Imatinib mesylate in a patient with metastatic disease originating from a dermatofibrosarcoma protuberans of the scalp

Dermatofibrosarcoma protuberans is a soft-tissue tumor that may recur locally and rarely causes metastases to vital organs. Dermatofibrosarcoma protuberans has specific chromosomal abnormalities involving the platelet-derived growth factor beta-chain locus that may render these tumors responsive to targeted therapy with the tyrosine kinase inhibitor imatinib mesylate. A patient with locally recurrent and metastatic dermatofibrosarcoma protuberans who had already undergone surgery 22 times was initially treated with imatinib mesylate 400 mg/day. The treatment dose was increased after 7 days to 400 mg twice daily. The patient was followed up for response and toxicity by physical examination and imaging studies, comprising computed tomography and fluorodeoxyglucose positron emission tomography. Clinical response could be demonstrated after the first month of treatment, and subsequent computed tomography and positron emission tomography documented a response to imatinib mesylate therapy. Our patient is now in sustained remission with minimal toxicity. We conclude that antitumor activity of metastatic dermatofibrosarcoma protuberans can be obtained with imatinib mesylate treatment with minimal side-effects.     

Metastatic gastrointestinal stromal tumor with long-term response after treatment with concomitant radiotherapy and imatinib mesylate

Total surgical excision of the tumor is considered to be the only hope in treatment of malignant mesenchymal tumors. The roles of radiotherapy and/or chemotherapy have not yet been established. We report here a case of metastatic gastrointestinal stromal tumors with a dramatic long duration of response after treatment with concurrent radiotherapy and imatinib mesylate. The patient had a long-term complete response at the radiotherapy region with concomitant imatinib therapy although previous metastatic sides persisted with partial response.     

A resectable case of gastrointestinal stromal tumor derived from the rectal wall after oral targeted molecular therapy with imatinib mesylate

We performed targeted molecular therapy in a patient with a non-resectable pelvic gastrointestinal stromal tumor (GIST). Imatinib mesylate was administered at 400-600 mg/day for 6 months, and the tumor became resectable. The patient was a 58-year-old female who visited a gynecologic hospital with the chief complaint of a swollen feeling in the lower abdomen. A pelvic tumor was found by imaging, and the patient was referred to our hospital. Laparotomy was performed, but it was found that the tumor arose from the intestinal serous membrane, rather than from the uterus, and complete excision was difficult. A portion of the tumor tissue was excised, and the abdomen was closed. GIST was diagnosed on postoperative pathological examination, and the tissue was positive for c-kit protein on immunostaining. The tumor had markedly shrunk after oral administration of imatinib mesylate for 6 months, and excision by laparotomy became possible.     

Renal dysfunction in a renal transplant patient treated concurrently with cyclosporine and imatinib

Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72?year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400?mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123?μmol/L to 196?μmol/L and an elevation in whole blood cyclosporine concentrations from 79?μg/L to 139?μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150-186?μmol/L) and cyclosporine concentrations (53-97?μg/L). A prolonged partial response to therapy for 19?months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1?ng/ml and 139?ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration.     

Decrease of CD117 expression as possible prognostic marker for recurrence in the resected specimen after imatinib treatment in patients with initially unresectable gastrointestinal stromal tumors: a clinicopathological analysis

Gastrointestinal stromal tumors (GIST) are the most common malignant mesenchymal tumors of the gastrointestinal tract. The principal treatment modality for primary GIST is surgery whereas for metastatic GIST, imatinib has an established role. In patients with locally advanced and metastatic GIST, the role of surgery in the imatinib era is still unclear. Fifteen patients with locally advanced (n=9) and/or metastatic GIST (n=6) were treated with imatinib followed by resection. Detailed histopathological examination was performed before and after treatment with imatinib, which was given for a median of 11 months before surgery. Ten patients showed a radiographic partial response, four patients had stable disease, and one patient progressed. At the time of surgery, the median tumor diameter was 6.5 cm. In all the nine patients with locally advanced GIST, a R0 resection could be performed. Histopathological examination showed imatinib effects in all tumors, including the case with progressive disease. All patients with locally advanced disease (n=9) were alive after a median follow-up of 40 months (range: 18-59), of which seven patients were free of disease. Four of the six patients treated for metastatic GIST died of disease after 30, 45, 50, and 74 months of follow-up. Remarkably, in five of six patients in whom CD117 expression was diminished or lost in the resection specimen, disease recurrence was observed. In patients with retained CD117 expression, one of the nine patients had recurrent disease. In conclusion, preoperative imatinib treatment in patients with locally advanced GIST resulted in a decrease of tumor load in most patients, enabling complete surgical resection. For patients with metastatic GIST, the role of surgery remains less clear. Loss or decrease of CD117 expression in the resected specimen after imatinib treatment may be associated with disease recurrence.     

Neoadjuvant imatinib for unresectable gastrointestinal stromal tumor

We have evaluated the feasibility of the use of neoadjuvant imatinib mesylate in the management of unresectable localized gastrointestinal stromal tumors. In a pilot experience, two patients with unresectable gastrointestinal tumors were treated with neoadjuvant imatinib. Their treatment course and surgical outcomes are described. In both cases, the patient attained sufficient tumor regression to enable complete resection of tumor. We conclude that in the management of unresectable gastrointestinal stromal tumors, neoadjuvant administration of imatinib may facilitate sufficient tumor regression to facilitate subsequent tumor resection with curative intent.     

Successful rescue of an apocrine gland carcinoma metastatic to the cervical lymph nodes by mitoxantrone coupled with trains of permeabilizing electrical pulses (electrochemotherapy)

Canine apocrine gland carcinoma is a locally aggressive neoplasm that can occasionally lead to metastatic spread, thus mimicking the behavior of their human counterpart. In this paper we describe the successful treatment of a cervical metastatic spread of this neoplasia by using mitoxantrone selectively driven within the tumor cells by trains of biphasic pulses. The dog experienced tumor reduction from the first cycle of electrochemotherapy (ECT) and complete remission by the time of its fourth session. Neither systemic or local toxicities were detected during the whole course of therapy. The dog is in complete remission after six months from his last treatment. Electrochemotherapy is a safe and efficacious therapy for metastatic carcinoma and warrants further investigation.     

Imatinib-associated bilateral gynecomastia and unilateral testicular hydrocele in male patient with metastatic gastrointestinal stromal tumor: a literature review

Imatinib mesylate is a drug that has been approved for treatment of advanced gastrointestinal stromal tumors (GISTs) and patients with leukemia such as chronic myeloid or Philadelphia chromosome-positive acute lymphoblastic. Although it has been described only in one patient with testicular hydrocele and gynecomastia in the literature, several cases of male gynecomastia have been reported with the use of imatinib mesylate in chronic myeloid leukemia (GML). Generally, male mastoplasia resolves after discontinuation of imatinib treatment. We report a 73-year-old male with metastatic GISTs who developed gynecomastia and unilateral testicular hydrocele while receiving imatinib mesylate. Nine months after commencing imatinib treatment, gynecomastia and testicular hydrocele were determined. Hormone analyses requested showed serum testosterone levels below and serum estrogen levels above normal limits. During the first month after discontinuing imatinib mesylate treatment, serum testosterone level was normal and there was a partial regression in gynecomastia and testicular hydrocele. To our knowledge, this is the second report of male gynecomastia following imatinib mesylate treatment of a patient with GIST. In conclusion, male patients who are to receive treatment with imatinib mesylate may be monitored for serum testosterone levels and for other reproductive hormone profiles before initiation of the treatment and their breasts may be examined during follow-up visits.     

格列卫治疗慢性粒细胞白血病急变期患者的临床疗效及毒性反应观察

目的 评价格列卫治疗慢性粒细胞白血病急变期患者的疗效及毒性反应.方法 36例患者中31例患者单用格列卫治疗,有5例加用亚砷酸治疗,根据患者耐受情况调整格列卫剂量.开始每2天复查外周血涂片、血常规,每周复查肝肾功能,1个月后每周复查外周血涂片、血常规,每2周复查肝肾功能,每1个月进行骨髓细胞形态学检查,每3个月进行细胞遗传学检查,记录治疗过程中的不良反应.结果 1个月时血液学缓解率(包括CHRT和NEL)66.7%,服用格列卫3个月后进行细胞遗传学检查,5例附加染色体异常消失,其中部分细胞遗传学缓解3例,完全细胞遗传学缓解2例.血液学不良反应以白细胞、血小板减少多见,非血液学不良反应以恶心、呕吐、水肿多见,其次为骨骼肌酸痛、乏力、头昏常见,而胸腔积液、头痛、皮疹等少见.结论 尽管格列卫是一种较安全的药物,其治疗慢粒急变期患者近期疗效明显,但远期疗效并不理想.     

Expression of Kit and platelet-derived growth factor receptors alpha and beta in cholangiocarcinoma, and case report of therapy with imatinib mesylate (STI571)

We have evaluated the expression of Kit, a receptor encoded by the c-kit protooncogene, and platelet-derived growth factor-receptors (PDGF-R) alpha and beta in cholangiocarcinoma specimens from 13 separate patients, and provide a case report of a therapeutic trial of imatinib mesylate in one patient. Archived pathologic samples from 13 patients with cholangiocarcinoma were obtained. Tissue sections were hybridized with anti-Kit, anti-PDGF-Ralpha and anti-PDGF-Rbeta monoclonal antibodies. Kit, PDGF-Ralpha and PDGF-Rbeta expression was seen in 31, 69 and 46% of samples, respectively. All patients with PDGF-Rbeta expression also expressed PDGF-Ralpha. Three out of four patients with Kit expression did not express either PDGF receptor and only one patient exhibiting expression of PDGF expressed Kit. Cohen's kappa statistic demonstrated that PDGF and Kit expression were inversely correlated with borderline significance (p=0.052; kappa=-0.4742, 95% confidence interval -0.9821 to 0.03364). In one case, strong Kit expression was noted in a tumor from a metastatic lymph node, but was absent in the primary tumor, suggesting that Kit may be related to invasive or metastatic potential. Given the high level of expression defined in this study, a prospective clinical trial incorporating imatinib mesylate, alone or in combination with cytotoxic chemotherapy, and especially in chemotherapy-naive patients, should be considered for patients with cholangiocarcinoma.     

Mechanistic Investigation of Imatinib-Induced Cardiac Toxicity and the Involvement of c-Abl Kinase

The Bcr-abl tyrosine kinase inhibitor imatinib mesylate is the frontline therapy for chronic myeloid leukemia. Imatinib has been reported to cause congestive heart failure and left ventricular contractile dysfunction in patients and cardiomyopathy in rodents, findings proposed to be associated with its pharmacological activity. To investigate the specific role of Abelson oncogene 1 (c-Abl) in imatinib-induced cardiac toxicity, we performed targeted gene inhibition of c-Abl by RNA interference in neonatal cardiomyocytes (NCMs). Suppression of c-Abl did not lead to cytotoxicity or induction of endoplasmic reticulum (ER) stress. To further dis associate c-Abl from imatinib-induced cardiac toxicity, we designed imatinib structural analogs that do not have appreciable c-Abl inhibition in NCMs. The c-Abl inactive analogs induced cytotoxicity and ER stress, at similar or greater potencies and magnitudes as imatinib. Furthermore, combining c-Abl gene silencing with imatinib and analogs treatment did not significantly shift the cytotoxicity dose response curves. Imatinib and analogs were shown to accumulate in lysosomes, likely due to their physicochemical properties, and disrupt autophagy. The toxicity induced by imatinib and analogs can be rescued by bafilomycin A pretreatment, demonstrating the involvement of lysosomal accumulation in cardiac toxicity. The results from our studies strongly suggest that imatinib induces cardiomyocyte dysfunction through disruption of autophagy and induction of ER stress, independent of c-Abl inhibition.     

A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal tumor

ABSTRACT

Introduction: For the last 15 years, imatinib mesylate has been the first line treatment of choice for advanced (metastatic) GIST.

Areas covered: This review describes key efficacy data on imatinib for the treatment of GIST, and focuses on safety and tolerability of imatinib, with emphasis on common adverse events management and long term toxicity profile.

Expert opinion: Imatinib has been the standard of care for metastatic GIST and probably will continue to be so for the next few years. Still, despite dramatic responses initially, imatinib drug resistance continues to be the major factor for treatment discontinuation. The toxicity profile of imatinib has been well characterized, and although the majority of patients experience an adverse event during treatment with imatinib, these side effects are usually mild and manageable, with the majority of patients continuing treatment uninterruptedly. Early concerns regarding imatinib related cardiotoxicity in GIST have not been confirmed in large prospective randomized trials, with reports indicating a low incidence of approximately 0.2%-0.4%. Future strategies for treatment of imatinib resistant GIST will probably include novel tyrosine kinase inhibitors, combination therapies or immunotherapy.     

Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes.     

伊马替尼停药后复发胃肠道间质瘤的临床特征与KIT/PDGFR基因突变分析

目的 探讨转移性胃肠道间质肿瘤(GIST)患者术后伊马替尼辅助治疗过程中,停药与复发的关系,以及KIT第11外显子突变的患者复发后,对伊马替尼的敏感性研究和预后监测. 方法 对GIST患者复发前后临床特征进行分析比较;利用免疫组织化学的方法 辅助诊断和分析复发前后CD117,CD34等GIST细胞标志物的表达情况;采用基因测序的方法 进行KIT/PDGFR基因突变检测. 结果GIST患者术后,规范伊马替尼治疗3年,停药后1年余腹部包块证实为GIST复发;患者KIT 基因第11外显子检测出有缺失突变：c.1667_1672delAGTGGA,提示该患者仍然对伊马替尼敏感;对于诊断GIST,DOG1比CD34更敏感. 结论 伊马替尼的连续用药延长无进展生存时间及延缓GIST复发,DOG1具有比CD34更好的敏感性,更加适合作为GIST的诊断标记物.     

Metabolism and disposition of imatinib mesylate in healthy volunteers.

Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of (14)C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t(max) 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 +/- 0.095 mug/ml (mean +/- S.D., n = 4) for imatinib and 0.115 +/- 0.026 mug/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 +/- 0.9 h for imatinib, 20.6 +/- 1.7 h for CGP74588, and 57.3 +/- 12.5 h for (14)C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC(0-24 h) (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.     

Specific targeted therapy of chronic myelogenous leukemia with imatinib

Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed.     

Dermatofibrosarcoma protuberans following tanning bed use

Dermatofibrosarcoma protuberans (DFSP) is a rare, slowly growing, malignant dermal tumor first described by Darier and Ferrand in 1924. It typically occurs in individuals aged 20 to 40 years and frequently arises on the trunk. Although the cellular origin of DFSP is not entirely clear, dermal stem cells or undifferentiated mesenchymal cells with fibroblastic, muscular, and neuroectodermal features have been implicated. DFSP is a locally aggressive tumor with a high recurrence rate, largely attributed to the spread of tumor by direct local invasion through peripheral and deeply penetrating neoplastic cells into subcutaneous tissue and muscle. As such, there is growing evidence that Mohs micrographic surgery is the treatment of choice. Although reports of chromosomal aberrations and gene mutations have been described in the literature, excessive sun exposure is not regarded as a risk factor for the development or progression of DFSP. We describe a case of DFSP in a patient with a history of prolonged tanning bed use.     

Quantitative approaches to analyzing imatinib-treated chronic myeloid leukemia

Progress in understanding the genetic changes that drive tumorigenesis has enabled the development of molecularly targeted anticancer therapy. The first small molecule targeted to a specific protein was imatinib mesylate (Gleevec, STI571), which is used to treat chronic myeloid leukemia (CML). A recent article presents a computational model with which to study the treatment response in CML patients and investigates the effect that imatinib exerts on leukemic stem cells. Here, I discuss insights derived from this study and their implications for imatinib therapy against CML.     

Translocation t(12;13)(p13;q14) in a patient with imatinib-sensitive MDS/MPD associated with resistance to treatment: review of the literature

The category of myelodysplastic syndromes/myeloproliferative diseases (MDS/MPD) is a relatively new group of malignant hematologic diseases developed by the World Health Organization. These hematologic disorders lack the BCR/ABL fusion gene, although they can be associated with chromosomal translocations that involve genes encoding other protein kinases. Imatinib mesylate was recognized as a potent inhibitor of some of those kinases. We present a patient with a previously treated acute myeloid leukemia, who, after a 9-year-long remission, developed an MDS/MPD with normal karyotype, which initially responded to imatinib mesylate. Translocation t(12;13)(p12;q14) was detected after loss of response to imatinib treatment. Translocation t(12;13) is rare. It has been described in several hematologic malignancies including chronic myelomonocytic leukemia but not in MDS/MPD, previously described as Philadelphia-negative chronic myelogenous leukemia. Moreover, the correlation of this molecular abnormality with loss of efficacy of imatinib is unique in the literature.     

甲磺酸伊马替尼治疗慢性粒细胞白血病疗效观察

目的观察甲磺酸伊马替尼（IM）治疗慢性粒细胞白血病（CML）慢性期（CP）及进展期的疗效。方法回顾性分析2009年1月～2013年12月我院采用IM治疗的60例CML患者临床资料,其中30例为进展期患者,30例为CP患者。结果进展期患者DA化疗后血液学完全缓解0例,部分缓解6例,未缓解24例,总有效率20%;行IM治疗后完全缓解13例,部分缓解6例,未缓解11例,总有效率63.3%,两者治疗有效率差异有统计学意义（χ^2=4.36,P〈0.05）。30例CP患者行IM治疗后完全缓解26例,部分缓解0例,未缓解4例,总有效率86.7%,进展期及CP组IM治疗有效率差异有统计学意义（χ^2=11.59,P〈0.05）;进展期患者中McyR及CmoR的患者分别为10例（33.3%）和6例（20%）;CP组分别为26例（86.7%）和24例（80%）;CP患者IM治疗后遗传学疗效较进展期好。结论 IM是各期CML的理想治疗方法,有效率高。血液学毒性是其主要副作用,其余反应较轻,患者耐受良好。