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Successful combination therapy-flunarizine, pentoxifylline, and cholestyramine-for spur cell anemia.

Aihara K, Azuma H, Ikeda Y, Akaike M, Abe M, Sugihara T, Matsumoto T. First Department of Internal Medicine, University of Tokushima School of Medicine, Japan.

Int J Hematol 2001 Apr;73(3):351-5

Spur cell anemia, a hemolytic anemia observed in patients with alcoholic cirrhosis, is characterized by unusual erythrocyte morphology and an increased ratio of free cholesterol to phospholipid in the erythrocyte membrane. The prognosis of spur cell anemia is usually extremely poor, however, we describe here a patient with spur cell anemia who was successfully treated with combination therapy consisting of flunarizine, pentoxifylline, and cholestyramine. Initial therapy with flunarizine alone for 6 weeks did not significantly decrease the number of spur cells on peripheral blood smears. So pentoxifylline was added to the regimen. The patient recovered from the anemia, showed remarkable improvement with regard to the hyperbilirubinemia, and the changes were accompanied by a significant decrease in the number of spur cells in peripheral blood smears. To correct the hypercholesterolemia, cholestyramine was added to the regimen, which resulted in a reduction in the serum level of free cholesterol and an increase in the molar ratio of free cholesterol to phospholipid in erythrocyte membrane. However, 6 months later a skin eruption developed that was considered an adverse reaction to the drugs, so the flunarizine and pentoxifylline were discontinued. With cholestyramine therapy alone, the remission of spur cell anemia was maintained for more than 11 months. These observations suggest that non-invasive combination therapy with flunarizine, pentoxifylline, and cholestyramine is effective and valuable in the treatment of patients with spur cell anemia.

Anemia caused by vitamin B12 deficiency in subjects aged over 75 years: new hypotheses. A study of 20 cases. [Article in French]

Andres E, Perrin AE, Kraemer JP, Goichot B, Demengeat C, Ruellan A, Grunenberger F, Constantinesco A, Schlienger JL. Service de medecine interne et nutrition, hopital de Hautepierre, Strasbourg, France.

Rev Med Interne 2000 Nov;21(11):946-54

PURPOSE: New hypotheses have recently been developed on vitamin B12 deficiency and the frequently observed occurrence in the elderly subject of food cobalamin malabsorption, i.e., the non-dissociation of B12 and its carrier protein (ND B12), and the possibility of rectifying this imbalance by oral crystalline B12 supplementation. The aim of this study was therefore to confirm these hypotheses in a series of patients aged over 75 years with anemia due to B12 deficiency.

METHODS: A retrospective study was carried out over a 5-year period on patients aged over 75 years presenting with megaloblastic anemia (hemoglobin [Hb] < 12 g/dL) and vitamin B12/cobalamin deficiency (B12 < 160 pg/mL).

RESULTS: Twenty cases were analyzed. The average age of the patient population was 82.5 +/- 6 years, and the F/M sex ratio was 1:2. Mean Hb levels were 7.9 +/- 2.4 g/dL, mean serum B12 levels were 83 +/- 24 pg/mL, and mean homocysteinemic levels were 35 +/- 27 mumol/L. The diagnosis was as follows: food cobalamin malabsorption/ND B12 (n = 10), Biermer's disease/pernicious anemia (n = 5), malabsorption due to pancreatic insufficiency (n = 1), and low dietary B12 levels (n = 1). Disorders associated with ND B12 were: atrophic gastritis and Helicobacter pylori infection (n = 6), antacid or biguanide intake (n = 3), alcohol abuse (n = 2), or idiopathic syndrome (n = 2). In the patients who were followed up (n = 10), i.m. (n = 5) or oral (n = 5) administration of crystalline B12 resulted in the correction of hematological abnormalities.

CONCLUSION: In the elderly subject, food cobalamin/ND B12 malabsorption appears to be the main cause of B12 deficiency, and is frequently associated with atrophic gastritis. In these cases, administration of oral crystalline B12 may be an efficient means of treating this disorder.

Measuring hunger in the Russian Federation using the Radimer/Cornell hunger scale.

Anon. (Welch, K.J., N. Mock, N., O. Netrebenko, O.).

Bull. World Health Org. 1998; 76(Suppl. 2): 34-7 (http://www.who.int/archives/pub/bull_76.html#Volume%2076,%20Number%202,%201998).

Vitamin B12 deficiency in the elderly.

Baik, H.W., Russell, R.M. USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111; e-mail: Baik_GI@HNRC.TUFTS.EDU; Russell@HNRC.TUFTS.EDU

Annu. Rev. Nutr. 1999. 19:357-377

KEY WORDS: atrophic gastritis, hypochlorhydria, malabsorption of protein-bound vitamin B12, food fortification Vitamin B12 deficiency is estimated to affect 10%-15% of people over the age of 60, and the laboratory diagnosis is usually based on low serum vitamin B12 levels or elevated serum methylmalonic acid and homocysteine levels. Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important. Absorption of crystalline vitamin B12 does not decline with advancing age. However, compared with the younger population, absorption of protein-bound vitamin B12 is decreased in the elderly, owing to a high prevalence of atrophic gastritis in this age group. Atrophic gastritis results in a low acid-pepsin secretion by the gastric mucosa, which in turn results in a reduced release of free vitamin B12 from food proteins. Furthermore, hypochlorhydria in atrophic gastritis results in bacterial overgrowth of the stomach and small intestine, and these bacteria may bind vitamin B12 for their own use. The ability to absorb crystalline vitamin B12 remains intact in older people with atrophic gastritis. The 1998 recommended daily allowance for vitamin B12 is 2.4 µg, but elderly people should try to obtain their vitamin B12 from either supplements or fortified foods (e.g. fortified ready-to-eat breakfast cereals) to ensure adequate absorption from the gastrointestinal tract. Because the American food supply is now being fortified with folic acid, concern is increasing about neurologic exacerbation in individuals with marginal vitamin B12 status and high-dose folate intake.

Testosterone replacement therapy for aging men.

Bain J. Department of Medicine, University of Toronto, Ontario.

Can Fam Physician 2001 Jan;47:91-7

OBJECTIVE: To review the rationale for treating symptomatic aging men whose testosterone levels are mildly reduced or low-normal with testosterone replacement therapy.

QUALITY OF EVIDENCE: Large-scale multicentre prospective studies on the value of treating andropausal men with hormone therapy do not exist because the whole area of hormone therapy is barely 10 years old. Evidence presented is based on physiologic studies, particularly studies in which treatment has been assessed. These were largely uncontrolled open studies. Studies to date report positive responses to testosterone treatment with very few serious side effects.

MAIN MESSAGE: Physicians should consider hypoandrogenism if male patients complain of loss of libido, erectile dysfunction, weakness, fatigue, lethargy, loss of motivation, or mood swings. Less obvious associations with reduced levels of testosterone are anemia and osteoporosis. The main cause of reduced testosterone production is primary gonadal insufficiency, but secondary causes, such as hypothalamic-pituitary disease, should be considered. Evidence shows that most men treated with testosterone will feel better about themselves and their lives.

CONCLUSION: Andropause is a term of convenience describing a complex of symptoms in aging men who have low testosterone levels. Physicians should be aware of its existence, should consider ordering tests for men who have symptoms, and should treat carefully selected patients whose serum testosterone levels are low.

Cytokines and malignant hemopathies: leukemias and bone marrow graft. [Article in French]

Blaise D, Stoppa AM, Maraninchi D. Unite de transplantation medullaire, Institut Paoli-Calmettes, Marseille.

Rev Prat 1993 Mar 1;43(5):574-9

Cytokines are now part of the modern armentarium utilized against malignant blood diseases. The essentially lymphocytic haematopoietic growth factors (G-CSF, GM-CSF, IL-3) reduce the infectious morbidity associated with the deep and prolonged neuropoenia induced by the myelo-ablative conditioning for autologous or allogeneic bone marrow transplantations, and widening their indications is tempting. The reluctance expressed about their use in chemotherapy of acute myeloid leukaemia is abating now that controlled studies have shown that they preserve the complete response rate and shorten the duration of leucopoenia. Moreover, they modify the leukaemia biological response, which makes it possible to increase the cytotoxicity of certain drugs and constitutes a new approach to drug-resistant leukaemias. Immuno-modulating cytokines (interferon alpha, interferon gamma, interleukin-2) act through mechanisms that are still ill-defined: antitumoral activity, modification of biological responses, immunoactivation. Nevertheless, interferon alpha has revolutionized the treatment of hairy cell leukaemia and myeloid leukaemia, with a 70% remission rate. The scarcity of complete responses (10% of hairy cell leukaemias) or cytogenetic responses (20% of chronic myeloid leukaemias) justifies a combined treatment (chemotherapy+immunotherapy?) to improve these patients' cure rate. The anti-leukaemic activity of interleukin-2, observed in patients with refractory relapses, produces 33% of responses, including 10% of complete responses, and it is tempting to test the impact of this immunotherapy on the control of residual leukaemia as adjuvant of complete remission using randomized trials.

The use of hematopoietic growth factors in the treatment of acute leukemia.

Bradstock KF. Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia. bradstok@icpmr.wsahs.nsw.gov.au

Curr Pharm Des 2002;8(5):343-55

Cytokines are centrally involved in the regulation of normal hematopoiesis, the production of mature blood cells by bone marrow stem cells. Cytokines influence stem survival, proliferation, and differentiation commitment, as well as controlling the orderly maturation of progenitor cells into functional leucocytes, erythrocytes, and platelets. Acute leukemias result from malignant transformation of bone marrow stem cells. Although cytokines do not appear to be centrally involved in the pathogenesis of acute leukemias, leukemic cells express receptors for many of the cytokines regulating normal hematopoiesis, particularly G-CSF, GM-CSF, IL-3, and stem cell factor. These molecules have demonstrable effects on acute leukemia cells in vitro, inducing proliferation and enhancing survival, but their biological activity when administered as recombinant proteins in pharmaceutical doses to patients with active leukemia are less well understood. Because of the stimulatory effects of cytokines such as G-CSF and GM-CSF on normal hematopoiesis in vitro and in normal individuals, these two molecules have been extensively studied in randomised clinical trials of chemotherapy for cancer, including acute leukemia. Concerns about the potential for G-CSF and GM-CSF to accelerate the growth of acute myeloid leukemia, which expresses receptors for both molecules, have not been realised. Conversely, the concept of using either of these two cytokines to induce acute myeloid leukemia cells into active DNA synthesis, thus potentially sensitising them to the effects of S-phase-specific drugs, has not been shown to be clinically beneficial. Both G-CSF and GM-CSF have been demonstrated to accelerate the recovery of normal granulopoiesis after intensive initial cytotoxic chemotherapy for acute leukemia, significantly shortening the duration of severe treatment-induced neutropenia, and resulting in a number of tangible benefits including reduction in infection, use of intravenous antibiotics, and duration of hospital stay. However, the final role for these agents in the treatment of acute leukemia remains controversial and still to be fully defined.

Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review.

Caro JJ, Salas M, Ward A, Goss G. Division of General Internal Medicine, McGill University, Montreal, Quebec, Canada. jcaro@caroresearch.com

Cancer 2001 Jun 15;91(12):2214-21

BACKGROUND: Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. Individual studies have compared the survival of patients with and without anemia and have shown reduced survival times in patients with various malignancies, including carcinoma of the lung, cervix, head and neck, prostate, lymphoma, and multiple myeloma. The objective of this study was to systematically review, to summarize, and to obtain an overall estimate of the effect of anemia on survival in patients with malignant disease.

METHODS: A comprehensive literature review was carried out using the

MEDLINE data base and reviewing the reference lists from published studies. Two hundred papers were identified. Of these, 60 papers that reported the survival of cancer patients according to either hemoglobin levels or the presence of anemia were included. Among these papers, 25% related to patients with lung carcinoma, 17% related to patients with head and neck carcinoma, 12% related to patients with multiple myeloma, 10% related to patients with prostate carcinoma, 8% related to patients with cervicouterine carcinoma, 7% related to patients with leukemia, 5% related to patients with lymphoma, and 16% related to patients with other types of malignancies.

RESULTS: The relative risk of death increased by 19% (95% confidence interval, 10-29%) in anemic patients with lung carcinoma, by 75% (37-123%) in anemic patients with head and neck carcinoma, by 47% (21-78%) in anemic patients with prostate carcinoma, and by 67% (30-113%) in anemic patients with lymphoma. The overall estimate increase in risk was 65% (54-77%).

CONCLUSIONS: Anemia is associated with shorter survival times for patients with lung carcinoma, cervicouterine carcinoma, head and neck carcinoma, prostate carcinoma, lymphoma, and multiple myeloma. Copyright 2001 American Cancer Society.

The role of copper, molybdenum, selenium, and zinc in nutrition and health.

Chan S, Gerson B, Subramaniam S. Quest Diagnostics Incorporated Nichols Institute, San Juan Capistrano, California, USA.

Clin Lab Med 1998 Dec;18(4):673-85

Copper, zinc, selenium, and molybdenum are involved in many biochemical processes supporting life. The most important of these processes are cellular respiration, cellular utilization of oxygen, DNA and RNA reproduction, maintenance of cell membrane integrity, and sequestration of free radicals. Copper, zinc, and selenium are involved in destruction of free radicals through cascading enzyme systems. Superoxide radicals are reduced to hydrogen peroxide by superoxide dismutases in the presence of copper and zinc cofactors. Hydrogen peroxide is then reduced to water by the selenium-glutathione peroxidase couple. Efficient removal of these superoxide free radicals maintains the integrity of membranes, reduces the risk of cancer, and slows the aging process. On the other hand, excess intake of these trace elements leads to disease and toxicity; therefore, a fine balance is essential for health. Trace element-deficient patients usually present with common symptoms such as malaise, loss of appetite, anemia, infection, skin lesions, and low-grade neuropathy, thus complicating the diagnosis. Symptoms for intoxication by trace elements are general, for example, flu-like and CNS symptoms, fever, coughing, nausea, vomiting, diarrhea, anemia, and neuropathy. A combination of observation, medical and dietary history, and analyses for multiple trace elements is needed to pinpoint the trace element(s) involved. Serum, plasma, and erythrocytes may be used for the evaluation of copper and zinc status, whereas only serum or plasma is recommended for selenium. Whole blood is preferred for molybdenum. When trace element levels are inconsistent with medical evaluations, a test for activity of the suspected enzyme(s) would support the differential diagnosis. Furthermore, it is important to differentiate whether trace element deficiency or toxicity is the primary cause of the disorder, or is secondary to other underlying diseases. Only successful treatment of the primary disorder will lead to complete recovery. In the event of sample contamination during collection or analysis, the physician may be misled by falsely elevated results. Royal blue top evacuated tubes containing negligibly low concentrations of the trace element or acid-washed plastic sterilized syringes should be used for blood, serum, or plasma collection. Powdered gloves must be avoided. When possible, mineral supplements are not to be administered to the patient for a minimum of 3 days prior to sample collection. Serum and plasma specimens are to be transported in acid-washed polypropylene and polyethylene tubes. Analysis is performed in a controlled environment to minimize or eliminate contamination. During analysis, all laboratory wares should be acid-washed for decontamination. A detailed description of these precautions may be found in reviews by Aitio and Jarvisalo and by Chan and Gerson. Copper and zinc analysis on serum and plasma are commonly performed by flame atomic absorption spectrometry, inductively coupled plasma-atomic emission spectrometry, and inductively coupled plasma-mass spectrometry. Serum and plasma selenium levels are determined by graphite furnace atomic absorption with Zeeman background correction and neutron activation analysis. Molybdenum levels are best determined by neutron activation and highly sensitive inductively coupled plasma-mass spectrometry. The reader is referred to reviews by Tsalev and Jarvis.

The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells.

De Caterina R, Cybulsky MI, Clinton SK, Gimbrone MA Jr, Libby P. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115.

Arterioscler Thromb 1994 Nov;14(11):1829-36

The mechanisms by which dietary fatty acids can modulate atherogenesis and inflammation are poorly understood. Induction in endothelial cells of adhesion molecules for circulating leukocytes and of inflammatory mediators by cytokines probably contributes to the early phases of atherogenesis and inflammation. We report here that incorporation into cellular lipids of docosahexaenoic acid (DHA), a specific fatty acid of the omega 3 family, decreases cytokine-induced expression of endothelial leukocyte adhesion molecules, secretion of inflammatory mediators, and leukocyte adhesion to cultured endothelial cells. DHA, but not eicosapentaenoic acid, decreased in a dose- and time-dependent fashion the expression of vascular cell adhesion molecule 1 (VCAM-1) induced by interleukin (IL)-1, tumor necrosis factor (TNF), IL-4, or bacterial lipopolysaccharide, with half-maximum inhibition at & 10 mumol/L. This reduction required prolonged (24- to 96-hour) exposure of endothelial cells to DHA and correlated with the degree of DHA incorporation into cellular lipids. DHA also limited cytokine-stimulated endothelial cell expression of E-selectin and intercellular adhesion molecule 1 and the secretion of IL-6 and IL-8 into the medium but not the surface expression of constitutive surface molecules. Cyclooxygenase inhibition did not block the effect of DHA on VCAM-1. In parallel with reduced surface VCAM-1 protein expression, DHA reduced VCAM-1 mRNA induction by IL-1 or TNF. DHA treatment also reduced the adhesion of human monocytes and of monocytic U937 cells to cytokine-stimulated endothelial cells. These properties of DHA may contribute to antiatherogenic and anti-inflammatory effects of omega 3 fatty acids.

Anti-inflammatory effect of warfarin and vitamin K1.

Eichbaum FW, Slemer O, Zyngier SB.

Naunyn Schmiedebergs Arch Pharmacol 1979 Jun 18;307(2):185-90

1. Sodium warfarin, given by oral or by parenteral route, displays a pronounced anti-inflammatory effect in the formaldehyde and carrageenan induced rat paw edema. This effect becomes patent not only when the warfarin application precedes the local injection of the irritant substance (prophylactic effect), but also when it is given to animals with already developed inflammatory reactions (therapeutic effect). 2. The active doses of Na warfarin lie between 0.5 and 5.0 mg/kg. Smaller as well as higher doses show a reduced anti-inflammatory effect. 3. A marked anti-inflammatory effect can be noted already 90 min after drug injection at a still normal prothrombin level. 4. Vitamin K1 (phylloquinone), given by oral or parenteral route, in doses from 1.6 mg/kg upwards, shows a marked anti-inflammatory effect both in the prophylactic and the therapeutic rat paw test. Vitamin K3 is devoid of any anti-inflammatory activity. 5. The anti-inflammatory effect of both sodium warfarin and of vitamin K1 in rats, is not interfered with by previous adrenalectomy.

Congenital dyschromia with erythrocyte, platelet and tryptophan metabolism abnormalities.

Foldes C, Wallach D, Launay JM, Chirio R. Department of Dermatology, Hopital Saint-Louis, Paris, France.

J Am Acad Dermatol 1988 Oct;19(4):642-55

The case of a female child with a unique generalized congenital dyschromia is reported. She had hypopimented skin, with hypomelanosis and hypomelanocytosis, and many pigmented macules, which consisted of epidermal and dermal hypermelanosis without hypermelanocytosis. Biochemical investigations revealed normal catecholamine metabolism but abnormal tryptophan metabolism, including a decrease in blood serotonin and melatonin. A slight platelet storage pool disease was demonstrated, and a recurrent megaloblastic folate-related anemia occurred. The possible relationship between the pigmentary disease and the biochemical abnormalities is discussed. We suggest that this case represents a previously undescribed association of dyschromia, erythrocyte, platelet, and tryptophan metabolism abnormalities.

Melatonin prevents oxidative stress resulting from iron and erythropoietin administration.

Herrera J, Nava M, Romero F, Rodriguez-Iturbe B. Renal Service and Laboratory, Hospital Universitario de Maracaibo and Instituto de Investigaciones Biomedicas, Fundacite-Zulia, Maracaibo, Venezuela.

Am J Kidney Dis 2001 Apr;37(4):750-7

Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 +/- 0.09 nmol/mL; 1 hour, 1.50 +/- 0.28 nmol/mL (< 0.001); GSH, baseline, 2.51 +/- 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 +/- 0.01 nmol/mg Hb (< 0.001); and CAT activity, baseline, 27.0 +/- 5.7 kappa/mg Hb; 1 hour, 23.3 +/- 4.2 kappa/mg Hb (< 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (< 0.001) at 3 hours (MDA, 1.24 +/- 0.34 nmol/mL; GSH, 1.52 +/- 0.23 nmol/mg Hb; CAT activity, 18.0 +/- 3.1 kappa/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.

Effect of all-trans and 9-cis retinoic acid on growth and metastasis of xenotransplanted canine osteosarcoma cells in athymic mice.

Hong SH, Kadosawa T, Mochizuki M, Matsunaga S, Nishimura R, Sasaki N. Pediatrics Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.

Am J Vet Res 2000 Oct;61(10):1241-4

OBJECTIVE: To determine effects of all-trans and 9-cis retinoic acid (RA) on tumor growth and metastatic ability of canine osteosarcoma cells transplanted into athymic (nude) mice. ANIMALS: Forty-five 5-week-old female BALB/c nude mice.

PROCEDURE: 1 X 10(7) POS osteosarcoma cells were transplanted subcutaneously into the intrascapular region of mice. All-trans RA (3 or 30 microg/kg of body weight in 0.1 ml of sesame oil), 9-cis RA (3 or 30 mg/kg in 0.1 ml of sesame oil), or sesame oil (0.1 ml; control treatment) were administered intragastrically 5 d/wk for 4 weeks beginning 3 days after transplantation (n = 4 mice/group) or after formation of a palpable tumor (5 mice/group). Tumor weight was estimated weekly by measuring tumor length and width, and retinoid toxic effects were evaluated daily. Two weeks after the final treatment, mice were euthanatized, and number of mice with pulmonary metastases was determined.

RESULTS: Adverse treatment effects were not detected. Tumor weight was less in mice treated with either dose of 9-cis RA than in control mice, although this difference was not significant. Treatment with 30 mg of 9-cis RA/kg initiated after tumor formation significantly reduced the incidence of pulmonary metastasis, compared with the control group.

CONCLUSIONS AND CLINICAL RELEVANCE: 9-cis RA decreased the incidence of pulmonary metastasis in nude mice transplanted with canine osteosarcoma cells and may be a potential adjunct therapy for treatment of osteosarcoma in dogs.

Biochemotherapy for advanced melanoma.

Keilholz U, Gore ME. Department of Medicine III (Hematology, Oncology, and Transfusion Medicine), University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany.

Semin Oncol 2002 Oct;29(5):456-61

The outcome of chemotherapy for patients with stage IV melanoma is unsatisfactory, since durable responses are rarely achieved. More experimental treatments, such as vaccine approaches, antibody treatments, and gene therapy are being developed and are of high scientific interest; however, their efficacy in advanced melanoma patients has so far been very limited. Based on the observation of a small proportion of long-term responses, the use of biotherapy or biochemotherapy is currently preferred in many institutions as first-line treatment in stage IV melanoma. Various interleukin-2 (IL-2) dosing schedules and combinations with interferon alpha (IFN-alpha) have been tested in patients with advanced melanoma during the past decade. The response rates reported with IL-2 as a single agent or in combination with IFN-alpha varies from 10% to 41%, with a small, but remarkable proportion of durable responses. Subsequently, biochemotherapy regimens combining IL-2, IFN-alpha, and chemotherapy have been evaluated in phase II trials, which have suggested improved response rates. Recent randomized trials have investigated the role of biochemotherapy as compared to biotherapy alone or as compared to chemotherapy for the treatment of advanced melanoma. So far, none of the approaches has been proven to confer a survival benefit and thus the uniform desire is to include as many patients as possible in controlled clinical trials. Copyright 2002, Elsevier Science (USA). All rights reserved.

Prognostic factors for survival and factors associated with long-term remission in patients with advanced melanoma receiving cytokine-based treatments: second analysis of a randomised EORTC Melanoma Group trial comparing interferon-alpha2a (IFNalpha) and interleukin 2 (IL-2) with or without cisplatin.

Keilholz U, Martus P, Punt CJ, Kruit W, Mooser G, Schadendorf D, Lienard D, Dummer R, Koller J, Voit C, Eggermont AM. Medizinische Klinik III, UKBF, Free University Berlin, Hindenburgdamm 30, 12200, Berlin, Germany. keilholz@ukbf.fu-berlin.de

Eur J Cancer 2002 Jul;38(11):1501-11

The aim of this study was to define prognostic factors for survival, and especially for long-term survival in a mature data-set of patients with stage IV melanoma treated within a randomised trial of cytokine-based protocols. Long-term follow-up data on patients enrolled into a European Organization for Research and Treatment of Cancer (EORTC) trial comparing interferon-alpha (IFNalpha) plus interleukin-2 (IL-2) with or without cisplatin were collected. Univariate and multivariate Cox regression analyses were performed to define prognostic factors for survival. The characteristics of patients alive at 2 and 5 years after randomisation were compared with the entire cohort using the chi(2) test. The minimum potential follow-up of the 131 evaluable patients was 5 years. 18 patients (14%) were alive 2 years after randomisation, and 11 (8%) 5 years after randomisation. Pretreatment performance status (PS), serum lactate dehydrogenase (LDH) and tumour mass were significant predictors for survival, whereas site of metastases and number of sites were non-significant. PS and LDH were the only independent prognostic factors. All except 1 patient alive at 2 and 5 years had a pretreatment PS of 100%, and only three long-term survivors had elevated pretreatment LDH. There was no association between the site of metastases and long-term survival. Response to treatment was a major predictor for long-term survival, whereas addition of cisplatin did not impact upon overall survival probability or on long-term survival. The probability of long-term survival in stage IV melanoma patients after IL-2-based treatments is governed by pretreatment PS, serum LDH and response to treatment. Site of metastases, the basis for the M-subcategories of the new AJCC staging system, was not informative in this study.

Five-year survival of older people with anemia: variation with hemoglobin concentration.

Kikuchi M, Inagaki T, Shinagawa N. Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya City, Japan.

J Am Geriatr Soc 2001 Sep;49(9):1226-8

OBJECTIVES: To investigate the significance of low hemoglobin concentration and longevity in older people.

DESIGN: Randomized prospective study.

SETTING: Nursing home and geriatric hospital ward in a metropolitan welfare center.

PARTICIPANTS: Apparently stable older residents from 1990 to 1996.

MEASUREMENTS: Survival rates were estimated by statistical analysis. Sixty-three older subjects with low hemoglobin (<11 g/dl) and age/sex-matched normal controls (< or =11 g/dl) were observed for 60 months. Scores of activities of daily living (ADLs) did not significantly differ between the two groups. Cerebrovascular disease was the main complication in both, and malignant neoplasms were not apparent initially.

RESULTS: After 60 months, the 5-year survival rate (FSR) of normal controls was significantly higher than that of cases with anemia (P =.0078). FSR was 67% in normal controls and 48% in anemic individuals age 70 to 79. The figures for individuals age 80 to 89 were 62% and 41%, respectively, and for individuals age 90 to 99 were 25% and 13%, respectively, the survival rate significantly decreasing with age in both groups ( < 001). FSR with severe anemia (< or = 8.9 g/dl) was 0% in males, and 27% in females. Values for moderate anemia (9.0 g/dl to 10.9 g/dl) were 25% and 51%, respectively, for normal hemoglobin (11.0 g/dl to 12.9 g/dl) were 44% and 61%, respectively, and for high hemoglobin (< or =Hb) were 50% and 70%, respectively. Advanced carcinomas were often detected at autopsy in anemic individuals. No death by cancer occurred in normal controls.

CONCLUSION: Low hemoglobin concentration predicts early death in nursing home residents. Anemia-associated conditions that might be life-threatening risks in older people require further investigation.

Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes.

Kipper-Galperin M, Galilly R, Danenberg HD, Brenner T. Laboratory of Neuroimmunology, Hadassah University Hospital, Jerusalem, Israel.

Int J Dev Neurosci 1999 Dec;17(8):765-75

Dehydroepiandrosterone (DHEA) is a native neurosteroid with immunomodulating activity. DHEA effectively protects animals from several viral, bacterial and parasitic infections and it was suggested that its age-associated decline is related with immunosenescence. In the present study we examined the ability of DHEA to inhibit the production of inflammatory mediators by mycoplasma-stimulated glial cells and to change the course of acute central nervous system (CNS) inflammatory disease in vivo. Addition of DHEA (10 microg/ml) markedly inhibited tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production (98 and 95%, respectively), whereas nitric oxide (NO) and prostaglandin E2 (PGE2) production was not affected. However, daily administration of 0.5 mg DHEA to mice or 5 mg to rats did not change the clinical outcome of experimental autoimmune encephalomyelitis (EAE).

Meta-analysis of efficacy and tolerability data on iron protein succinylate in patients with iron deficiency anemia of different severity.

Kopcke W, Sauerland MC. Institut fur Medizinische Informatik und Biomathematik, Westfalische Wilhelms-Universitat Munster, Germany.

Arzneimittelforschung 1995 Nov;45(11):1211-6

Iron proteinsuccinylate (ITF 282, CAS 93615-44-2) is an iron derivative for the oral treatment of iron deficiency anemia. Its efficacy and tolerability have been proved in about 1800 patients, enrolled in 3 multicenter clinical trials. The first aim of this meta-analysis is to verify the increase of hemoglobin (Hb) in these patients (891 treated with ITF282, 644 treated with iron sulphate and 236 treated with iron-polysterene sulphonate). The 3 studies show homogeneous Hb increases. ITF 282 appeared to provide, from time 0 to the 30th day of treatment, a similar or lesser increase in Hb in comparison to the reference drugs, while from the 30th day of treatment to the 60th day its efficacy was always greater than that of the reference medications. The data have been further analyzed by subdividing the patients in three classes, according to the severity of the anemia: basal Hb < or = <  or = 11 g/dl, < g/dl. During the 60-day treatment, both ITF 282 and the reference drugs induced the most significant increase in Hb in the patients affected by the most severe anemia. The meta-analytic evaluation of the 3 trials results has been extended to tolerability data. Most side effects were related to the gastrointestinal tract. Their incidence resulted signficantly lower for ITF 282 than that for the reference drugs (9.4% vs. 20.4%, < 0.01). The comparative sub-analysis of the side effect distribution into the patients populations shows that ITF 282 is definitely better tolerated in pregnant women (relative risk 0.321, < 0.01). The time course of Hb increases and the tolerability data suggest a different mechanism by which ITF 282 and the reference drugs are effective. Since the main difference between ITF 282 and the reference drugs is the form in which the iron is presented to the gastrointestinal mucosa, it may be supposed that the reference drugs, providing free divalent iron ions for absorption, could induce some kind of irritative condition of the gastrointestinal mucosa, which results in a reduced long-term absorption capacity, as well as in a higher incidence of gastroenteric adverse events. ITF 282, providing protein-bound iron, would not permit the process supposed with divalent iron, thus resulting in prolonged absorption capacity (that is higher hemoglobin recovery) and higher gastrointestinal tolerability.

The relationship between clinical stage, natural killer activity and related immunological parameters in adenocarcinoma of the prostate.

Lahat N, Alexander B, Levin DR, Moskovitz B. Immunology Research Unit, Lady Davis Carmel Hospital, Haifa, Israel.

Cancer Immunol Immunother 1989;28(3):208-12

Several immunological in vitro tests were performed on peripheral blood mononuclear cells of patients with adenocarcinoma of the prostate, stages A, B, C, D. The cytotoxicity of effector natural killer cells towards K-562 targets decreased with increasing disease spread, while their percentage was not significantly changed. The proportion of CD4 (helper/inducer) cells tended to fall with tumor advance, but the proportion of CD8 (suppressor/cytotoxic) cells remained almost constant. Secretion of interleukin-2 from peripheral blood mononuclear cells was diminished with disease progression. Pretreatment of a patient's lymphocytes with cimetidine (antagonist of H-2-bearing suppressor T cells) or indomethacin (inhibitor of prostaglandin synthesis) enhanced natural killer activity. Our data point to the existence of aberrant immune functions in early stages of carcinoma of the prostate and to aggravation of these immune abnormalities in advanced disease.

Is there a role for melatonin in supportive care?

Lissoni P. U.O. di Oncologia Medica e Radioterapia, Ospedale S. Gerardo dei Tintori, 20052 Monza (MI), Italy. oncologia@genie.it

Support Care Cancer 2002 Mar;10(2):110-6

Melatonin (MLT) is the main hormone released from the pineal gland and has proved to have physiological antitumor activity. MLT has been shown to exert anticancer activity through several biological mechanisms: antiproliferative action, stimulation of anticancer immunity, modulation of oncogene expression, and anti-inflammatory, anti-oxidant and anti-angiogenic effects. Several experimental studies have shown that MLT may inhibit cancer cell growth, and preliminary clinical studies seem to confirm its anticancer property in humans. In addition, MLT may have other biological effects, which could be useful in the palliative therapy of cancer, namely anticachectic, anti-asthenic and thrombopoietic activities. On this basis, the present clinical investigation was performed in an attempt at better definition of the therapeutic properties of MLT in human neoplasms. In a first clinical study, we evaluated the effects of MLT in a group of 1,440 patients with untreatable advanced solid tumors, who received supportive care alone or supportive care plus MLT. In a second study, we evaluated the influence of MLT on the efficacy and toxicity of chemotherapy in a group of 200 metastatic patients with chemotherapy-resistant tumor histotype, who were randomized to receive chemotherapy alone or chemotherapy plus MLT. In both studies, MLT was given orally at 20 mg/day during the dark period of the day. The frequency of cachexia, asthenia, thrombocytopenia and lymphocytopenia was significantly lower in patients treated with MLT than in those who received supportive care alone. Moreover, the percentage of patients with disease stabilization and the percentage 1-year survival were both significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone. The objective tumor response rate was significantly higher in patients treated with chemotherapy plus MLT than in those treated with chemotherapy alone. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity and neurotoxicity. These clinical results demonstrate that the pineal hormone MLT may be successfully administered in medical oncology in the supportive care of untreatable advanced cancer patients and for the prevention of chemotherapy-induced toxicity.

Immunotherapy with subcutaneous low-dose interleukin-2 plus melatonin as salvage therapy of heavily chemotherapy-pretreated ovarian cancer.

Lissoni P.; Ardizzoia A.; Barni S.; Tancini G.; Muttini M.P. Address: Dr. P. Lissoni, Divisione di Radioterapia Oncologica, Ospedale San Gerardo, Via Donizetti 106, 20052 Monza, MI , Italy

Oncol. Rep. 1996; 3(5): 947-9.

Preliminary results showed that IL-2 immunotherapy may be effective in the treatment of recurring advanced ovarian cancer. The pineal neurohormone melatonin (MLT) has been proven to amplify IL-2 efficacy by counteracting macrophage-mediated immunosuppression. On this basis, a pilot phase II study of low-dose IL-2 plus MLT was performed in advanced ovarian cancer patients progressing after at least 3 previous polychemotherapeutic lines. The study included 12 evaluable patients. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks, by repeating the cycle after a 21-day rest period in nonprogressing patients, MLT was given orally at 40 mg/day. No complete response was seen. A partial response was achieved in 2/12 (16%) patients. A stable disease was obtained in 5 other patients, whereas the remaining 5 patients progressed. The treatment was well tolerated. This preliminary study suggests that immunotherapy with low-dose IL-2 plus MLT may represent a well tolerated and promising therapy of advanced ovarian cancer progressing on standard medical treatments.

Efficacy of the concomitant administration of the pineal hormone melatonin in cancer immunotherapy with low-dose IL-2 in patients with advanced solid tumors who had progressed on IL-2 alone.

Lissoni P, Barni S, Cazzaniga M, Ardizzoia A, Rovelli F, Brivio F, Tancini G. Division of Radiation Oncology, San Gerardo Hospital, Monza, Italy.

Oncology 1994 Jul-Aug;51(4):344-7

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effect and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state.

Lissoni P; Paolorossi F; Ardizzoia A; Barni S; Chilelli M; Mancuso M; Tancini G; Conti A; Maestroni GJ Divisione di Radioterapia Oncologica, Ospedale S, Gerardo, Monza, Milan, Italy.

J Pineal Res (Denmark) Aug 1997, 23 (1) p15-9

Recent studies suggest that the pineal hormone melatonin may reduce chemotherapy -induced immune and bone marrow damage. In addition, melatonin may exert potential oncostatic effects either by stimulating host anticancer immune defenses or by inhibiting tumor growth factor production. On this basis, we have performed a randomized study of chemotherapy alone vs. chemotherapy plus melatonin in advanced non-small cell lung cancer patients (NSCLC) with poor clinical status. The study included 70 consecutive advanced NSCLC patients who were randomized to receive chemotherapy alone with cisplatin (20 mg/m2/day i.v. for 3 days) and etoposide (100 mg/m2/day i.v. for 3 days) or chemotherapy plus melatonin (20 mg/day orally in the evening). Cycles were repeated at 21-day intervals. Clinical response and toxicity were evaluated according to World Health Organization criteria. A complete response (CR) was achieved in 1/34 patients concomitantly treated with melatonin and in none of the patients receiving chemotherapy alone. Partial response (PR) occurred in 10/34 and in 6/36 patients treated with or without melatonin, respectively. Thus, the tumor response rate was higher in patients receiving melatonin (11/34 vs. 6/35), without, however, statistically significant differences. The percent of 1-year survival was significantly higher in patients treated with melatonin plus chemotherapy than in those who received chemotherapy alone (15/34 vs. 7/36, < 0.05). Finally, chemotherapy was well tolerated in patients receiving melatonin, and in particular the frequency of myelosuppression, neuropathy, and cachexia was significantly lower in the melatonin group. This study shows that the concomitant administration of melatonin may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition.

Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin.

Lissoni P, Tancini G, Barni S, Paolorossi F, Ardizzoia A, Conti A, Maestroni G. Division of Radiation Oncology, S. Gerardo Hospital, Monza (Milan), Italy.

Support Care Cancer 1997 Mar;5(2):126-9

Experimental data have suggested that the pineal hormone melatonin (MLT) may counteract chemotherapy-induced myelosuppression and immunosuppression. In addition, MLT has been shown to inhibit the production of free radicals, which play a part in mediating the toxicity of chemotherapy. A study was therefore performed in an attempt to evaluate the influence of MLT on chemotherapy toxicity. The study involved 80 patients with metastatic solid tumors who were in poor clinical condition (lung cancer: 35; breast cancer: 31; gastrointestinal tract tumors: 14). Lung cancer patients were treated with cisplatin and etoposide, breast cancer patients with mitoxantrone, and gastrointestinal tract tumor patients with 5-fluorouracil plus folates. Patients were randomised to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day p.o. in the evening). Thrombocytopenia was significantly less frequent in patients concomitantly treated with MLT. Malaise and asthenia were also significantly less frequent in patients receiving MLT. Finally, stomatitis and neuropathy were less frequent in the MLT group, albeit without statistically significant differences. Alopecia and vomiting were not influenced by MLT. This pilot study seems to suggest that the concomitant administration of the pineal hormone MLT during chemotherapy may prevent some chemotherapy-induced side-effects, particularly myelosuppression and neuropathy. Evaluation of the impact of MLT on chemotherapy efficacy will be the aim of future clinical investigations.

Ambulatory management of common forms of anemia.

Little DR. Wright State University School of Medicine, Dayton, Ohio, USA.

Am Fam Physician 1999 Mar 15;59(6):1598-604

Anemia is a prevalent condition with a variety of underlying causes. Once the etiology has been established, many forms of anemia can be easily managed by the family physician. Iron deficiency, the most common form of anemia, may be treated orally or, rarely, parenterally. Vitamin B12 deficiency has traditionally been treated with intramuscular injections, although oral and intranasal preparations are also available. The treatment of folate deficiency is straightforward, relying on oral supplements. Folic acid supplementation is also recommended for women of child-bearing age to reduce their risk of neural tube defects. Current research focuses on folate's role in reducing the risk of premature cardiovascular disease.

Immune restoration and/or augmentation of local xenogeneic graft versus host reaction by Cimetidine in vitro.

Mavligit GM, Calvo DB 3rd, Patt YZ, Hersh EM.

J Immunol 1981 Jun;126(6):2272-4

The immunorestorative effect of Cimetidine in vitro on the T cell-induced local GVH reaction in vivo was studied in 43 cancer patients and 43 normal healthy donors. Both low dose (10(-5) M) and high dose (10(-4) M) Cimetidine induced significant, albeit partial, immune restoration among GVHR-negative cancer patients (p less than 0.05, p less than 0.01, respectively) with the high dose being significantly more effective (p less than 0.05). In contrast, similar Cimetidine doses induced only moderate augmentation (p greater than 0.05) among GVHR-positive cancer patients and a marginal one among normal healthy donors. In the latter 2 groups, Cimetidine was found to be occasionally detrimental in that it induced a conversion from a positive to a negative GVH reaction. These results support the concept of anti-suppressor cell activity ascribed to Cimetidine. However, the possibility of a detrimental effect should be born in mind in planning future clinical trials. We propose that the use of Cimetidine be limited to cancer patients with documented increase in suppressor cell activity associated with defective T cell function under close serial monitoring.

Transfusion in the management of patients with megaloblastic anaemia.

McMullin MF, Cuthbert RJ. Department of Haematology, Queen's University of Belfast, Northern Ireland, UK.

Int J Clin Pract 1999 Mar;53(2):104-6

Transfusion has been associated with significant morbidity and mortality in megaloblastic anaemia (MA). This retrospective study was undertaken to examine the usefulness of transfusion in the management of MA. Fifty-two patients with MA were identified. Of the 20 transfused patients 13 were treated with diuretics and six with potassium supplements. The mean haemoglobin (Hb) of the transfused group was 6.5 g/dl (range 4.8-10.4 g/dl), and of the 32 non-transfused patients 10.5 g/dl (range 5.6-17.0 g/dl). The Hb and packed cell volume (PCV) were significantly lower in the transfused group. Only two of 32 non-transfused group were given potassium supplements. In this small group of patients with MA, transfusion appeared to be safe and no complications of transfusion were identified. However, advice was not being followed. We would suggest that, although transfusion has a minor role in the management of MA, consideration must be given to the general hazards of transfusion.

Effects of pentoxifylline on the haematologic status in anemic patients with advanced renal failure.

Navarro JF, Mora C, Garcia J, Rivero A, Macia M, Gallego E, Mendez ML, Chahin J. Department of Nephrology, Hospital Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.

Scand J Urol Nephrol 1999 Apr;33(2):121-5

OBJECTIVE: Erythropoietin (EPO) deficiency is the main cause of renal anaemia. However, inhibition of erythropoiesis by cytokines such as tumour necrosis factor alpha (TNF-a) may play an important role. The aim of this work was to study the effects of pentoxifylline, an agent with anti-TNF-a properties, on the haematologic status in anaemic patients with advanced renal failure.

MATERIAL AND METHODS: In a prospective study, 7 anaemic patients with advanced renal disease (creatinine clearance < 30 ml/min) were treated with pentoxifylline (400 mg orally daily) for 6 months. The evolution of haemoglobin, haematocrit, creatinine clearance and serum EPO and TNF-a a concentrations were compared with those obtained from an untreated control group.

RESULTS: Haemoglobin and haematocrit significantly increased in the pentoxifylline-treated patients (9.9+/-0.5 g/dl and 27.9+/-1.6% at baseline; 10.6+/-0.6 g/dl and 31.3+/-1.9% at the 6th month, respectively, < 0.01), whereas no variation was seen in the control group. Serum EPO levels remained stable in all patients. However, the serum TNF-a concentration decreased significantly in patients receiving pentoxifylline (basal 623+/-366 pg/ml; 6th month 562+/-358 pg/ml, < 0.01), but not in the control group.

CONCLUSIONS: Our findings suggest that the inhibition of erythropoiesis by cytokines may play a significant role in renal anaemia. The administration of agents with anti-cytokine properties, such as pentoxifylline, can improve the haematologic status in anaemic patients with advanced renal failure.

Melatonin as biological response modifier in cancer patients.

Neri B; de Leonardis V; Gemelli MT; di Loro F; Mottola A; Ponchietti R; Raugei A; Cini G Oncological Day Hospital, Department of Internal Medicine, University of Florence, Italy.

Anticancer Res (Greece) Mar-Apr 1998, 18 (2B) p1329-32

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences ( < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Clinical relevance of cytokine production in hemodialysis.

Pertosa G, Grandaliano G, Gesualdo L, Schena FP. Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Policlinico, Bari, Italy. g.pertosa@nephro.uniba.it

Kidney Int Suppl 2000 Aug;76:S104-11

Blood-dialyzer interaction in hemodialysis has the potential to activate mononuclear cells leading to the production of inflammatory cytokines. The extent of activation is dependent on the dialyzer material used and is considered an index of biocompatibility. Cytokines, such as interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6, may induce an inflammatory state and are believed to play a significant role in dialysis-related morbidity. The interleukin hypothesis suggests that the release of proinflammatory cytokines acts as an underlying pathophysiologic event in hemodialysis-related acute manifestations, such as fever and hypotension. Nevertheless, a cytokine overproduction may alter sleep pattern in chronic hemodialyzed patients, thus explaining the presence of sleep disorders in these patients. A potential role of cytokines in chronic-related morbidity has also been suggested. High levels of some inflammatory cytokines are often associated with anemia caused by hyporesponsiveness to erythropoietin. Cytokine production may also play a relevant role in bone remodeling by regulating osteoblast/osteoclast cell functions and parathyroid hormone (PTH). Finally, cytokine release may have a long-term deleterious effect on mortality of uremic patients by altering immune response and increasing susceptibility to infections. Bioincompatibility of dialytic membranes may also contribute to malnutrition in dialysis patients by increasing the monocyte release of catabolic cytokines such as TNF-alpha and IL-6. Bioincompatible dialytic treatment may induce an inappropriate monocyte activation and cytokine production, which, in turn, may mediate some of the immune and metabolic dysfunction associated with hemodialysis. The use of biocompatible dialytic membranes appears to reduce the monocyte activation and to improve the survival of hemodialysis patients.

Some biological actions of alkylglycerols from shark liver oil.

Pugliese PT, Jordan K, Cederberg H, Brohult J. Karolinska Institute (Soderjukhuset), Stockholm, Sweden.

J Altern Complement Med 1998 Spring;4(1):87-99

Shark liver oil has been used for over 40 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkylglycerols. Initial clinical use was for treating leukemias, and later to prevent radiation sickness from cancer x-ray therapy. Studies over the last 30 years have shown that alkylglycerols are multifunctional. The level of natural alkylglycerols rises within tumor cells, apparently in an effort to control cell growth. Recent studies indicate that the activation of protein kinase C, an essential step in cell proliferation, can be inhibited by alkylglycerols. This action suggests a competitive inhibition of 1.2-diacylglycerol by alkylglycerols. Further studies on the immunostimulatory action of alkylglycerols suggest a primary action on the macrophage. The process of macrophage activation has been demonstrated with both synthetic and natural alkylglycerols. While the exact mechanism has not been found, both an autocrine and paracrine system have been suggested. Shark liver is a major natural source of alkylglycerols, which have no known side effects in dosages of 100 mg three times a day. The information presented in this article suggests that alkylglycerols may be used both as an adjunct therapy in the treatment of neoplastic disorders and as an immune booster in infectious diseases.

In vitro studies on anemia in chronic inflammatory disease: influence of interleukin-6 on human erythropoietin. [Article in Polish]

Ratajczak MZ, Ratajczak J, Skorski T. Instytutu-Centrum Medycyny Doswiadczalnej i Klinicznej PAN, Warszawie.

Pol Merkuriusz Lek 1997 Jan;2(9):172-5

The influence of interleukin-6 (Il-6) on human erythropoietic progenitors growth in vitro was evaluated. It was found Il-6 causes approximately 35% inhibition of early BFU-E growth stimulated with erythropoietin, kit ligand and interleukin-3, Il-6 did not inhibit erythroid colony formation by late BFU-E and CFU-E progenitors. This data suggests the role Il-6 as one of inflammatory cytokines in pathogenesis of anemia of chronic disease acting inhibitory at early BFU-E erythroid progenitors level.

Retinoids in pancreatic cancer.

Riecken EO, Rosewicz S. Dept. of Gastroenterology, Klinikum Benjamin Franklin, Berlin, FRG, Germany. riecken@ukbf.fu-berlin.de

Ann Oncol 1999;10 Suppl 4:197-200

Prognosis of advanced, unresectable pancreatic adenocarcinoma remains dismal and has not significantly improved over the past 20 years. In a broad panel of preclinical experimental settings we have therefore evaluated the effects of retinoids on human pancreatic carcinoma cells in vitro and in vivo. We found that retinoid treatment results in inhibition of growth, induction of cellular differentiation and decreased adhesion to certain components of the extracellular matrix, all features compatible with a "less malignant" phenotype. Furthermore, retinoids act synergistically antiproliferative when combined with interferon-alpha. Using transient and stable genetic transfer studies we were able to identify two retinoid receptor subtypes responsible for mediating the growth inhibitory effects as well as retinoid sensitivity. In addition we observed a crucial functional interplay between the retinoid signalling pathway and the expression of a distinct protein kinase C isoenzyme, which determines the direction of the growth regulatory effects of retinoids. Based on these encouraging preclinical results we initiated a phase II clinical trial in which patients with advanced pancreatic carcinoma were treated with retinoic acid in combination with interferon-alpha. This therapeutic regimen was well tolerated and resulted in prolonged stable disease in approximately two thirds of the patients. In summary, these studies suggest that retinoids might be beneficial in the treatment of advanced pancreatic carcinoma patients based on their pleiotropic effects on tumor cell biology.

Drug-induced thrombocytopenia.

Rizvi MA, Shah SR, Raskob GE, George JN. Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.

Curr Opin Hematol 1999 Sep;6(5):349-53

Many drugs can induce thrombocytopenia mediated by drug-dependent antiplatelet antibodies. Recent studies have documented specific epitopes for drug-dependent antibody binding on glycoprotein Ib-IX, glycoprotein IIb-IIIa, and platelet-endothelial cell adhesion molecule-1. Molecular identification of antibody binding sites may help to identify susceptible individuals. Management of patients with unexpected thrombocytopenia who are taking multiple drugs remains a difficult clinical problem. A recent systematic review of all published case reports of drug-induced thrombocytopenia ranks drugs according to the strength of clinical evidence for a causal relation to thrombocytopenia. This database is available online at http://moon.ouhsc.edu/jgeorge.

Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome.

Rook AH, Masur H, Lane HC, Frederick W, Kasahara T, Macher AM, Djeu JY, Manischewitz JF, Jackson L, Fauci AS, Quinnan GV Jr.

J Clin Invest 1983 Jul;72(1):398-403

The recently described acquired immune deficiency syndrome (AIDS) is characterized by the occurrence of severe opportunistic infections and an aggressive form of Kaposi's sarcoma. A variety of profound defects in cell-mediated immunity have been reported in association with the AIDS, including deficiencies in natural killer (NK) cell activity and cytomegalovirus (CMV)-specific cytotoxicity. In the present study, the in vitro effects of interleukin-2 (IL-2) and interferon beta (IFN Beta) on these abnormalities were examined to assess the potential use of these lymphokines in the immunotherapeutic treatment of this syndrome. The peripheral blood lymphocytes (PBL) from six male homosexuals with AIDS and an active CMV infection exhibited markedly depressed NK cell and CMV-specific cytotoxic lymphocyte responses compared with uninfected, heterosexual control subjects. Incubation of PBL with IFN Beta enhanced the NK cell activity and the CMV-specific cytotoxicity of only one of six and neither of two AIDS patients, respectively, while enhancing the NK cell activity of all six control subjects. In contrast, IL-2 dramatically enhanced both the NK cell and the CMV-specific cytotoxic lymphocyte activities of all of the patients. These results indicate that IL-2 can substantially potentiate the depressed cytotoxic effector functions of PBL from AIDS patients, while IFN Beta has little effect.

Immunomodulatory treatment with low-dose interferon-alpha and oral retinoic acid in lymphangioma-like Kaposi's sarcoma.

Somos S, Farkas B. Dermatological Department, Medical University of Pecs, Hungary. som@freemail.c3.hu

Anticancer Res 2000 Jan-Feb;20(1B):541-5

BACKGROUND: The presence of lymphangiectasis without the characteristic spindle cell proliferation may lead to diagnostic difficulties in Kaposi's sarcoma. Although the literary data mention that the lymphangioma-like tumors may occur in Kaposi's sarcoma, there have been few specific reports and case presentations published.

OBSERVATIONS: A case of lymphangioma-like Kaposi's sarcoma in association with IgG/lambda type paraproteinaemia is reported in a 60-year-old man. The HSV8 DNA sequence could be detected by PCR analysis from lesional skin.

CONCLUSION: The beneficial effect of alpha-2 interferon (4.5 million units per week) combined with retinoic treatment (0.5 mg/body weight of isotretinoin) caused the regression of the skin rashes while improving the values of immunological tests (T cell function, quantity of paraproteins). The patient's improved general condition and the ameliorating immunological parameters were due to the combination of two regimens applied in a low-dose the alpha-2 interferon (tumor regression) and the oral isotretinoid (antitumor activity, reduction of IL-6 receptor display) treatment.

Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: results from the multistate adult and adolescent spectrum of HIV disease surveillance project.

Sullivan PS, Hanson DL, Chu SY, Jones JL, Ward JW. Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Atlanta, Georgia, USA.

Blood 1998 Jan 1;91(1):301-8

To study the incidence of, the factors associated with, and the effect on survival of anemia in human immunodeficiency virus (HIV)-infected persons, we analyzed data from the longitudinal medical record reviews of 32,867 HIV-infected persons who received medical care from January 1990 through August 1996 in clinics, hospitals, and private medical practices in nine United States cities. We calculated the 1-year incidence of anemia (a hemoglobin level of < 10 g/dL or a physician diagnosis of anemia); the adjusted odds ratios showing excess risk of anemia associated with demographic factors, prescribed therapies, and concurrent diseases; the risk of death for patients who developed anemia compared with risk for patients who did not develop anemia; and, of patients who did develop anemia, the risk of death for those who did not recover from anemia compared with the risk for those who did recover. The 1-year incidence of anemia was 36.9% for persons with one or more acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (clinical AIDS), 12.1% for patients with a CD4 count of less than 200 cells/micron or CD4 percentage of < 14 but not clinical AIDS (immunologic AIDS), and 3.2% for persons without clinical or immunologic AIDS. Of anemia diagnoses, 22% were identified by physicians as drug related. Incidence of anemia was associated with clinical AIDS, immunologic AIDS, neutropenia, thrombocytopenia, bacterial septicemia, black race, female sex, prescription of zidovudine, fluconazole, and ganciclovir, and lack of prescription of trimethoprim-sulfamethoxazole. The increased risk of death associated with anemia differed by first CD4 count: for patients with a CD4 count of < =200 cells/microL at the beginning of the survival analysis, the risk of death was 148% (99% confidence interval [CI], 114 to 188) greater for those who developed anemia; for patients whose first CD4 count was < 200 cells/microL, the risk of death was 56% (99% CI, 43 to 71) greater for those in whom anemia developed. For persons in whom anemia developed, the risk of death was 170% (99% CI, 132 to 203) greater for persons who did not recover from anemia compared with those who did recover. Anemia is a frequent complication of HIV infection, and its incidence is associated with progression of HIV disease, prescription of certain chemotherapeutics, black race, and female sex. Anemia, particularly anemia that does not resolve, is associated with shorter survival of HIV-infected patients.

Effectiveness of oral vitamin B12 therapy for pernicious anemia and vitamin B12 deficiency anemia. [Article in Japanese]

Takasaki Y, Moriuchi Y, Tsushima H, Ikeda E, Koura S, Taguchi J, Fukushima T, Tomonaga M, Ikeda S. Department of Hematology, Sasebo City General Hospital, Sasebo, Japan.

Rinsho Ketsueki 2002 Mar;43(3):165-9

We investigated the efficacy of oral vitamin B12 (B12) therapy in patients with B12-deficiency anemia. Between June 1994 and June 2000, 17 patients, who were diagnosed as having B12-deficiency anemia and gave their informed consent, were enrolled in this study. Of these patients, 7 were further treated with a maintenance dose of methylcobalamin (1,500 micrograms daily for 7 days every 1-3 months). Correction of hematological and neurological abnormalities was prompt. The hemoglobin level and serum concentration of B12 were normalized within two months after starting the treatment. Recovery from neurological disturbance was observed within one month. To maintain a normal serum concentration of B12, a 7-day regime of administration was needed every month in 3 patients, every 2 months in 3 patients, and every 3 months in 1 patient. These results demonstrate the effectiveness of oral cobalamin therapy, and also that oral intermittent therapy is useful for maintaining a normal serum B12 concentration. Oral cobalamin therapy might be as effective as conventional injection therapy, and useful for long-term treatment.

Classic Kaposi's sarcoma: low-dose interferon alfa treatment.

Tur E, Brenner S. Department of Dermatology, Sourasky Medical Center, Tel Aviv University, Sackler School of Medicine, Israel. Tur@eng.tau.ac.il

Dermatology 1998;197(1):37-42

BACKGROUND: Classic Kaposi's sarcoma, a rare form of cancer, has no definitive cure. A beneficial effect of low-dose interferon (IFN) alfa was indicated by some case reports. In the present report, we summarize the results of our experience with subcutaneous low-dose IFN alfa treatment of 11 patients with extensive classic Kaposi's sarcoma and review the literature.

DESIGN: Eleven patients, 56-96 years old, were treated: 10 men, 1 woman, 3 of whom had an associated malignancy. Subcutaneous injections of IFN alfa were given, starting with 3 million units 5 times a week, and modified according to side effects and response after 2 weeks (2-6 million units, 3-6 times a week). This treatment was continued for 6 months, except for 1 patient who died after 4 months and another who stopped treatment at 4 months due to surgery but was treated again after recurrence. Treatment was continued after 6 months when a partial response was noted, but further improvement was desired (1 patient).

RESULTS: In 9 out of the 11 patients, initial response was noted after 3-13 weeks of treatment. This was manifested by a reduction of lesion size and fading of color, leading to a partial resolution. Maximum response was achieved after 4-6 months. Remission lasted 4-72 months. Recurrences were retreated, with additional remissions after only 5-8 weeks of treatment. Side effects included fever and fatigue, which were overcome by dose reduction.

CONCLUSION: Whereas in AIDS-related Kaposi's sarcoma patients become refractory to IFN, this was not observed in our patients with classic Kaposi's sarcoma. Moreover, unlike AIDS-related Kaposi's sarcoma, continuous treatment was not needed in classic Kaposi's sarcoma, and recurrences were responsive to retreatment.

Dysregulation of melatonin metabolism in chronic renal insufficiency: role of erythropoietin-deficiency anemia.

Vaziri ND, Oveisi F, Reyes GA, Zhou XJ. Department of Medicine, University of California, Irvine, USA.

Kidney Int 1996 Aug;50(2):653-6

Chronic renal failure (CRF) is associated with a variety of neurological and endocrine disorders. In this study, we examined the effect of CRF and the associated anemia on circadian variation of pineal hormone, melatonin. Animals were studied six weeks after 5/6 nephrectomy (CRF group, N = 26) or sham operation (control group, N = 28). A group of erythropoietin-treated CRF animals (CRF/EPO, N = 6) was included to discern the possible role of EPO-deficiency anemia. Compared with the normal control group, the CRF group showed a marked attenuation of the nocturnal surge in serum melatonin concentration. In addition, pineal gland melatonin content measured after a 12-hour dark cycle (< or = 2 lux) was significantly depressed in the CRF group when compared to that obtained in the control group. However, the CRF animals exhibited appropriate suppression of serum concentration and pineal tissue melatonin content in response to bright light (< or = 2500 lux). Administration of EPO led to correction of the CRF anemia and a marked improvement of the defective nocturnal rhythm of serum melatonin. Based on our results, experimental CRF is associated with a marked attenuation of the normal nocturnal surge of serum melatonin concentration. Regular EPO administration results in the correction of anemia and substantial reversal of this abnormality suggesting the partial role of EPO deficiency. The possible role of melatonin dysregulation in the pathophysiology of CRF and the potential value of melatonin supplementation in this condition is uncertain and awaits future investigations.

Modulation effect of cimetidine on the production of IL-2 and interferon-gamma in patients with gastric cancer. [Article in Chinese]

Wen QS, Zhang GZ, Kong XT. Changzheng Hospital, Second Military Medical University, Shanghai.

Zhonghua Zhong Liu Za Zhi 1994 Jul;16(4):299-301

The modulation effects of cimetidine on the production of IL-2 and IFN-gamma by the peripheral blood mononuclear cells in 31 patients with gastric cancer and 32 normal subjects were studied. Their T lymphocyte subsets were also assayed. The IL-2 and IFN-gamma activity in patients were significantly lower than that in normal subjects (< 0.01). Cimetidine could significantly promote IL-2 and IFN-gamma production. There was a significant negative correlation between OKT8 subsets and the activity of IL-2 and IFN-gamma (< 0.01). The results showed that cimetidine could be used as an adjunct in the treatment of advanced neoplasm.

Blood transfusion in elderly patients with acute myocardial infarction.

Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Division of Cardiovascular Diseases, Brown University Medical School, Providence, RI, USA.

N Engl J Med 2001 Oct 25;345(17):1230-6

BACKGROUND: Anemia may have adverse effects in patients with coronary artery disease. However, the benefit of blood transfusion in elderly patients with acute myocardial infarction and various degrees of anemia is uncertain.

METHODS: We conducted a retrospective study of data on 78,974 Medicare beneficiaries 65 years old or older who were hospitalized with acute myocardial infarction. Patients were categorized according to the hematocrit on admission (5.0 to 24.0 percent, 24.1 to 27.0 percent, 27.1 to 30.0 percent, 30.1 to 33.0 percent, 33.1 to 36.0 percent, 36.1 to 39.0 percent, or 39.1 to 48.0 percent), and data were evaluated to determine whether there was an association between the use of transfusion and 30-day mortality.

RESULTS: Patients with lower hematocrit values on admission had higher 30-day mortality rates. Blood transfusion was associated with a reduction in 30-day mortality among patients whose hematocrit on admission fell into the categories ranging from 5.0 to 24.0 percent (adjusted odds ratio, 0.22; 95 percent confidence interval, 0.11 to 0.45) to 30.1 to 33.0 percent (adjusted odds ratio, 0.69; 95 percent confidence interval, 0.53 to 0.89). It was not associated with a reduction in 30-day mortality among those whose hematocrit values fell in the higher ranges. In one of seven subgroup analyses (among patients who survived at least two days), transfusion was not associated with a reduction in mortality for patients with hematocrit values of 30.1 percent or higher.

CONCLUSIONS: Blood transfusion is associated with a lower short-term mortality rate among elderly patients with acute myocardial infarction if the hematocrit on admission is 30.0 percent or lower and may be effective in patients with a hematocrit as high as 33.0 percent on admission.

Hormone substitution in male hypogonadism.

Zitzmann M, Nieschlag E. Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48149, Munster, Germany.

Mol Cell Endocrinol 2000 Mar 30;161(1-2):73-88

Male hypogonadism is characterised by androgen deficiency and infertility. Hypogonadism can be caused by disorders at the hypothalamic or pituitary level (hypogonadotropic forms) or by testicular dysfunction (hypergonadotropic forms). Testosterone substitution is necessary in all hypogonadal patients, because androgen deficiency causes slight anemia, changes in coagulation parameters, decreased bone density, muscle atrophy, regression of sexual function and alterations in mood and cognitive abilities. Androgen replacement comprises injectable forms of testosterone as well as implants, transdermal systems, sublingual, buccal and oral preparations. Transdermal systems provide the pharmacokinetic modality closest to natural diurnal variations in testosterone levels. New injectable forms of testosterone are currently under clinical evaluation (testosterone undecanoate, testosterone buciclate), allowing extended injection intervals. If patients with hypogonadotropic hypogonadism wish to father a child, spermatogenesis can be initiated and maintained by gonadotropin therapy (conventionally in the form of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or, more recently, purified or recombinant follicle stimulating hormone (FSH)). Apart from this option, patients with disorders at the hypothalamic level can be stimulated with pulsatile gonadotropin-releasing hormone (GnRH). Both treatment modalities have to be administered on average for 7-10 months until pregnancy is achieved. In individual cases, treatment may be necessary for up to 46 months. Testosterone treatment is interrupted for the time of GnRH of gonadotropin therapy, but resumed after cessation of this therapy.

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