Pneumologie 2011; 65(6): 347-358
DOI: 10.1055/s-0030-1256118
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Paraneoplastische Syndrome beim Lungenkarzinom

Paraneoplastic Syndromes in Lung CancerH.-P.  Hauber1
  • 1Medizinische Klinik, Forschungszentrum Borstel, Borstel (Ärztlicher Direktor: Prof. Dr. P. Zabel)
Further Information

Publication History

eingereicht 22.11.2010

akzeptiert nach Revision 7.12.2010

Publication Date:
25 January 2011 (online)

Zusammenfassung

Paraneoplastische Syndrome treten bei ca. 10 % aller Patienten mit Lungenkrebs auf. Sie können die Erstmanifestation der Erankung oder ein erstes Zeichen für ein Rezidiv sein. Nach der klinischen Symptomatik können endokrine, hämatologische, neurologische, dermatologische, skelettale, renale, metabolische, kollagenose-vaskulitische und konstitutionelle Syndrome unterschieden werden. In der vorliegenden Übersichtsarbeit werden die Epidemiologie, Pathogenese, klinische Symptomatik und Therapieoptionen der wichtigsten paraneoplastischen Syndrome beim Lungenkarzinom dargestellt.

Abstract

Paraneoplastic syndromes occur in approximately 10 % of all patients with lung cancer. They can be the first manifestation of the disease or of a recurrence. Endocrine, haematological, neuromuscular, dermatological, renal, and metabolic syndromes as well as syndromes involving the connective tissue and constitutional syndromes can be distinguished based on their clinical symptoms. In this review, the epidemiology, pathogenesis, clinical signs and treatment options for the clinically important paraneoplastic syndromes in lung cancer are discussed.

Literatur

  • 1 Bunn P A, Ridgway E C. Paraneoplastic syndromes.. In: DeVita V T, et al., eds. Cancer: Principles and Practice of Oncology. 4th edn. Philadelphia: Lippincott Co; 1993: 2026-2071
  • 2 Navani N, Spiro S G. Symptoms and signs of lung cancer.  In: Spiro SG, Huber RM, Janes SM, eds. Thoracic Malignancies. Eur Respir Monograph. 2009;  44 71-87
  • 3 Richardson G E, Johnson B E. Paraneoplastic syndromes in lung cancer.  Curr Opin Oncol. 1992;  4 323-333
  • 4 Heinemann S, Zabel P, Hauber H P. Paraneoplastic syndromes in lung cancer.  Cancer Therapy. 2008;  6 687-698
  • 5 Monsieur I, Meysman M, Noppen N et al. Non-small-cell lung cancer with multiple paraneoplastic syndromes.  Eur Respir J. 1995;  8 1231-1234
  • 6 Spiro S G, Gould M K, Colice G L. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. ACCP evidence-based clinical practice guidelines (2nd edition).  Chest. 2007;  132 149S-160S
  • 7 Hiraki A, Ueoka H, Takata I et al. Hypercalcemia-leukocytosis syndrome associated with lung cancer.  Lung Cancer. 2004;  43 301-307
  • 8 Burtis W J, Brady T G, Orloff J J et al. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with hypercalcemia of cancer.  N Engl J Med. 1990;  322 1106-1112
  • 9 Moseley J M, Kubota M, Diefenbach-Jagger H et al. Parathyroid hormone-related protein purified from a human lung cancer cell line.  Proc Natl Acad Sci. 1987;  84 5048-5052
  • 10 Abou-Samra A B, Juppner H, Force T et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium.  Proc Natl Acad Sci. 1992;  89 2732-2736
  • 11 Horiuchi N, Caulfield M P, Fisher J E et al. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro.  Science. 1987;  238 1566-1568
  • 12 Danks J A, Ebeling P R, Hayman J et al. Parathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin.  J Bone Min Res. 1989;  4 273-278
  • 13 Asa S L, Henderson J, Goltzman D, Drucker D J. Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues.  J Clin Endocrinol Metab. 1990;  71 1112-1118
  • 14 Clines G A, Guise T A. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis in bone.  Endocr Rel Cancer. 2005;  12 549-583
  • 15 Juppner H, Abou-Samara A B, Freeman M et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide.  Science. 1991;  254 1024-1026
  • 16 Mahon M J, Donowitz M, Yun C C, Segre G V. Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling.  Nature. 2002;  417 858-861
  • 17 Swarthout J T, D’Alonzo R C, Selvamurugan N, Partridge N C. Parathyroid hormone-dependent signalling pathways regulating genes in bone cells.  Gene. 2002;  282 1-17
  • 18 Luparello C, Burtis W J, Raue F et al. Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects.  Mol Cell Endocrinol. 1995;  111 225-232
  • 19 Luparello C, Ginty A F, Gallagher J A et al. Transforming growth factor-beta 1, beta 2, and beta 3, urokinase and parathyroid hormone-related peptide expression in 8701-BC breast cancer cells and clones.  Differentiation. 1993;  55 73-80
  • 20 Li H, Seitz P K, Selvanayagam P et al. Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2).  Endocrinol. 1996;  137 2367-2374
  • 21 Chen H L, Demiralp B, Schneider A et al. Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells.  J Biol Chem. 2002;  277 19 374-19 381
  • 22 Yoshimoto K, Yamasaki R, Sakai H et al. Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia.  J Clin Endocrinol Metabol. 1989;  68 976-981
  • 23 Nielsen P K, Rasmussen A K, Feldt-Rasmussen Um Brandt M et al. Ectopic production of intact parathyroid hormone by a squamous cell lung carcinoma in vivo and in vitro.  J Clin Endocrinol Metabol. 1996;  81 3793-3796
  • 24 Seymour J F, Gagel R F, Hagemeister F B et al. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma.  Ann Intern Med. 1992;  121 633-640
  • 25 Mawer E B, Hayes M E, Heys S E et al. Constitutive synthesis of 1,25-dihydroxyvitamin D3 by human small cell lung cancer cell line.  J Clin Endocrinol Metabol. 1994;  79 554-560
  • 26 Bertolini D R, Nedwin G E, Bringman T S et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumor necrosis factors.  Nature. 1986;  319 516-518
  • 27 Yates A J, Boyce B F, Favarato G et al. Expression of human transforming growth factor alpha by Chinese hamster ovarian tumors in nude mice causes hypercalcemia and increased osteoclastic bone resorption.  J Bone Min Res. 1992;  7 847-853
  • 28 Ibbotson K J, Twardzik D R, D’Souza S M et al. Stimulation of bone resorption in vitro by synthetic transforming growth factor-alpha.  Science. 1995;  228 1007-1009
  • 29 Bender R A, Hansen H. Hypercalcemia in bronchogenic carcinoma.  Ann Intern Med. 1974;  80 205-208
  • 30 Bethune J E, Turpin R A. A study of urinary excretion of parathyroid hormone in man.  J Clin Invest. 1968;  47 1583-1589
  • 31 Thomas L, Kwok Y, Edelman M J. Management of paraneoplastic syndromes in lung cancer.  Curr Opin Pulm Med. 2007;  13 362-367
  • 32 List A F, Hainsworth J D, Davis B W et al. The syndrome of inappropriate secretion of antidiuretic hormone (SIDAH) in small-cell lung cancer.  J Clin Oncol. 1986;  4 1191-1198
  • 33 Patel A M, Davila D G, Peters S G. Paraneoplastic syndromes associated with lung cancer.  Mayo Clin Proc. 1993;  68 278-287
  • 34 Maurer L H, O'Donnell J F, Kennedy S et al. Human neurophysins in carcinoma of the lung.  Cancer Treat Rep. 1994;  79 971-976
  • 35 Bliss Jr. D P, Battey J F, Linnoila R I et al. Expression of atrial natriuretic factor gene in small lung cancer tumors and tumor cell lines.  J Natl Cancer Inst. 1990;  82 305-310
  • 36 Moses A M, Scheinman S J. Ectopic secretion of neurophyseal peptides in patients with malignancy.  Endocrinol Metab Clin North Am. 1991;  20 489-506
  • 37 Hansen O, Sorensen P, Hansen K H. The occurence of hyponatremia in SCLC and the influence on prognosis: a retrospective study of 453 patients treated in a single institution in a 10-year period.  Lung Cancer. 2010;  68 111-114
  • 38 Vorherr H. Para-endocrine tumor activity with emphasis on ectopic ADH secretion.  Oncology. 1974;  29 382-416
  • 39 Nielsen S, Frokiaer J, Marples D et al. Aquaporins in the kidney: from molecule to medicine.  Physiol Rev. 2002;  82 205-244
  • 40 Jaenike J R, Waterhouse C. The renal response to sustained administration of vasopressin and water in man.  J Clin Endocrinol Metab. 1961;  21 231-242
  • 41 Hannon M J, Thompson C J. The syndrome of inappropriate antidiuretic hormone: prevalence, causes, and consequences.  Eur J Endocrinol. 2010;  162 S5-S12
  • 42 Schrier R W, Gross P, Gheorghiade M et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.  N Engl J Med. 2006;  355 2099-2112
  • 43 Mendelsohn G, Baylin S B. Ectopic hormone production: biological and clinical implications.  Prog Clin Biol Res. 1984;  142 291-316
  • 44 Hansen M. Paraneoplastic syndromes and tumor markers for small-cell and non-small-cell lung cancer.  Curr Opin Oncol. 1990;  2 345-351
  • 45 Mennecier B, Moreau L, Goichot B, Quoix E. Paraneoplastic Cushing’s syndrome and small cell bronchial carcinoma.  Rev Pneumol Clin. 1999;  55 77-80
  • 46 Shepherd F A, Laskey J, Evans W K et al. Cushing’s syndrome associated with ectopic corticotropin production and small-cell lung cancer.  J Clin Oncol. 1992;  10 21-27
  • 47 Terzolo M, Reimondo G, Ali A et al. Ectopic ACTH syndrome: molecular bases and clinical heterogeneity.  Ann Oncol. 2001;  12 (Suppl) S83-S87
  • 48 Odell W D, Wolfesen A R, Bachelot I, Hirose F M. Ectopic production of lipotropin by cancer.  Am J Med. 1979;  66 631-638
  • 49 Oliver R L, Davis J R, White A. Characterization of ACTH related peptides in ectopic Cushing's syndrome.  Pituitary. 2003;  6 119-126
  • 50 Stewart M F, Crosby S R, Gibson S et al. Small cell lung cancer cell lines secrete predominantly ACTH precursor peptides not ACTH.  Br J Cancer. 1989;  60 20-24
  • 51 White A, Stewart M F, Farrell W E et al. Proopiomelanocortin gene expression and peptide secretion in human small-cell lung cancer cell lines.  J Mol Endocrinol. 1989;  3 65-70
  • 52 Crosby S R, Stewart M F, Farrell W E et al. Comparison of ACTH and ACTH precursor peptides secreted by human pituitary and lung tumour cells in vitro.  J Endorcinol. 1990;  125 147-152
  • 53 Kosmidis P, Krzakowski M. Anemia profiles in patients with lung cancer: what have we learned from the European Cancer Anemia Survey (ECAS)?.  Lung Cancer. 2005;  50 401-412
  • 54 Glaspy J, Degos L, Dicato M, Demetri G D. Comparable efficacy of epoetin alfa for anemic cancer patients receiving platinum- and nonplatinum-based chemotherapy: A retrospective subanalysis of two large, community-based trials.  The Oncologist. 2002;  7 126-135
  • 55 Groopman J E, Itri L M. Chemotherapy-induced anemia in adults: incidence and treatment.  J Natl Cancer Inst. 1999;  91 1616-1634
  • 56 Bohlius J, Schmidlin K, Brillant C et al. Erythropoetin or darbepoetin for patients with cancer – meta-analysis based on individual patient data.  Cochrane Database Syst Rev. 2009;  3 CD007303
  • 57 Glaspy J, Crawford J, Vansteenkiste J et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes.  Br J Cancer. 2010;  102 301-315
  • 58 Goeckenjan G, Sitter H, Thomas M et al. Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Interdisziplinäre S3-Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Krebsgesellschaft.  Pneumologie. 2010;  64 (Suppl. 2) S23-S155
  • 59 Asano S, Urabe A, Okabe T et al. Demonstration of granulopoetic factors in the plasma of nude mice transplanted with a human lung cancer and in the tumor tissue.  Blood. 1977;  49 845-852
  • 60 Sawyers C L, Golde D W, Quan S, Nimer S D. Production of granulocyte-macrophage colony stimulating factor in two patients with lung cancer, leukocytosis and eosinophilia.  Cancer. 1992;  69 1342-1346
  • 61 Matsuguchi T, Okamura S, Kawasaki C et al. Constitutive production of granulocyte colony-stimulating factor and interleukin-6 by a human lung cancer cell line, KSNY: gene amplification and increased mRNA stability.  Eur J Haematol. 1991;  47 128-133
  • 62 Tesselaar M E, Osanto S. Risk of venous thromboembolism in lung cancer.  Curr Opin Pulm Med. 2007;  13 362-367
  • 63 Chew H K, Davies A M, Wun T et al. The incidence of venous thromboembolism among patients with lung cancer.  J Thromb Haemost. 2008;  6 601-608
  • 64 Girard P, Raynaud C, Meyer G et al. Thrombosis and lung cancer.  Rev Pneumol Clin. 2008;  64 85-91
  • 65 Molnar S, Guglielmone H, Lavarda M et al. Procoagulant factors in patients with cancer.  Hematology. 2007;  12 555-559
  • 66 Goldin-Lang P, Tran Q V, Fichtner I et al. Tissue factor expression pattern in human non-small cell lung cancer tissues indicates increased blood thrombogenicity and tumour metastasis.  Oncol Rep. 2008;  20 123-138
  • 67 Akl E A, Rohilla S, Barba M et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer.  Cochrane Database Syst Rev. 2008;  23 CD006649
  • 68 Akl E A, Kamath G, Kim S Y et al. Oral anticoagulation for prolonging survival in patients with cancer.  Cochrane Database Syst Rev. 2007;  18 CD006466
  • 69 Nalluri S R, Chu D, Keresztes R et al. Risk of venous thromboembolism with angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis.  JAMA. 2008;  300 2277-2285
  • 70 Hicks L K, Cheung M C, Ding K et al. Venous thromboembolism and nonsmall cell lung cancer: a pooled analysis of National Cancer Institute of Canada Clinical Group trials.  Cancer. 2009;  115 5516-5525
  • 71 Sridhar K S, Lobo C F, Altman R D. Digital clubbing and lung cancer.  Chest. 1998;  114 1535-1537
  • 72 Stenseth J H, Clagett O T, Woolner L B. Hypertrophic pulmonary osteoarthropathy.  Dis Chest. 1967;  52 62-68
  • 73 Prakash U. Hypertrophic pulmonary osteoarthropathy and clubbing.. In: Sackner M A, ed. Weekly updates: pulmonary medicine; lesson 30. Princeton, NJ: Biomedia; 1978: 2-7
  • 74 Myers K A, Farquhar D ER. Does this patient have clubbing?.  JAMA. 2001;  286 341-347
  • 75 Shneerson J M. Digital clubbing and hypertrophic osteoarthropathy.  Br J Dis Chest. 1981;  75 113-131
  • 76 Atkinson S, Fox S B. Vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing.  J Pathol. 2004;  203 721-728
  • 77 Olan F, Portela M, Navarro C et al. Circulating vascular endothelial growth factor concentrations in a case of pulmonary hypertrophic osteoarthropathy.  J Rheumatol. 2004;  31 614-616
  • 78 Silveira L H, Martínez-Lavín M, Pineda C et al. Vascular endothelial growth factor and hypertrophic osteoarthropathy.  Clin Exp Rheumatol. 2000;  18 57-62
  • 79 Pracht M, LeRoux C, Kerjouan M et al. Clubbing and hypertrophic osteoarthropathy in two patients taking long-term bevacizumab for metastatic colorectal cancer.  J Gastrointest Cancer. 2010;  [epub ahead of print May 28, 2010]
  • 80 Uppal S, Diggle C P, Carr I M et al. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy.  Nat Genet. 2008;  40 789-793
  • 81 Amital H, Applbaum Y H, Vasiliev L, Rubinow A. Hypertrophic pulmonary osteoarthropathy: control of pain and symptoms with pamidronate.  Clin Rheumatol. 2004;  23 330-332
  • 82 Hill C L, Zhang Y, Sigugeirsson B et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.  Lancet. 2001;  357 96-100
  • 83 Fujita J, Tokuda M, Bandoh S et al. Primary lung cancer associated with polymyositis/dermatomyositis, a review of the literature.  Rheumatol Int. 2001;  20 81-84
  • 84 Yang Y, Fujita J, Tokuda M et al. Lung cancer associated with several connective tissue diseases: a review of the literature.  Rheumatol Int. 2001;  21 106-113
  • 85 Casciola-Rosen L, Nagaraju K, Plotz P et al. Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy.  J Exp Med. 2005;  201 591-601
  • 86 Krathen M S, Fiorentino D, Werth V P. Dermatomyositis.  Curr Dis Autoimmun. 2008;  10 313-323
  • 87 Levine S M. Cancer and myositis: new insights into an old association.  Curr Opin Rheumatol. 2006;  18 620-624
  • 88 Iorizzi 3rd L J, Jorizzo J L. The treatment and prognosis of dermatomyositis: an updated review.  J Am Acad Dermatol. 2008;  59 99-112
  • 89 Mollina-Garrido M J, Guillen-Ponce C, Martinez S, Guirado-Risueno M. Diagnosis and current treatment of neurological paraneoplastic syndromes.  Clin Transl Oncol. 2006;  8 796-801
  • 90 Swash M, Schwartz M S. Paraneoplastic syndromes. In: Johnson R T, eds. Current therapy of neurologic disease.. Philadelphia, PA: BC Decker; 1990: 236-243
  • 91 Elrington G M, Murray N MF, Spiro S G, Newsom-Davis J. Neurological paraneoplastic syndromes in patients with small cell lung cancer: a prospective survey of 150 patients.  J Neurol Neurosurg Psychiatry. 1991;  54 764-767
  • 92 Seute T, Leffers P, ten Velde G PM, Twiynstra A. Neurologic disorders in 432 consecutive patients with small cell lung carcinoma.  Cancer. 2004;  100 801-806
  • 93 Martina T, Clay A S. A 50-year-old woman with bilateral vocal cord paralysis and hilar mass.  Chest. 2005;  128 1028-1031
  • 94 Anderson N E, Rosenblum M K, Graus F et al. Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer.  Neurology. 1988;  38 1391-1398
  • 95 Szabo A, Dalmau J, Manley G et al. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elva and sex-lethal.  Cell. 1991;  67 325-333
  • 96 King P H, Dropcho E J. Expression of Hel-N1 and Hel-N2 in small-cell lung carcinoma.  Ann Neurol. 1996;  39 679-681
  • 97 Darnell R B, Posner J B. Paraneoplastic syndromes involving the nervous system.  N Engl J Med. 2003;  349 543-1554
  • 98 Sillevis Smitt P A, Manley G T, Posner J B. Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice.  Neurology. 1995;  45 1873-1878
  • 99 Carpentier A F, Rosenfeld M R, Delattre J Y et al. DNA vaccination with HuD inhibits growth of neuroblastoma in mice.  Clin Cancer Res. 1998;  4 2819-2824
  • 100 Posner J B, Dalmau J. Paraneoplastic syndromes.  Curr Opin Immunol. 1997;  9 723-729
  • 101 Molinuevo J L, Graus F, Serrano C et al. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy.  Ann Neurol. 1998;  44 976-980
  • 102 Dalmau J, Graus F, Rosenblum M K et al. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuropathy.  Medicine. 1992;  71 9-72
  • 103 Graus F, Keine-Gribert F, Rene R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.  Brain. 2001;  124 1138-1148
  • 104 Spiegelman D, Maurer L H, Ware J H et al. Prognostic factors in small-cell carcinoma of the lung: an analysis of 1521 patients.  J Clin Oncol. 1989;  7 344-354
  • 105 Anderson N E, Budde-Steffen C, Rosenblum M K et al. Opsoclonus, myoclonus, ataxia, and encephalopathy in a adults with cancer: a distinct paraneoplastic syndrome.  Medicine (Baltimore). 1988;  67 100-109
  • 106 Bataller L, Graus F, Saiz A, Vilchez J J. and for the Spanish Opsoclonus-Myoclonus Study Group . Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus.  Brain. 2001;  124 437-443
  • 107 Margery J, Ferroir J P, Epaud C et al. Paraneoplastic opsoclonus-myoclonus syndrome associated with small-cell lung cancer.  Rev Pneumol Clin. 2003;  59 321-324
  • 108 Hassan K A, Kalemkerian G P, Trobe J D. Long-term survival in paraneoplastic opsoclonus-myoclonus syndrome associated with small cell lung cancer.  J Neuroophthalmol. 2008;  28 27-30
  • 109 Lennon V A, Kryzer T J, Greismann G E et al. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes.  New Engl J Med. 1995;  332 1467-1474
  • 110 Mareska M, Gutmann L. Lambert-Eaton myasthenic syndrome.  Semin Neurol. 2004;  24 149-153
  • 111 Maddison P, Lang B. Paraneoplastic neurological autoimmunity and survival in small-cell lung cancer.  J Neuroimmunol. 2008;  201 159-162
  • 112 Henson R A, Ulrich H. Encephalomyelitis with carcinoma.. In: Henson R A, Ulrich H, eds. Cancer and the nervous system. Oxford: Blackwell Scientific; 1982: 314-345
  • 113 Graus F, Cordon-Cardo C, Posner J B. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer.  Neurology. 1985;  35 538-543
  • 114 Graus F, Elkon K B, Cordon-Cardo C, Posner J B. Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor.  Am J Med. 1986;  80 45-52
  • 115 Clamno G H, Evans W K, Shepherd F A et al. Myasthenic syndrome and small cell cancer of the lung.  Arch Intern Med. 1984;  144 999-1000
  • 116 Dropcho E J. Autoimmune central nervous system paraneoplastic disorders.  Ann Neurol. 1995;  37 S102-S113
  • 117 Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome.  Cochrane Database Syst Rev. 2005;  18 CD003279
  • 118 Quartel A, Turbeville S, Lounsbury D. Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment.  Curr Med Res Opin. 2010;  26 1363-1375
  • 119 Keime-Guibert F, Graus F, Fleury A et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone.  J Neurol Neurosurg Psychiatry. 2000;  68 479-482
  • 120 Rosenfeld M R, Dalmau J. Current therapies for paraneoplastic neurologic syndromes.  Curr Treat Options Neurol. 2003;  5 69-77
  • 121 Vernino S, O'Neill B P, Marks R S et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders.  Neuro Oncol. 2004;  5 55-62
  • 122 Higgins S P, Freemark M, Prose N S. Akanthosis nigricans: a practical approach to evaluation and management.  Dermatol Online J. 2008;  14 2
  • 123 Horiuchi Y, Katsuoka K, Yoshimura H et al. Acanthosis nigricans and Leser-Trelat sign associated with squamous cell carcinoma and adenocarcinoma of the lung.  Int J Dermatol. 1986;  25 459-460
  • 124 Menzies D G, Choo-Kang J, Bruxton P K, Campbell I W. Acanthosis nigricans associated with alveolar cell carcinoma.  Thorax. 1988;  43 414-415
  • 125 Onai T, Mori M, Akuzawa M et al. A case of lung carcinoma associated with acanthosis nigricans and increased titer of anti-nuclear antibody.  Nippon Naika Gakkai Zhasshi. 1989;  78 1607-1608
  • 126 Krwaczyk M, Mykala-Ciesla J, Kolodziej-Jaskula A. Acanthosis nigricans as a paraneoplastic syndrome.  Pol Arch Med Wewn. 2009;  119 180-183
  • 127 Lenzner U, Ramsauer J, Petzoldt W et al. Acanthosis nigricans maligna.  Hautarzt. 1998;  49 41-47
  • 128 Schwindt W D, Bernhardt L C, Johnson S AM. Tylosis and intrathoracic neoplasms.  Chest. 1970;  57 590-591
  • 129 Nomori H, Horio H, Iga R et al. Squamous cell carcinoma of the lung associated with palmo-plantar hyperkeratosis.  Niho Kyobu Shikkan Gakkai Zasshi. 1996;  34 76-79
  • 130 Engin H, Akdogan A, Altundaq O et al. Non-small-cell lung cancer with nonfamilial diffuse palmoplantar keratoderma.  J Exp Clin Cancer Res. 2002;  21 45-47
  • 131 Burgdorf W HC, Goltz R W. Figurate erythemas.. In: Fitzpatrick T B, Eisen A Z, Wolff K, et al., eds. Dermatology in Internal Medicine.. New York: McGraw-Hill; 1987: 1010-1018
  • 132 Bazex A, Griffiths A. Acrokeratosis Paraneoplastica: a new cutaneous marker of malignancy.  Br J Dermatol. 1980;  103 301-306
  • 133 Pecora A L, Landsman L, Imgrund S P et al. Acrokeratosis Paraneoplastica (Bazex' Syndrome): Report of a case and Review of the Literature.  Arch Dematol. 1983;  119 820-826
  • 134 Sharma V, Sharma N L, Ranjan N. Acrokeratitis paraneoplastica (Bazex syndrome): Case report and review of the literature.  Dermatol Online J. 2006;  12 11
  • 135 Lelbach A, Muzes G, Feher J. Current perspectives of catabolic mediators of cancer cachexia.  Med Sci Monit. 2006;  13 168-173
  • 136 Dworzak F, Ferrari P, Gavazzi C et al. Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover.  Cancer. 1998;  82 42-48
  • 137 Giordano A, Calvani M, Petillo O et al. Skeletal muscle metabolism in physiology and in cancer disease.  J Cell Biochem. 2003;  90 170-186
  • 138 Harvie M N, Campbell I T, Thatcher N, Baildam A. Changes in body composition in men and women with advanced nonsmall cell lung cancer (NSCLC) undergoing chemotherapy.  J Hum Nutr Diet. 2003;  16 323-326
  • 139 Argiles J M, Moore-Carrasco R, Fuster G et al. Cancer cachexia: the molecular mechanism.  Int J Biochem Cell Biol. 2003;  35 405-409
  • 140 Argiles J M, Moore-Carrasco R, Busquets S, Lopez-Soriano F J. Catabolic mediators as targets for cancer cachexia.  Drug Discov Today. 2008;  8 838-844
  • 141 Lelbach A, Munez G, Feher J. Molecular mechanisms of cancer cachexia.  Orv Hetil. 2004;  46 2329-2334
  • 142 Brink M, Anwar D, Delafontaine P. Neurohormonal factors in the development of catabolic/anabolic imbalance and cachexia.  Int J Cardiol. 2002;  85 111-121
  • 143 Laviano A, Russo M, Freda F et al. Neurochemical mechanisms for cancer anorexia.  Nutrition. 2002;  18 100-105
  • 144 Schaur R J, Fellier H, Gleispach H et al. Tumor host relations I. Increased plasma cortisol in tumor-bearing humans compared with patients with benign surgical diseases.  J Cancer Res Clin Oncol. 1979;  93 281-285
  • 145 Knapp M L, al-Sheibani S, Riches P G et al. Hormonal factors associated with weight loss in patients with advanced breast cancer.  Ann Clin Biochem. 1991;  28 480-486
  • 146 Cariuk P, Lorite M J, Todorov P T et al. Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients.  Br J Cancer. 1997;  76 606-613
  • 147 Hiraki K, Ishiko O, Tisdale M. Mechanisms of depletion of liver glycogen in cancer cachexia.  Biochem Biosphys Res Commun. 1997;  241 49-52
  • 148 Cella D, Davis K, Breitbart W, Curt G, Fatigue C oalition. Cancer-related fatigue: Prevalence of proposed diagnostic criteria in a United States sample of cancer survivors.  J Clin Oncol. 2001;  19 3385-3391
  • 149 Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults.  Lancet. 2003;  362 640-6509
  • 150 Chaudhuri A, Behan P O. Fatigue in neurological disorders.  Lancet. 2004;  363 978-988
  • 151 Ronnback L, Hansson E. On the potential of glutamate transport in mental fatigue.  J Neuroinflammation. 2004;  1 22
  • 152 Ryan J L, Carroll J K, Ryan E P et al. Mechanisms of cancer-related fatigue.  Oncologist. 2007;  12 (Suppl. 1) 22-34
  • 153 Castell L M, Yamamoto T, Phoenix J, Newsholme E A. The role of tryptophan in fatigue and different conditions of stress.  Adv Exp Med Biol. 1999;  467 697-704
  • 154 Badawy A A, Morgan C J, Llewelyn M B et al. Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome.  J Psychopharmacol. 2005;  19 385-391
  • 155 Andrews P LR, Morrow G R, Hickok J T. Mechanisms and models of fatigue associated with cancer and its treatment: Evidence of pre-clinical and clinical studies. In: Armes J, Krishnasamy M, Higginson I, eds. Fatigue in Cancer. Oxford: Oxford University Press; 1988: 51-87
  • 156 Cleare A J. The neuroendocrinology of chronic fatigue syndrome.  Endocr Rev. 2003;  24 236-252
  • 157 Focan C, Focan-Henrard D, Collette J et al. Cancer-associated alteration of circadian rhythms in carcinoembryonic antigen (CEA) and alpha-feto-protein (AFP) in humans.  Anticancer Res. 1986;  6 1137-1144
  • 158 Mormont M C, Levi F. Circadian-system alterations during cancer processes: A review.  Int J Cancer. 1997;  70 241-247
  • 159 Vgontzas A N, Chrousos G P. Sleep, the hypothalamic-pituitary-adrenal axis, and cytokines: Multiple interactions and disturbances in sleep disorders.  Endocrinol Metab Clin North Am. 2002;  31 15-36
  • 160 Sephton S, Spiegel D. Circadian disruption in cancer: A neuroendocrine-immune pathway from stress to disease?.  Brain Behav Immun. 2003;  17 321-328
  • 161 Levin R D, Daehler M A, Grutsch J F et al. Circadian function in patients with advanced non-small-cell lung cancer.  Br J Cancer. 2005;  93 1202-1208
  • 162 McCully K K, Natelson B H, Iotti S et al. Reduced oxidative muscle metabolism in chronic fatigue syndrome.  Muscle Nerve. 1996;  19 554-560
  • 163 Lane R J, Barrett M C, Taylor D J et al. Heterogeneity in chronic fatigue syndrome: Evidence from magnetic resonance spectroscopy of muscle.  Neuromuscul Disord. 1998;  8 204-209
  • 164 Forsyth L M, Preuss H G, MacDowell A L et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome.  Ann Allergy Asthma Immunol. 1999;  82 185-191
  • 165 Konsman J P, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: Mechanisms and implications.  Trends Neurosci. 2002;  25 154-159

PD Dr. med. Hans-Peter Hauber

Medizinische Klinik
Forschungszentrum Borstel

Parkallee 35
23845 Borstel

Email: hphauber@fz-borstel.de

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