Presence Of C-kit Mutation Research Articles

Abstract 1777: Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST)

Abstract Aim: C-KIT exon mutations were assessed in patients with gastrointestinal stromal tumor (GIST) in relation to patients’ characteristics, response to treatment and survival rates. Methods: C-KIT mutations were assessed in the representative formalin fixed paraffinembedded tissues (FFPETs) of 89 patients with GIST compared to 35 normal control (NC) subjects using the Real Time PCR (Rt-PCR) and immunohistochemistry (IHC). Results: C-KIT mutations were detected in 61/89 (68.5%) patients, compared to none of the NC subjects (P=<0.001). Most mutations were detected in exon 11 (50.8%), followed by exon 9 (24.5%), exon 13 (19.6%), exon 7 (4.1%), and exon 12 (only 1%). C-KIT protein expression was detected in 69 (77.5%) patients compared to none of the NC subjects (p=<0.001). Significant measure of agreement was detected between C-KIT expression by IHC and and RT-PCR (K=0.774, p=0.0001). The presence of C-KIT mutations associated significantly with large tumor size (P=0.01), High mitotic rate, lymph nodes metastasis and high tumor risk (p=0.001, for all). Patients with exon 11 mutations 26/31 (83.9%) had a better response to treatment compared to those with exon nine 7 (46.7%) and exon 13 mutation 1/12 (8.3%; P=0.001). Exon 11 mutations associated significantly with better PFS and OS compared to those with exon 9 and 13 mutations (P= 0.001, P= 0.0001; respectively). On univariate analysis, Exon 13 mutations was the most significantly associated with reduced PFS (P=0.0001), whereas advanced disease stage, absence of adequate safety margins and the site of exon mutation associated significantly with reduced OS. (P=0.012, P=0.05 and P=0.005; respectively. Conclusion: GIST patients with C-KIT exon 11 mutations have a better response to imatinib treatment (predictive value), better OS and lower risk of disease progression than those with exon 9 and 13 mutations. Our specified mutations in exons 9& 13 mutations could be used as an independent prognostic factor for GIST patients. Citation Format: Abeer A. Bahnnasy, Ola Khorshid, Mona S. Abdellateif, Ghada Y. Zakaria, Nasr M. Allahloubi, Auhood Nassar, Abdel-Rahman N. Zekri. Correlation between different C-KIT exon mutation and clinical outcome to Imatinib Mesylate treatment in patients with gastro-intestinal stromal tumors (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1777.

Prevalence and Prognostic Significance of c-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Comprehensive Large-Scale Study from a Single Chinese Center

Introduction CBF-acute myeloid leukemia (AML) is a heterogeneous disease that requires prognostic factors for patient differentiation. c-KIT mutations are predominantly detected in CBF-AML among AML cases, and reported frequencies vary significantly. To date, the clinical significance of c-KIT mutations in CBF-AML has been intensively studied; however, the results are controversial and a final conclusion has not been reached. Large-scale studies with subgroup analysis should be performed to elucidate the clinical effects of c-KIT mutations in CBF-AML.Methods A total of 351 patients with CBF-AML [t(8;21) (n = 253) or inv(16) (n = 98)] were included in this study. Overall, 250 patients [42 pediatric t(8;21);146 adult t(8;21); 11 pediatric inv (16) and 51 adult inv (16)] received standard treatment and underwent follow up. Induction therapy consisted of one or two cycles of combined anthracycline and cytarabine for adult patients, whereas cytarabine, idarubicin, and etoposide were used for pediatric patients. 131, 17, and 93 of the patients further received intermediate-dose cytarabine-based chemotherapy, chemotherapy with auto-hematopoietic stem cell transplantation (HSCT), and chemotherapy with allogeneic (allo)-HSCT for consolidation, respectively. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Patients who received allo-HSCT were censored at the time of transplantation for relapse and survival analysis to exclude the effects of allo-HSCT on outcome. The median follow up time was 10 months (3 to 93 months) for the 211 living patients.Results Overall, 36.5% (128/351) of the patients were found to have a c-KIT mutation. The frequencies of c-KIT mutations were similar between pediatric and adult patients with t(8;21) AML (41.7% vs. 38.5%, P > 0.05), whereas pediatric patients tended to have higher frequency of c-KIT mutations than the adult patients with inv(16) AML (53.8% vs 25.9%, P = 0.053). In adults, the frequency of c-KIT mutations was significantly higher in patients with t (8;21) than those with inv(16) (P = 0.043). In adults, the frequency of mutations in exon 17 was significantly higher in t(8;21) than inv(16) AML (P < 0.0001). In pediatric group, the frequencies of mutations in exon 17 and exon 8 were similar for t(8;21) and inv(16) AML (P > 0.05). The low PLT count (¡Ü 30∙109/L) in pediatric t(8;21) AML tended to be associated with the presence of c-KIT mutations ( P = 0.063). High white blood cell (WBC) count (>10∙109/L), WBC index, and AML1-ETO transcript levels in adult t(8;21) AML patients were significantly correlated with the presence of c-KIT mutations (P = 0.015, 0.0051, and 0.030, respectively). Moreover, low CBF¦Â-MYH11 transcript levels in adult inv(16) AML tended to be significantly related to c-KIT mutations (P = 0.059). No difference was observed in CR rates between patients with and without c-KIT mutations (P > 0.05). c-KIT mutations were significantly associated with less reduction in fusion transcript levels after the first induction therapy in adult inv(16) patients (P = 0.021). c-KIT mutations in adult t(8;21) AML patients (n = 137) significantly correlated with higher CIR rates at 2 years and low 2-year DFS and OS rates (73.2% vs. 46.2%, P = 0.0070; 26.8% vs. 49.1%, P = 0.013; 48.9% vs. 65.7%, P = 0.0055, respectively. Figure 1). In contrast, c-KIT mutations had no impact on CIR, DFS, and OS rates in pediatric t(8; 21)(n = 42), as well as in adult inv (16) (n = 51; all P > 0.05. Figure 1). Multivariate analysis demonstrated that c-KIT mutation was the only independent prognostic factor for relapse (hazard ratio (HR) = 2.47, 95% CI = 1.25 to 4.86, P = 0.009) and DFS (HR = 2.23, 95% CI = 1.17 to 4.41, P = 0.016). Moreover, c-KIT mutation and PLT count were independent prognostic factors for OS (HR = 3.68, 95% CI = 1.57 to 8.63, P = 0.003; HR = 0.37, 95% CI = 0.16 to 0.87, P = 0.023).Conclusion CBF-AML is a heterogeneous disease with regard to c-KIT mutations. c-KIT mutations have a strong adverse impact on relapse and survival in adult t(8;21) AML.Grant support Nature Science Foundation of China (81170483 and 81370639) and Beijing Municipal Science & Technology Commission£¨Z141100000214011). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia

Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P = 0.355), but was a factor when using MB-PCR (P = 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P = 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML.

C-KIT with D816Y/V Mutations Cooperate with CBFB-MYH11 to Accelerate Leukemogenesis in Mice.

Abstract 274CBF leukemia is a group of acute myeloid leukemia (AML) caused by the fusion genes involving core binding factors (CBFs), which include RUNX1 and CBFB. C-KIT mutations are common in CBF leukemias. For example, 10–45% of AML cases with inv(16), which generates a fusion gene between CBFB and MYH11, carry activating mutations in c-KIT. In general, the presence of c-KIT mutations in inv(16) AML suggests poor clinical prognosis. Therefore, it is important to verify that c-KIT mutations cooperate with CBFB-MYH11, and to investigate the underlying mechanism during leukemogenesis. Here, we transduced bone marrow (BM) cells from conditional Cbfb-MYH11 knockin mice with retroviral vectors carrying c-KIT mutations,D816V and D816Y (located in the kinase domain of c-KIT and can cause constitutive activation of c-KIT), which are common in inv(16) AML. Wild type c-KIT and empty retroviral vectors were used as controls. The transduced BM cells were then transplanted to sub-lethally irradiated recipient mice. In 2–5 months, 60% of mice carrying D816Y and 50% of mice carrying D816V c-KIT mutations developed leukemia, while none of the mice transduced with the control vectors developed leukemia up to one year after transplantation. In addition, BM cells from wildtype mice transduced with the c-KIT mutant vectors did not induce leukemia >5 months after transplantation. Analysis of signaling pathways revealed that Stat3-serine phosphorylation and P44/42 MAPK pathways, but not AKT and Stat5 pathways, were activated (phosphorylated) in the leukemia cells from the Cbfb-MYH11 knockin mice expressing mutated c-KIT. In vitro colony forming assays indicated that Cbfb-MYH11 BM cells expressing c-KIT D816V/Y mutants produced similar number of colonies as Cbfb-MYH11 BM cells transduced with wild type c-KIT control vector. However, they had increased CFU-G and CFU-GEMM and decreased CFU-E colonies, suggesting that the c-KIT mutants drove Cbfb-MYH11 BM cells towards an earlier progenitor state. Secondary transplantation with 1×106 leukemia cells from donors with c-KIT mutations showed an average life span of three weeks compared to six weeks from donors without c-KIT mutation. Further limiting dilution transplantation with 100 leukemia cells from one donor with c-KIT mutation led to lethal leukemia in 4 out of 5 mice 2.5 months after transplantation, indicating a very high frequency of leukemia initiating cells in this sample. These data suggest a strong cooperation between the mutant c-KIT and Cbfb-MYH11 for leukemogenesis in mice. This mouse model can also serve as a clinically relevant model for small chemical screening and the development of novel therapeutic approaches. Disclosures:No relevant conflicts of interest to declare.

Imatinib Mesylate in Patients with WHO B3 Thymomas and Thymic Carcinomas

Thymic malignancies are rare tumors of the mediastinum. c-KIT is highly expressed in thymic carcinomas (TC) but infrequently in thymomas. Anecdotal experience suggests activity of imatinib mesylate in TC. Patients with unresectable World Health Organization B3 thymomas or TC, performance status 0 to 2, good organ function, and measurable disease were enrolled in this study. Imatinib was administered at 600 mg PO daily. Seven patients were recruited at one institution: two World Health Organization B3 thymomas and five TC. Imatinib treatment was generally well tolerated. Two patients had stable disease and five progressed. Median survival was 4 months, and median time to progression was 2 months. c-KIT expression was found in one of four samples by immunohistochemistry. No mutations were detected in the c-KIT or PDGFRA genes in three samples analyzed. Imatinib has no major activity in this rare tumor. Given the small number of patients treated in this study, selection based on presence of c-KIT mutations might be warranted.

A phase II study of imatinib mesylate as adjuvant treatment for curatively resected high-risk localized gastrointestinal stromal tumors

e21515 Background: In our previous study, the presence of c-kit mutation as well as tumor size and mitotic count was an independent poor risk factor for relapse after curative resection of primary localized GIST. The patients with all the 3 poor risk factors had only 30% of 2 year relapse free survival rate (RFSR). (Kim, et al. Clin Cancer Res, 2004) It is also well known that c-kit exon 11 mutant GISTs respond better to imatinib treatment than the other mutant or wild type GISTs. Therefore, the patients who have primary localized GISTs with large size, high mitotic count, and c-kit exon 11 mutation may be the best candidate of adjuvant imatinib treatment. In this phase II study, we have evaluated the efficacy and safety of adjuvant imatinib for this patient group. Methods: Patients who underwent complete resection of a primary GIST with 1) c-kit exon 11 mutation, and 2) ≥10 mitoses/50 HPF, or tumor size ≥10 cm, or ≥5 mitoses/50 HPF and tumor size ≥5 cm were eligible. Patients received imatinib 400mg p.o. daily until recurrence of disease, intolerable toxicities, or for 2 years. The primary end point was relapse-free survival (RFS). Results: A total of 47 patients from 4 centers in Korea were enrolled. The median age was 57.0 years. Stomach was the most common primary site (n=31). Median primary tumor size was 7.5cm and median mitoses index was 12/50 HPF. With a median follow-up of 26.9 months, the median RFS and overall survival (OS) have not yet been reached. RFSR was 97.7% at 1-year and 92.7% at 2-years. Six relapses (12.8%) were documented among the 47 patients. The treatments were generally well tolerated. Grade 3–4 toxicities included neutropenia 27.7%, rash 8.5%, constipation 4.3%, anorexia 2.1%, vomiting 2.1%, and pruritis 2.1%. There were no episode of febrile neutropenia and treatment-related death. Conclusions: Postoperative adjuvant imatinib for 2 years were safe and could prolong the RFS in patients with high-risk of recurrence following complete surgical resection of the primary GIST. However, it remains unknown if this benefit in RFS can be translated into OS benefit. So, further follow-up is needed with comparison of OS with historical controls who could be use imatinib after recurrence. [Table: see text]

Expression and Mutation Analysis of the Tyrosine Kinase c-Kit in Poorly Differentiated and Anaplastic Thyroid Carcinoma

Poorly differentiated and anaplastic thyroid carcinoma are aggressive tumors failing to res-pond to conventional therapy. Imatinib mesylate offers an effective therapeutic option in patients with various types of malignancies by inhibiting tyrosine kinases such as c-kit. In this study we investigated c-kit expression in anaplastic and poorly differentiated thyroid carcinoma compared to differentiated carcinoma and adenoma and the presence of c-kit mutations. In total, 224 thyroid tissues were analyzed by immunohistochemistry. Mutation analysis of exon 9, 11, 13, and 17 of the c-kit gene was performed in anaplastic and poorly differentiated carcinoma. c-Kit expression was negative in all anaplastic thyroid carcinoma, while c-kit expression of poorly differentiated carcinoma showed a high variability with a more intense staining in tumors showing obvious differentiated malignant follicular tumor areas. Differentiated carcinoma showed a slight, but not significantly stronger c-kit expression than poorly differentiated carcinoma. All tumors revealed wild type sequences of c-kit gene in exons 9, 11, 13, and 17. The low or lacking c-kit expression in undifferentiated thyroid carcinoma together with the lack of mutations argue against a crucial role of c-kit in thyroid carcinoma cell proliferation. Further molecular targets of imatinib mesylate have to be analyzed to estimate a potential benefit of this drug for patients with dedifferentiated thyroid carcinoma.

The GIST of a stromal tumor

The GIST of a stromal tumor

Prognostic Impact of C-Kit Mutations in Core Binding Factor-Leukemia.

C-KIT gene mutations are not a rare event in Core Binding Factor Leukemia (CBFL). To investigate their prognostic impact in this setting , we attempted at correlating the KIT mutational status with the WBC count, the level of the WBC-index, the presence of extramedullary disease (EMD) and the outcome, in t(8;21)(n=30) and inv(16) (n=20) AML patients. On the basis of genomic DNA analysis of c-KIT gene exons 2, 8, 10, 11, 17 for mutation detection, we categorized 21 patients (42%) in the “KIT mutated group” (KIT+) and 29 patients (58%) in the “KIT unmutated group” (KIT−). The median age at diagnosis was 46.4 and 45.6 years for the KIT(+) and KIT(−) groups, respectively (P=0.872). Among the KIT(+) patients, we found mutations in exon 8 (n = 4), exon 10 (n =1), exon 11 (n = 1) and exon 17 (n = 15). We recorded mean WBC counts of 28.6 x 109/L vs 34.5 x 109/L (P=0.051), and a mean WBC-index, expressed as WBC x (% Bone Marrow blasts/100), of 37.2 vs 15.5 (P=0.0395), for KIT(+) and KIT(−), respectively. Seven out of 50 patients experienced an EMD: in 6 cases (28.57%) this event occurred in the KIT(+) group. 40 patients (age < 60 years) were evaluable for clinical response; 18 out of them were KIT mutated. At a median follow-up of 24 months (range 10–107), we recorded for KIT(+) and KIT(−), respectively: CR incidence of 88.8 % (16/18) vs 100% (22/22) (P=0.38); Relapse Incidence 81.3% (13/16) vs 31.81% (7/22), P=0.0072; OS 27.7% (5/18) vs 77.3% (17/22), P=0.0049; DFS 16.7% (3/18) vs 77.3% (17/22), P=0.0005. Using a log-it linear model for univariate and multivariate regression analysis, we found a significant contribution to death (P=0.048) and relapse (P= 0.045) exerted by mutation in the whole group of patients; this effect was more evident when the analysis was restricted to patients <60 years (P=0.003 and P=0.014, respectively). In conclusion, this study confirms the correlation between c-KIT mutational status and high WBC-index in CBFL patients. Furthermore, our data indicate a statistical correlation between the presence of c-KIT mutations and both the OS and the DFS.

CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens.

The diagnosis of systemic mastocytosis (SM) is based primarily on the histologic and immunohistochemical evaluation of a bone marrow trephine biopsy specimen. Although mast cell (MC) specific antigens like tryptase and chymase are detectable in routinely processed tissue, no immunohistochemical markers that can be used to discriminate between normal and neoplastic MCs are yet available. We have investigated the diagnostic value of an antibody against CD25 for the immunohistochemical detection of MCs in bone marrow sections in 73 patients with SM and 75 control cases (reactive marrow, n = 54; myelogenous neoplasms, n = 21) and correlated the results with the presence of c-kit mutations. While MCs in almost all patients with SM (72 of 73) expressed CD25, none of the control samples contained CD25-positive MCs. Irrespective of the SM subtype, most of neoplastic MCs expressed CD25. In 3 patients with advanced MC disease, pure populations of neoplastic MCs were obtained and found to express CD25 mRNA by RT-PCR analysis. In addition, all patients with CD25-positive MCs contained c-kit mutations, while all control cases exhibited wild type c-kit. CD25 therefore appears to be a reliable immunohistochemical marker for the discrimination of neoplastic from normal/reactive MCs, with potential as a diagnostic tool in SM.

P53 mutations in gastrointestinal stromal tumor: Pattern and prognostic significance

9026 Background: Mutational activation of c-kit gene is recognized as a relatively early event in GIST tumorigenesis, and additional genetic alteration is needed for malignant transformation of GIST. The objective of this study was to evaluate the pattern and prognostic significance of p53 mutation as an additional genetic change. Methods: Previously, we analyzed c-kit mutations and clinical characteristics of 86 localized GISTs which were curatively resected between Jan 1990 and Dec 2001, and observed that presence of c-kit mutation and mitosis ≥ 5/50 HPF were independent poor prognostic factors for relapse-free survival (Kim, et al. Proc ECCO 2003). For these cases, clinical data were updated, and mutation analyses for p53 exons 4, 5, 6, 7, and 8 were performed with PCR and direct sequencing. Results: In 64 cases, p53 mutations were fully analyzed at exons 4, 5, 6, 7, and 8. Polymorphism at exon 4 was observed in 27 cases. P53 mutations were found in 19 (29.7%) cases; 4 in exon 4, 3 in exon 5, 6 in exon 6, 2 in exon 7, and 4 in exon 8, respectively. All were missense mutations in a single amino acid. Fifteen (31.3%) out of 48 patients with c-kit mutation and 4 (25.0%) out of 16 patients without c-kit mutation had p53 mutation (p = 0.785). By univariate analyses for relapse-free survival, mitosis (< 5/50 HPF vs. ≥ 5/50 HPF), tumor size (< 5cm vs. ≥ 5cm), c-kit mutation (presence vs. absence), cell type (spindle cell vs. others), necrosis (presence vs. absence), and cellularity (dense vs. sparse) were statistically significant factors. Multivariate analysis including p53 mutation (presence vs. absence) and above factors showed that mitosis ≥ 5/50 HPF (p = 0.0001), presence of c-kit mutation (p =0.02), presence of p53 mutation (p = 0.002) were significant independent poor prognostic factors for relapse-free survival. Conclusions: P53 mutation was found in a proportion of GISTs, and evenly distributed from exon 4 to exon 8 without any specific hot spots. P53 mutation was identified as an independent poor prognostic factor for relapse in addition to c-kit mutation and high mitosis in localized GISTs. P53 mutation may have a role in the malignant transformation of GISTs. No significant financial relationships to disclose.

Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors.

Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial. We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced. Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts < 5 mitoses/50 high power field, spindle-cell histology, tumor size < 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count > or = 5 of 50 high power fields; odds ratio (OR) = 3.0], presence of c-kit mutations (OR = 5.6), and a larger tumor size (> or = 5 cm; OR = 4.2). The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.

Receptor tyrosine kinase mutations in myeloid neoplasms.

Receptor tyrosine kinase mutations in myeloid neoplasms.

Mastocytosis: recent advances in defining the disease.

Mastocytosis is a rare disease characterized by a primary pathological increase in mast cells in different tissues, which may present in a variety of clinical patterns. Major advances have been made in recent years in the understanding of the pathogenesis of mastocytosis. This review is aimed at familiarizing dermatologists with these recent findings, and at exploring their possible implications for the diagnosis and treatment of the condition. The heterogeneous clinical presentation of mastocytosis is detailed with respect to the type of skin lesions, age at onset, family history, organ systems involved, associated haematological disorders and prognosis. Recent genetic findings also indicate different pathogenetic forms of mastocytosis, as adult patients and those with associated haematological diseases usually express activating mutations of the stem cell factor receptor c-kit, whereas most cases of childhood-onset and familial mastocytosis seem to lack these mutations. Despite the presence of c-kit mutations, patients with cutaneous lesions generally have a good prognosis, even when there is involvement of other organs. Some patients, particularly those with childhood-onset disease, experience spontaneous remission, mostly by puberty. c-kit mutations do not explain the initial cause of mastocytosis, and their prognostic significance is as yet unclarified, as is the pathogenesis in patients without the mutations. Furthermore, these novel findings have as yet not resulted in a more effective treatment of the cause of the disease, so that counselling, prevention of exposure to mast cell secretory stimuli, and symptomatic treatment remain the mainstays of current patient management.