Long-Term Outcomes of Autologous Hematopoietic Stem Cell Transplant (HSCT) for Multiple Myeloma: While New Horizons Emerge, It Is Still Only a Silver Lining for Resource-Constrained Settings.

Background Significant hurdles impede the optimal implementation of hematopoietic stem cell transplantation (HSCT) in low-middle income countries (LMICs). Herein, we highlight the challenges faced in LMICs while performing HSCT and report the long-term outcomes of patients with newly diagnosed multiple myeloma (MM) who underwent autologous HSCT (AHSCT) at our center. Besides, we provide a comprehensive review of studies reporting long-term outcomes of AHSCT in MM from the Indian subcontinent. Methodology This study was conducted at the State Cancer Institute, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India. Case records of all patients with MM who received AHSCT from December 2010 to July 2018 were reviewed retrospectively. A non-systematic literature search was performed using PubMed and Google Scholar databases. Data regarding clinicopathological parameters and long-term follow-up were extracted from relevant studies and for patients included in our study. Results At our center, 47 patients (median age 52.0 years) with MM underwent AHSCT. Majority of patients had stage III disease (ISS) and median time to transplant was 11.5 months. The five-year progression free survival (PFS) and overall survival (OS) were 59.1% and 81.2%, respectively. Studies from the Indian subcontinent have observed a five-year OS of ~50% to ~85%. However, a greater variability in the five-year PFS has been reported, ranging from ~20% to ~75%. The median time to transplant has ranged from seven to 17 months (indicating time delays) with median CD34 cell counts of 2.7-6.3×106 cells/kg (lower than developed countries). Conclusions Despite significant resource limitations in LMICs, AHSCT is increasingly been performed in MM with encouraging long-term outcomes.

Clinical Profile and Efficacy of Antivirals in Hepatitis B Virus Reactivation, in Patients With Cancer Receiving Chemotherapy.

BACKGROUND/PURPOSE: Hepatitis B virus reactivation (HBVR) is common in patients withcancer. The aim of the present study was to find out clinical profile of patients with cancer receiving chemotherapy with HBVR and to study the efficacy of entecavir (ETV) and tenofovir in the treatment of HBVR. METHODS: This is a prospective study in which all consecutive patients with cancer with evidence of HBVR were included. HBVR was defined as: New onset transaminitis with alanine aminotransferase (ALT) >3 times upper limit of normal and >10 fold increase in HBV DNA levels from baseline levels or detection of HBV DNA ≥100,000 IU/ml in patients with no baseline HBV DNA. Patients with HBVR were put on ETV or tenofovir and were closely monitored for efficacy and safety for minimum of 1 year. RESULTS: Of 204 Hepatitis B surface antigen (HBsAg)-positive patients with different cancers, 92 met the inclusion criteria. Of 92, 46 received ETV 0.5 mg/day and 46 received tenofovir disoproxil fumarate (TDF) 300 mg/day. At 6 months, there was 4.7 log reduction in HBV DNA level in the ETV group and 5.2 log reduction in the TDF group (P = 0.029). Proportion of patients with undetectable HBV DNA (75.7% vs 87.5%), ALT normalization (89.2% Vs 87.5%), HBsAg negativity (25% vs 28.1%), and seroconversion (2.8% vs 3.1%) at 1 year were almost similar in both groups with P value > 0.05 for all efficacy end points. There was no HBVR-related mortality in any group. CONCLUSION: Both ETV and tenofovir are very effective in the treatment of HBVR and reduce the liver-related mortality and morbidity in such patients.

Entecavir is Safe and Effective in Long Term for the Treatment of Hepatitis B in Immunocompromised Children.

OBJECTIVE: Hepatitis B infection is common in patients with cancer, and prompt treatment is necessary; otherwise, it can result in life-threatening complications. The objective of this study was to assess the long-term safety and efficacy of entecavir in immunocompromised children with hepatitis B. METHODS: This single-center prospective study was conducted on children with different malignancies referred to our department with evidence of hepatitis B infection. Only those children were included in the study who had HBsAg positive and alanine aminotransferase (ALT) more than 2 times the upper limit of normal and whose hepatitis B virus (HBV) DNA was more than 20,000IU/ml. These children were put on entecavir and prospectively observed upto 192 weeks. Primary efficacy end point was the proportion of patients who achieved undetectable HBV DNA at 48 weeks of treatment. Other efficacy end points were the proportion of patients with HBeAg seroconversion, undetectable HBV DNA, and ALT normalization at weeks 48 and 96 weeks. RESULTS: A total of 41 children met the inclusion criteria, of which 5 children died because of malignancy and 5 were lost to follow-up. Mean log DNA was 7.67 at the start which after starting entecavir reduced to 4.1, 2.8, 1.19, 1.09, and 0.84 at 12, 24, 48, 72, and 96 weeks, respectively (P value < 0.0001). Mean ALT decreased from 332.5 which reduced to 190, 115, 63, and 46 at 4, 12, 24, and 48 weeks, respectively (P < 0.0001). 67.7% achieved the primary outcome and had undetectable DNA at 48 weeks which increased to 26 (83.9%) at 96 weeks. At 48 weeks, 80.6% patients achieved ALT normalization. Thirty percent developed HBeAg seroconversion. Two patients developed virological breakthrough, one at 96 weeks and another at 192 weeks. No significant adverse effects were observed. CONCLUSION: Entecavir is safe and effective in long term for the treatment of hepatitis B in immunocompromised children.

Influence of bcr-3 PML-RARα transcript on outcome in Acute Promyelocytic Leukemia patients of Kashmir treated with all-trans retinoic acid and/or arsenic tri-oxide.

AIMS: Distinct types of PML-RARα hybrid transcripts viz bcr-1, bcr-2 and bcr-3 result from translocation between chromosomes 15 and 17 t(15;17) in Acute Promyelocytic Leukemia patients. We aimed to determine the frequencies of the PML-RARα transcripts and FLT3-ITD mutations in APL patients to evaluate their prognostic implications and also to analyze their impact on disease outcome. MAIN METHOD: RT-PCR and Rq-PCR were adopted for transcript typing and quantitation of PML-RARα transcripts while FLT3-ITD was detected by PCR in APL patients. KEY FINDINGS: PML-RARα bcr-1, bcr-2 and bcr-3 transcripts were found in 26, 3 and 16 cases respectively. 64.4% patients achieved complete remission, 22.2% expired early wherein majority of the cases expressed bcr-3 transcript (p = 0.03). 50% relapse rate was observed in patients with bcr-3 transcripts. Multivariate analysis showed expression of bcr-3 transcript associated with early death (p = 0.027) and increased relapse risk (P = 0.046). Patients expressing bcr-3 hybrid transcript showed lowest OS of 28.0 months (±â€¯5.26) (p = 0.027). FLT3-ITD mutation was detected in 5 (11.1%) patients and presence of these mutations was not associated either with PML-RARα transcripts or with disease outcome. SIGNIFICANCE: bcr-3 transcript has a more lethal outcome and is also associated with frequent relapse risk in APL patients of our region.

p15Ink4b Loss of Expression by Promoter Hypermethylation Adds to Leukemogenesis and Confers a Poor Prognosis in Acute Promyelocytic Leukemia Patients.

PURPOSE: The p15Ink4b gene exerts its influence as an inhibitor of cyclin-dependent kinases and is frequently associated with hematological malignancies. Inactivation of this gene through DNA methylation has been found to be the most prevalent epigenetic alteration reported, with a high frequency in all French-American-British subtypes of acute myeloid leukemias, including acute promyelocytic leukemia (APL). In this study,we investigated the prognostic significance of p15 gene promoter hypermethylation and its expression in APL patients of Kashmir (North India). MATERIALS AND METHODS: p15 gene promoter hypermethylation was conducted by methylation-specific polymerase chain reaction, while its subsequent expression analysiswas carried out by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Of the 37 patients, 16 (43.2%) were found to have methylated p15 genes. Of these 16 cases, seven (43.8%) were methylated partially and nine (56.2%) were found to have complete methylation. Moreover, nine of the 37 patients (24.3%) who presented with leukocytosis at their baseline had complete p15 gene methylation as well (p < 0.05). Semiquantitative RT-PCR showed a complete loss of p15 expression in nine patients with complete methylation coupled with leukocytosis (p=0.031), while seven patients with partial methylation showed decreased p15 expression. Six patients relapsed during the maintenance phase of treatment and were found to have a completely methylated p15 gene and no p15 mRNA. CONCLUSION: Complete methylation and loss of p15 gene expression causes susceptibility to relapse and decreased survival in APL patients. Thus, p15 promoter hypermethylation is a prospective prognostic indicator and a reliable clinical aid in assessment of patients with APL.

A Profile of Pediatric Solid Tumors: A Single Institution Experience in Kashmir.

AIMS: The purpose of this retroprospective study was to study the epidemiological characteristics and outcomes of children with solid tumors at our institution. SUBJECTS AND METHODS: Three hundred and three pediatrics patients registered at Regional Cancer Centre (RCC), Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Kashmir, between January 2008 and June 2014, were analyzed with regard to demographic status, presenting complaints, investigations, treatment, morbidity, and outcomes. Standard statistical methods were used for analysis. RESULTS: Among 19,880 patients registered at RCC, SKIMS from January 2008 till June 2014, 986 (4.9%) were of pediatric age group. Of these, 303 (30.7%) patients had pediatric solid tumors. The male-to-female ratio was 1.04, there were no infants (up to 27 days), 6% were infants and toddlers (28 days-23 months), 39% were children (2-11 years), and 55% were adolescents (12-19 years). There were 86% rural patients and 14% urban patients. Most common were central nervous system tumors (25.74%), followed by germ cell tumors (14.52%), primitive neuroectodermal tumor/Ewing sarcoma (13.86%), Wilms' tumor (8.9%), osteosarcoma (6.6%), rhabdomyosarcoma (5.6%), colorectal cancer (5.28%), neuroblastoma (4.9%), and retinoblastoma (2.6%). Outcomes: 33.9% patients went into remission, 35.64% were defaulters, 2.97% had stable disease, 2.31% had partial response, 20.79% expired, and 3.96% were still on treatment. Of all these patients, 5.28% had a relapse. CONCLUSIONS: Across the series, advanced stage of presentation, a high incidence of default and poor follow-up was seen. Multiple interrelated factors are responsible for the poorer outlook of childhood cancer in Kashmir.

PHA-Induced Peripheral Blood Cytogenetics and Molecular Analysis: a Valid Diagnostic and Follow-up Modality for Acute Promyelocytic Leukemia Patients Treated with ATRA and/or Arsenic Tri-oxide.

BACKGROUND: Acute promyelocytic leukemia (APML) is characterized by the reciprocal translocation t(15;17) (q22;q12) resulting in the PML-RARα fusion gene. A dual diagnostic and follow up approach was applied including cytogenetic demonstration of the t(15;17) translocation and detection of PML-RARα chimeric transcripts by molecular means. PURPOSE: Conventional cytogenetics involving bone marrow is beset with high probability of poor metaphase index and was substituted with phytohemagglutinin (PHA)-induced peripheral blood culture based cytogenetic analysis as a diagnostic and follow up modality in APML patients of Kashmir (North India). Both qualitative (RT-PCR) and quantitative (Q-PCR) tests were simultaneously carried out to authenticate the modified cytogenetics. MATERIALS AND METHODS: Patient samples were subjected to the said techniques to establish their baseline as well as follow-up status. RESULTS: Initial cytogenetics revealed 30 patients (81%) positive for t(15;17) whereas 7 (19%) had either cryptic translocation or were negative for t(15;17). Two cases had chromosome 16q deletion and no hallmark translocation t(15;17). Q-PCR status for PML-RARα was found to be positive for all patients. All the APML patients were reassessed at the end of consolidation phase and during maintenance phase of chemotherapy where 6 patients had molecular relapse, wherein 4 also demonstrated cytogenetic relapse. CONCLUSIONS: It was found that PHA-induced peripheral blood cytogenetics along with molecular analysis could prove a reliable modality in the diagnosis and assessment of follow up response of APML patients.

COX-2 overexpression and -8473 T/C polymorphism in 3' UTR in non-small cell lung cancer.

A new class of compounds targeting cyclooxygenase 2 (COX-2) together with other different clinically used therapeutic strategies has recently shown a promise for the chemoprevention of several solid tumors including lung cancer. The aim was to study the possible role of COX-2 -8473 T/C NP and its expression in the pathogenesis of non-small cell lung cancer. One hundred ninety non-small cell lung cancer (NSCLC) patients and 200 healthy age-, sex-, and smoking-matched controls were used for polymorphic analysis, and 48 histopathologically confirmed NSCLC patients were analyzed for COX-2 messenger RNA (mRNA) and protein expression. Our results showed that the frequencies of variant genotypes 8473 CT/CC were significantly less common in the cases (30.0%) than in the controls (36%), suggesting that the 8473 C variant allele is related with lower susceptibility in NSCLC (OR = 0.79, 95% CI 0.54-1.4). However, the frequency of COX-2 -8473 TC and CC genotypes were significantly associated with age in NSCLC (P = 0.02). Quantitative real-time expression analysis showed a significant increase in the COX-2 mRNA in tumor tissues as compared to their adjacent normal tissues [delta cycle threshold (ΔCT) = 9.25 ± 4.67 vs 5.63 ± 3.85, P = 0.0001]. Multivariate logistic regression analyses revealed that the COX-2 expression was associated significantly with age (P = 0.044). Also, an increasing trend was observed in stages I and II and in female patients compared to stages III and IV and male patients, respectively, but no statistical significance was observed. However, COX-2 mRNA expression shown no association with the -8473 C variant allele. Our findings indicate that the COX-2 T8473C polymorphism may contribute to NSCLC cancer susceptibility in the Kashmiri population, while our expression analysis revealed a significant increase of COX-2 in tumor tissues as compared to their adjacent normal tissues, suggesting that it could become an important therapeutic marker in NSCLC in the future.