Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Prednisolone Prophase for a Week Versus Upfront Multiagent Chemotherapy in Childhood Acute Lymphoblastic Leukemia: An Analysis With Reference to Induction Mortality in a Developing Country.

In childhood acute lymphoblastic leukemia, high treatment-related mortality, especially in the induction phase of treatment, is a major challenge for developing countries. The reasons are multifactorial, including a late presentation with higher disease burden, malnourishment, and limited support services. These factors may aggravate the toxic effects of upfront multiagent chemotherapy in terms of severe neutropenic sepsis and tumor lysis. Therefore, instead of upfront chemotherapy, we offered prednisolone prophase for 1 week with the objective of balancing the antileukemic versus the toxic effect of treatment. The data of 538 patients who received induction with this approach (cohort B) are compared for induction mortality with previous records of 438 patients (cohort A) treated with upfront chemotherapy. In the presence of similar clinical characteristics including age, sex, risk group, and phenotype in both cohorts, a significant difference was found in overall induction mortality of 9% in cohort B versus 14% in cohort A (P<0.05). This difference was also significant in the high-risk and T-cell phenotype, which strengthens our hypothesis that patients with higher burden of disease may experience more fatal toxic effects with upfront intensive chemotherapy. Therefore, we suggest that the prednisolone prophase approach is beneficial to control the disease with less severe toxic effects in our settings.

Clinical Features and Treatment Outcomes of Children With Anaplastic Large Cell Lymphoma in Pakistan: A Multicenter Study.

BACKGROUND: Different approaches have been adopted in the treatment of anaplastic large cell lymphoma (ALCL); there is a lack of consensus with regard to standard treatment. Because of paucity of data from low and middle-income countries, we reviewed the clinical features and treatment outcomes of children with ALCL. METHODS: All ALCL patients under 16 years of age diagnosed from 2005 to 2015 at Aga Khan University Hospital and The Indus Hospital were identified. Clinical features and treatment outcomes were analyzed. RESULTS: Thirty-two (n=32) patients met the inclusion criteria. Cervical Lymphadenopathy was the most common presentation (34.3%, n=11). Advanced disease was seen in 68.7% (n=22) (stages III and IV). Fourteen (42.4%) were treated on ALCL-99, 30.3% (n=10) on multicenter protocol-842 regimen, 9% (n=3) on adriamycin-prednisolone-oncovin (doxorubicin, prednisone, vincristine) regimen, and 16% (n=5) were treatment abandonments. Five-year overall survival was 70.6% (95% confidence interval: 47.8%-84.9%), and 5-year event-free survival (EFS) considering treatment abandonment and death as an event was 52.3 % (95% confidence interval: 23.5%-74.8%). CONCLUSIONS: Significant therapy-related mortality (27.7%) was observed. Treatment abandonment and therapy-related toxicity were the major barriers for better outcomes. However, less intensive outpatient regimens, such as adriamycin-prednisolone-oncovin regimen, may decrease the number of hospitalizations, hence reducing treatment abandonment in the low and middle-income country.

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.

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.

MECC regional initiative in pediatric palliative care: Middle Eastern course on pain management.

In all the major medical centers throughout the Middle East, there is a functioning pediatric hematology oncology department. In almost all countries, opioids such as morphine, oxycodone, and fentanyl are available. Pediatric palliative care services are still in their infancy and await further recognition and development. Unfortunately, there are still countries in the Middle East where children with cancer are diagnosed when the disease is already at stage III or IV, when the only option left is palliation. To decrease the incidence of late presentation, more effort is needed concerning public awareness, and concomitantly, an urgent need to develop hospital-based and community-based palliative and supportive care services. The initial step in this direction would involve more training of health care providers: Pediatricians, Pediatric Oncologists, Oncology Nurses, and Social Workers with updated pharmacological and nonpharmacological modalities of treatment.

Ewing's sarcoma/PNET of kidney in 13-year-old girl.

Ewing's sarcoma is the second most common primary tumour of bone in childhood. Less frequently it occurs in soft tissues. Ewing's sarcoma/primitive neuroectodermal tumour (ES/PNET) is an extra ordinarily rare primary tumour in the kidney. Only very few cases of primary renal Ewing's sarcoma have been reported in the literature to date. We present a case of primary right renal Ewing's sarcoma in a 13-year-old girl who was diagnosed as a case of stage IV ES/PNET of kidney with metastases to lung and liver. Right nephrectomy was done followed by adjuvant radiotherapy and chemotherapy with complete response to local and distant area.

Karachi Cancer Registry (KCR): Age-Standardized Incidence Rate by Age-Group and Gender in a Mega City of Pakistan.

OBJECTIVES: To estimate the cancer incidence by age group and gender for the population of Karachi Division by analyzing the Karachi Cancer Registry data of 2017-19. SETTINGS: The population of Karachi division is 16.1 million according to national census 2017. 'Karachi Cancer Registry' which is a part of 'National Cancer Registry' is collecting data from eight major hospitals in Karachi since 2017. For outcome measures, cancer counts and the age standardized incidence rates (ASIR) per 100,000 population were computed for age groups (0-14, 15-19 and ≥20 years), in both genders and all cancer site/type. METHODS: The population denominators were based on the population of Karachi division estimated at 16.1 million in the population census, 2017. Counts and age-standardized incidence rates (ASIR) were calculated for each of the three age categories. RESULTS: From Jan 2017 till Dec 2019 a total of 33,309 malignant cases were recorded in KCR database comprising 17,490 (52.5%) females and 15,819 (47.5%) males. ASIRs in age groups 0-14, 15-19 and ≥ 20 years, among female were 11.5, 2.4 and 223.6 and in males were 17.6, 3.2 and 216.7 respectively. The commonest diagnosis in children, adolescent and adults were (1) among females: children; bone (3.12),  leukemia (2.09) brain/CNS (1.26); in adolescents: bone (0.78), brain/CNS (0.27), connective and soft tissue (0.11), in adults: breast cancer (76.07), oral cancer (16.68) and ovary (10.89) respectively, and (2) among males: children; bone (4.56),  leukemia (2.79) and brain/CNS (1.88); in adolescent; bone (1.19), brain/CNS (0.31) and leukemia (0.21) and in adults: oral cancer (42.83), liver (16.10) and bone (13.37) respectively. CONCLUSION: Oral Cancer, a largely preventable cancer is the leading cancer in Karachi adult males while in female adults Breast Cancer is the leading cancer followed by Oral Cancer. In children and adolescents Bone, Leukemia and Brain/CNS malignancies are most common.
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Childhood acute lymphoblastic leukaemia; epidemiology and clinicopathological features.

OBJECTIVE: To study epidemiology, clinical presentation and laboratory features of childhood Acute Lymphoblastic Leukaemia. METHOD: This retrospective review included all newly diagnosed children with acute lymphoblastic Leukaemia less than 15 years of age registered from April 1999 to December 2004 at oncology unit of National Institute of Child Health and Children Cancer Hospital, Karachi. The objective was to look for epidemiological data, the clinical features and laboratory findings at presentation and compare it with reported literature. RESULTS: Acute lymphoblastic Leukaemia constituted 32% (611 /1890) of all cancers in this study. Majority of patients hailed from Karachi (59%) and interior Sindh (27%) while rest from other parts of country. Patient's referral increased over the years, from 42 in 1999 to 127 in 2004. The age ranged between 3 months to 15 years with a median age of 6.5 years. Male to female ratio was 1.7:1 Family history of cancer was present in 5% of patients. Fever and pallor were the commonest presenting features. Anaemia (86%), lymphadenopathy (75%) hepatomegaly (67%) and splenomegly (58%) were common findings on physical examination. Initial high white cell count (> 50,000) was observed in 34% patients. Haemoglobin < 7gm/dl was seen in 54% and Platelet counts less than 20,000 was observed in 33% cases. CNS disease was present in 5% and HBsAg was positive in 14% patients at diagnosis. CONCLUSION: Acute Lymphoblastic Leukaemia accounts for one third of total registered cases. Age distribution in this series shows less prominemt early peak and more significant late peak and a median age of 6 years. Consangunity was found in 47% cases. The fraction with a WBC count above 50,000 mm3 (30%), a higher proportion with lymphadenopathy (75%) and haemoglobin less than 7 gm/dl (54%) suggest that Pakistani children have significantly higher burdens of Leukaemia cells at presentation. These may have prognostic implication resulting in poor outcome of Leukaemia in this part of the world.

Rhabdomyosarcoma in Karachi 1998-2002.

The epidemiological features of rhabdomyosarcoma (RMS), an uncommon malignancy composed of cells with histopathologic features of striated muscle, were studied in Pakistan. Incident RMS cases recorded at the Karachi Cancer Registry during 1998 to 2004 were reviewed and to ensure maximum completeness of data, only those registered between 1998 and 2002 were considered for the present study. Two hundred and seventeen cases were reported to the Karachi Cancer Registry during this five-year period. One hundred and forty eight of the patients (60.4% males; 39.6% females) were residents of Karachi. The crude and standardized annual incidence rates/100,000 were 0.3 for males and 0.2 for females. The incidence was 0.5 in children below 15 years of age. The primary RMS sites in males were head and neck (28.1%), extremities (25.8%), genitourinary (GU) tract (17.9%), trunk (9.0%), orbit (7.9%), and retroperitoneum (3.4%). RMS occurred at other sites in 7.9% of the patients. Corresponding frequencies in females were head and neck (35.6%), extremities (16.9%), GU tract (16.9%), trunk (8.5%), orbit (8.5%) and other sites in 13.6%. Approximately 60% of the cases were childhood RMS and three fourths were below 21 years. The mean age of RMS cases all sites, males, was 18.5 years (95% CI 15.6; 21.4); for childhood RMS, 7.5 years (95% CI 6.0; 9.2); and for adult RMS 34.2 years (95% CI 28.3;40.2). In females, the corresponding figures were 18.2 (95% CI 13.7; 22.7); 6.6 (95% CI 5.0; 8.1) and 33.9 (95% CI 27.5; 40.5), respectively. One hundred cases were retraceable, and the mean survival time, RMS all sites and ages in both genders, was 1.5 years (95% CI 1.1; 1.9). The 5-year survival was 10%, and 3-year survival was 30% whereas 16.7% of the patients died within a year of diagnosis. The indicators of poor prognosis, a late presentation, rapid evolution, advanced disease, tumor burden (tumor size >5.cms) and regional lymph node involvement, are characteristic of RMS in Karachi. Recent advances in RMS multimodality treatment protocols have improved RMS prognosis in patients with limited disease. Pakistan should focus on early diagnosis and prompt treatment of malignancies. This requires health education for the general population to create awareness and training of health professionals at all levels to promote early diagnosis. An RMS group is required, which would monitor the treatment, recurrence, patient education and provide psychosocial support. Cytogenetic studies are advised for a better understanding of biologic differences in RMS cases in this population.

Autoclaved tumor bone for skeletal reconstruction in paediatric patients: a low cost alternative in developing countries.

We reviewed in this series forty patients of pediatric age who underwent resection for malignant tumors of musculoskeletal system followed by biological reconstruction. Our surgical procedure for reconstruction included (1) wide en bloc resection of the tumor; (2) curettage of tumor from the resected bone; (3) autoclaving for 8 minutes (4) bone grafting from the fibula (both vascularized and nonvascularized fibular grafts used); (5) reimplantation of the autoclaved bone into the host bone defect and fixation with plates. Functional evaluation was done using MSTS scoring system. At final followup of at least 18 months (mean 29.2 months), 31 patients had recovered without any complications. Thirty-eight patients successfully achieved a solid bony union between the graft and recipient bone. Three patients had surgical site infection. They were managed with wound debridement and flap coverage of the defect. Local recurrence and nonunion occurred in two patients each. One patient underwent disarticulation at hip due to extensive local disease and one died of metastasis. For patients with non-union, revision procedure with bone graft and compression plates was successfully used. The use of autoclaved tumor grafts provides a limb salvage option that is inexpensive and independent of external resources and is a viable option for musculoskeletal tumor management in developing countries.