• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7893-7895
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• 2015

Background: Acute promyelocytic leukemia (APL) is a distinctive clinical, biological and molecular subtype of acute myeloid leukemia. However, data from Pakistan are scarce. Therefore we reviewed the demographic and clinical profile along with risk stratification of APL patients at our center. Materials and Methods: In this descriptive cross sectional study, 26 patients with acute promyelocytic leukemia were enrolled from January 2011 to June 2015. Data were analyzed with SPSS version 22. Results: The mean age was $31.8{\pm}1.68years$ with a median of 32 years. The female to male ratio was 2:1.2. The majority of our patients had hypergranular variant (65.4%) rather than the microgranular type. The major complaints were bleeding (80.7%), fever (76.9%), generalized weakness (30.7%) and dyspnea (15.38%). Physical examination revealed petechial rashes as a predominant finding detected in 61.5% followed by pallor in 30.8%. The mean hemoglobin was $8.04{\pm}2.29g/dl$ with the mean MCV of $84.7{\pm}7.72fl$. The mean total leukocyte count of $5.44{\pm}7.62{\times}10^9/l$; ANC of $1.08{\pm}2.98{\times}10^9/l$ and mean platelets count were $38.84{\pm}5.38{\times}10^9/l$. According to risk stratification, 15.3% were in high, 65.4% in intermediate and 19.2% in low risk groups. Conclusions: Clinico-epidemiological features of APL in Pakistani patients appear comparable to published data. Haemorrhagic diathesis is the commonest presentation. Risk stratification revealed predominance of intermediate risk disease.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3963-3967
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• 2013

Background: The presence of Epstein-Barr virus (EBV) in Non-Hodgkin's lymphoma can be identified by immunohistochemistry for detection of EBV latent membrane protein (LMP). The role of EBV as an etiologic agent in the development of non-Hodgkin lymphoma has been supported by detection of high levels of latent membrane protein 1 (LMP-1) expression in tumors. However, no study has been conducted in a Pakistani population up till now to determine the frequency of Epstein-Barr virus positivity. The objective of our study was to determine a value for non-Hodgkin lymphoma patients using EBV LMP-1 immunostaining in our institution. Materials and Methods: This study was carried out at the Department of Histopathology, Armed Forces Institute of Pathology (AFIP), Pakistan from December 2011 to December 2012. It was a cross sectional study. A total of 71 patients who were diagnosed with various subtypes of NHL after histological and EBV LMP-1 immunohistochemical evaluation were studied. Sampling technique was non-probability purposive. Statistical analysis was achieved using SPSS version 17.0. Mean and SD were calculated for quantitative variables like patient age. Frequencies and percentages were calculated for qualitative variables like subgroup of NHL, results outcome of IHC for EBV and gender distribution. Results: Mean age of the patients was $53.6{\pm}16$ years (Mean${\pm}$SD). A total of 50 (70.4%) were male and 21 (29.6%) were female. Some 9 (12.7%) out of 71 cases were positive for EBV-LMP-1 immunostaining, 2 (22.2%) follicular lymphoma cases, 1 (11.1%) case of T-cell lymphoblastic lymphoma, 4 (44.4%) cases of diffuse large B cell lymphomas, 1 (11.1%) mantle cell lymphoma and 1 (11.1%) angioimmunoblastic T cell lymphoma case. Conclusion: In our study, frequency of EBV in NHL is 12.7% and is mostly seen in diffuse large B cell lymphoma. This requires further evaluation to find out whether this positivity is due to co-infection or has a role in pathogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.2307-2309
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• 2016

Background: Acute lymphoblastic leukemia (ALL) is a malignant disease in which early lymphoid precursors proliferate and replace the normal hematopoiesis. It has distinctive clinical and biological features. In respect to adult ALL, available data from Pakistan are limited. Therefore we reviewed the demographical and clinicohematological profiles along with FAB stratification of adult patients with ALL presented at our hospital. Materials and Methods: In this cross sectional study, 51 adults (${\geq}15years$) patients with ALL were enrolled from January 2010 to December 2014. Results: The mean age was $23.8{\pm}12.9years$ with the median age of 18.0 years. The male to female ratio was 2:1. The major complaints were fever (60.7%), generalized weakness (47.0%), overt bleeding (19.6%) and weight loss (13.7%). Physical examination revealed lymphodenopathy as a predominant finding detected in 43.1% followed by splenomegaly and hepatomegaly in 23.5% and 21.5%, respectively. The mean hemoglobin level was $9.0{\pm}2.75g/dl$ with a mean MCV of $82.2{\pm}15.4fl$, a mean total leukocyte count of $31.1{\pm}64.0{\times}10^9/l$, a mean ANC of $2.1{\pm}3.0{\times}10^9/l$ and a mean platelet count of $71.7{\pm}85.7{\times}10^9/l$. According to FAB classification, 47.1% were L1 type, 45.1% L2 and 7.8% L3 variant. Conclusions: Clinico-pathological features appeared comparable to published data. Febrile illness associated with lymphodenopathy was the commonest presentation. FAB classification revealed a predominance of ALL-L1 variant in Pakistani adult patients with ALL.

• Journal of Genetic Medicine
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• v.12 no.1
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• pp.19-24
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• 2015

Speech and language are uniquely human-specific traits, which contributed to humans becoming the predominant species on earth. Disruptions in the human speech and language function may result in diverse disorders. These include stuttering, aphasia, articulation disorder, spasmodic dysphonia, verbal dyspraxia, dyslexia and specific language impairment. Among these disorders, stuttering is the most common speech disorder characterized by disruptions in the normal flow of speech. Twin, adoption, and family studies have suggested that genetic factors are involved in susceptibility to stuttering. For several decades, multiple genetic studies including linkage analysis were performed to connect causative gene to stuttering, and several genetic studies have revealed the association of specific gene mutation with stuttering. One notable genetic discovery came from the genetic studies in the consanguineous Pakistani families. These studies suggested that mutations in the lysosomal enzyme-targeting pathway genes (GNPTAB, GNPTG and NAPGA) are associated with non-syndromic persistent stuttering. Although these studies have revealed some clues in understanding the genetic causes of stuttering, only a small fraction of patients are affected by these genes. In this study, we summarize recent advances and future challenges in an effort to understand genetic causes underlying stuttering.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7169-7174
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• 2014

Background: NPAS2 is a product of the circadian clock gene. It acts as a putative tumor suppressor by playing an important role in DNA damage responses, cell cycle control and apoptosis. Chronic lymphocytic leukemia (CLL) appears to be an apoptosis related disorder and alteration in the NPAS2 gene might therefore be directly involved in the etiology of CLL. Here, the Ala394Thr polymorphism (rs2305160:G>A) in the NPAS2 gene was genotyped and melatonin concentrations were measured in a total of seventy-four individuals, including thirty-seven CLL cases and an equal number of age- and sex-matched healthy controls in order to examine the effect of NPAS2 polymorphism and melatonin concentrations on CLL risk in a Pakistani population. Materials and Methods: Genotyping of rs2305160:G>A polymorphism at NPAS2 locus was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Melatonin concentrations were determined by enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed using Statistical Package for Social Sciences software. Results: Our results demonstrated no association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with risk of CLL. Similarly, no association of rs2305160 with CLL was observed in either females or males after stratification of study population on a gender basis. Moreover, when the subjects with CLL were further stratified into shift-workers and non-shift-workers, no association of rs2305160 with CLL was seen in either case. However, significantly low serum melatonin levels were observed in CLL patients as compared to healthy subjects (p<0.05). Also, lower melatonin levels were seen in shift-workers as compared to non-shift-workers (p<0.05). There was no significant difference (p>0.05) in the melatonin levels across NPAS2 genotypes in all subjects, subjects with CLL who were either shift workers or non-shift-workers. General Linear Model (GLM) univariate analysis revealed no significant association (p>0.05) of the rs2305160 polymorphism of the NPAS2 gene with melatonin levels in any of the groups. Conclusions: While low melatonin levels and shift-work can be considered as one of the risk factors for CLL, the NPAS2 rs2305160 polymorphism does not appear to have any association with risk of CLL in our Pakistani population.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7187-7191
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• 2013

Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobiotic processing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites are generally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymes determines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certain conditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolites that can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed to test the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile of metabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controls using Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same study cohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as compared to the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expression of GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). This down regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions. Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared to controls. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV, p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizing genes may be involved in brain tumor development in Pakistani population. Investigation of expression of these genes may provide information not only for the prediction of individual cancer risk but also for the prevention of cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7589-7595
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• 2014

Apurinic/apyrimidinic endonuclease 1 (APEX1) is a multifunctional protein which plays a central role in the BER pathway. APEX1 gene being highly polymorphic in cancer patients and has been indicated to have a contributive role in Apurinic/apyrimidinic (AP) site accumulation in DNA and consequently an increased risk of cancer development. In this case-control study, all exons of the APEX1 gene and its exon/intron boundaries were amplified in 530 breast cancer patients and 395 matched healthy controls and then analyzed by single-stranded conformational polymorphism followed by sequencing. Sequence analysis revealed fourteen heterozygous mutations, seven 5'UTR, one 3'UTR, two intronic and four missense. Among identified mutations one 5'UTR (rs41561214), one 3'UTR (rs17112002) and one missense mutation (Ser129Arg, Mahjabeen et al., 2013) had already been reported while the remaining eleven mutations. Six novel mutations (g.20923366T>G, g.20923435G>A, g.20923462G>A, g.20923516G>A, 20923539G>A, g.20923529C>T) were observed in 5'UTR region, two (g.20923585T>G, g.20923589T>G) in intron1 and three missense (Glu101Lys, Ala121Pro, Ser123Trp) in exon 4. Frequencues of 5'UTR mutations; g.20923366T>G, g.20923435G>A and 3'UTR (rs17112002) were calculated as 0.13, 0.1 and 0.1 respectively. Whereas, the frequency of missense mutations Glu101Lys, Ser123Trp and Ser129Arg was calculated as 0.05. A significant association was observed between APEX1 mutations and increased breast cancer by ~9 fold (OR=8.68, 95%CI=2.64 to 28.5) with g.20923435G>A (5'UTR), ~13 fold (OR= 12.6, 95%CI=3.01 to 53.0) with g.20923539G>A (5'UTR) and~5 fold increase with three missense mutations [Glu101Lys (OR=4.82, 95%CI=1.97 to 11.80), Ser123Trp (OR=4.62, 95%CI=1.7 to 12.19), Ser129Arg (OR=4.86, 95%CI=1.43 to 16.53)]. The incidence of observed mutations was found higher in patients with family history and with early menopause. In conclusion, our study demonstrates a significant association between germ line APEX1 mutations and breast cancer patients in the Pakistani population.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.603-606
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• 2013

Background: Ovarian cancer is the second most common malignancy in Pakistani women, accounting for 4% of all cancers in the female population. The aim of this study was to determine sensitivity, specificity, positive and negative predictive values and 95% confidence intervals for ultrasound in characterization of ovarian masses in patients presenting at public and private tertiary care hospitals in Karachi, Pakistan. Materials and Methods: We adopted a cross-sectional analytical study design to retrospectively collect data from January 2009-11 from medical records of two tertiary care hospitals. Using a non-probability purposive sampling technique, we recruited a sample of 86 women aged between 15 and 85 years fulfilling inclusion criteria with histopathologically proven ovarian masses presenting for an ultrasound examination in our radiology departments. Results: Our retrospective data depicted sensitivity and specificity of ultrasound to be 90.7%, 95%CI (0.77, 0.97) and 91.4%, 95%CI (0.76, 0.98) respectively. Positive predictive value was 93%, 95%CI (0.79, 0.98) and negative predictive value was 89%, 95%CI (0.73, 0.96). A total of 78 ovarian masses were detected, out of which 42 were malignant and 36 were benign. Conclusions: Results of our study further reinforce the conclusion that ultrasound should be used as an initial modality of choice in the workup of every woman suspected of having an ovarian mass. It not only results in decreasing the mortality but also avoids unnecessary surgical interventions.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3005-3010
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• 2013

Background: To present the overall clinical and histological perspective of benign and malignant prostatic disease as seen in our practice in the Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi, Pakistan. Materials and Methods: All consecutive prostate specimens (transurethral resection or TUR, enucleation, needle biopsies) received between July 1, 2012 and December 31, 2012 were included in the study. Results: Of the total of 785 cases, 621 (79.1%) were TUR specimens, 80 (10.2%) enucleation specimens, and 84 (10.7%) needle biopsies. Some 595 (75.8%) were benign, while 190 (24.2%) were malignant. Mean weight of BPH specimens was 19 grams and 43 grams for TUR and enucleation specimens respectively. Almost 67% of adenocarcinomas were detected on TUR or enucleation specimens. Of the above cases, 41.7% were clinically benign while 58.3% were clinically malignant. The average volume of carcinoma in all cases ranged between 60 to 65%. The average number of cores involved in needle biopsies was 5. In general, higher Gleason scores were seen in TUR/enucleation specimens than in needle biopsies. Overall, in all types of specimens, commonest Gleason score was 7, seen in 74 (38.9%) cases, followed by Gleason score 9 seen in 47 (24.7%) cases. Out of the 63 needle biopsies with carcinoma, radical prostatectomy was performed in 16 cases (25.4%). Conclusions: Benign prostatic hyperplasia (BPH) is extremely common and constitutes the bulk of prostate specimens. TMajority of prostatic carcinomas are still diagnosed on TUR or enucleation specimens. These included both clinically benign and clinically malignant cases. The volume of carcinoma in these specimens was quite high indicating extensive disease. Gleason scores were also generally high compared with scores from needle biopsies. Commonest Gleason score in all type of specimens was 7. Pathologic staging was possible in very few cases since radical prostatectomies are rarely performed.

• Journal of Genetic Medicine
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• v.16 no.2
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• pp.85-89
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• 2019

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder. HHH is caused by a deficiency of the mitochondrial ornithine transporter protein, which is encoded by the solute carrier family 25, member 15 (SLC25A15) gene. Recently, government supported Korean newborn screening has been expanded to include a tandem mass spectrometry (MS/MS) measurement of ornithine level. We report a case of a neonate with HHH syndrome showing a normal MS/MS measurement of ornithine level. A female newborn was admitted to neonatal intensive unit due to familial history of HHH syndrome. Her parents were consanguineous Parkistani couple. The subject's older sister was diagnosed with HHH syndrome at age of 30 months based on altered mental status and liver dysfunction. Even though the subject displayed normal ammonia and ornithine levels based on MS/MS analysis, a molecular test confirmed the diagnosis of HHH syndrome. At 1 month of age, amino acid analysis of blood and urine showed high levels of ornithine and homocitrulline. After 11 months of follow up, she showed normal growth and development, whereas affected sister showed progressive cognitive impairment despite no further hyperammonemia after protein restriction and standard therapy. Our report is in agreement with a previous Canadian study, which showed that neonatal samples from HHH syndrome patients demonstrate normal ornithine levels despite having known mutations. Considering the delayed rise of ornithine in affected patients, genetic testing, and repetitive metabolic testing is needed to prevent patient loss in high risk patients.