Hepatoblastoma: 16-years’ experience from a tertiary cancer centre in India

Background: Hepatoblastoma is a rare pediatric tumor arising from the liver. The present study was conducted to ascertain the clinical profile and survival outcomes of patients with hepatoblastoma treated at our centre. Methods: We collected the case records of patients with hepatoblastoma treated between January 2000 to December 2016 and analysed the baseline characteristics, treatment details and outcomes. Survival was analysed using Kaplan Meier method. Results: Twenty-seven patients with hepatoblastoma received treatment at our centre during the study period. Median age of the patients was 12 months and 76% were males. The commonest presenting symptom was abdominal mass and the median Alpha Fetoprotein (AFP) level at the time of diagnosis was 40,000 ng/ml. PRETEXT stage II was documented in 11 and III in 11 patients. High risk disease (PRETEXT IV or metastatic disease or portal venous invasion or AFP < 100 ng/ml) was documented in 8/27 (30%) patients. Neoadjuvant chemotherapy (NACT) was given to 23/27 patients and complete surgical resection was possible in 15/23 (65%) after NACT. Infusional cisplatin and doxorubicin (PLADO) was given in 24/27 patients. Liver transplantation was done in 1 patient. The median follow-up was 51 months and the 5-year overall survival for standard risk and high-risk patients was 78.8% and 40% respectively. Conclusion: Patients with standard risk hepatoblastoma have survival outcomes comparable to Western countries, however, outcomes in patients with high risk non-metastatic inoperable disease remains low due to financial constraints in performing liver transplantation. Multimodality treatment including NACT with PLADO based regimens followed by resection is a feasible strategy. Keywords: Hepatoblastoma, PLADO, Pediatric cance

Evaluation of a polymorphism in MYBPC3 in patients with anthracycline induced cardiotoxicity

Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3–5% in the Indian population. Polymorphism in intron 32 (deletion of 25 bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3–8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467 bp fragment while in the presence of the 25 bp deletion only a 442 bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25 bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442 bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401 bp and 66 bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity. Keywords: MYBPC3, Polymorphism, Anthracycline, Cardiotoxcit

Methyl DNA adducts, DNA repair, and hypoxanthine-guanine phosphoribosyl transferase mutations in peripheral white blood cells from patients with malignant melanoma treated with dacarbazine and hydroxyurea

Dacarbazine (DTIC) is a DNA-methylating drug used in the treatment of malignant melanoma. Among the DNA dducts induced by DTIC are N7-methylguanine (N7-meG) and O6-methylguamne (O6-meG). The latter adduct, in particular, may be important in the mutagenic as well as the cytotoxic activity of DTIC. Repair of O6-meG is carried out by the enzyme O6-alkylguanine-DNA-alkyltransferase (AGT) by a process which results in its autoinactivation. N7-meG is lost from DNA partly spontaneously and partly by enzymatic depurination followed by excision repair of the resulting apurinic site. The purpose of this study was to determine the in vivo kinetics of formation and repair of O6-meG and N7-meG and the changes in AGT in peripheral WBCs with repeated doses of DTIC, and to determine the effects on these processes of concomitant administration of hydroxyurea. In addition, we examined the induction of mutations at the HPRT gene locus. Thirty-four patients with malignant melanoma received 1.0 g/m2 DTIC i.v. every 3 weeks. Hydroxyurea was added to the second and subsequent doses of DTIC in 19 patients. The concentrations of O6-meG, N7-meG, and AGT in peripheral blood lymphocytes were determined up to 24 h after each of the first two doses of DTIC. Mutations at the HPRT gene locus were determined using the T-cell clonal assay. Peak O6-meG levels were detected 1 and 4 h after the first and second dose of DTIC, respectively. AGT concentrations declined to 56.7% (range, 40.3-76.9%) and 55.0% (range, 45.4-58.9%) of pretreatment levels 24 h after the first and second doses of DTIC, respectively, and were still approximately 25% below their initial levels just prior to administration of the second dose of DTIC. An increase in formation of O6-meG was observed at all time points after the second dose of DTIC (P = 0.0001), which was not affected by cotreatment with hydroxyurea (P > 0.5). There was a negative correlation between pretreatment AGT levels and the O6-meG concentration at 24 h after therapy (r = -0.554, P = 0.014). N7-meG levels peaked at 6 h after DTIC therapy and were not significantly influenced by the cycle number. Cotreatnient with hydroxyurea tended to be associated with lower levels of N7-meG (P = 0.08). There was no correlation between either O6-meG or N7-meG levels and the grade of neutropenia. On the basis of a limited series of blood samples analyzed, there was no firm evidence that chemotherapy with DTIC resulted in induction of HPRT mutations in lymphocytes. In conclusion, repeated administrations of DTIC resulted in higher concentrations of O6-meG, probably due to reduction in cellular AGT. Hydroxyurea did not significantly influence the kinetics of O6-meG, and N7-meG adduct formation. There was no significant induction of HPRT gene mutations with DTIC. This study suggests that sequencing of DTIC doses should be evaluated using the time course of cellular AGT depletion and DNA adduct formation to achieve higher cytotoxic efficiency. Chemicals/CAS: 7-methylguanine, 578-76-7; Dacarbazine, 4342-03-4; DNA Adducts; Guanine, 73-40-5; Hydroxyurea, 127-07-1; Hypoxanthine Phosphoribosyltransferase, EC 2.4.2.8; O(6)-Methylguanine-DNA Methyltransferase, EC 2.1.1.63; O-(6)-methylguanine, 20535-83-

Risk Factors and Trends Associated With Mortality Among Adults With Hip Fracture in Singapore

10.1001/jamanetworkopen.2019.19706JAMA network open32e191970

Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

10.18632/oncotarget.13485Oncotarget857521-753