Developing a prognostic model for localized Ewing sarcoma family of tumors: A single institutional experience of 224 cases treated with uniform chemotherapy protocol.

BACKGROUND: Data on patients with localized Ewing sarcoma family of tumors (ESFT) who have received a uniform chemotherapy protocol are minimal. METHODS: This is a single institutional review of patients with ESFT treated between June 2003 and November 2011. RESULTS: 224/374 (60%) patients with ESFT presented with localized disease; median age was 15 years (range: 0.1-55). Ninety-nine patients underwent surgery of which 50 received adjuvant radiotherapy; 80 patients received radical radiotherapy following neoadjuvant chemotherapy. At median follow-up of 40.2 months (range: 1.3-129), 5-year EFS, OS, and local-control-rate, were 36.8 ± 3.6%, 52.4 ± 4.3%, and 63 ± 4.3%, respectively. In multivariate analysis, tumor diameter > 8 cm (P = 0.03), symptom duration > 4 months (P = 0.04), and WBC > 11 × 10(9) /L (P = 0.003) predicted inferior EFS; spine/abdomino-pelvic primary (P = 0.009) and WBC > 11 × 10(9) /L (P = 0.003) predicted inferior OS. Tumor size > 8 cm (P = 0.03) and radical radiotherapy as local treatment (P = 0.01) predicted inferior local-control-rate. CONCLUSION: Prognostic hazard models for EFS and OS based on significant prognostic factors suggested that patients with combination of ESFT of spine/abdomino-pelvic region and baseline WBC > 11 × 10(9) /L had inferior OS (hazard ratio 4.44, P < 0.001) while patients with combination of ESFT with symptom duration > 4 months, tumor diameter > 8 m and baseline WBC > 11 × 10(9) /L had inferior EFS (hazard ratio 3.89, P = 0.002).

Patient tracking during treatment of children with cancer in India - An exploratory study.

BACKGROUND: Abandonment of treatment, a major cause of treatment failure in low- and middle-income countries like India, is particularly high during the diagnostic and initial phase of treatment. Tracking of patients during this risk period may reduce treatment abandonment rates and increase quality of care. AIM: The primary aim was to pilot the use and check the acceptability of a tool for tracking children with cancer in New Delhi during the initial part of their treatment. Secondary aim was to estimate abandonment rates among these patients. METHODS: This prospective study was carried out in two centers of North India in New Delhi and enrolled children less than 18 years diagnosed with cancer at these centers and who had registered with Cankids for social support. Parent support group (PSG) workers maintained contact with the child's family at least once a week for the first 12 weeks. Details of each contact and subsequent action were recorded in a customized book (called "You are not alone" or YANA Book). Descriptive analysis of these contacts was done in Microsoft Excel and presented in frequencies and percentages. The five-point Likert scale was used to check the acceptability of the tool among the PSG workers. RESULTS: Seven PSG workers enrolled and tracked 81 patients (73% male with a median age of 6 years). During the 12-week study period, 986 contacts were attempted and three (3.7%) patients had abandoned their treatment. All PSG workers strongly agreed that the YANA book was simple to understand and use, decreased their workload, and helped provide better assistance to patients. CONCLUSION: The tool for patient tracking was well accepted by the PSG workers and considered easy to use. We now plan to implement our model as a routine service at all the partnering hospitals in India.

Association of TYRP1 with hypoxia and its correlation with patient outcome in uveal melanoma.

PURPOSE: Molecular mechanisms of uveal melanoma development in association with high pigmentation are unclear. Tyrosinase Related Protein (TYRP1) is not only one of the important melanogenesis marker that contributes to melanin synthesis, but can also prevents the melanocyte death. The induction of melanogenesis leads to induction of HIF-1α which can affect the behavior of melanoma cells and its surrounding environment. The aim of our study was to determine the expression of TYRP1 and HIF-1α at the protein and RNA level and determine its prognostic significance. METHODS: In the present study, the expression of TYRP1 and HIF-1α was investigated on 61 formalin-fixed paraffin-embedded choroidal melanoma samples by immunohistochemistry. Fresh 50 samples were validated by real-time PCR. Results were correlated with clinicopathological parameters and Kaplan-Meier was performed to determine the prognostic significance. RESULTS: High immunoexpression of TYRP1 and HIF-1α was present in 61 and 54% of patients, respectively. Both TYRP1 and HIF-1α correlated well with high pigmentation and BAP1 (BRCA1 Associated Protein-1) loss (p < 0.05) at IHC level as well as transcriptional level. There was reduced metastatic free survival in patients with necrosis and this was statistically significant (p = 0.010). CONCLUSION: Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field.

Constitutive expression of c-REL in uveal melanoma patients: correlation with clinicopathological parameters and patient outcome.

PURPOSE: Uveal melanoma (UM) is the most common intraocular cancer with a high mortality rate that requires new research in the field of prevention and treatment. c-REL is a member of the nuclear factor κB (NF-κB) transcription factor family and an emerging regulator of tumorigenesis. Therefore, the objective of the study is to evaluate the constitutive expression of c-REL in uveal melanoma patients and its prognostic significance. METHODS: Detection of c-REL expression was carried out by immunohistochemistry in all 75 patients, and qRT-PCR performed on 58 fresh cases of uveal melanoma along with IL-6 status. Immunoblot was performed to validate immunohistochemistry results. Expression of c-REL protein correlated with clinicopathological parameters and overall survival of patients. RESULTS: Immunohistochemistry results revealed nuclear expression of the c-REL protein (56%) in our cases. Out of 75 cases, 31 cases showed nuclear expression, and 11 cases had cytoplasmic expression. qRT-PCR showed upregulation of the REL gene in 56.89% cases at the transcriptional level. There was a statistically significant difference in the overall survival of patients with c-REL nuclear immunopositivity (p = 0.0048). On multivariate analysis, scleral invasion and c-REL nuclear expression found to be an independent prognostic factor (p < 0.05) CONCLUSIONS: To the best of our knowledge, this was the first study reporting the expression of the c-REL protein in uveal melanoma. Strong nuclear immunoexpression of c-Rel suggests NFκB pathway activation which might be involved in the progression of the disease. Differential expression of c-REL protein may be used as an attractive target for the development of anticancer strategies.

Primary testicular non-Hodgkin lymphoma: a single institution experience from India.

BACKGROUND: Primary testicular non-Hodgkin lymphoma (NHL) is an uncommon extra nodal presentation, constituting 1% of all NHL. Median age at time of presentation is 60 years. Anthracycline based chemotherapies are most frequently used. There is not enough data on use of monoclonal antibody (Rituximab) in testicular NHL. METHODS: We screened approximately eight hundred and fifty NHL cases registered from January 2002 to May 2008 and found six primary testicular NHL patients. These six cases were analyzed for baseline clinical features, investigations, staging, treatment and outcome variables. RESULTS: Median age was 55 years (range 7-72 years) and median duration of symptoms was 3.5 months (range 1-8 months). All patients had testicular swelling and abdominal lymphadenopathy. Five patients (83%) had stage IV and one had stage IE disease. Majority had diffuse large B-cell histology (83%). All patients were treated with anthracycline based combination chemotherapy and CNS prophylaxis after local therapy except one pediatric patient who did not receive any local therapy. Four patients completed therapy and are on follow up while two patients having extensive disease with poor performance status died of neutropenic sepsis after 1-2 cycles of chemotherapy. The surviving four patients achieved complete remission and are without any recurrence with a median follow up of 26 months (1-78 months). CONCLUSION: Primary testicular NHL is an uncommon entity and with current combined modality treatment and CNS prophylaxis, the outcome may be as good as nodal NHL.

Does NEMO/IKKγ protein have a role in determining prognostic significance in uveal melanoma?

PURPOSE: Uveal melanoma, although a rare form of cancer, is the most common primary malignancy of the eye in adults. Nuclear factor-κB (NF-κB) is a transcription factor that transactivates genes involved in the regulation of cell growth, apoptosis, angiogenesis, and metastasis, but the molecular mechanisms that negatively regulate NF-κB activation are not fully understood. NF-κB can also be activated by DNA damage pathway through NEMO protein. Therefore, the objective of this study is to elucidate the role of NEMO/IKKγ protein in uveal melanoma patients. METHODS: Seventy-five formalin-fixed paraffin-embedded prospective tissues of uveal melanoma were included in the present study. These cases were reviewed and investigated for the expression of NEMO/IKKγ protein by immunohistochemistry and validated by western blotting along with the qRT-PCR for mRNA expression. Expression levels were correlated with the clinicopathological parameters and patients' outcome. RESULTS: Immunohistochemistry showed cytoplasmic expression of NEMO/IKKγ expression in only 22 out of 75 (29.33%) cases. This result was confirmed by western blotting, and correlated well with the immunohistochemical expression of NEMO/IKKγ protein (48 kDa). In addition, downregulation of this gene was found in 87.93% of the cases when compared with the normal tissues. On statistical analysis, loss of NEMO/IKKγ protein was correlated with neovascularization, high mitotic count, and presence of vascular loop (p < 0.05). There was less overall survival rate with low expression of NEMO/IKKγ protein in patients with uveal melanoma. CONCLUSION: This was the first study suggesting the relevant role of NEMO/IKKγ protein, and highlights the prognostic significance with outcome in uveal melanoma patients. This protein might be used as a screening biomarker in these patients after large-scale validation and translational studies.

Short stature in retinoblastoma survivors: a cross-sectional study of 138 patients.

PURPOSE: Short stature has been reported in pediatric cancer survivors. Data on retinoblastoma survivors are limited. We conducted a cross-sectional study to assess the height in retinoblastoma survivors. METHOD: The recorded height was compared with median height for age and sex as per the Indian Academy of Pediatrics. Z-score less than -2 was considered short statured. RESULT: Thirty percent of the survivors were short statured. The mean height was shorter than the mean 50th percentile height (119.7 ± 14.8 vs 128.7 ± 15 cm, p < 0.001). Previous chemotherapy showed a trend toward association (p = 0.09). CONCLUSION: Short stature affects a significant number of retinoblastoma survivors.

Long-term visual outcomes in intraocular retinoblastoma with eye preservation.

PURPOSE: Inconsistent data exist on long-term visual outcomes in survivors of retinoblastoma. No studies have been reported on role of ocular coherence tomography (OCT) in predicting visual acuity. We assessed visual acuity in patients with retinoblastoma treated at our center in whom affected eyes were preserved. METHODS: Patients who had completed a 2-year follow-up and were more than 5 years of age at assessment were included. Clinical data were obtained from database and factors predicting visual acuity were analyzed. OCT was performed in these patients to assess central macular thickness (CMT). RESULTS: Visual outcomes were assessed in 45 eyes of 43 patients, of which 38 (88 %) had bilateral retinoblastoma. The median age at diagnosis was 12 months. Sixty percent (27/45) had International classification of retinoblastoma group C or D disease with 40 % eyes showing macular lesions. The far visual acuity was better than 6/12 in 53 % (24/45), 6/12 to 6/60 in 40 % (18/45) and 6/60 in 7 % (6/60). Macular location and International classification of retinoblastoma predicted poor vision (p = 0.06 and 0.07, respectively). CMT was less than 200 µm in 3 of 36 eyes (8 %) and 1 eye showed epiretinal membrane. Radiotherapy was associated with foveal thinning (p = 0.003). Two of 3 eyes with foveal thinning had a vision of 6/60. CONCLUSIONS: Good visual outcomes were observed in half of retinoblastoma patients treated with eye preservation. Macular location and International classification of retinoblastoma group C and D predicted poor visual acuity, while previous radiotherapy predicted foveal thinning, which was associated with poor visual acuity.

Prognosticating metastatic osteosarcoma treated with uniform chemotherapy protocol without high dose methotrexate and delayed metastasectomy: a single center experience of 102 patients.

PURPOSE: Data on prognostic factors in patients with metastatic osteosarcoma treated with uniform chemotherapy protocol are lacking. The objective of this study was to analyze demographic data, treatment outcome and prognostic factors for patients with metastatic osteosarcoma at our center treated with a uniform chemotherapy protocol without high dose methotrexate. METHODS: This is a single-institutional data review of patients treated between June 2003 and December 2012 with neoadjuvant chemotherapy, local site surgery followed by adjuvant chemotherapy and metastasectomy at completion of adjuvant chemotherapy. RESULTS: 102 patients of metastatic osteosarcoma were treated with a median age of 18 years (range 8-48 years), male to female ratio of 3.3:1 and median symptom duration of 4 months. EFS and OS at 5 years were 12.7 ± 0.1 and 28.1 ± 0.1 %, respectively. On multivariate analysis, elevated serum alkaline phosphatase (p < 0.001) and number of metastasis >3 (p = 0.04) were predictive of lower EFS, whereas elevated serum alkaline phosphatase (p = 0.01), number of metastasis >3 (p = 0.05), and margin positivity (p < 0.001) were predictive of lower OS. CONCLUSIONS: This is the largest data on metastatic osteosarcoma treated with a uniform chemotherapy protocol without high dose methotrexate. The data showed prognostic factors similar to what have been observed previously such as elevated serum alkaline phosphatase and >3 metastatic lesions in lung predicting inferior outcome. Notably our survival was comparable to data from other studies despite our practice of delaying metastasectomy to completion of chemotherapy rather than performing the same along with local site surgery.

Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients.

BACKGROUND: Data on treatment outcome and prognostic factors in patients with metastatic soft tissue sarcoma (STS) are limited in the literature. METHODS: A total of 119 patients with metastatic STS treated between June 2003 and December 2012 were analyzed for treatment outcome and prognostic factors. RESULTS: Median age was 37 years (range 2-72 years) with a male to female ratio of 1.5:1. Most common histologic subtypes were synovial sarcoma (36 %) and leiomyosarcoma (16 %). Median tumor size was 12 cm (range 1.6-30 cm). Twenty-four (20 %) patients were treated with multimodality therapy and 80 % patients received systemic chemotherapy alone. At a median follow-up of 10 months (range 1-66 months), the 2-year EFS and OS were 10 and 19 %, respectively, with a median EFS and OS of 6 and 10 months, respectively. Univariate analysis identified albumin ≤4 g/dl (p = 0.001), histologic subtypes other than synovial sarcoma (p = 0.02), non-extremity tumors (p = 0.03) and single modality treatment (p = 0.03) as factors predicting poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.02), tumor size >10 cm (p = 0.01) and single modality treatment (p = 0.04) were identified as poor prognostic factors. Multivariate analysis identified only serum albumin ≤4 g/dl (p = 0.002, HR 0.47, 95 % CI 0.29-0.75) associated with poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.009, HR 0.49, 95 % CI 0.29-0.83), tumor size >10 cm (p = 0.003, HR 2.11, 95 % CI 1.28-3.47) and single modality treatment (p = 0.01, HR 0.47, 95 % CI 0.25-0.86) emerged as poor prognostic factors. CONCLUSIONS: Serum albumin, tumor size, hemoglobin and treatment modality affect survival in metastatic STS.

Indicators of malnutrition in children with cancer: A study of 690 patients from a tertiary care cancer center.

BACKGROUND: Large data pertaining to indicators of malnutrition in children with cancer is lacking from India. In view of this, we prospectively analyzed consecutive de novo childhood patients with cancer presenting at a tertiary care center. MATERIALS AND METHODS: Height and weight of each child (n = 690) were compared with World Health Organization child growth standards-2006 for that particular age and sex to get weight-for-age, height-for-age, and weight-for-height indices and below 2SD of the reference median on these indices were considered as underweight, stunted, and wasted, respectively. Body mass index (BMI) for age was also analyzed for thinness and obesity. RESULTS: Prevalence of malnutrition based on Z-score for weight-for-age, height-for-age, weight-for-height, and BMI-for-age was 30%, 31%, 35%, and 41%, respectively. Weight-for-age (underweight) was significantly associated (P = 0.018) with solid tumors. Height-for-age, weight-for-age, and BMI-for-age were significantly associated (P = 0.007, P = 0.016, and P ≤ 0.001, respectively) with rural community. CONCLUSION: Malnutrition was observed in approximately one-third of children with cancer. Malnutrition is associated with solid tumors and those coming from rural community. Wasting has a higher prevalence in children with cancer in <5 years of age group.

Adiponectin correlates with obesity: A study of 159 childhood acute leukemia survivors from India.

BACKGROUND: Acute lymphoblastic leukemia survivors are predisposed to obesity. However, the exact underlying mechanisms are not known. AIMS: The study was done to assess the role of biomarkers of obesity in acute leukemia survivors. SETTINGS AND DESIGNS: This is a cross-sectional study conducted at All India Institute of Medical Sciences in survivors of acute leukemia who had completed treatment at least 1 year before enrollment in this study. MATERIALS AND METHODS: Obesity was studied by determining the body mass index. Potential biomarkers were studied by assessing serum leptin, resistin, and adiponectin by enzyme-linked immunosorbant assay, and the results were compared in obese versus nonobese survivors. STATISTICAL ANALYSIS: Descriptive analysis for baseline demographic factors and Student's t-test for comparing the mean levels of biomarkers among the obese and nonobese survivors. RESULTS: One hundred and fifty-nine acute leukemia patients were enrolled in this study with a median follow-up of 36.8 months. The median age was 10 (range: 3-18) years, and 123 (77.3%) patients were males. The overall prevalence of overweight/obesity was 26.4%, and this was similar in acute myeloid leukemia and acute lymphoblastic leukemia sub-groups (26.2% vs. 27.3%, P = 0.9). Mean serum leptin and resistin were similar in obese and nonobese leukemia survivors (3.7 vs. 2.85 pg/mL, P = 0.064; 8.01 vs. 9.33 ng/mL, P = 0.36). However, mean serum adiponectin was significantly lower in obese leukemia survivors (7.97 vs. 11.5 µg/mL, P = 0.023). CONCLUSIONS: Obese leukemic survivors had lower serum adiponectin levels than nonobese survivors. However, serum resistin and leptin levels were similar in the two groups.

An outbreak of tuberculosis in a children's hospital.

A 3-year-old girl was admitted to a children's hospital; subsequently her mother was found to have pulmonary tuberculosis with smear-positive sputum. Of over 400 patients, their families and staff at risk in the hospital, 30 inpatients, three outpatients, two sibling visitors and one staff member became infected. A retrospective cohort study of exposed inpatients identified exposure duration, exposure proximity and primary diagnosis as independent predictors of infection risk. Children with neoplastic disease who were being treated with cytotoxic and immunosuppressive therapy with clotting factors were at a greater risk of developing clinical disease including disseminated infection. Altogether three generations of infected children and adults were diagnosed amongst community and hospital contacts in this extended outbreak. These findings support current recommendations for the follow-up of highly susceptible casual contacts of cases of pulmonary tuberculosis with smear-positive sputa.

Olivopontocerebellar atrophy: a case report.

A family with olivopontocerebellar atrophy is presented. Out of 7 siblings two male and one female were involved at a similar age of 5 years. Early onset of the disease is striking. The index case presented with progressively increasing choreiform movements and cerebellar signs. Magnetic resonance imaging morphology revealed the diagnosis.

Etiopathophysiology of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) involves activation of clotting as well as fibrinolytic pathways. Thrombosis from thrombin release results in end-organ damage, whereas consumption of coagulation factors results in bleeding. Sepsis is the commonest cause of DIC. The consumption of antithrombin in sepsis abrogates its anti-inflammatory role and so its low level is a poor prognostic marker in sepsis. The increased release of plasminogen activator inhibitor-1 (PAI-1) as seen in sepsis decreases fibrinolysis and promotes increased microvascular thrombosis. Here, we discuss the role of inhibitors of coagulation, cytokines, kinins, complement and vasoactive peptides in DIC.

Ecological analysis of ethnic differences in relation between tuberculosis and poverty.

OBJECTIVE: To examine the effect of ethnicity on the relation between tuberculosis and deprivation. DESIGN: Retrospective ecological study comparing incidence of tuberculosis in white and south Asian residents of the 39 electoral wards in Birmingham with ethnic specific indices of deprivation. SETTING: Birmingham, 1989-93. SUBJECTS: 1516 notified cases of tuberculosis. MAIN OUTCOME MEASURES: Rates of tuberculosis and measures of deprivation. RESULTS: Univariate analysis showed significant associations of tuberculosis rates for the whole population with several indices of deprivation (P<0.01) and with the proportion of the population of south Asian origin (P<0.01). All deprivation covariates were positively associated with each other but on multiple regression, higher level of overcrowding was independently associated with tuberculosis rates. For the white population, overcrowding was associated with tuberculosis rates independently of other variables (P=0.0036). No relation with deprivation was found for the south Asian population in either single or multivariable analyses. CONCLUSIONS: Poverty is significantly associated with tuberculosis in the white population, but no such relation exists for those of Asian ethnicity. These findings suggest that causal factors, and therefore potential interventions, will also differ by ethnic group.