Imatinib Mesylate Treatment Research Articles

Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3(+) TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3(+) TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST.

P-0140 - Experience of Managing Patients with Metastatic Gastrointestinal Stromal Tumour with Imatinib Mesylate at an Indian Centre

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Most commonly originate in the stomach and small intestine. Historically, these lesions were classified as leiomyomas or leiomyosarcomas. They are submucosal lesions, which grow endophytically in parallel with the lumen. One third of high risk, malignant GIST have poor prognosis after surgery. Imatinib mesylate is a KIT tyrosine kinase inhibitor with effect on metastatic GIST. About 80% of patients with GIST would experience tumor recurrence or metastasis after radical resection. The most common site of the metastasis is the liver. We report our long term follow up in patients with metastatic GIST receiving Imatinib. Methods: Retrospective analysis of patients diagnosed with metastatic GIST from 2004 to 2012 at our centre, who received Imatinib mesylate at an dose of 400 mg per day over 6 months. Patients profile, tumor response, side effects, time to progression and survival were evaluated. Results: Ten C-Kit or CD 117 positive GIST patients were enrolled at our centre, there were 8 (80%) male and 2 (20%) female. Median age of patients was 64 years (range 38 to 86 years). Five GISTs originated from stomach, 3 from rectum, 1 each from jejunum & ileum. Most common symptoms were anaemia and pain abdomen. Liver metastasis in 6, lung in 3 and breast in 1. Five patients underwent surgical treatment. Majority of them (80%) were of the high-risk malignant category. All of them started on Imatinib, all had palliative benefit, half had significant shrinkage of tumour mass. Most common side effects were periorbital oedema, muscle cramps, and diarrhea. Histologically, the majority had a pure spindle cell morphology. Follow-up of 5 cases, treated with adjuvant Imatinib for 6 months after surgical resection showed stable disease for periods from 5 to 8 years. However, 3 cases treated with Imatinib for longer than 6 months had problems due to recurrent, metastatic, or inoperable disease. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up of 48 months (range 15 to 112 months), the 5 year survival rate was 88%. Conclusion: Adjuvant therapy Imatinib should be used for patients with high-risk advanced GISTs. The Imatinib mesylate treatment can prolong the survival of the patients who have metastatic GIST before or after radical surgery without toxicity of chemotherapy.

Multiple skin lesions caused by imatinib mesylate treatment of chronic myeloid leukemia

Multiple skin lesions caused by imatinib mesylate treatment of chronic myeloid leukemia

Hypereosinophilic syndrome – lymphocytic variant transforming into peripheral T-cell lymphoma with severe oral manifestations

Hypereosinophilic syndrome (HES) is a rare disease defined by organ damage directly attributable to hypereosinophilia of any type. Here, we report for the first time the case of a patient with a lymphocytic type of HES (HES-L) who had liver, skin, spleen, lung, bone marrow, digestive track, and mouth involvement. Associated T-cells displayed an aberrant CD30+ phenotype and were monoclonal. Thymus activated and regulated chemokine serum level was positive. Despite steroids (Cortancyl 20 mg [Sanofi Aventis, France], imatinib mesylate [Glivec 400 mg; Novartis Europharm], interferon alpha 2A [Roferon-A 3 MUI/0.5 ml; Roche]) and other lines of therapy including imatinib mesylate treatment, an oral necrotic lesion developed, and finally progressed into a peripheral CD30+ T-cell lymphoma. CHOP chemotherapy (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone), interferon-α, and mepolizumab were ineffective. Although progression into peripheral T-cell lymphoma is documented as a rare complication of HES-L, severe oral extension of HES-L is described for the first time.

Bcr/Abl-induced deregulation of the IL-33/ST2 pathway in CD34(+) progenitors from chronic myeloid leukemia patients (P6284)

Abstract Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myeloid leukemia (CML) and resistance to imatinib mesylate (IM) treatment remain poorly investigated. Here, we report that CD34(+) progenitors from CML patients at diagnosis are selectively targeted by the cytokine/alarmin IL-33. Indeed, CML CD34(+) progenitors up-regulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following IM therapy, while IL-33 counteracts in-vitro IM-induced growth arrest in CML CD34(+) progenitors via re-activation of the STAT5 pathway. Clinically, CML is associated with high circulating levels of soluble ST2, commonly used as a functional signature of IL-33 signaling in vivo. Taken together, our results support the hypothesis that the IL-33/ST2 pathway facilitates Bcr/Abl-induced leukemogenesis and contributes to IM resistance in CML patients.

Clinical analysis of efficacy and prognosis of intermediate risk gastric stromal tumor patients

To explore the clinical efficacy and prognosis of the patients with intermediate risk gastric stromal tumor (GST). The data of intermediate risk GST patients confirmed by pathology and immunohistochemistry at Center of Gastrointestinal Surgery, West China Hospital, Sichuan University, between January 2007 and July 2011 were collected and retrospectively analyzed. And univariate and multivariate analyses were performed to assess the efficacy of imatinib mesylate (IM) according to recurrence-free survival (RFS). A total of 46 intermediate risk GST patients were enrolled with a median follow-up period of 31 (9-64) months. Among them, 20 patients received IM treatment and 1 had hepatic metastasis at 16 months after withdrawal. In contrast, 5 of 26 patients refusing IM treatment recurred or had a distant metastasis. The 1-, 2-, 3-year recurrence-free survival in IM treatment group and no IM treatment group were: 20/20 vs 25/26, 14/14 vs 17/20 and 6/7 vs 10/14, respectively. Cox proportion hazards regression: hazard ratio(HR) = 0.265, 95%CI: 0.025-2.761, P = 0.267. Among 6 patients with recurrence and(or) metastasis, 5 had mitotic count > 5/50 HPF. Cox proportion hazards regression (HR = 0.059, 95%CI: 0.004 - 0.976, P = 0.048) showed that IM can improve the progression free survival of mitotic count > 5/50 HPF group versus mitotic count < 5/50 HPF. The most common IM-related side effects were edema, nausea, abdominal discomfort, leukemia, etc. Most of them were Grade 1-2. Intermediate risk GST has a low rate of recurrence or metastasis. And 1-year IM treatment may improve the prognosis of the patients with mitotic counts > 5/50 HPF. Furthermore, IM treatment is safe in intermediate risk GST patients.

Abstract 3927: Evaluating new therapies in Gastrointestinal Stromal Tumor using in vivo molecular optical imaging.

Abstract Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors with an estimated annual incidence of ∼6,000 new cases in the United States. The majority (∼75%) of GISTs possess gain-of-function mutations in KIT exons 9, 11, 13 or 17, causing constitutive activation of the kinase receptor, with smaller subsets possessing either gain-of-function mutations in PDGFRA (exons 12, 14 or 18) or BRAF (exon 15). Management of GIST has been transformed by the identification of these tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite the efficacy of IM, most patients experience primary and/or secondary resistance within 2 years of treatment. Therefore additional therapies are needed and methods to optimize screening of novel approaches are warranted. Efficacy of treatment is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. Using RECIST, patients with advanced disease have equivalent survival when they have stable disease as when they have complete or partial responses. The Choi criteria define treatment response as a &amp;gt;10% decrease in tumor size or a &amp;gt;15% decrease in tumor density of tumor lesions assessed on CT scans. Response by Choi criteria has been shown to correlate better with FDG-PET than RECIST response, but can only be used with contrast enhanced CT imaging. RECIST and Choi both require a period of time on therapy before changes indicative of response can be observed. None of these criteria however informs us directly about cell death. Here we evaluate the use of molecular imaging technology using near-infrared (NIR) imaging probes in combination with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determine the potential of two NIR probes (PSVueTM794 and KcapQ647) for detecting apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. PSVueTM794, used as a marker of apoptosis, binds to phosphatidylserine residues exposed on the surface of apoptotic cells and, in addition, binds to negatively-charged necrotic regions found in various tumors. KcapQ647, a cell penetrating activatable probe was used to detect apoptosis-associated caspase acitivity. Our studies revealed statistically significant increases in apoptotic activity due to IM treatment (compared to control) using both the PSVue TM794 and KcapQ647 probes (p=1.41e-04, 0.002 respectively) as early as 24 hours post IM treatment. These findings were confirmed by IHC. We believe that this methodology will allow for faster and more effective screening of novel therapies in preclinical GIST models. Citation Format: Lori A. Rink, Harvey Hensley, Karthik Devarajan, James R. Johnson, David Piwinica-Worms, Andrew K. Godwin, Margaret von Mehren. Evaluating new therapies in Gastrointestinal Stromal Tumor using in vivo molecular optical imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2013-3927

A Case of Type 1 Neurofibromatosis Associated with Multiple Metastatic Gastrointestinal Stromal Tumors

1 Type 1 neurofibromatosis (von Recklinghausen's disease, NF-1) is an autosomal-dominant neurocutaneous- disorder characterized by systemic cafe'-au-lait spots, multiple cutaneous neurofibromas, axillary or inguinal freckling, and Lisch nodules (pigmented iris hamartomas). Approximately 10-25% of NF1 patients have gas- trointestinal neoplasms. Gastrointestinal stromal tumor (GIST) in patients with neurofibromatosis is most commonly found in the small bowel and the stomach, and approximately 60% of such patients have multiple tumors or multiple tumor sites. Although, the increased incidence of GIST in patients with neurofibromatosis is well documented in pathology literature in English, but has rarely been documented in Korea. Here, we report a case of multiple GISTs in a 48-year-old woman accompanied by NF1. She was admitted to Yeung- nam University Hospital with complaints of melena and dyspnea. A contrast-enhanced computed tomog- raphy (CT) scan revealed that multiple soft tissue masses were occupying the entire peritoneal cavity. An ultrasonogram- guided biopsy was performed and the tumors were found to have been composed of tumor cells that were positive for c-kit protein. The patient was put on Imatinib mesylate treatment, and further follow-up will be carried out.

Plantar Keratoderma with Pachyonychia Likely Induced by Imatinib Mesylate

Dear Editor: Imatinib mesylate (Gleevec®; Novartis, Basel, Switzerland) is a tyrosine kinase inhibitor that targets BCR-ABL protein, c-kit, and platelet-derived growth factor receptor1. It is widely used in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Cutaneous adverse effects are common, the most common form being erythematous maculopapular eruption affecting the forearms and trunk2. However, palmoplantar hyperkeratosis has been rarely described2. Herein, we report on a patient who developed plantar keratoderma and pachyonychia after four months of imatinib mesylate administration. A 52-year-old male was referred to our department in July 2011 with a three-month history of asymptomatic hyperkeratotic plaques on his soles. He had been diagnosed with CML in 2001, and had received stem cell transplantation in June 2002. He had begun imatinib mesylate 400 mg a day starting in December 2010, and skin rash and peripheral blood eosinophilia developed four months later. Also, hyperkeratosis of the soles and nails developed. At presentation his soles were covered with asymptomatic, symmetrically distributed, diffuse, hyperkeratotic, yellow-brownish plaques with fissures (Fig. 1A). The lesions were more prominent on the pressure-bearing areas. Palmar thickening was also seen, but to a milder degree. He also showed hyperkeratosis of the toe nails and finger nails (Fig. 1B), and pruritic scaly erythematous patches involving his back, elbows and legs. There was no personal or familial history of similar skin disease. Eosinophil count was elevated to 8%, but other laboratory findings were within normal limits. Skin biopsy of the hyperkeratotic plaque and fissured area of the sole revealed marked hyperkeratosis with parakeratosis and papillomatosis in the epidermis, and mild perivascular lymphocytic infiltrations in the upper dermis. Imatinib mesylateinduced plantar keratoderma and pachyonychia were suspected, and imatinib was therefore withdrawn. The plantar lesion gradually disappeared with topical application of 20% salicylic acid and 20% urea cream. Also, pachyonychia of the finger nails and toe nails was noted to have improved on the 17-month follow-up visit (Fig. 2). In addition, KOH mounting and fungus culture of scrapings from the nails and soles were performed at this time, and both were negative for fungal infection. Fig. 1 (A) Symmetrically distributed, diffuse, hyperkeratotic, yellow-brownish plaques with fissures on the soles, and (B) hyperkeratosis of the finger nails and toe nails. Fig. 2 Follow-up 17 months later. (A) Improvement of pachyonychia of thumb nails. (B, C) Improvement of hyperkeratosis of toenails. In our patient, the bilaterally symmetric distribution pattern and sudden onset of the lesions suggested that this case was drug-related. Other differential diagnoses manifesting hyperkeratosis of the soles were also considered. Psoriasis was ruled out due to a lack of psoriasiform dermatitis in the pathologic findings and because the distribution of the lesion was confined to the weight-bearing areas of the soles. Hyperkeratotic eczema was also excluded because the patient did not suffer from pruritus. Since none of his family members had similar symptoms, other inherited forms of palmoplantar keratoderma could be excluded. Moreover, the improvement in the skin lesions after the cessation of imatinib mesylate supports a drug-related causality. To date, two case series of palmoplantar hyperkeratosis associated with imatinib mesylate treatment have been reported in the literature1,2. In addition, there has been one case report of multiple hyperkeratotic crusted papules of the buttock, thighs, and the right ear helix caused by sorafenib, another tyrosine kinase inhibitor3. These agents are known to interact with downstream molecules of the epidermal growth factor receptor pathways, leading to cutaneous epithelial proliferation. Our case suggests that plantar keratoderma and pachyonychia should be included in the list of cutaneous adverse reactions of imatinib mesylate.

Hepatic metastasis with heterologous rhabdomyoblastic differentiation in a patient with gastrointestinal stromal tumor treated with imatinib

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the intestinal tract. In patients with locally advanced and/or metastatic GIST, the introduction of tyrosine kinase inhibitor, imatinib mesylate, has transformed the management of this previously untreatable neoplasm into a treatable entity. Approximately 80% of advanced metastatic GISTs respond to imatinib treatment. However, the majority of patients suffer disease progression at a median of 2 years due to drug resistance. Generally progressing GISTs retain their typical morphology. Herein, we report an extremely rare case of progressive metastatic GIST with heterologous rhabdomyoblastic differentiation after, imatinib mesylate treatment. We also review the relevant literature.

Long-Term Follow-Up Outcome of Imatinib Mesylate Treatment for Recurrent and Unresectable Gastrointestinal Stromal Tumors

Background: The follow-up study of up to 71 months of a randomized phase II B2222 trial has demonstrated a long-term survival in patients with recurrent or unresectable gastrointestinal stromal tumors (GISTs). One subset of the patients (17.7%) has been alive for over 9 years with continuous imatinib mesylate (imatinib) treatment. Here, we report the retrospective analysis of recurrent or unresectable GIST patients with imatinib treatment at our institution. Methods: We summarized the data of 20 patients with recurrent or unresectable GIST treated with imatinib. Results: Patients were followed for a median of 40 months (range 2.5–103) under imatinib treatment. The median progression-free survival (PFS) was 89 months and overall survival for 8 years was 67%. Fifteen patients showed continuous partial response or stable disease with imatinib treatment. The median PFS was 45 months and the median size of the primary tumor was 7.6 cm (range 2.8–18). Four patients showed progressive disease. The median PFS was 56 months and the median size of the primary tumor was 11.9 cm (range 6.7–19). Grade 3 or 4 adverse events occurred in neutropenia (10%), anemia (15%) and renal dysfunction (5%). However, all patients were well managed by supportive treatment and none were discontinued from imatinib treatment due to toxicity or adverse events. Conclusion: Imatinib had a high efficacy in patients with unresectable and recurrent GIST during long-term follow-up. All patients were well managed by supportive treatment against adverse events and they were able to take imatinib without discontinuation. The management of adverse events was a key factor for achieving a long-term survival. In addition, the potential risk of imatinib-resistant GISTs tends to depend on the size of the primary GISTs.

Lichenoid Drug Eruption after Low-Dose Imatinib Mesylate Treatment

Dear Editor: Imatinib mesylate, a selective antitumor tyrosine kinase inhibitor, has been approved as the first-line therapy for gastrointestinal stromal cell tumor and chronic myeloid leukemia. Lichenoid drug eruption (LDE) is known to cause uncommon adverse cutaneous reactions of imatinib mesylate, usually appearing with 400 mg or more of imatinib mesylate per day1,2. Here, we present a case of severe LDE after low-dose imatinib mesylate treatment for gastrointestinal stromal cell tumor. A 77-year-old Korean male patient came to our dermatology clinic in March 2011 for skin rash over the entire body. He was diagnosed with gastrointestinal stromal cell tumor with multiple liver metastasis, and began imatinib with 400 mg per day on September 2007. Two months later, violaceous pruritic papules developed symmetrically on both legs. The skin lesion progressed to the whole body despite a dose reduction to 300 mg per day. His skin lesion was markedly improved after a medication change to sunitinib. However, his kidney function gradually worsened and consequently, sunitinib was changed to imatinib again with a reduced dose to 300 mg per day from December 2010. Extensive skin lesion reappeared soon and a dose reduction to 200 mg per day had no effect on improving skin lesion. On physical examination, violaceous, slightly elevated papules symmetrically covered the extensive body surface (Fig. 1A). The distribution was mainly on both extremities (Fig. 1B). Skin biopsy was performed on his left lower leg. Specimen showed lichenoid lymphocytic infiltration on the upper dermis and deep dermal perivascular lymphocytic infiltration (Fig. 2A). In the high-magnification, 'saw-toothed' rete-ridges were similar to those of lichen planus; however, the finding of cytoid bodies in the granular layer was favorable to LDE (Fig. 2B). Based on the clinical and histologic findings, a diagnosis of LDE due to imatinib was made. Fig. 1 (A) Symmetrically involved erythematous to violaceous papules and plaques, covered extensive body surface area. (B) Slightly elevated violaceous papules and plaque on the right thigh. Fig. 2 Histopathological findings. (A) Dense band like lymphocytic infiltration in the upper dermis and deep dermal lymphocytic infiltration (H&E, ×40). (B) Lichenoid lymphocytic infiltration with 'saw-toothed' rete ridges and vacuolar degeneration ... Adverse cutaneous reactions after imatinib are quite common and various2. Among them, imatinib-induced LDE is a relatively uncommon adverse skin reaction and has been reported in 15 cases to date2. In the PubMed online research, all 15 affected patients took more than 400 mg per day of imatinib, except 1 case which showed a lasting LDE despite the dose reduction from 400 mg per day to 200 mg per day3. One case of a Korean patient with LDE after imatinib was reported to date; yet, the case differs with our case in that the eruption was well-controlled with a dose reduction to 300 mg per day4. Ugurel et al.5 reported that imatinib acts as a dose dependent inducer of the development of LDE and may show mild reactivity to low or intermediate dose (200 to 600 mg/day). However, in this case, the patient suffered from extensive drug eruption in spite of the low dose of 200 mg per day. We present here LDE after imatinib treatment of 400 mg per day to a low dose of 200 mg per day. This case presented that a low dose of imatinib does not always prevent LDE and can induce severe eruption in some patients. We suggest clinicians to keep in mind that all patients taking imatinib mesylate have the possibility of extensive LDE even in a low dose and therefore should carry a close observation.

A Case of Nonleukemic Myeloid Sarcoma With FIP1L1-PDGFRA Rearrangement

Rearrangement of the PDGFRA gene defines a distinct group of hematopoietic neoplasms that commonly present with persistent eosinophilia and are highly sensitive to low-dose imatinib mesylate treatment. Although rare cases of PDGFRA rearrangement-associated acute myeloid or lymphoblastic leukemia can occur, nonleukemic myeloid sarcoma has not been reported, and its sensitivity to imatinib treatment is unknown. Herein, we report a 31-year-old man with nonleukemic myeloid sarcoma and marked peripheral blood and bone marrow eosinophilia. Fluorescent in situ hybridization studies demonstrated that both bone marrow hematopoietic precursors and blasts of the myeloid sarcoma were positive for FIP1L1-PDGFRA rearrangement. The patient consequently received imatinib treatment at a dosage of 100 mg daily. After 3 weeks of therapy, his eosinophilia and myeloid sarcoma completely resolved, and at evaluation after 3 months he had attained bone marrow cytogenetic remission. To our knowledge, this is the first case of a nonleukemic myeloid sarcoma with the FIP1L1-PDGFRA rearrangement. Despite its aggressive clinical behavior attributed to myeloid sarcoma in general, the presence of PDGFRA rearrangement in this case conferred a high sensitivity to imatinib treatment and a favorable clinical outcome.

Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

ObjectiveThe aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. MethodsA retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. ResultsAt the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8%) and myelotoxicity (25.7%) were the most frequent reasons for interruption. The adherence rate was < 90% in 47% of the cases. The low adherence influenced the cytogenetic response (p-value = 0.020) and molecular response (p-value = 0.001). Very high adherence (> 95%) induced complete cytogenetic response, major cytogenetic response and major molecular response. ConclusionThe population of this study obtained lower-than-expected therapeutic responses compared to other studies.

HOXA4Gene Promoter Hypermethylation as an Epigenetic Mechanism Mediating Resistance to Imatinib Mesylate in Chronic Myeloid Leukemia Patients

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673–12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.

Laparoscopic versus open resection of gastrointestinal stromal tumors of the stomach

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Surgical treatment is the only chance of cure for patients with a primary localized GIST. A laparoscopic approach has been considered reasonable for these tumors of gastric origin. The current study compares the outcome of laparoscopic versus open resection of gastric GISTs and compares our series with the few published studies comparing the open versus the laparoscopic approach. From a prospectively collected database, we found 53 primary gastric GIST resections that were performed in our department. Laparoscopic (LAP) resections were performed in 37 patients and traditional (OPEN) resections in 16 patients. Clinical and pathologic characteristics and surgical outcomes were analyzed according to surgical procedure. Patients who underwent LAP or OPEN resection of gastric GISTs did not differ with respect to age at operation, gender, clinical presentation, and tumor size. Operative time was significantly lower for LAP than for OPEN resection, with a mean duration of 45 and 132.5 min, respectively (p < 0.001). LAP resection yielded a significantly shorter length of stay (median 7 vs. 14 days; p = 0.007) and lower 30-day morbidity rate (2.7 % vs. 18.9 %; p = 0.077). The operative mortality was 12.5 % after OPEN resection and there was no operative mortality after LAP (p = 0.087). The recurrence rate was significantly lower after LAP surgery (0 % vs. 37.5 %; p < 0.001). All patients in the LAP group are alive without recurrence, and 25 % (4/16) of the OPEN group are alive with recurrence but in complete remission under imatinib mesylate treatment. Two patients of the open group died due to progression of GIST (p = 0.087). Compared to open resection, laparoscopic resection of gastric stromal tumors is associated with a shorter operation time, a shorter hospital stay, and a lower recurrence rate.

Abstract 19381: Imatinib Mesylate Modifies Induced Pathological Hypertrophy by Altering Myocyte Calcium

Background — Imatinib mesylate (IM) is a small molecule inhibitor of the fusion protein Bcr-Abl, which causes chronic myelogenous leukemia. There is some concern that IM can induce cardiac dysfunction in cancer patients. A previous study showed that chronic treatment of adult mice with IM for 3-4 weeks leads to deterioration in contractile function and LV mass decrease. We investigated the effects of IM on neonatal rat ventricular myocytes (NRVMs). The hypothesis is that calcium regulatory mechanisms are altered to induce pathological hypertrophy. Methods and Results — NRVMs were treated with a clinical dosage (2 µM) of IM. Western analysis showed a significant increase in phospholamban phosphorylation at T-17, signifying activation of CaMKII. The rate of decay of the systolic Ca 2+ transient was increased, consistent with an increase in rate of Ca 2+ resequestration into the SR. Coulter counter analysis was used to determine cell size and showed that average NRVM volume increased significantly (Con-102 pl; IM-133 pl. p&lt;0.05). Myocyte surface area also increased with IM treatment (Con-6277 μm 2 ; imatinib-10259 μm 2 p&lt;0.05). Western analysis showed significant increases in ANP abundance, a pathological hypertrophy marker, after IM administration. NRVMs were infected with AdNFATc3-GFP and NFAT nuclear translocation was analyzed as nuclear/cytoplasmic GFP. Nuclear translocation was significantly increased with IM treatment. The calcineurin inhibitor FK506 inhibited IM induced NFAT nuclear translocation (Con-0.8162 ± 0.032; imatinib-2.233 ± 0.13; imatinib+FK506-0.6277 ± 0.037. p&lt;0.05). Conclusions — These data show that clinical doses of IM activate pathological hypertrophy signaling pathways by enhancing SR function. This could be a mechanism for adverse cardiac effects of IM.

CML Patients Show Sperm Alterations At Diagnosis That Are Not Improved On Tyrosine Kinase Inhibitor Treatment

AbstractAbstract 1669Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively).Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013.In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.

Imatinib mesylate treatment for a Chinese patient with metastatic and recurrent dermatofibrosarcoma protuberans

Imatinib mesylate treatment for a Chinese patient with metastatic and recurrent dermatofibrosarcoma protuberans

Two cases with hypereosinophilic syndrome shown with real-time PCR and responding well to imatinib treatment

The aim of this work was to report two cases of hypereosinophilic syndrome (HES). FIP1L1-PDGFRA fusion was assessed with two protocols at RNA level. The fusion transcript was found positive at the RNA level with both PCR methods in two cases. In this study, the efficiency of imatinib treatment and a dramatic response in two HES cases with multisystemic involvement showing the characteristics of a chronic myeloproliferative disease were presented. Both cases showed complete responses confirming that imatinib mesylate treatment could be successful even in patients with advanced HES having myeloproliferative disease.