Sameer Bakhshi

Post-treatment PET-CT Rather than Interim PET-CT Using Deauville criteria Predicts Outcome in Pediatric Hodgkin Lymphoma: a Prospective Study Comparing PET-CT versus Conventional Imaging

Data about the significance of 18F-FDG PET at interim assessment and end of treatment in pediatric Hodgkin lymphoma (HL) are limited. Methods: Patients (≤18 y) with HL were prospectively evaluated with contrast-enhanced CT (CECT) and PET combined with low-dose CT (PET/CT) at baseline, after 2 cycles of chemotherapy, and after completion of treatment. Revised International Working Group (RIW) criteria and Deauville 5 point-scale for response assessment by PET/CT were used. All patients received doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine chemotherapy along with involved-field radiotherapy (25 Gy) for early stage (IA, IB, and IIA) and advanced stage (IIB–IV) with bulky disease. Results: Of the 57 enrolled patients, median follow-up was 81.6 mo (range, 11–97.5 mo). Treatment decisions were based on CECT. At baseline, PET/CT versus CECT identified 67 more disease sites; 23 patients (40.3%) were upstaged and of them in 9 patients (39%) upstaging would have affected treatment decision; notably none of these patients relapsed. The specificity of interim PET/CT based on RIW criteria (61.5%) and Deauville criteria (91.4%) for predicting relapse was higher than CECT (40.3%) (P = 0.03 and P < 0.0001, respectively). Event-free survival based on interim PET/CT (RIW) response was 93.3 ± 4.1 versus 89.6 ± 3.8 (positive vs. negative scan, respectively; P = 0.44). The specificity of posttreatment PET/CT (Deauville) was 95.7% versus 76.4% by CECT (P = 0.006). Posttreatment PET/CT (Deauville) showed significantly inferior overall survival in patients with positive scan versus negative scan results (66.4 ± 22.5 vs. 94.5 ± 2.0, P = 0.029). Conclusion: Interim PET/CT has better specificity, and use of Deauville criteria further improves it. Escalation of therapy based on interim PET in pediatric HL needs further conclusive evidence to justify its use. Posttreatment PET/CT (Deauville) predicts overall survival and has better specificity in comparison to conventional imaging.

Unusual Orbital Involvement in Erdheim Chester Disease: A Radiological Diagnosis

Erdheim–Chester disease (ECD) is an exceedingly rare, disseminated non-Langerhan cell histiocytosis with multisystem involvement, having characteristic sclerotic skeletal lesions. We present an unusual case primarily manifesting as an extensive orbital disease, with low-grade systemic involvement. Owing to its rarity and therefore lack of general awareness it remains a difficult clinical and pathologic diagnosis. Immuno-histochemistry of the biopsy specimen is diagnostic.

Expression of vascular endothelial growth factor in Ewing's sarcoma.

PurposeVascular endothelial growth factor (VEGF) is the most potent stimulator of angiogenesis. The aim of this study was to evaluate the role of serum VEGF as a diagnostic, predictive and prognostic marker in Ewing’s sarcoma.MethodsPatients with histopathologically proven diagnosis of Ewing’s sarcoma without prior chemotherapy or radiotherapy were invited to take part in the study. Pre-chemotherapy, post-chemotherapy and post-surgery blood samples were collected for analysis of serum VEGF levels. Blood samples from ten sex- and age-matched healthy volunteers were collected for estimation of VEGF levels to act as control. Human VEGF Elisa kit (Bender Medsystem, Austria) was used to assess the serum VEGF levels.ResultsA total of nine cases of Ewing’s sarcoma were included in the study. Mean age in the group was 12.44 years (range, seven to 18 years). Mean and median serums VEGF level in the study population were 4,547.78 pg/ml and 3,780.00 pg/ml, respectively. Ten age- and sex-matched healthy volunteers were selected as controls. No significant correlation was obtained between serum VEGF, age, sex and tumour size. Mean serum VEGF was significantly raised in the study group as compared to controls (pxa0=xa00.001). We observed a significant decline in serum VEGF level following neoadjuvant chemotherapy (p = 0.008). No correlation could be established between serum VEGF level pulmonary metastasis and overall survival.ConclusionSerum VEGF might have a role as a diagnostic and predictive marker in patients with Ewing’s sarcoma.

Management and outcomes in massive bilateral Wilms' tumors.

Purpose: To evaluate the outcome of children with bilateral Wilms’ tumor (BWT) treated on All India Institute of Medical Sciences-Wilms Tumor-99 (AIIMS-WT-99) protocol. Materials and Methods: All children with BWT, registered in our solid tumor clinic from August 1999 through December 2010 were included. Results: Of the 178 fresh cases of Wilms Tumor (WT) treated during this period, 11 (6.2%) had bilateral involvement. All patients except one (12 and 3 cm), had massive bilateral tumors of more than 10 cm on each side. There were eight boys and three girls in the age range 6–30 months. One patient had Denys-Drash syndrome. Twenty renal units were operated upon (12 tumorectomy, five partial nephrectomy, and three nephrectomies), while one patient with inferior vena cava (IVC) thrombus died of renal failure. Tumor spill occurred in three units, lymphnode was positive in two patients. Local recurrence occurred in four patients (six of 18 renal units (33%)—two bilateral and two unilateral). There was one recurrence in the liver that was treated with radio-frequency ablation. The 5-year overall survival (OS) was 90% (95% confidence interval (CI) = 50.8–98.6) and the relapse free survival (RFS) was 38% (95% CI = 6.1–71.6). Conclusion: Massive BWT respond poorly to preoperative chemotherapy, are often not amenable to partial nephrectomy/tumorectomy and have a higher local recurrence rate, giving a poor RFS.

Abstract 1868: Clinical significance of cathepsin L and B expression in pediatric acute myeloid leukemia

Introduction: Cathepsin L and B are commonly expressed cysteine proteinases that play a major role in lysosomal bulk proteolysis, protein processing, matrix degradation, and tissue remodelling. In tumors there is deregulation of these proteases that interferes with these normal biological processes. In a pilot study done in our lab expression of cathepsin L and B were found to be significantly elevated in peripheral blood mononuclear cells (PBMCs) of pediatric AML patients. However the expression of these proteases in bone marrow aspirate, which represents almost true population of blasts, has never been studied before. Methods: Enzymatic activities of cathepsin L and B were assayed in PBMCs and bone marrow mononuclear cells (BMMCs) of AML patients and healthy controls. Further expression of these proteases and its inhibitor were confirmed by western blotting and real time assay. Cell cycle analysis in PBMCs and BMMCs of these patients was performed by flow cytometry using propidium iodide. Results: In the PBMCs of pediatric AML patients activity of cathepsin L and B was found to be significantly elevated as compared to healthy controls. Similarly, increased activity of cathepsin L and B was also observed in the BMMCs when compared with PBMCs of these patients. Furthermore, protein and mRNA expression also confirmed the increased level of these proteases in pediatric AML. The protein and mRNA expression of their endogenous inhibitor cystatin-C was found to be decreased in PBMCs and BMMCs of AML patients. Moreover, expression of these proteases correlated positively with the percentage of blasts and percentage of cells in S-phase. Conclusion: This study for the first time demonstrates the increased expression of cathepsin L and B in the BMMCs and PBMCs of pediatric AML patients, along with a positive correlation with percentage of blasts, thereby suggesting a potential role of these proteases in the severity of this disease. Citation Format: Garima Pandey, Sameer Bakhshi, Ratnakar Singh, Shyam S. Chauhan. Clinical significance of cathepsin L and B expression in pediatric acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1868. doi:10.1158/1538-7445.AM2014-1868

Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival

Studies on mitochondrial DNA copy number reveal an increase or decrease in copy number that appears to be cancer specific, but data on acute lymphoblastic leukemia have been inconsistent regarding the significance of changes in mitochondrial DNA copies. The purpose of this pilot study was to analyze mitochondrial DNA copy number and mitochondrial DNA integrity.

Prognostic significance of cathepsin L expression in pediatric acute myeloid leukemia

Abstract Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (pu2009<u2009.0001), protein (pu2009<u2009.05), and mRNA levels (pu2009<u2009.01) in both PBMCs and BMMCs of patients as compared with controls. BMMCs displayed higher activity of CTSL than PBMCs (pu2009<u2009.01). A dramatic reduction in CTSL activity was recorded after chemotherapy in a significant proportion (74%) of patients (pu2009<u2009.0001). By multivariate analysis, CTSL in BMMCs emerged as a strong independent prognostic marker for overall survival (OS) (pu2009=u2009.004). Thus, our results suggest the potential utility of CTSL in predicting the outcome of pediatric AML.

Cytogenetic Profiles of 472 Indian Children with Acute Myeloid Leukemia

ObjectiveTo analyze the cytogenetic abnormalities of a large cohort of consecutive pediatric Acute Myeloid Leukemia (AML) patients, treated on a uniform protocol.DesignReview of case records.SettingPediatric Cancer Center of tertiary care hospital between June 2003 and June 2016.Participants617 consecutive de novo pediatric AML patients were screened and 472 patients were found eligible. Eligibility criteria included non M3 patients, successful cytogenetic profile and availability of complete recordsMain outcome measureCytogenetic profile.ResultsGum-hypertropy, chloromas and rate of complete remission were significantly different between European Leukemia Network classification (ELN) cytogenetic risk groups (P<0.01). t (8;21) (141, 29.8%), loss of Y chromosome (61,12.9%) and trisomy 8 (39, 8.3%) were the most common abnormalities. Among the chromosomal gains, trisomy 8 and trisomy 21 (both P<0.01) were significantly different among the three ELN risk groups. Among the chromosome losses, monosomy 5, 7 (both P<0.01) and 9 (P=0.03), loss of X and loss of Y (both P<0.01) were statistically different amongst three cytogenetic risk groups. Event-free survival (P<0.01) and overall survival (P<0.01) were found to be significantly different among the three risk groups.ConclusionsThe higher frequency of t (8; 21) and its association with chloroma in Indian pediatric patients is different from other studies around the world.

Peripheral Precocious Puberty Caused by Human Chorionic Gonadotropin Producing Pineal Gland Tumor

BackgroundPineal gland lesions usually present with central precocious puberty.Case characteristicsA 3½-yr-old boy presented with precocious puberty. Clinically and biochemically, it was gonadotropin releasing hormone (GnRH) independent. Serum and CSF beta-hCG levels were increased. Thin section magnetic resonance imaging of brain revealed a pineal gland tumor.OutcomeHe received chemotherapy followed by radiotherapy and responded well.MessageCSF β-hCG should be measured in all cases of peripheral precocity, and if CSF beta-hCG is elevated, thin section magnetic resonance imaging of brain should be considered.

Reply: Neither post-treatment PET-CT nor interim PET-CT using Deauville criteria predicts outcome in pediatric Hodgkin lymphoma

ularly considering the high specificity of this imaging modality. However, we strongly disagree with this conclusion. First, the fact that posttreatment 18F-FDG PET had a sensitivity of only 25% indicates that most patients who are not cured actually have negative posttreatment 18F-FDG PET findings. This is due to the limited spatial resolution of PET, as a result of which residual disease can never be excluded (4), as has been shown by several studies (5). The diagnostic performance of a test comprises both sensitivity and specificity. Any test with such a low sensitivity can generate a high specificity if the threshold to define positivity is simply raised. The combination of the very low sensitivity and the generally good prognosis of patients with Hodgkin lymphoma underlines that the number of patients needed to be scanned in order to detect one case of residual disease is actually quite high. 18F-FDG PET scans are expensive, are not available in all institutions, provide ionizing radiation, and cause discomfort to the patient. Furthermore, according to the study of Bakhshi et al. and several other studies (6), the false-positive rate of posttreatment 18F-FDG PET is actually very high. This applies to both the Revised International Workgroup criteria and the Deauville criteria, with false-positive rates of 85.7% and 66.7%, respectively, in the study by Bakhshi et al. (1). Awareness of this high false-positive rate is of the utmost importance, because it may result in unjustified initiation of second-line therapies and erroneous prognostication (if biopsy confirmation of 18F-FDG–avid lesions is not possible), lead to a high number of unnecessary conformational biopsies, and cause unnecessary patient anxiety. The fact that an early 18F-FDG PET–based detection of residual disease has not been proven to improve patient outcome further nullifies the need to acquire posttreatment 18F-FDG PET scans (7). In conclusion, interim 18F-FDG PET fails to predict outcome in Hodgkin lymphoma, and posttreatment 18F-FDG PET scans have a strikingly low sensitivity for the detection of residual disease. Furthermore, most 18F-FDG–avid lesions seen on posttreatment 18F-FDG PET scans appear to be false-positive findings. Therefore, neither interim nor posttreatment 18F-FDG PET predicts outcome in Hodgkin lymphoma.