ZAP-70 Protein Expression in B-cell Chronic Lymphoid Leukemia: a Single Center Experience from Pakistan

Zeeshan, Rozina,Irfan, Syed Mohammed,Sultan, Sadia,Bhimani, Sanjana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.4

Background: Chronic lymphoid leukemia (CLL) is the most frequent type of adult leukemia. The Rai and Binet staging systems have been well recognized as standards for assessing the treatment requirements and overall survival in CLL patients. However, there is a need to seek newer prognostic markers to identify stable or progressive forms of CLL that will facilitate risk-adapted treatment strategies. Currently a molecular biomarker ZAP-70 has attracted interest as providing prognostic information in CLL patients. Objective: To determine the frequency of ZAP-70 positivity in B-CLL patients at disease presentation. Materials and Methods: From January 2011 to September 2014, 89 patients were diagnosed to have chronic lymphoid leukemia. Complete blood count was done on an automated analyzer (Cell Dyne, Abott Architect, USA), while immunophenotyping was conducted for each patient to establish the diagnosis of the disease. ZAP-70 expression was evaluated by flow cytometry. Data were compiled and analyzed by SPSS version 21. Results: Out of the total of 89 B-CLL patients, 62 (69.7%) were male and 27 (30.3%) were females with a male to female ratio of 2:1. The mean age was $57.5{\pm}12.1years$. The frequency of ZAP-70 positivity in our B-CLL patients was found to be 13.5%. ZAP-70 positivity was significantly correlated with stage III disease and high absolute lymphocytic count (P<0.05). No correlation of ZAP-70 could be established with age and gender (p>0.05). Conclusions: The frequency of ZAP-70 in our patients appears low. It is approximately half that in international data. We would recommend to screen all the newly diagnosed patients with CLL for ZAP-70 protein expression for risk stratification, family counseling and to predict overall survival.

Direct Coombs Test Positivity in B-Chronic Lymphoid Leukemia: a Marker of Advanced Clinical Disease

Abbas, Syeda Alia,Zeeshan, Rozina,Sultan, Sadia,Irfan, Syed Mohammad Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Background: Chronic lymphoid leukemia (CLL) is a malignant hematopoietic disorder, the most common of all adult leukemias with a distinctive immunophenotype. It is well established that CLL patients can have autoimmune complications, amongst them autoimmune hemolytic anemia as the most frequent. This study was carried out to determine the frequency of direct Coombs Test positivity in CLL patients and its possible correlation with Rai staging, hematological parameters and biochemical markers. Materials and Methods: This descriptive cross sectional study was carried at Liaquat National Hospital from January 2011 to June 2013. Sixty untreated patients with B- chronic lymphoid leukemia were enrolled. Complete blood count, direct Coombs test, serum urea, creatinine, uric acid and LDH levels were determined. Data were compiled and analyzed using SPSS version 21. Results: Out of 60 patients, 42(70%) were males and 18(30%) were females. Mean age was $59{\pm}9.2years$. Male to female ratio was 2.1: 1. The frequency of direct antiglobulin test (DAT) positivity was found to be 23.3%. The monospecific IgG was positive in 11 patients (18.3%); C3d positivity was evident in 1 patient (1.6%) and 2 patients (3.3%) had dual IgG and C3d positivity. The mean hemoglobin was $10.8{\pm}2.4gm/dl$. Significantly low mean hemoglobin of $8.3{\pm}3.0gm/dl$ was seen in Coombs positive patients compared with negative patients having a mean hemoglobin level of $11.7{\pm}1.6gm/dl$ (P<0.001). DAT positivity also demonstrated a positive association with advanced Rai stage III disease (P<0.01). No associations were noted with age, gender and biochemical markers. Conclusions: Direct Coombs test positivity in CLL in our patients, unlike in Western studies, appears relatively high, indicating significant autoimmune hemolytic anemia and advanced Rai stage in our setting. DAT positivity can be considered as a surrogative marker for advanced clinical disease.

림프구 증식증과 유사한 형태로 말단 회장부와 대장을 침범한 만성 림프구성 백혈병 1예

이민지,이향이,고훈,이윤정,정성희,양현웅,김안나,차상우 대한소화기내시경학회 2009 Clinical Endoscopy Vol.39 No.4

Follicular lymphoid hyperplasia is commonly seen when performing pediatric endoscopy. But in adults, these findings can imply an underlying gastrointestinal or systemic illness, besides the normal variant. On the other hand, colonic involvement of chronic lymphocytic leukemia (CLL) is seen in about 5% to 20% of autopsy cases. However, there have been few reports on the colonoscopic appearance that corresponds to colonic involvement by CLL, and the reported colonoscopic appearances have included polyps, ulcers, granularity, submucosal nodules, erythema, the red ring sign etc. We report here on a case of CLL neoplastic lymphocyte involvement of the terminal ileum and colon as a form of lymphoid hyperplasia, and this was seen when performing colonoscopy. 만성 림프구성 백혈병의 대장 침범은 사체부검에 의한 연구에 의하면 약 5∼20% 정도이다. 그러나 실제 침범된 대장의 내시경 소견이 보고된 경우는 드물며 용종, 궤양, 과립상, 점막하 결절, 발적, red ring sign 등의 소견들이 보고된 바 있다. 한편 림프구 증식증은 림프계 이외의 조직에 주로 림프구가 침윤하는 것으로 소아에서는 비교적 흔히 발견되고 건강한 성인에서도 발견될 수 있으며 내시경적으로 작은 무경성 용종이나 적색 반점 등으로 관찰된다. 최근 저자들은 내시경 소견상 림프구 증식증과 유사한 형태로 만성 임파구성 백혈병이 말단 회장부 및 대장을 침범한 증례를 경험하여 보고한다.

The Cytologic Features of Chronic Myelogenous Leukemia and Its Lymphoid Blast Phase in Body Fluid - A Case Report -

임소영,유창영,이연수,강창석,심상인,이교영 대한병리학회 2009 Journal of Pathology and Translational Medicine Vol.43 No.2

Although chronic myelogenous leukemia (CML) may be involved in any part of the body, infiltration of the body fluid has rarely reported in the literature. Here we report on a 35 year-old male patient who was diagnosed chronic myelogenous leukemia ten years previously and he received allogenic hematopoietic stem cell transplantation. He then presented with left knee pain eight years after the initial diagnosis. MRI revealed a soft tissue mass at the distal femur. Cytology of the joint fluid revealed myeloblasts, promyelocytes, eosinophilic myelocytes, band neutrophils, megakaryocytes and orthochromatic erythroblasts, which was all consistent with leukemic infiltration of the knee joint fluid. The immunohistochemistry was positive for CD34, CD117 and myeloperoxidase (MPO). Despite that the patient underwent radiation therapy, MRI revealed growth of the mass, and ten months later, the lymphoid blast phase of CML was confirmed after biopsy. The patient received an above knee amputation. Five months later, multiple masses were revealed on PET-CT at the left iliopsoas muscle, abdominal wall and bones. Bilateral pleural effusion occurred shortly after this. Cytologic evaluation of the pleural fluid also revealed blast-like cells, and histologic evaluation of the abdominal mass confirmed the lymphoid blast phase of CML with positivity for CD3, UCHL-1, CD34 and CD117, but negativity for MPO.

Serum 25-hydroxyvitamin D Insufficiency in B-Chronic Lymphoid Leukemia at the Time of Disease Presentation in Pakistan

Parveen, Saira,Zeeshan, Rozina,Sultan, Sadia,Irfan, Syed Mohammad Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Background: Serum 25-hydroxyvitamin D insufficiency is very common in Pakistan and is often related to inferior prognosis in some cancers but limited data exist for hematopoietic malignancies. This study was conducted to determine the vitamin D insufficiency in B-chronic lymphoid leukemia (CLL) cases at the time of presentation and its possible correlation with clinical staging, hematological parameters and biochemical markers. Materials and Methods: This descriptive cross sectional study was carried at Liaquat National Hospital from January 2011 to June 2013. Sixty patients with B-chronic lymphoid leukemia were enrolled. Complete blood count, vitamin D levels, serum urea, creatinine, uric acid and LDH levels were assessed. Data were compiled and analyzed using SPSS version 21. Results: Out of 60 patients, 42 (70%) were male and 18 (30%) were female. Mean age was $59.0{\pm}9.2years$. The frequency of vitamin D insufficiency was found to be 56.7%. Overall insufficiency was more frequently seen in male gender (40%). Vitamin D insufficiency demonstrated a positive association with low lactate dehydrogenase levels (P=0.005). No links were established with age, clinical stage, hematological and other biochemical markers. Conclusions: Vitamin D insufficiency is high compared with Western studies. Whether normalization of vitamin D insufficiency in deficient B-CLL patients could improve the clinical outcome or delay disease progression will require further studies.

Clinico-Hematological Profile of Patients with B-Chronic Lymphoid Leukemia in Pakistan

Zeeshan, Rozina,Sultan, Sadia,Irfan, Syed Muhammad,Kakar, Jamaludin,Hameed, Muhammad Asif Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.2

Background: Chronic lymphoid leukemia (CLL) is not an uncommon hematological malignancy which primarily affects elderly individuals. It is more common in developed world than in developing countries. The rational of this study was to determine the clinico-hematological profile in Pakistan. Materials and Methods: In this prospective cross sectional study, sixty patients with CLL were enrolled from January 2011 to June 2013. Data were analyzed with SPSS version 21. Results: The mean age was $59.0{\pm}9.2years$ (range 40-82) and the male to female ratio was 2.1:1. Peak age group was 60-70 years (38.3%) and 18.3% were under 50 years old. Major complaints were weakness (51.7%), fever (18.3%) and abdominal discomfort (13.3%). Main clinical findings were splenomegaly (46.6%), lymphadenopathy (36.6%) and pallor (26.7%). Some 16.7% were diagnosed incidentally. The mean hemoglobin was $10.8{\pm}2.4g/dl$, with a total leukocyte count of $91.5{\pm}87.8{\times}10^9/l$ and platelets $197.8{\pm}103.2{\times}10^9/l$. Anemia and thrombocytopenia were seen in 26.7% and 21.7% of cases, respectively. High LDH and hyperuricemia were detected in 15% each and elevated serum creatinine was seen in 11.6%. According to Rai staging 11.6% were in stage 0, 13.3% stage 1, 26.7% each for stage II and stage III while 21.7% patients were in stage IV. Conclusions: CLL in our patients in Pakistan, unlike in the West, is seen in a relatively young population with male predominance. Primarily disease is of B-cell origin and about 2/3 of the patients present at advanced stage.

Synthesis and Antitumor Evaluation of Acyclic 1-[∞-(N¹-2-chloroethyl-N¹-nitrosoureido)alkyl]thymidine Nucleoside Analogues

Kim, Young-Hyun,Kim, Seon-Hee,Park, Jin Il,Kim, Jack C.,Choi, Soon-Kyu 東亞大學校附設基礎科學硏究所 1998 基礎科學硏究論文集 Vol.15 No.1

In the preparation of acyclic thymidine nucleoside analogues, K₂CO₃(or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite ????????? to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5:1 ratios. Reduction of the cyano function 2a-d with NaBH₄/CoCl₂· 6H₂O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in 3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N¹2-chloroethylureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N¹-2-chloroethylureido)pentyl]thymine (4d) with glacial acetic acid and dry NaNO₂powder in anhydrous CH₂Cl₂gave two types of regioisomeric nitrosoureas, 1-[5-(N¹-2-chloroethyl-N¹-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N¹-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5:1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and 5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as ?? values. Compounds 3b and 4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

Synthesis and Antitumor Evaluation of Acyclic 1-[${\omega}$-(N^I-2-chloroethyl-N^I-nitrosoureido)alkyl]thymidine Nucleoside Analogues

Kim, Jack-C.,Kim, Young-Hyun,Park, Jin-Il,Kim, Seon-Hee,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1997 Archives of Pharmacal Research Vol.20 No.3

In the preparation of acyclic thymidine nucleoside analogues, $K_2CO_3$(or NaH) treated thymine in DMSO was alkylated with .omega.-chloroalkyl nitrite (Cl-(CH_2)n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(${\omega}$-cyanoalkyl)thymine (2a-d) and 1,3-bis(${\omega}$-cyanoalkyl)thymine in approximately 5:1 ratios. Reduction of the cyano function 2a-d with $NaBH_{4}/CoCl_{2}$ center dot$ 6H_{2}O$gave the corresponding 1-(${\omega}$aminoalkyl)thymine (3a-d). The newly formed primary amino function in 3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[.omega.($N^{I}$-2-chloroethylureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-($ N^{I}-2$-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry $NaNO_{2}$-powder in anhydrous $CH_{2}Cl_{2}$gave two types of regioisomeric nitrosoureas, 1-[5-($N^{I}$--chloroethyl-$N^{I}$--nitrosoureido)pentylithymine (5d) and 1-[5-($N^{I}-2$-chloroethyl-N-nitrosoureido)pentyllthymine in approximately 5 :1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and 5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as $IC^{50}$ values. Compounds 3b and 4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.

Synthesis of a series of cis-diamminaedichloro-platinum (II) Complexes Linked to Uracil and Uridine as Candidate An-titumor Agents.

Kim, Jack-C.,Kim, Mi-Hyang,Kim, Seon-Hee,Choi, Soon-Kyu The Pharmaceutical Society of Korea 1995 Archives of Pharmacal Research Vol.18 No.6

The search for patinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichlorplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are ; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II)(3a), [N-2(2-aminoethyl)uracil-6-carboxmide]dichloroplatinum (II) (3b),[5-(2-aminorthyl)carbamoyl-2',3',5',-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)-carbamoyl]-2',3',5',-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoylu-ridine]dihloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxmide (2a) land N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes 3a and 3b were obtained through the reaction of the respective 2a and 2b ficiently introduced on the .betha.-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitfile to yield the sterospecific .betha.-anomeric 5-carboxy-2',3',5'-tri-O-acetyluridine (4a) and 6-carboxy-2',3',5'-tri-O-acetyluridine (4b), respective 5-(2-aminoethyl)carbamoyl-2',3',5'-tri-O-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2',3',5'-tri-O-acetyluridine (5b). The diamino-uridines 5a and 5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes, 6a and 6b respectively which were deacetylated into the free nucleosides, 7a and 7b by the treatment with CH/sub 3/ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).