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.

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.

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.

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.

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.

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.

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.

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.

Malignant mediastinal mass in children: a single institutional experience from a developing country.

OBJECTIVE: To determine the clinical spectrum and management outcomes of paediatric patients with modiastinal mass in a Karachi hospital. METHODS: Medical records of all cases of mediastinal masses in children diagnosed and treated between January 2005 and December 2011 were retrospectively reviewed to evaluate the mode of presentation, histopathological diagnosis, radiologic findings and management outcomes at Aga Khan University Hospital, Karachi, Pakistan. SPSS 19 was used for data analysis. RESULTS: A total of 37 patients of mediastinal masses were identified, and malignancy was found in 32 (86%) cases. The median age at diagnosis was 9 years (interquartile range: 4.7 years). Lymphoma 23 (72%) and leukaemia 8 (25%) were the most common causes of mediastinal mass. Nonspecific symptoms such as fever 26 (81%), cough 15 (47%) and dyspnoea 12 (37%) constituted the most commonly presenting complaints. Overall, 22 (68.7%) patients underwent surgical procedures (complete/partial resection of mass); local lymph node biopsy was performed in 5 (15.6%) cases; and computed tomography or ultrasound-guided biopsy was done in 2 (5.4%) patients. Besides, 27 (84.4%) patients were admitted to paediatric intensive care unit for supportive care, and assisted ventilation was required in 20 (62.5%) patients. The mean length of hospital stay was 9.3 +/- 6 days. None of the patients died due to complications related to mediastinal mass or diagnostic procedure. CONCLUSIONS: Although mortality rate has reduced significantly with refinements in the management protocols, but a high index of suspicion and comprehensive multidisciplinary approach is crucial to improve the morbidity and mortality.

Ovarian haemorrhage: a rare presentation and diagnostic dilemma in factor XIII deficiency.

Factor XIII (FXIII) deficiency is a rare (autosomal recessive) genetic disorder which is associated with delayed bleeding symptoms that occur hour or days after trauma. Spontaneous rupture of visceral organs due to FXIII deficiency is a rare cause of abdominal pain with grave consequences and can be easily confused with other abdominal pathologies because of normal standard coagulation profile in these patients. We report a 15-year-old girl with spontaneous ovarian haemorrhage and splenic haematoma with FXIII deficiency. She had normal coagulation screen along with normal FXIII screen initially on the 5M urea testing which lead to delay in her diagnosis.

Childhood acute lymphoblastic leukaemia: experience from a single tertiary care facility of Pakistan.

OBJECTIVE: To evaluate the demographic features, outcome and prognostic factors seen in children with acute lymphoplastic leukaemia at a tertiary care hospital. METHODS: The retrospective descriptive study was conducted at Aga Khan University Hospital, Karachi, comprising data related to children below 15 years of age and treated between January 1997 and December 2006. Kaplan Meir survival curves were used to describe overall and event-free survival rates. Cox Proportional Hazards model was used to describe factors associated with death and relapse. SPSS 16 was the main statistical tool. RESULTS: Of the total 121 children diagnosed with the condition, 79 (65.3%) were males; 86 (71.1%) patients were between 1-9 years of age; Immunophenotyping was done in 99 (81.81%) patients: 86 (87%) cases had precursor B and 13 (13.13%) had precursor T. Of the total, 106 (87.6%) patients opted for treatment, while 15 (11.6%) were lost to follow-up. Besides, 26 (21.7%) patients had at least one relapse; the most common site being bone marrow in 13 (50%) followed by central nervous system in 9 (36.6%). There were 20 (16.5%) deaths in the sample. Infection was the most frequent cause of death. The event-free survival and overall survival was 63% (n = 76) and 65% (n = 79) respectively. CONCLUSION: Through the clinical characteristics of children with acute lymphoblastic leukamia were similar to those reported in literature, the outcomes were inferior. The high rate of infections and relapse warrant better supportive care and risk-based approach.

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.

Acute myeloid leukaemia in children: experience at a tertiary care facility of Pakistan.

OBJECTIVE: To document the demographics and outcome of children with Acute Myeloid Leukemia (AML) treated at a tertiary care facility of Pakistan. METHODS: A retrospective study was conducted at Aga Khan University on children (less than 15 years) diagnosed to have AML between January 2000 to May 2007.Total 40 cases were diagnosed out of which 37 charts were available for review. RESULTS: The average age of presentation was 8.5 +/- 4.5 years and 75% were males. The most common presenting feature was fever in 83% followed by bleeding in 41% and pallor in 39%. Initial WBC of > 100,000 was seen in 19% of patients. The most common FAB subtype was M4 39%. Twenty three patients underwent treatment out of which 12 patients are alive and in remission. Majority were followed up around 2 years and 6 months. Out of the 11 patients who died three had resistant disease, four relapsed and rest died due to sepsis mostly during induction. CONCLUSIONS: The most common sub type in our study is AML M4 although AML M2 is reported as predominant subtype. About a third of the patients could not start or complete therapy due to financial constraints. The overall survival for our patients who completed therapy was 52%.

Aplastic anemia: clinicohaematological features, treatment and outcome analysis.

OBJECTIVE: To determine the clinicohaematological features, treatment and outcome of children diagnosed with aplastic anemia at a single institution. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from January 1999 till December 2008. METHODOLOGY: Medical records of children aged less than 15 years of age diagnosed with aplastic anemia were reviewed. Clinicohaematological features, treatment and its response to therapy and outcome were recorded. Results were described in percentages. RESULTS: Ninety patients were diagnosed to have aplastic anemia (AA); 65 were male during the study period. Age ranged from 1 to 15 years. Fever in 65 patients (72.2%), pallor in 53 (58.8%), skin bleeding in 49 (54.4%) and epistaxis in 31(34.4%) were the most common and frequent presenting features. Congenital (Fanconi's) anemia was found in 15 (16.6%) and acquired idiopathic in 75 (83.4%) of patients. Very severe aplastic anemia (VSAA) was seen in 29 (32.2%), 26 (28.9%) had severe AA and 17 (18.9%) had moderate AA. Eight patients (8.9%) underwent haematopoietic stem cell transplantation (HSCT), 12 (13.3%) received immunosuppressive therapy (IST) and 70 patients (77.7%) received other and supportive therapy. Five (62.5%) patients showed complete response to HSCT and 3 (37.5%) failed to engraft. IST showed complete response in 3 (25%), partial response in 5 (41.6%) and no response in 4 (33.3%). Twenty two patients (24.4%) expired either due to infection in 16 (72.7%, fungal in 6, bacterial in 10) and intracranial haemorrhage in 6 (27.3%) cases. CONCLUSION: Majority of cases with AA were acquired and idiopathic in etiology. VSAA and SAA were frequent. Response to HSCT and IST was sub-optimal.

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.

Vaccination guidelines for children with cancer and hematopoietic stem cell transplantation living in resource-poor countries.

There is no consensus on the immunization guidelines for immunocompromised children. Some recommendations are, however, available for children living in developed countries. The spectrum of infectious diseases is different in resource-poor countries. Vaccinations against some of these infections are not a part of the immunization schedule for children living in developed countries. We have tried to include vaccinations against diseases, which are still prevalent and a major cause of morbidity and mortality in resource-poor countries. In these guidelines, the focus has been on the vaccine-preventable diseases prevalent in Pakistan but the same can be applied to other resource-poor countries.

Pediatric lymphoma: a 10-year experience at a tertiary care hospital in Pakistan.

SUMMARY: Lymphoma is the third most common childhood malignancy. Less information is available on this disease and its outcome from our country. We present here a single institute experience. A retrospective study was carried out at Aga Khan University Hospital, Karachi on children (<15 y) diagnosed with lymphoma from 1998 to 2007. Sixty-eight patients were identified. Fifty-one children were diagnosed as non-Hodgkin lymphoma (NHL). Mean age of presentation was 8.4 years with male-to-female ratio of 5.8 : 1. Most common histopathologic subtype of NHL was Burkitt lymphoma (55%). Abdominal mass was the main presenting feature of Burkitt and diffuse large B cell lymphoma. T-lymphoblastic lymphoma presented mainly as mediastinal mass. Ten children died, 4 secondary to tumor lysis syndrome, 5 because of disease progression, and 1 with chemotherapy-induced toxicity. One-third of the patients left without treatment. Seventeen children were diagnosed as Hodgkin lymphoma with mixed cellularity as the commonest subtype (65%). Overall survival of children with NHL and Hodgkin lymphoma was 62% and 94%, respectively. A greater proportion of NHL, advanced stage, and profound male preponderance were observed. Improvement in survival can only be achieved with increasing awareness, identifying and tackling causes of abandonment, early referral, and better supportive care.