Top

Published in:

Open Access 01-09-2012 | Review and Perspectives

EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations

Authors: Erik Thunnissen, Lukas Bubendorf, Manfred Dietel, Göran Elmberger, Keith Kerr, Fernando Lopez-Rios, Holger Moch, Wlodzimierz Olszewski, Patrick Pauwels, Frédérique Penault-Llorca, Giulio Rossi

Published in: Virchows Archiv | Issue 3/2012

Abstract

In non-small cell lung cancer, epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have a major impact upon the level of response to treatment with specific tyrosine kinase inhibitors. This review describes the molecular basis of ALK inhibition, summarizes current data on the effectiveness and safety of ALK inhibition therapy, describes the different testing methodologies with their advantages and disadvantages, provides a suggested testing algorithm and puts forward a proposal for an external quality assessment program in ALK testing.

Available only for authorised users

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRef

Berghmans T, Pasleau F, Paesmans M, Bonduelle Y, Cadranel J, Cs Toth I, Garcia C, Giner V, Holbrechts S, Lafitte JJ, Lecomte J, Louviaux I, Markiewicz E, Meert AP, Richez M, Roelandts M, Scherpereel A, Tulippe C, Van Houtte P, Van Schil P, Wachters C, Westeel V, Sculier JP (2012) Surrogate markers predicting overall survival for lung cancer: ELCWP recommendations. Eur Respir J 39:9–28PubMedCrossRef

Gaughan EM, Costa DB (2011) Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities. Ther Adv Med Oncol 3:113–125PubMedCrossRef

Hamburg MA, Collins FS (2010) The path to personalized medicine. N Engl J Med 363:301–304PubMedCrossRef

Horn L, Pao W (2009) EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27:4232–4235PubMedCrossRef

Janku F, Garrido-Laguna I, Petruzelka LB, Stewart DJ, Kurzrock R (2011) Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 6:1601–1612PubMedCrossRef

Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381PubMedCrossRef

Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, Sakamoto H, Tsuta K, Furuta K, Shimada Y, Iwakawa R, Ogiwara H, Oike T, Enari M, Schetter AJ, Okayama H, Haugen A, Skaug V, Chiku S, Yamanaka I, Arai Y, Watanabe SI, Sekine I, Ogawa S, Harris CC, Tsuda H, Yoshida T, Yokota J, Shibata T (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375–377PubMedCrossRef

Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, Kim YT, Kim JI, Kang JH, Seo JS (2012) A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 22:436–445PubMedCrossRef

10.

Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566PubMedCrossRef

11.

Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007) Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 6:3314–3322PubMedCrossRef

12.

Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (2007) An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408–4417PubMedCrossRef

13.

Camidge DR, Bang BR, Kwak EL, Shaw A, lafrate AJ, Maki RG, Solomon J, Ou SI, Salgia R, Wilner K, Costa DB, Shapiro GI, LoRusso P, Stephenson P, Tang Y, Ruffner K, Clark JW (2011) Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 29:suppl. abstr. 2501

14.

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703PubMedCrossRef

15.

Crino L, Kim D, Riely G, Janne PA, Blackhall DR, Camidge V, Hirsch V, Mok T, Solomon B, Park K, Gadgeel M, Martins R, Han J, De Pas TM, Bottomley A, Polli A, Petersen J, Tassell VR, Shaw A (2011) Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 29:suppl. abstract 7514

16.

Food and Drug Administration (2011) Summary review (application number: 202570Orig1s000). Food and Drug Administration, Silver Spring

17.

Lamant L, Meggetto F, al Saati T, Brugieres L, de Paillerets BB, Dastugue N, Bernheim A, Rubie H, Terrier-Lacombe MJ, Robert A, Rigal F, Schlaifer D, Shiuta M, Mori S, Delsol G (1996) High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. Blood 87:284–291PubMed

18.

Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 263:1281–1284PubMedCrossRef

19.

Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, Delsol G, Morris SW (2004) The emerging normal and disease-related roles of anaplastic lymphoma kinase. Cell Mol Life Sci 61:2939–2953PubMedCrossRef

20.

Sasaki T, Rodig SJ, Chirieac LR, Janne PA (2010) The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 46:1773–1780PubMedCrossRef

21.

Camidge DR, Theodoro M, Maxson DA, Skokan M, O'Brien T, Lu X, Doebele RC, Baron AE, Varella-Garcia M (2012) Correlations between the percentage of tumor cells showing an ALK (anaplastic lymphoma kinase) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer. Cancer. doi:10.1002/cncr.27411

22.

Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H (2008) Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 14:6618–6624PubMedCrossRef

23.

Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, Takada S, Ueno T, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15:3143–3149PubMedCrossRef

24.

Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, Stubbs H, Law K, Lindeman N, Mark E, Janne PA, Lynch T, Johnson BE, Iafrate AJ, Chirieac LR (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15:5216–5223PubMedCrossRef

25.

Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247–4253PubMedCrossRef

26.

Varella Garcia ea (2011) ALK diagnostics (session MTE36.1)14th World Conference on Lung Cancer, Amsterdam

27.

Kim H, Yoo SB, Choe JY, Paik JH, Xu X, Nitta H, Zhang W, Grogan TM, Lee CT, Jheon S, Chung JH (2011) Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol 6:1359–1366PubMedCrossRef

28.

Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, Sekine I, Fukayama M, Shibata T, Furuta K, Tsuda H (2011) Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol 35:1226–1234PubMedCrossRef

29.

Popat S, Gonzalez D, Min T, Swansbury J, Dainton M, Croud JG, Rice AJ, Nicholson AG (2012) ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma. Lung Cancer 75:300–305PubMedCrossRef

30.

Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M, Choi YL, Niki T, Mano H, Ishikawa Y (2008) EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 3:13–17PubMedCrossRef

31.

Sakairi Y, Nakajima T, Yasufuku K, Ikebe D, Kageyama H, Soda M, Takeuchi K, Itami M, Iizasa T, Yoshino I, Mano H, Kimura H (2010) EML4-ALK fusion gene assessment using metastatic lymph node samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration. Clin Cancer Res 16:4938–4945PubMedCrossRef

32.

Shaw A, Yeap B, Solomon B, Riely G, lafrate AJ, Shapiro GI, Costa DB, Butaney M, Ou S, Maki RG, Bang YJ, Varella-Garcia M, Salgia R, Wilner KD, Kulig K, Selaru P, Tang Y, Kwak EL, Clark JW, Camidge DR (2011) Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. J Clin Oncol 29:abstract 7507

33.

Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, Wilner KD (2011) CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol 29:e443–e445PubMedCrossRef

34.

Scagliotti G, Stahel RA, Rosell R, Thatcher N, Soria JC (2012) ALK translocation and crizotinib in non-small cell lung cancer: an evolving paradigm in oncology drug development. Eur J Cancer 48:961–973PubMedCrossRef

35.

Doebele RC, Pilling AB, Aisner D, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482PubMedCrossRef

36.

Kerr KM (2012) Personalized medicine for lung cancer: new challenges for pathology. Histopathology 60:531–546PubMedCrossRef

37.

Thunnissen E, Kerr KM, Herth FJ, Lantuejoul S, Papotti M, Rintoul RC, Rossi G, Skov BG, Weynand B, Bubendorf L, Katrien G, Johansson L, Lopez-Rios F, Ninane V, Olszewski W, Popper H, Jaume S, Schnabel P, Thiberville L, Laenger F (2012) The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 76:1–18PubMedCrossRef

38.

Atkins D, Reiffen KA, Tegtmeier CL, Winther H, Bonato MS, Storkel S (2004) Immunohistochemical detection of EGFR in paraffin-embedded tumor tissues: variation in staining intensity due to choice of fixative and storage time of tissue sections. J Histochem Cytochem 52:893–901PubMedCrossRef

39.

DiVito KA, Charette LA, Rimm DL, Camp RL (2004) Long-term preservation of antigenicity on tissue microarrays. Lab Invest 84:1071–1078PubMedCrossRef

40.

Oyama T, Ishikawa Y, Hayashi M, Arihiro K, Horiguchi J (2007) The effects of fixation, processing and evaluation criteria on immunohistochemical detection of hormone receptors in breast cancer. Breast Cancer 14:182–188PubMedCrossRef

41.

Prinsen CF, Klaassen CH, Thunnissen FB (2003) Microarray as a model for quantitative visualization chemistry. Appl Immunohistochem Mol Morphol 11:168–173PubMedCrossRef

42.

Werner M, Chott A, Fabiano A, Battifora H (2000) Effect of formalin tissue fixation and processing on immunohistochemistry. Am J Surg Pathol 24:1016–1019PubMedCrossRef

43.

Yang P, Kulig K, Boland JM, Erickson-Johnson MR, Oliveira AM, Wampfler J, Jatoi A, Deschamps C, Marks R, Fortner C, Stoddard S, Nichols F, Molina J, Aubry MC, Tang H, Yi ES (2012) Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol 7:90–97PubMedCrossRef

44.

Boland JM, Erdogan S, Vasmatzis G, Yang P, Tillmans LS, Johnson MR, Wang X, Peterson LM, Halling KC, Oliveira AM, Aubry MC, Yi ES (2009) Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 40:1152–1158PubMedCrossRef

45.

Hofman P, Ilie M, Hofman V, Roux S, Valent A, Bernheim A, Alifano M, Leroy-Ladurie F, Vaylet F, Rouquette I, Validire P, Beau-Faller M, Lacroix L, Soria JC, Fouret P (2011) Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma. Ann Oncol. doi:10.1093/annonc/mds137

46.

Yi ES, Boland JM, Maleszewski JJ, Roden AC, Oliveira AM, Aubry MC, Erickson-Johnson MR, Caron BL, Li Y, Tang H, Stoddard S, Wampfler J, Kulig K, Yang P (2011) Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 6:459–465PubMedCrossRef

47.

Paik JH, Choe G, Kim H, Choe JY, Lee HJ, Lee CT, Lee JS, Jheon S, Chung JH (2011) Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. J Thorac Oncol 6:466–472PubMedCrossRef

48.

McLeer-Florin A, Moro-Sibilot D, Melis A, Salameire D, Lefebvre C, Ceccaldi F, de Fraipont F, Brambilla E, Lantuejoul S (2012) Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. J Thorac Oncol 7:348–354PubMedCrossRef

49.

Mino-Kenudson M, Chirieac LR, Law K, Hornick JL, Lindeman N, Mark EJ, Cohen DW, Johnson BE, Janne PA, Iafrate AJ, Rodig SJ (2010) A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561–1571PubMedCrossRef

50.

Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, Chenard MP, Penault-Llorca F, Nagelmeier I, Schlake W, Hofler H, Kreipe HH (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 457:299–307PubMedCrossRef

51.

Bartlett AI, Starcyznski J, Robson T, Maclellan A, Campbell FM, van de Velde CJ, Hasenburg A, Markopoulos C, Seynaeve C, Rea D, Bartlett JM (2011) Heterogeneous HER2 gene amplification: impact on patient outcome and a clinically relevant definition. Am J Clin Pathol 136:266–274PubMedCrossRef

52.

Savic S, Glatz K, Schoenegg R, Spieler P, Feichter G, Tamm M, Bubendorf L (2006) Multitarget fluorescence in situ hybridization elucidates equivocal lung cytology. Chest 129:1629–1635PubMedCrossRef

53.

Bartlett JM, Starczynski J, Atkey N, Kay E, O'Grady A, Gandy M, Ibrahim M, Jasani B, Ellis IO, Pinder SE, Walker RA (2011) HER2 testing in the UK: recommendations for breast and gastric in-situ hybridisation methods. J Clin Pathol 64:649–653PubMedCrossRef

54.

Camidge DR, Kono SA, Flacco A, Tan AC, Doebele RC, Zhou Q, Crino L, Franklin WA, Varella-Garcia M (2010) Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res 16:5581–5590PubMedCrossRef

55.

Just PA, Cazes A, Audebourg A, Cessot A, Pallier K, Danel C, Vacher-Lavenu MC, Laurent-Puig P, Terris B, Blons H (2011) Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of Caucasian non-smokers. Lung Cancer 76(3):309–315PubMedCrossRef

56.

Salido M, Pijuan L, Martinez-Aviles L, Galvan AB, Canadas I, Rovira A, Zanui M, Martinez A, Longaron R, Sole F, Serrano S, Bellosillo B, Wynes MW, Albanell J, Hirsch FR, Arriola E (2011) Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer. J Thorac Oncol 6:21–27PubMedCrossRef

57.

Yang P (2011) Anaplastic lymphoma kinase (ALK) status and clinical outcomes by IHC and FISH: a reterospective study of never-smoker, adenocarcinoma lung cancer cases. Lung Cancer 71:S26–S28CrossRef

58.

Jokoji R, Yamasaki T, Minami S, Komuta K, Sakamaki Y, Takeuchi K, Tsujimoto M (2010) Combination of morphological feature analysis and immunohistochemistry is useful for screening of EML4-ALK-positive lung adenocarcinoma. J Clin Pathol 63:1066–1070PubMedCrossRef

59.

Yoshida A, Tsuta K, Nitta H, Hatanaka Y, Asamura H, Sekine I, Grogan TM, Fukayama M, Shibata T, Furuta K, Kohno T, Tsuda H (2011) Bright-field dual-color chromogenic in situ hybridization for diagnosing echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-positive lung adenocarcinomas. J Thorac Oncol 6:1677–1686PubMedCrossRef

60.

Li C, Fang R, Sun Y, Han X, Li F, Gao B, Iafrate AJ, Liu XY, Pao W, Chen H, Ji H (2011) Spectrum of oncogenic driver mutations in lung adenocarcinomas from East asian never smokers. PLoS One 6:e28204PubMedCrossRef

61.

Garrido P, de Castro J, Concha A, Felip E, Isla D, Lopez-Rios F, Paz-Ares L, Ramirez J, Sanz J, Gomez JJ (2012) Guidelines for biomarker testing in advanced non-small-cell lung cancer. A national consensus of the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol 14:338–349PubMedCrossRef

62.

National Comprehensive Cancer Network (2011) NCCN Flash Update: NCCN Guidelines Updated. National Comprehensive Cancer Network, Fort Washington

63.

Rothschild S, Zippelius A, Betticher DC, Bubendorf L, Gugger M, Savic S, Soltermann A, Letovanec I, Diebold J, Henzi M-T, Brutsche M, Pless M, Gautschi O (2011) Neue Therapiekonzepte beim Bronchuskarzinom. Schweiz Med Forum 11:7

64.

Mitsudomi T, Tomizawa K, Horio Y, Hida T, Yatabe Y (2011) Comparison of high sensitive IHC, FISH, and RT-PCR direct sequencing for detection of ALK translocation in lung cancer. J Clin Oncol 29:abstract 7534

65.

Martinez P, Hernandez-Losa J, Castellvi J, Tallada N, Cedres S, Montero MA, Rodriguez-Freixinos V, Nuñez I, Argiles G, Mulet-Margalef N, Torrejon D, Ramon y Cajal S, Felip E (2011) ALK rearrangement in a selected population of advanced non-small cell lung cancer patients: FISH and inmunohistochemistry diagnostic methods, prevalence, and clinical outcomes. J Clin Oncol 29:abstr 7566

66.

Paik JH, Choi CM, Kim H, Jang SJ, Choe G, Kim DK, Kim HJ, Yoon H, Lee CT, Jheon S, Choe JY, Chung JH (2011) Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 76(3):403–409PubMedCrossRef

Title: EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations
Authors: Erik Thunnissen
Lukas Bubendorf
Manfred Dietel
Göran Elmberger
Keith Kerr
Fernando Lopez-Rios
Holger Moch
Wlodzimierz Olszewski
Patrick Pauwels
Frédérique Penault-Llorca
Giulio Rossi
Publication date: 01-09-2012
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 3/2012
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-012-1281-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2012

Gliomatosis peritonei is associated with frequent recurrence, but does not affect overall survival in patients with ovarian immature teratoma

BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression

Clear cell sarcoma expressing a novel chimerical transcript EWSR1 exon 7/ATF1 exon 6

Thyroid-like follicular carcinoma of the kidney: report of two cases with detailed immunohistochemical profile and literature review

Erratum to: FGFR1 expression and gene copy numbers in human lung cancer

Erratum to: Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study