Regression of cutaneous squamous cell carcinoma in a patient with chronic myeloid leukaemia on imatinib mesylate treatment.
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ABSTRACT: Hydroxyurea is an antimetabolite agent used in the treatment of myeloproliferative disorders and sickle cell anaemia. Although hydroxyurea is relatively well tolerated, adverse effects often involve skin and mucous membrane during long-term therapy. A group of 510 patients affected by chronic myeloid leukaemia from 1977 to 1998 has been considered. Only 158 patients were treated with hydroxyurea and fulfilled inclusion/exclusion criteria of this study. A spectrum of severe cutaneous and mucosal changes (inflammatory and neoplastic) was seen in about 13% of patients (21 patients out of 158) and was studied in detail. Cutaneous and mucosal atrophy were observed in all 21 patients. Skin atrophy was often characterized by numerous telangiectases, especially on legs and on sun-exposed sites (16/21). Cutaneous, mucosal and nail hyperpigmentation was evident, albeit with variable extent, in 10 of the 21 patients. Severe stomatitis and glossitis with flattening of papillae were another common finding. Five patients, who received a particularly long treatment with hydroxyurea, developed squamous-cell neoplasms on sun-exposed sites (both squamous-cell carcinomas and keratoacanthomas). Acral changes were characteristic and constant, including acral erythema (21/21), dermatomyositis-like changes on the dorsa of hands (7/21), ulcers localized on acral areas of legs, on genitalia and oral mucosae (20/21). The frequency and the variety of these muco-cutaneous changes are reported and the mechanisms by which hydroxyurea may induce this muco-cutaneous syndrome-like group of changes, are proposed.Clinical and Experimental Dermatology 04/2001; 26(2):141-8. · 1.33 Impact Factor
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ABSTRACT: STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases. One of these enzymes, the Bcr-Abl oncoprotein, results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome. The Philadelphia chromosome occurs in 95% of people with chronic myeloid leukemia. ABL is the cellular homologue of the oncogene found in murine Abelson leukemia virus, and BCR refers to breakpoint cluster region. The Bcr-Abl oncoprotein exhibits elevated protein-tyrosine kinase activity, which is strongly implicated in the mechanism of development of chronic myeloid leukemia. STI-571 is effective in the treatment of the stable phase of chronic myeloid leukemia. The c-Abl protein kinase domain exists in an active and inactive conformation. STI-571 binds only to the inactive state of the enzyme as shown by X-ray crystallography. The drug binds to a portion of the ATP-binding site and extends from there into adjacent hydrophobic regions. STI-571 is a competitive inhibitor of Abl kinase with respect to ATP. Resistance to STI-571 is often the result of mutations in residues of the Bcr-Abl kinase that ordinarily bind to the drug. Inhibition of target protein kinases represents an emerging therapeutic strategy for the treatment of cancer.Biochemical and Biophysical Research Communications 11/2003; 309(4):709-17. · 2.41 Impact Factor
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ABSTRACT: There is remarkable recent progress in our understanding of the biology of chronic myelogenous leukemia (CML). First, the BCR/ABL rearrangement was identified as the molecular basis of the disease. Second, animal models support the notion that the BCR/ABL gene product causes a syndrome similar to CML. Third, recent advances in understanding the functions of the normal ABL protein have given clues to the mechanism(s) of ABL-induced leukemias and approaches to blocking this process. Extrapolating these findings to humans seems reasonable. The challenge now is to determine how the BCR/ABL gene product causes chronic phase CML. Also unresolved is whether BCR/ABL also plays a role in the acute phase of the disease. Finally, the relationship between the two common forms of BCR/ABL, the P190 and P210 configurations, and different disease phenotypes, like CML and Philadelphia (Ph1)-chromosome positive acute lymphoblastic leukemia (ALL), needs to be clarified. There is also substantial progress in treating CML. Bone marrow transplants have emerged as the preferred therapy. These result in long-term leukemia-free survival in more than one-half of appropriately selected subjects. How transplants cure CML is complex and controversial. Some data suggest high-dose treatment is the dominant factor whereas other data implicate antileukemia effects of the immune system. Interferon treatment has also proven effective in CML. Whether it prolongs survival of persons with CML remains to be determined, as does its mechanism of action. Certainly the most important and difficult challenge in CML therapy is determining how to use knowledge about the causes CML to treat the disease. These and other issues in the biology and therapy of CML were the subject of a recent meeting of basic and clinical scientists. The meeting, third in a series begun in 1987, was held on Martha's Vineyard, Cape Cod, Massachusetts, USA from 4-7 April, 1992. Four major topics were considered in five sessions: molecular biology, cell biology, Ph1-chromosome positive ALL, and therapy of CML. This report summarizes meeting highlights.Leukemia 05/1993; 7(4):653-8. · 10.16 Impact Factor
© 2008 Acta Dermato-Venereologica. ISSN 0001-5555
Acta Derm Venereol 88
Letters to the Editor
Cutaneous squamous cell carcinoma (SCC) is a common
malignant neoplasm derived from suprabasal epidermal
keratinocytes. Treatment modalities for SCC include con-
ventional surgical excision, Mohs micrographic surgery,
radiation, and non-excisional ablative techniques. For
aggressive lesions refractory to conventional treatments,
chemotherapy has been performed (1), although it is often
discontinued due to adverse side-effects. We report here
a case of chronic myeloid leukaemia (CML) complicated
by SCC of the face. Unexpectedly, there was a significant
regression of SCC during the treatment of CML with the
tyrosine kinase inhibitor imatinib mesylate (Gleevec®,
Novartis, Tokyo, Japan).
An 84-year-old Japanese man presented in September
2006 with a skin lesion on his left cheek. The lesion had
appeared 3 years earlier and had gradually increased
in size. He had been diagnosed with Philadelphia (Ph)
chromosome-positive CML in January 1995. Initial
treatment comprised interferon-alpha and hydroxyurea,
followed by hydroxyurea alone. Due to intolerance,
hydroxyurea treatment was discontinued 11 years later.
In August 2006, he was started on imatinib mesylate
treatment, 400 mg daily.
Clinical examination demonstrated an ill-defined
ulcerated plaque, measuring 20×25 mm (Fig. 1a). Skin
biopsy showed irregular masses of squamoid cells pro-
liferating downward into the dermis. The invading cells
were composed of variable degrees of atypical cells with
mitosis and showed keratinization (Fig. 1b). Immunohi-
stochemically, the tumour was positive for cytokeratin
(CK), but negative for c-kit (CD117). Ziehl-Neelsen
staining for Mycobacterium, and periodic acid-Schiff
and Grocott-Gomori methenamine-silver nitrate stains
for fungi were all negative. Computed tomography
(CT) did not reveal any signs of lymphadenopathy or
Because a laboratory blood test demonstrated thrombo-
cytopaenia associated with CML, surgical excision of
SCC was postponed while waiting for recovery from
thrombocytopaenia. Meanwhile, there was a gradual
regression of SCC, and after 4 months of imatinib
therapy, the skin lesion had flattened significantly (Fig.
2a) and the biopsy specimen taken from the centre of
the pre-existing lesion showed normal epidermis with
no tumour cells (Fig. 2b). Since December 2006, the
patient has been receiving 200 mg of imatinib daily.
There has been no recurrence of the skin lesion for
4 months after the last skin biopsy.
In our case, the skin lesion appeared 11 years after
treatment with hydroxyurea. As occurrence of SCCs
has been reported on sun-exposed sites in patients with
Regression of Cutaneous Squamous Cell Carcinoma in a Patient with Chronic Myeloid Leukaemia
on Imatinib Mesylate Treatment
Yoshio Kawakami1, Koichiro Nakamura2, Akiko Nishibu1, Hirokatsu Yanagihori1, Hideo Kimura3 and Toshiyuki Yamamoto1
Department of Dermatology, 1Fukushima Medical University Graduate School of Medicine, Hikarigaoka-1, Fukushima 960-1295, 2Saitama Medical Uni-
versity Faculty of Medicine, Saitama, and 3Division of Hematology, Kita-Fukushima Medical Center, Fukushima, Japan. E-mail: firstname.lastname@example.org
Accepted August 27, 2007.
Fig. 1. (a) Ulcerated plaque with ill-defined border on the left cheek (arrow).
(b) Irregular proliferation of tumour mass in the dermis in continuity with
epidermis (H&E ×25). Inset: tumour cells showing variable degrees of atypical
squamous cells with mitosis (H&E ×400).
Fig. 2. After four months treatment with imatinib mesylate for CML. (a)
The skin lesion shown in Fig. 1 had flattened significantly (arrow). (b) Skin
biopsy obtained from the centre of the pre-existing lesion showed no evidence
of SCC (H&E ×25).
Letters to the Editor
Acta Derm Venereol 88
CML who are on long-term treatment with hydroxy-
urea (2), it is thought that hydroxyurea treatment may
be involved in the development of this tumour. To our
knowledge, this is the first report describing the regres-
sion of SCC in a patient with CML during treatment
with imatinib. It is possible that the discontinuation of
hydroxyurea and the restoration of immune function
following treatment of CML with imatinib might play a
role in the regression of SCC. However, the possibility
of the participation of imatinib in the regression of SCC
cannot be excluded.
Imatinib is a tyrosine kinase inhibitor with selecti-
vity for bcr-abl, c-abl, platelet-derived growth factor
receptor (PDGFR) and c-kit (3, 4). It is a novel drug
for the treatment of CML, which is associated with the
reciprocal translocation between chromosomes 9 and
22, resulting in the formation of the Ph chromosome that
generates bcr-abl fusion gene (5). Imatinib is also useful
in the treatment of gastrointestinal stromal tumours,
which overexpress c-kit (6). Furthermore, imatinib
shows efficacy in a large proportion of patients with
hyper-eosinophilic syndrome, which is associated with
rearrangements of PDGFR genes (7).
The potential efficacy of imatinib is also being evalua-
ted in SCC. Previous studies have shown that imatinib
exerts a significant inhibitory effect on cell growth in
head and neck SCC cell lines (8). In addition, imatinib
can enhance the tumour growth reduction induced by
radiotherapy in human epidermoid carcinoma cells (9)
or by cisplatin in head and neck SCC cell lines (10).
Although immunohistochemical studies confirmed the
expression of c-abl, PDGFR and c-kit in head and neck
SCC cell lines, their expression did not change after
imatinib treatment (8), suggesting the existence of an
unidentified target inducing tumour growth reduction.
On the other hand, recent in vitro studies have demon-
strated that imatinib stimulates the activity of epidermal
growth factor receptor tyrosine kinase in head and neck
squamous tumour despite causing a dose-dependent
decrease in the cell number (11). In addition, clinical
observation demonstrated the appearance of new, and
the progression of existing, squamous epithelial cancers
in 2 patients treated with imatinib for CML (12); thus
care is required when administering this drug to some
cancer patients. Because of such discrepancies, further
investigations are required in order to elucidate the
difference between cases showing regression or ag-
gravation of SCC. Nevertheless, imatinib is generally
well tolerated, with mild side-effects, including oedema,
skin rash, arthralgias and myalgias (13), and our case
highlights the possibility that imatinib may be beneficial
in some cancer patients.
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