Clinical Characteristics And Treatment Outcome Of Paediatric Non-Hodgkin's Lymphoma At A Tertiary Care Hospital In Pakistan.

Objectives: To highlight the clinical characteristics of paediatric patients presenting with non-Hodgkin's lymphoma, treatment toxicities, and outcome. METHODS: The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of all paediatric patients aged 0-18 years diagnosed with non-Hodgkin's lymphoma from 2010 to 2020. Demographic characteristics, presentation, treatment provided, complications, if any, and treatment outcome were recorded. Data was analysed using SPSS 21. RESULTS: Of the 92 patients, 69(75.0%) were males. The overall mean age was 14.35±5.80 years. The most common presenting complaint was pyrexia 42(45.7%), the most common diagnosis was Burkitt lymphoma 40(43.5%), the most common complication related to gastrointestinal issues 8(15.7%), and most toxicities were reported with the use of FAB-LMB96 (French American-British Mature B-Cell Lymphoma 96) for B-cell non-Hodgkin's lymphoma 23 (45.1%). Mortality was the outcome in 17(18.5%) cases, while 19(20.7%) patients were lost to follow-up. PFS and OS was 60.4%, and OS 81.3% respectively at 10 years follow-up, median PFS was 17.5 months ([IQR]: 4.5-43.5 months) (p=0.011) and median OS was 33.5 months (IQR: 19.5-84 months) (p=0.007). CONCLUSIONS: Early recognition of symptoms, specialist care, and proper planning can decrease treatment-related complications that result in abandonment.

Karachi Cancer Registry (KCR): Consolidated Data of 5-years 2017-2021.

OBJECTIVE:  To collect and analyse epidemiologic data of all malignancies by age group and gender for the Karachi population to estimate the cancer incidence of 5-years (2017-2021) and identify major risk factors for setting priorities towards cancer control programs. STUDY DESIGN: Observational study. Place and Duration of the Study: Karachi Cancer Registry (KCR) Secretariat, Pakistan Health Research Council (PHRC), JPMC, Karachi, from 2017-2021. METHODOLOGY: Cancer data of seven tertiary care hospitals of Karachi submitted to KCR during the study period were analysed including age, gender, date of first contact, primary site and ICD coding. All the data was cleaned, merged, and analysed. All patients 0-14 years were classified as 'children', all aged 15-19 years were classified as 'adolescents', and those age 20-years and above as 'adults'. Age standardised incidence rates (ASIR) were determined for both genders. RESULTS: During the last five years (2017-2021), a total of 65,886 malignant cases were received. The distributions seen amongst males and females were 33,510 (51%) and 32,376 (49%), respectively with 60,145 (91.3%) tumours found in adults (≥20 years), 4844 (7.3%) in children, and 897 (1.4%) in adolescents. The three most common tumour sites were oral, liver, and colorectal in males; breast, oral and ovary in females; bone, brain and connective tissue in adolescents; and leukaemia, brain and bone in children. The overall ASIR (%) in males was 89.20 for adults, 9.19 for children, and 1.61 for adolescents. The overall ASIR (%) in females was 93.44 for adults, 5.45 for children, and 1.11 for adolescents. CONCLUSION: Oral cancer, a largely preventable cancer is the leading cancer in males while breast cancer is the leading cancer in females followed by oral cancer. In adolescents and children, the incidence closely matches most of the world. KEY WORDS: Karachi, Cancer registry, Oral cancer, Breast cancer, Age-standerdised ratio.

Genetic aberrations involved in relapse of pediatric acute myeloid leukemia: A literature review.

Globally, 15-20% of all children diagnosed with leukemia suffer from acute myeloid leukemia (AML), a rapidly progressive, clinically and biologically heterogeneous disease leading to the impaired differentiation of myeloid blast cells. Although 80% of patients achieve complete remission after induction chemotherapy, many relapse, negatively affecting overall out comes. The mechanisms underlying relapse have not been fully elucidated. This review aims to provide an overview of genetic aberrations involved in relapse of disease. A literature review on molecular mechanisms implicated in pediatric AML relapse spanning from 2003 to 2017 was conducted. PubMed, Medline, and Google Scholar were interrogated using relevant search terms. Of note, we examined a total of final 10 research papers from four large study groups that have utilized whole genome sequencing and molecular targeting of trio or paired samples of initial diagnosis, remission, and relapse. Their findings reveal that the genomic landscape of pediatric AML varies from diagnosis to relapse in different populations. Pediatric AML relapse is a systemic evolutionary illness accompanied by synchronized mutational hits impairing differentiation function. The irregular proliferative function is a consequence of mutations in signal transduction genes such as FLT3, RAS, PTPN11, and c-KIT and genes that code for transcription factors such as CEBPα, WT1, SATB1, GFI1, KLF2, and TBP are associated with relapse of disease. Identification of molecular markers unique to different stages of the disease in distinct populations can provide valuable information about disease prognosis and management.

Metachronous translocation renal cell carcinoma in a child with successfully treated medulloblastoma.

BACKGROUND: The most common primary CNS tumor in children is the medulloblastoma, which generally occurs in the posterior fossa and can spread through the CNS and spinal cord. Although the recurrence of renal cell carcinoma as a secondary tumor to neuroblastoma has been reported with successful anti-neoplastic treatment, the rare occurrence of a child who initially had medulloblastoma and then developed translocation renal cell carcinoma has never been reported before. CASE PRESENTATION: We report the case of a 12-year-old boy who initially presented with complaints of vomiting and headache. An MRI head confirmed the presence of 4 × 4 × 3 cm lesion which was resected completely and histopathology report confirmed the diagnosis of medulloblastoma Grade IV. Four years later, the child came for a follow-up visit and during routine screening, a CT scan showed heterogeneous lesion arising from the lower pole calyx of right kidney. The patient was referred to pediatric surgery for right radical nephrectomy involving the right adrenal gland. The histopathology report was consistent with the diagnosis of translocation renal cell carcinoma. CONCLUSION: Central nervous system (CNS) tumors remain the leading cause of death among pediatric neoplasms. We advise genetic testing of index cases and the establishment of an international tumor registry for a challenging disease.

Intracranial tumors in children: a 10-year review from a single tertiary health-care center.

OBJECTIVE: Brain tumors are the second most common pediatric malignancy and the most common cause of cancer-related mortality and morbidities. Major advances in terms of surgery, radiation, and chemotherapy have led to better outcomes in developed countries. Delayed diagnosis, advanced disease at presentation, late referrals, nosocomial infections, delays to radiotherapy, and poor support services are the major reasons for poorer outcomes in developing countries. Little is known about the profile of brain tumors in Pakistan. This study aims to evaluate the epidemiology, management, and clinical outcomes of children with brain tumors in Pakistan in a single tertiary care center. METHODS/MATERIALS: All children (0-16 years) with primary CNS tumors from 2004 to 2014 at Aga Khan University Hospital were reviewed retrospectively for clinical data, demographics, radiological findings, management, and outcome. RESULTS: One hundred seventy-five children were included in the study. Male to female ratio was 1.4:1. Most of the patients were in 5-10 years age group (38.9%). Most common presenting complains were headache 115 (65.7%) and vomiting 100 (57.1%). Predominant site was infratentorial 93 (53%). Glial tumors were 105 (60%) followed by embryonal 40(22.9%), craniopharyngiomas 25 (14.3%), and germ cell 1 (0.6%). Astrocytomas (25.7%) were the most common glial tumors while medulloblastoma (15.4%) was the most common embryonal tumor. Majority of the patients underwent surgical resection (78.8%). Radiation was given to 47 (26.8%) patients. A half of the patients, 89 (50%), were lost to follow-up. Forty-two (24%) patients expired, 20 (11.4%) are alive with residual disease while 15 patients (8.5%) were cured with no evidence of recurrence and regular follow-ups. CONCLUSION: This is the only study from Pakistan showing demographics of the childhood brain tumors. Significant improvement needs to be made for timely diagnosis, early referrals, and collaborated team efforts with multidisciplinary tumor board to improve outcome.

Upshaw-Schulman Syndrome With c.2728C>T Mutation in ADAMTS13 Gene.

Congenital thrombotic thrombocytopenic purpura is a rare autosomal recessive disorder presenting with hemolytic anemia, thrombocytopenia, micro vascular thrombosis, and end organ damage. Here, we present a case of a 7-year-old girl having recurrent neonatal hemolysis, developmental delay, frequent seizures, and thrombocytopenia. Characteristic clinical picture and gene sequencing of a disintegrin and metalloproteinase with thrombospondin motifs 13 confirmed the diagnosis of Upshaw-Schulman syndrome. She was treated successfully with plasma infusion. The patient is alive at 6-month post follow-up, and on regular plasma therapy. Congenital thrombotic thrombocytopenic purpura should be considered in the differential diagnosis of thrombocytopenia with hemolytic anemia in infants.

Metachronous renal Ewing sarcoma/primitive neuroectodermal tumour in a survivor of Burkitt lymphoma.

We present a case of a 14-year-old girl who was diagnosed with Burkitt lymphoma in 2014. She was managed with chemotherapy and remained in remission for 3 years. On her surveillance imaging in 2017, a left-sided renal neoplastic mass was incidentally discovered. She underwent nephrectomy and pathology of the resected specimen revealed small cell tumour of the kidney with features favouring renal Ewing sarcoma/primitive neuroectodermal tumour. Molecular genetic analysis by fluorescence in situ hybridisation was performed which showed translocation of 22q12, thereby confirming the diagnosis. This is a rare secondary malignancy and an unusual association. This case highlights the importance and diagnostic dilemmas of rare secondary tumours in patients with such haematological malignancies and discusses its possible pathogenetic aspects.

Clinical Profile and Short-Term Outcome of Pediatric Hyperleukocytic Acute Leukemia from a Developing Country.

This study was conducted to determine the frequency, clinical profile, and short-term outcome of children with hyperleukocytosis at two pediatric oncology centers in Karachi. Of a total 1,045 patients, 13.97% (n=146) patients had hyperleukocytosis. Majority (61.7%, n=90) were under 10 years of age and 76% (n=146) were male. The symptom duration before diagnosis was more than 30 days in 49.3% (n=72). The median WBC count was 181 x109/L(IQR=130.45298.3) and extreme hyperleukocytosis (>200 x109/L) was observed in 44.5% (n=65) patients. Majority (94.5%, n=138) of patients were diagnosed with acute lymphoblastic leukemia. One or more complications developed in 78% (n=114) of cases. Clinical and laboratory tumor lysis syndrome (TLS) was observed in 17.1% (n=25) and 39% (n=57) patients, respectively. Pulmonary and neurological complications related to leukostasis were noted in 9.5% (n=14) and 27.3% (n=40) of cases, respectively. Infectious complications occurred in 23.2% (n=34) patients. The case-specific mortality was 20.5% (n=30). No mortality was related to early complications of hyperleukocytosis.

Burden of Cardiac Siderosis in a Thalassemia-Major Endemic Population: A Preliminary Report From Pakistan.

OBJECTIVE: To describe the initial experience and demographics of T2* cardiac magnetic resonance-based myocardial-iron quantification of transfusion-dependent thalassemia-major (TM) patients from Pakistan and the correlation with serum ferritin. METHODS: Eligible TM patients presenting between April 2014 and April 2015 to Aga Khan University Hospital, Pakistan, for T2*CMR were included. The severity of myocardial-iron deposition was defined as follows: normal T2*>20 ms, mild-moderate T2*10 to 20 ms, and severe T2*<10 ms. Cardiac symptoms were classified using the NYHA functional classification. Echocardiographic systolic and diastolic functions were performed. Continuous variables were presented as the median (minimum-maximum value). Correlation was measured using the Spearman rank correlation. Multivariate logistic regression was used to determine factors associated with the NYHA functional class. RESULTS: A total of 83 patients (49 male and 34 female) with TM, age 19 (5 to 45) years at presentation for T2*CMR, were reviewed. At presentation, 70% of the patients were classified as NYHA class II or worse. T2*<20 ms was observed in 62.6% of the patients, with 47% showing severe iron deposition (T2<10 ms). No correlation of T2*<20 ms (r=-0.157, P=0.302) and T2*<10 ms (r=-0.128, P=0.464) was observed with serum ferritin. On multivariate analysis, lower T2* values correlated with a worsening NYHA functional class. CONCLUSIONS: There is a high prevalence of severe myocardial iron load in Pakistani TM patients. Serum ferritin did not correlate with T2* values. Lower T2* was the only clinical factor associated with the NYHA functional class.

Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. METHODS: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. RESULTS: Analyses revealed a mutation detection sensitivity of 97.3%, an average coverage per gene of 98.0%, and adequate coverage over 98.6% of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38%). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. CONCLUSIONS: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.

Congenital (infantile) fibrosarcoma of the scalp: a case series and review of literature.

INTRODUCTION: Congenital infantile fibrosarcoma (CIFS) is a soft tissue sarcoma of infants mainly involving lower extremities usually presenting during the first year of life. A subset of cases occur in the head and neck, but scalp involvement is exceptionally rare. PATIENTS AND METHODS: We report clinicopathological features of three cases of CIFS involving the scalp diagnosed between 2011 and 2012. RESULTS: The ages of the three patients at the time of diagnosis ranged from 12 to 90 days (mean 48 days). All were males and presented with scalp swelling at birth which grew rapidly in size. The tumor was located in the left temporal region in two cases and the right temporoparietal region in one case. On imaging, underlying bone involvement was noted in two cases. The mean size of the resected tumors was 8 cm. All cases exhibited a cellular tumor arranged in sheets of uniform oval to spindle cells, increased mitosis, and hemangiopericytoma-like vessels. All patients are alive after a mean follow-up of 39.6 months. Recurrence was seen in one case due to incomplete excision. No metastasis was seen in any of the cases. CONCLUSION: CIFS of the scalp is rare and carries a good prognosis. Underlying bone erosion is rare but was noted seen in two of our cases. A male predominance was seen in our cases.

Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations.

BACKGROUND: Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations. PROCEDURE: We retrospectively searched our database for patients from families with siblings carrying biallelic PRF1 missense mutations where at least one sibling did not develop HLH, and for patients with biallelic PRF1 missense mutations and an atypical presentation of disease. We reviewed their clinical, genetic, and immunological characteristics. RESULTS: In all, we identified 10 such patients, including three sibling pairs with discordant manifestations. Interestingly, in two families, siblings of late-onset HLH patients developed Hodgkin lymphoma but no HLH. In a third family, one sibling presented with recurrent HLH episodes, whereas the other remains healthy. Of note, the affected sibling also suffered from systemic lupus erythematosus. Additional unrelated patients with biallelic PRF1 missense mutations were affected by neurological disease without classical signs of HLH, gastrointestinal inflammation as initial presentation of disease, as well as a hematological malignancy. Compared to early-onset FHL2 patients, the patients with an atypical presentation displayed a partial recovery of NK cell cytotoxicity upon IL-2 stimulation in vitro. CONCLUSIONS: Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families. PRF1 mutations should, therefore, be considered as a cause of several diseases disparate to HLH.

Peripherally Inserted Central Venous Catheters in Pediatric Hematology/Oncology Patients in Tertiary Care Setting: A Developing Country Experience.

PURPOSE: Peripherally inserted central venous catheters (PICC) have been successfully used to provide central access for chemotherapy and frequent transfusions. The purpose of this study was to assess the feasibility of PICCs and determine PICC-related complications in pediatric hematology/oncology patients in a resource-poor setting. METHODS: All pediatric patients (age below 16 y) with hematologic and malignant disorders who underwent PICC line insertion at Aga Khan University Hospital from January 2008 to June 2010 were enrolled in the study. Demographic features, primary diagnosis, catheter days, complications, and reasons for removal of device were recorded. RESULTS: Total of 36 PICC lines were inserted in 32 pediatric patients. Complication rate of 5.29/1000 catheter days was recorded. Our study showed comparable complication profile such as infection rate, occlusion, breakage, and dislodgement. The median catheter life was found to be 69 days. CONCLUSIONS: We conclude that PICC lines are feasible in a resource-poor setting and recommend its use for chemotherapy administration and prolonged venous access.

Clinical features and induction outcome of childhood acute lymphoblastic leukemia in a lower/middle income population: A multi-institutional report from Pakistan.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Some evidence suggests differences in clinical and cytogenetic characteristics of ALL based on geographic and ethnic variations. However, data on ALL characteristics and early outcome of therapy from low/middle-income countries such as Pakistan are scanty. PROCEDURE: A prospective, multi-institutional cohort study in Karachi enrolled 646 newly diagnosed children with ALL over 3 years. Standard forms were used to collect demographic, clinical, and laboratory data at presentation and at the end of induction. RESULTS: Of the total, 66.1% (n = 427) were males. Median age was 6 (mean ± SE 6.87 ± 0.16; range 0.16-18) years. The most common clinical presentation was fever (88.7%). BPC-ALL was diagnosed in 78.5%, while 17.5% had T-ALL; 28.8% had a WBC >50 × 10(9) /L. With 316 patients karyotyped, hypodiploidy and hyperdiploidy were seen in 5.1% and 10.7%, respectively. Of those tested, ETV6-RUNX1 translocation was detected in 13.2%, while BCR-ABL1 translocation and MLL gene rearrangements were seen in 7.3% and 4.6%, respectively. The cumulative loss to follow up before and during induction was 12.8% (n = 83) and 11.5% (n = 74) died before or during this phase. Induction was successfully completed by only 75.6% (n = 489) of the entire cohort and 69.6% (n = 450) achieved remission. CONCLUSION: These patients had ALL with higher risk features than that reported from developed countries. One quarter failed to complete induction chemotherapy. This suboptimal result requires further study and development of innovative interventions, particularly focusing on the causes and solutions for late referral, abandonment, and infections.

Congenital Factor VII Deficiency in Children at Tertiary Health Care Facility in Pakistan.

This study presents the demographics, clinical spectrum, and outcome of patients with congenital factor VII (FVII) deficiency at a tertiary care center over a period of 12 years. Of the 49 patients, 27 (55%) patients were males. Consanguinity was found in 92% of the patients. The median age of symptom onset was 2.4 (interquartile range [IQR]: 1.1-6.5) years with a median age of 5.8 (IQR: 3.1-10) years at diagnosis. Life-threatening complications like intracranial bleeding (ICB) and intra-abdominal bleeding (IAB) were observed in 8 (16.4%) patients. We found that 11 (55%) of the 20 patients with FVII coagulant activity (FVIIc) <1% were either asymptomatic or showed mild phenotype. In contrast, 9 (53%) of the 17 patients with FVIIc >5% were affected by severe symptoms. Age <1 year was the only identified risk factor associated with development of life-threatening bleeding episodes (P = .042; odds ratio 6.46). Overall, 4 (8.2%) died as a consequence of ICB (3 patients) and IAB (1 patient).

Effect of L-type calcium channel blocker (amlodipine) on myocardial iron deposition in patients with thalassaemia with moderate-to-severe myocardial iron deposition: protocol for a randomised, controlled trial.

INTRODUCTION: Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca(2+) channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy. OUTCOMES: The primary outcome is to compare the efficacy of amlodipine+chelation (intervention) versus standard chelation (control) in retarding myocardial iron deposition. Secondary outcomes include the effect of amlodipine therapy on systolic and diastolic function, strain and strain rate and liver iron content. METHODS AND ANALYSIS: This is a single-centre, parallel-group, prospective randomised control trial. Twenty patients will be randomised in a 1:1 allocation ratio into the intervention and control arms. In addition to conventional echocardiography, MRI T2* values for assessment of cardiac and liver iron load will be obtained at baseline and at 6 and 12 months. Cardiac T2* will be reported as the geometric mean and per cent coefficient of variation, and an increase in cardiac T2* values from baseline will be used as an end point to compare the efficacy of therapy. A p Value of <0.05 will be considered significant. STUDY SETTING: Department of Pediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Review Committee and Clinical Trials Unit at The Aga Khan University with respect to scientific content and compliance with applicable research and human subjects regulations. Findings will be reported through scientific publications and research conferences and project summary papers for participants. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov. Registration no: NCT02065492.

Chromosomal abnormalities in Pakistani children with acute lymphoblastic leukemia.

BACKGROUND: Cytogenetic abnormalities have important implications in diagnosis and prognosis of acute leukemia and are now considered an important part of the diagnostic workup at presentation. Karyotype, if known at the time of diagnosis, guides physicians to plan appropriate management strategies for their patients. AIM AND OBJECTIVES: To determine the cytogenetic profile of acute lymphoblastic leukemia (ALL) in Pakistani children in order to have insights regarding behavior of the disease. MATERIALS AND METHODS: A retrospective analysis of all the cases of ALL (<15years old) diagnosed at Aga Khan University from January 2006 to June 2011 was performed. Cytogenetic analysis was made for all cases using the trypsin-Giemsa banding technique. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) criteria. RESULTS: A total of 153 patients were diagnosed as ALL during the study period, of which 127 samples successfully yielded metaphase chromosomes. The male to female ratio was 1.8:1. A normal karyotype was present in 51.2% (n=65) of the cases whereas 48.8% (n=62) had an abnormal karyotype. Most of the abnormal cases showed hyperdiploidy(13.4%) followed by t(9;22)(q34;q11.2) (7.08%). CONCLUSIONS: This study revealed a relative lack of good prognostic cytogenetic aberrations in Pakistani children with ALL.