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.

Dual surrogate markers for rapid prediction of epidermal growth factor receptor mutation status in advanced adenocarcinoma of the lung: A novel approach in resource‑limited setting.

INTRODUCTION: Tyrosine kinase inhibitors have revolutionized the treatment of metastatic lung cancer in patients with epidermal growth factor receptor (EGFR) mutations. Amplified refractory mutation system (ARMS)‑reverse transcription‑polymerase chain reaction (RT‑PCR), the current standard for detecting EGFR mutation status is time‑consuming and highly expensive. Consequently any surrogate test which are cheaper, faster and as accurate as the PCR method will help in early diagnosis and management of patients with lung cancer, especially in resource‑limited settings. MATERIALS AND METHODS: Eighty‑five patients, all of South Indian origin, with adenocarcinoma of lung, registered between October 2009 and January 2013, were evaluated for EGFR mutation status by using scorpion probe based ARMS RT‑PCR method. Immunohistochemical (IHC) was performed using the phosphorylated AKT (P‑AKT) and thyroid transcription factor‑1 (TTF‑1) on above patient’s sample, and the results were compared with EGFR mutation tests. RESULTS: EGFR mutation was positive in 34 of 85 patients (40%). P‑AKT and TTF‑1 were positive in 50 (58.8%) and 68 (80%) patients respectively. Both P‑AKT and TTF‑1 had statistically significant correlation with EGFR mutation status. Positive and negative predictive value of P‑AKT in diagnosing EGFR mutation was 58% and 85.5% and that for TTF‑1 was 48.5% and 94.1%, respectively. The problem of low positive predictive value can partly be overcome by testing P‑AKT and TTF‑1 simultaneously. CONCLUSION: P‑AKT and TTF‑1 using IHC had statistically significant correlation with EGFR mutation with high negative predictive value. In the case of urgency of starting treatment, EGFR mutation testing may be avoided in those patients who are negative for these IHC markers and can be started on chemotherapy.

Nutritional profile of pediatric cancer patients at Cancer Institute, Chennai.

BACKGROUND: Malnutrition is widely prevalent in the pediatric population in India. There is paucity of data on the prevalence of malnutrition in pediatric cancer patients and the impact of cancer treatment on nutritional status of Indian children. AIMS: The study was conducted to look at the prevalence of malnutrition and assess the impact of treatment on nutritional status of pediatric cancer patients. SETTINGS AND DESIGN: This was a retrospective study. MATERIALS AND METHODS: Data on the weight of pediatric cancer patients <16 years of age treated at Cancer Institute, Chennai, from January 2013 to May 2014 were analyzed at systematic time points in therapy. Patients’ weight were plotted on the Centre for Disease Control (CDC) growth charts. Patients were defined to be undernourished if their weight for age was ≤3rd centile in CDC growth charts and obese if their weight for age was ≥97th centile on CDC growth charts. RESULTS: A total of 295 patient case records were analyzed. Acute lymphoblastic leukemia was the most common malignancy. At diagnosis, under‑nutrition was seen in 44% patients, this increased to 46% midway during treatment (end of induction in acute leukemia and completion of 50% of planned treatment in solid tumors) and decreased to 27% at the end of treatment (beginning of maintenance in acute leukemia and completion of planned treatment in solid tumors) (P = 0.0005). There was no significant difference in nutritional status between patients with hematological malignancies and solid tumors (P = 0.8). CONCLUSION: Under‑nutrition is present in close to half of the pediatric cancer patients presenting to our institute. Active nutritional intervention and education were able to significantly reduce the prevalence of under‑nutrition in patients at the end of treatment.

Gastrointestinal stromal tumor: Analysis of outcome and correlation with c-kit status in Indian population.

AIMS: The aim of the present study is to analyse the outcome and genotypic pattern of metastatic GIST patients which is largely unknown in India. MATERIALS AND METHODS: The present study was a retrospective analysis of 24 patients of metastatic GIST. The case records were analysed for clinical profile, treatment response and prognostic factors. The archival samples were retrieved for c‑kit mutation analysis in all but 5 patients for mutation analysis. RESULTS: The median age of the study population was 56 years. At a median follow up of 29 months, the PFS was 45% at 2 years. Activating c‑kit mutations were detected in 10 cases (52.6%). 80% of the mutations were located in Exon 11. CONCLUSIONS: The outcome of metastatic GIST patients has definitely improved from a virtually incurable state to a disease where median OS has reached 60 months. The genotype of Indian patients with GIST may be different from the western population which needs to be confirmed in a larger study.

The relevance of "Nonsmoking-associated lung cancer" in India: A single-centre experience.

Background: Lung cancer remains a major cause of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. Aim: The aim of this study was to analyze the clinical profile and the epidemiological trends in lung cancer patients from a single centre with an emphasis on the smoking practices. Materials and Methods: This is a retrospective analysis of prospectively collected data of 258 consecutive hospital in-patients with a proven diagnosis of lung cancer at a tertiary care oncology centre between 2003 and 2007. Results: The median age of patients in our study was 56 years; the male to female ratio was approximately 3.5:1. Non-small-cell lung cancer (NSCLC) was the predominant histology in 224 patients; the histology in the remaining 34 patients was small-cell carcinoma. Within NSCLC, the most common histology was adenocarcinoma followed by squamous cell carcinoma. One hundred and two patients were never-smokers as compared to 156 patients who were ever-smokers. Among the smokers, the majority of them were found to be cigarette smokers compared to 28.2% bidi smokers. There was a very significant correlation found with adenocarcinoma among nonsmokers, and with squamous cell carcinoma among the smokers compared to non-smokers. Conclusions: Our study suggests that the epidemiology of lung cancer in India is possibly changing, with close to 40% of our lung cancer patients being nonsmokers. More importantly, our study reflects the global trend of rise in adenocarcinoma histology. These observations need to be substantiated in similar studies of larger magnitude, preferably population-based.

Familial germ cell tumor.

Familial testicular germ cell tumors are well known in literature. Only few cases are reported where both brother and sister of the same family suffered from germ cell malignancies. We present a family where the proband is a survivor of ovarian dysgerminoma stage IA. Her elder male sibling became acutely ill and was detected to have disseminated testicular malignancy with grossly elevated markers and vegetations in the mitral valve leaflets. Despite all measures he could not be saved. Presence of germ cell malignancies in the siblings of different sex in the same family points toward a genetic susceptibility. Literature review revealed only six similar cases. A discussion regarding the rare occurrence of familial germ cell malignancies with the affected family members may be worthwhile.

Time trend in frequency of occurrence of major immunophenotypes in paediatric acute lymphoblastic leukemia cases as experienced by Cancer Institute, Chennai, south India during the period 1989-2009.

Background: Pediatric acute lymphoblastic leukemia (ALL) is a biologically heterogeneous disease and socioeconomic and environmental factors are considered to be an important determinant of its immunophenotype. The aim of this analysis is to study the time trend in the immunophenotype of pediatric acute lymphoblastic leukemia (ALL) cases in our geographic setting. Materials and Methods: A total of 639 new pediatric ALL cases immunophenotyped during 1989-2009 forms the basis of this analysis. Representative bone marrow or peripheral blood of these patients was immunophenotyped flowcytometrically using an extensive panel of monoclonal antibodies. Results: During early phase of our study we noticed a relative excess of T-ALL and a paucity of common acute lymphoblastic leukemia (C-ALL) in contrast to western data. Over a period of 20 years we witnessed a gradual reduction in pediatric T-ALL cases and a proportionate increase in C-ALL cases. Conclusion: We find that this change of pattern is synchronizing with the socioeconomic and industrial development prevailing in our geographic setting and suggest a possible link between the predominant immunophenotype of pediatric ALL cases and the environmental and socioeconomic factors prevailing in that locality.

Quality of life among young women with breast cancer: Study from a tertiary cancer institute in south India.

Background : The incidence of breast cancer in young patients less than 35 years is less than 1%. The physical and psychosocial morbidity may affect their ability to successfully function in their social roles. Hence we studied the quality of life (QOL) issues in this subset. Materials and Methods :Younger women with age less than 35 years, diagnosed with non-metastatic breast cancer at our Institute, from 1995 to 2005, were included in the study. Quality of life issues were studied during the follow-up using EORTC QOL C30 and BR23. Descriptive and inferential statistics were used in order to analyze the data. Results : A total of 51 patients were included for the study. The mean age at diagnosis was 30 years. The effect of breast cancer on the occupation and marital status was minimal. The global health status and the functional scores were high, while the overall sexual function was lower. The global health status was higher in the mastectomy group. The arm symptoms (P = 0.027) and pain were higher in the Breast conservation surgery (BCS) group. The sexual symptoms appeared to be higher in the ovary ablated group when compared to the ovary preserved group. The sexual functional scores (P = 0.02) and sexual enjoyment scores (P = 0.003) were better in the mastectomy group. Conclusion : The overall QOL in younger patients with breast cancer appeared to be good. The QOL and sexual function were marginally worse in the breast conservation group when compared to mastectomy group.

Role of GSTM1 (Present/Null) and GSTP1 (Ile105Val) polymorphisms in susceptibility to acute lymphoblastic leukemia among the South Indian population.

Acute lymphoblastic leukaemia (ALL) is the most common pediatric malignancy worldwide. The origin of this disease may be explained by a combination of genetic and environmental factors. Glutathione-s-transferases are a multi-gene family of enzymes involved in the detoxification of a wide variety of environmental carcinogens. A total of 92 immunophenotyped cases (below 25 years of age) and 150 cord blood controls were here analysed by PCR for GSTM1(Present/Null) and RQ-PCR allelic discrimination assay for GSTP1(Ile105Val). We found a significant increased risk for ALL with the GSTM1 null genotype (OR: 1.96, 95%CI=1.08-3.57), but no significant risk was found with the GSTP1 (Ile/Val) genotype (OR: 1.32, 95%CI = 0.74-2.37) and the GSTP1 Val/Val genotype (OR: 1.41, 95%CI=0.5-3.96) alone. Combined analysis of GSTM1 and GSTP1 showed significant higher risk associated with the GSTM1 (null/null) and GSTP1 [(Ile/Val)/ (Val/Val)] genotype (OR=2.78: 95%CI=1.16-6.69).

Late solitary skeletal metastasis to the patella from retinoblastoma.

Isolate metastasis to the patella is rare. A young girl treated with bilateral enucleation for retinoblastoma, reported 9 years later with solitary patellar metastasis. Treatment options for distant metastasis from retinoblastoma are not well defined but include combinations of chemotherapy, radiotherapy and surgery. Late skeletal metastasis from retinoblastoma should be differentiated from second primary bone malignancies, with immunohistochemistry, cytogenetic and electron microscopic features, as the prognosis and management are different.

Primary esophageal T-cell non-Hodgkin's lymphoma.

Primary non-Hodgkin's lymphoma of the esophagus is a rare disease. We report a 52-year-old man who had a polypoid mass in the esophagus at endoscopy. Histology was suggestive of non-Hodgkin's lymphoma; immunohistochemistry was positive for CD3, CD45 RO, LCA. He was treated with 6 cycles of CHOP and is disease-free 14 months later.

Bone marrow involvement in a primary mediastinal extragonadal non-seminomatous germ cell tumour.

A case of primary mediastinal extragonadal germ cell tumour with involvement of bone marrow, a rare finding, is reported with a review of literature.

Persistent Müllerian Duct Syndrome (PMDS) with testicular seminoma.

Persistent Mullerian Duct Syndrome (PMDS) is characteristically associated with unilateral or bilateral cryptoorchidism. Like other undescended testis, these gonads are at an increased risk of malignant transformation. We report a case of intra abdominal seminoma in cryptorchid testis of a patient with the Persistent Mullerian Duct Syndrome, hitherto uncommonly reported in India.

Acute lymphoblastic leukemia presenting as breast mass.

We present here a 34 years female who presented with bilateral breast lumps as the initial manifestation of acute lymphoblastic leukemia. She was treated with consolidation chemotherapy and showed good response.

Antibiotics in febrile neutropenia: a randomized prospective comparison of two combinations.

BACKGROUND. Problems of initial empirical antibiotic therapy in febrile neutropenia are further complicated by other factors such as cost and the pattern of infective organisms in a particular institution. We, therefore, conducted a randomized study comparing the efficacy of two sets of antibiotics which differed in their spectrum of action, availability and price. METHODS. Sixty episodes of febrile neutropenia in 40 patients who were not on any prophylactic antibiotics were randomized into one of two arms--cefotaxime and gentamicin or ciprofloxacin and gentamicin. Depending upon the response by 72 hours, they were crossed over to the other arm or continued with the same combination. Empirical antifungal therapy was added in those who did not become afebrile. RESULTS. Infection was documented either clinically, bacteriologically or radiologically in 42% of the febrile episodes. The commonest organism isolated was Klebsiella and the commonest organism producing bacteraemia was the Staphylococcus. The temperature was reduced to normal without cross-over in 53% of the febrile episodes with cefotaxime and gentamicin and in 60% with ciprofloxacin and gentamicin (p > 0.05). After cross-over the temperature came down in 30% of the episodes with cefotaxime and gentamicin (initial combination) and 40% with ciprofloxacin and gentamicin (initial combination; p > 0.05). The overall response rate without empirical antifungal therapy was 83% in the patients on cefotaxime and gentamicin (initial combination; p > 0.05). While both the arms of the study had a 100% response rate, there was no significant difference between the efficacy of the antibiotic combinations. The ciprofloxacin-gentamicin combination is one-third as expensive as cefotaxime-gentamicin and is more readily available. CONCLUSION. We recommend the use of ciprofloxacin and gentamicin as the initial drug combination and cefotaxime and gentamicin only when the former is not effective.

Induction chemotherapy in non-metastatic high grade osteo sarcomas--results of pilot study at Cancer Institute (WIA), Madras.

Twelve patients with high grade osteosarcomas of the extremities were treated with two cycles of induction chemotherapy using adriamycin and cis-platinum and sandwich radiation between the two cycles (4000 rads). Ten patients underwent amputation or disarticulation, two patients had wide excision followed by endoprosthesis. The specimen was assessed for grade of necrosis. The Disease Free Survival at a minimum follow-up period of 26 months and median follow-up period of 35.5%. All the five patients who developed distant metastases had shown only a grade I necrosis in the tumour.