrodysesthesia (PPE) developed usually after two or more courses of treatment and was schedule dependent with shorter dosing intervals leading to increased frequency and severity of skin manifestations. Myelosuppression, mainly as leukopenia/neutropenia, was dose dependent but mild and uncomplicated in most cases. Hair loss was infrequent (< 7%) and always of limited extent. Despite high cumulative doses up to 1500 mg/m(2), cardiac toxicity was observed in only 1 patient who received prior mitoxantrone and mediastinal radiotherapy. Objective responses, improvements, and durable stabilizations were observed in 9, 6, and 14 patients, respectively, indicating significant antitumor activity of Doxil in previously treated MBC patients. Doxil pharmacokinetics was well described by a monoexponential elimination curve with a long T(1/2) (median, 79 hours), a slow clearance (median, 40 mL/hour), and a small volume of distribution (median, 3.9 L). Cmax (peak plasma concentration) and AUC (area under the concentration*time curve) increased linearly with dose with a statistically significant correlation. Correlation analysis of dose and pharmacokinetic parameters with Doxil toxicites revealed that stomatitis grade and leukocyte nadir were correlated strongly with dose and Cmax, and weakly with AUC, whereas PPE grade was correlated significantly with only 1 parameter, T(1/2). CONCLUSIONS: The toxicity of Doxil is dose and schedule dependent and well correlated with pharmacokinetic parameters. Pharmacokinetic guidance of Doxil dosing may be a useful tool.

Continuous interleukin-2 infusion combined with cyclophosphamide- based combination chemotherapy in the treatment of hemato-oncological malignancies. Results of a phase I-II study.

The combination of a cyclophosphamide (CTX)-based chemotherapy regimen and interleukin-2 (IL-2) has been shown to provide synergistic effects against malignancy in animal models. We therefore conducted a phase I-II trial combining CTX-based combination chemotherapy or CTX alone with high-dose IL-2 in patients with advanced and refractory malignant disease. Fifteen patients with hemato-oncological malignancies (malignant lymphoma 8, multiple myeloma 3, solid tumor 2, leukemia 2) were enrolled in the study. Continuous high-dose IL-2 infusion was shown to be safely administered, starting as soon as recovery of white blood cell count. All patients developed rebound lymphocytosis 24-48 h after termination of IL-2 infusion. Although grade IV toxicity was observed in 5 patients (7 episodes), all side effects completely subsided. Triple chemotherapy (CTX, etoposide and Ara-C) seemed rather toxic (in this group of heavily treated patients) while CTX alone was well tolerated. Four out of 13 (31%) evaluable patients had partial response and another patient (7%) had stabilization of disease progression lasting 2-8 months. Our conclusion is that the combination of CTX and continuous infusion of IL-2 is feasible and should be investigated in patients with various malignant neoplasms.

Should soybean agglutinin purging be performed in breast cancer patients undergoing autologous stem cell transplantation? A retrospective analysis of 48 patients.

High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) has gained an increasing role in the treatment of high-risk Stage II-III and/or metastatic breast cancer patients. Several investigators reported on a high rate of tumor cells contaminating the bone marrow and peripheral blood stem cell collection. Nevertheless, the clinical implication of reinfusion of tumor cells with the stem cells to the relapse rate is still uncertain. In this retrospective analysis we compare the outcome and the toxicity of 29 patients with high-risk Stage II-III and 19 metastatic breast cancer patients who underwent HDC with ASCT. Thirteen patients underwent transplant with soybean agglutinin (SBA)-purged graft, while 35 consecutive patients received unmanipulated graft. Engraftment was significantly faster for the nonpurged transplant. No differences in disease-free survival, freedom from relapse, or overall survival were noted in both groups during a median follow up time of 14 months. We conclude that tumor cell purging using SBA in breast cancer patients is not warranted. New purging methods are needed to assess the role of tumor cell purging in breast cancer patients.

[Evolving role of radiation therapy in nonmalignant disorders].

Various nonmalignant disorders have traditionally been treated with radiation therapy. It has almost completely been discontinued due to reports of secondary malignancy. During the past 15 years there has been an evolving role for radiation therapy in various nonmalignant disorders such as meningioma, A-V malformation, prevention of vascular restenosis and heterotopic bone formation. Appropriate follow-up of such patients for diagnosis of secondary malignancy is recommended. Radiation therapy should be carefully considered in diseases not successfully treated with conventional means.

Mucosal melanoma following autologous stem cell transplantation for non-Hodgkin's lymphoma (NHL).

The incidence of secondary malignancy following autologous stem cell transplantation (ASCT) is increasing. We describe a patient with stage IVB Hodgkin's disease who developed primary amelanotic malignant melanoma of the tongue 18 months following autologous stem cell transplantation. She was treated by partial glossectomy and supra-omohyoid neck dissection followed by cytokine-mediated immunotherapy. Malignant melanoma of the skin is a frequent secondary solid tumor seen in patients undergoing stem cell transplantation. However, mucosal melanoma which is rare by itself (0.2-8%) has never been reported in NHL patients following ASCT. Early diagnosis and initiation of combined local and systemic treatments including immuno-therapy may improve the outcome of this rare but lethal complication.

Intrapericardial minocycline sclerosis for malignant pericardial effusion.

STUDY OBJECTIVE: To evaluate the effectiveness and safety of minocycline hydrochloride (minocycline) intrapericardially in patients with malignant pericardial effusion. DESIGN: Consecutive patients admitted to the hospital during a 32-month period received intrapericardial minocycline. SETTING: A 900-bed university hospital. PATIENTS: Fourteen consecutive patients with malignant pericardial effusion. INTERVENTION: Following percutaneous insertion of a pericardial drain, minocycline was administered at a dosage of 10 mg/kg every 48 h until fluid drainage stopped or until further therapy was deemed necessary. MEASUREMENTS: Complications associated with therapy, total minocycline requirements, immediate and late failure of therapy, and clinical and echocardiographic follow-up of at least 6 months. RESULTS: Mean amount of minocycline administered was 1.9 +/- 1.0g given in 2.4 divided doses. Total drainage time was 5.4 +/- 2.5 days. Recurrence of malignant pericardial effusion was seen in only 1 of 14 patients. Death occurred in 10 patients due to severe metastatic disease in all. Minocycline instillation was associated with severe chest pain in seven patients, and with ECG changes suggesting pericardial or subepicardial injury in two patients. CONCLUSION: (1) Intrapericardial minocycline instillation is very effective in preventing recurrence of malignant pericardial effusion. (2) Minocycline is irritative to the pericardium and may cause severe chest pain with transient ECG changes, suggesting pericardial or subepicardial injury.

Contrasting reactions of loggerhead shrikes to two types of chemically defended insect prey.

Feeding tests with loggerhead shrikes (Lanius ludovicianus) showed this bird to acceptUtetheisa ornatrix, a moth (Arctiidae) protected by pyrrolizidine alkaloids, but to avoidLytta polita, a beetle (Meloidae) containing cantharidin.

Direct clinical comparison of ultrasound and radiative electromagnetic hyperthermia applicators in the same tumours.

Hyperthermia in conjunction with radiation therapy is a promising method for the treatment of superficially or eccentrically located recurrent or advanced primary malignant tumours. The external hyperthermia applicators most commonly used are radiative electromagnetic (including microwave) or ultrasound devices. Each type of device has its own limitations. The aim was to evaluate the temperature distributions obtained as well as the acute and subacute toxicities in patients that were treated with both radiative radiative electromagnetic and ultrasound applicators to the same tumours. Thirty-nine patients treated to 41 hyperthermia fields for a total of 197 hyperthermia treatments were analysed. Thermal parameter include mean, Tmax, mean Tave, mean Tmin, T50, T90, %T > 43.5 degrees C and %T < 41 degrees C. Acute toxicities including pain in field, referred pain, blister/ulceration, positional discomfort and subacute toxicities (occurring with 24 h of treatment) were determined for each type of hyperthermia applicator. Although there were increased acute toxicities (in-field or referred pain) associated with the ultrasound treatments no significant differences between the two methods of heating were observed in temperature distributions or subacute toxicities. We conclude that there is no generally preferred method of heating superficially or eccentrically located tumours and the type of applicator should be selected on a tumour-size and site-specific basis.