Ceritinib in anaplastic lymphoma kinase-positive nonsmall cell lung cancer among patients who were previously exposed to crizotinib: Experience from the Indian subcontinent.

Ceritinib is a novel ALK inhibitor approved for advanced stage NSCLC with ALK gene rearrangement, progressed and/or intolerant to crizotinib. 13 patients were included in our study who received ceritinib. Majority of them were women and never smokers with a median age of 47 yrs. Nearly half of them had a compromised performance status and received ceritinib in third line and beyond. Ceritinib showed nearly 50% response rates. With a median follow up of 9 months for the entire cohort, median PFS and OS were not reached. However, the mean values for PFS and OS were 10.9 and 14.8 months,with an estimated 1 year PFS and OS being 56% and 78% respectively.1/3 of the patients had gastrointestinal and liver toxicities. Metabolic abnormalities were seen in 1/4 th of them. ceritinib was permanently discontinued in one patient due to pneumonitis. In conclusion, ceritinib has a favorable efficacy and side effect profile in our patient population., similar to that reported in large clinical trials. It has shown promising efficacy even in patients with compromised performance status; presence of brain metastases and heavily pre-treated disease.

Repeat biopsy in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer: Feasibility, limitations, and clinical utility in Indian patients.

INTRODUCTION: The feasibility and success rate of repeat biopsy for epidermal growth factor receptor (EGFR) mutation-positive lung cancers that have progressed on tyrosine kinase inhibitors (TKIs) are varied and merits further assessment. MATERIALS AND METHODS: EGFR mutation-positive lung cancers were offered repeat biopsy upon progression on TKIs. Two groups of patients, first one on a clinical trial and second one from a database, were included for analysis. The feasibility to perform a repeat biopsy was analyzed in the first group. Success rate of biopsy and tissue adequacy for molecular testing was analyzed in both groups. Descriptive statistics were used for analyzing the demography, EGFR mutation type, tissue adequacy, and molecular profile at repeat biopsy. Kolmogorov-Smirnov test was used to assess normality of data. Two sample t-tests were used for comparison of proportions. RESULTS: The feasibility of undergoing repeat biopsy was 77% (95% confidence interval [CI] of 69.4%-83.5%) in the first group (114/148 patients). Feasibility was not analyzed in the second group of patients. Out of 196 patients who underwent a repeat biopsy, 154 patients (78.6%; 95% CI: 72.2%-84.1%) had tumor tissue adequate for performing molecular testing. 27/196 (13.8%) patients did not have any evidence of malignancy on repeat biopsy whereas 15/196 (7.6%) patients had scanty tissue on repeat biopsy prohibiting molecular testing. Six patients (3.06%; 95% CI: 1.1%-6.5%) had small cell transformation. T790M mutation was detected in 12 out of the 42 patients (28.6%; 95% CI: 15.7-44.6) in whom EGFR testing was performed on repeat biopsy specimen. CONCLUSION: Repeat biopsy was able to provide adequate tissue acquisition in only two-thirds of the patients. Liquid biopsy represents an important tool to bridge this gap.

ROS1 rearranged nonsmall cell lung cancer and crizotinib: An Indian experience.

ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. Crizotinib is approved in this situation both in treatment naïve and pre-treated patients. Here we report our experience with crizotinib in patients with advanced NSCLC harbouring ROS1 rearrangement. Eleven patients were included in our study. More than half of our patients had associated comorbidities and one fourth of them had a compromised performance status. Out of 11 patients, 5 of them were exposed to crizotinib .The response rates among crizotinib treated patients was 80%. With a median follow up of 9 months, median PFS and OS were 5.4 months and 8.5 months respectively for the entire population. Analyzing the outcomes separately , median PFS and OS was not reached for those who received crizotinib compared to median PFS of 2.5 months and median OS of 4.2 months in those who were not exposed to crizotinib. The difference was statistically significant. Estimated 1 year OS was 80% for those who received crizotinib compared to 18% for who did not receive crizotinib. In conclusion, crizotinib is effective with acceptable side effect profile in patients with ROS1 rearranged NSCLC in our population.

Epidermal growth factor receptor T790M testing in progressed lung cancer: A review of sensitive methods for analysis of tissue and liquid biopsy samples.

Lung cancer is one of the major causes of mortality worldwide and is on the rise in India. The identification of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has paved the way for personalized therapy in lung cancer with EGFR-tyrosine kinase inhibitors (TKIs). Despite the proven efficacy of EGFR-TKIs in patients harboring EGFR mutations, their clinical utility is limited by the development of acquired resistance mechanisms by the tumor cells. T790M mutation accounts for 60% of all resistance mechanisms to EGFR TKIs and is responsible for treatment failure with first- and second-generation TKIs. With the development of novel therapeutic agents such as osimertinib to overcome this resistance mechanism, it is essential to detect patients harboring T790M mutation. There are several limitations with the use of tissue biopsy specimens for molecular testing such as poor quality and quantity of sample, tumor heterogeneity, occurrence of complications, and issues with repeat biopsy. Liquid biopsy offers a noninvasive approach that can be used for diagnostic purposes as well as for monitoring treatment response and evaluation of resistance mechanisms. This review focuses on the methods for molecular testing of tissue and liquid biopsy specimens for EGFR mutations, particularly EGFR T790M mutation.

FTO association and interaction with time spent sitting.

BACKGROUND/OBJECTIVES: Multiple studies have revealed an interaction between a variant in the FTO gene and self-reported physical activity on body mass index (BMI). Physical inactivity, such as time spent sitting (TSS) has recently gained attention as an important risk factor for obesity and related diseases. It is possible that FTO interacts with TSS to affect BMI, and/or that FTO's putative effect on BMI is mediated through TSS. SUBJECTS/METHODS: We tested these hypotheses in two cohorts of the Framingham Heart Study (FHS) (Offspring: n=3430 and Third Generation: n=3888), and attempted to replicate our results in the Women's Health Initiative (WHI; n=4756). Specifically, we examined whether an association exists between FTO and self-reported TSS, and whether an interaction exists between FTO and TSS on BMI, while adjusting for several important covariates such as physical activity. RESULTS: In FHS, we find a significant positive association between the BMI-increasing FTO allele and TSS. We find a similar trend in WHI. Mediation analyses suggest that the effect of FTO on BMI is mediated through TSS. In FHS, we find a significant interaction of FTO and TSS on BMI, whereby the association of TSS with BMI is greatest among those with more FTO risk alleles. In WHI, we also find a significant interaction, although the direction is opposite to that in FHS. In a meta-analysis of the two data sets, there is no net interaction of FTO with TSS on BMI. CONCLUSIONS: Our study suggests that FTO exerts its effect on BMI, at least partly, through energy expenditure mechanisms such as TSS. Further research into the intersection of genetics, sedentary behavior and obesity-related outcomes is warranted.

Haematologic and immunophenotypic profile of acute myeloid leukemia: an experience of Tata Memorial Hospital.

OBJECTIVES: To study the hematologic and immunophenotypic profile of 260 cases of acute myeloid leukemia at diagnosis. MATERIAL AND METHODS: This is a retrospective analysis of 260 cases of AML diagnosed at our institution between 1998 and 2000. Diagnosis was based on peripheral blood and bone marrow examination for morphology cytochemistry and immunophenotypic studies. SPSS software package, version 10, was used for statistical analysis. RESULTS: Seventy-six percent of our cases were adults. The age of the patients ranged from one year to 78 years with a median age of 27.2 years. There were 187 males and 73 females. The commonest FAB subtype, in both children and adults, was AML-M2. The highest WBC counts were seen in AML-M1 and the lowest in AML-M3 (10-97 x 10(9)/L, mean 53.8 x 10(9)/L). The mean values and range for hemoglobin was 6.8 gm/l (1.8 gm/l to 9.2 gm/l), platelet count 63.3 x 10(9)/L (32-83 x 10(9)/L), peripheral blood blasts 41.4% (5 to 77%) and bone marrow blasts 57.6% (34-96%). Myeloperoxidase positivity was highest in the M1, M2 and M3 subtypes. CD13 and CD33 were the most useful markers in the diagnosis of AML. CD14 and CD36 were most often seen in monocytic (38%) and myelomonocytic (44%) leukemias. Lymphoid antigen expression was seen in 15% of cases. CD7 expression was the commonest (11%). CONCLUSION: AML accounted for 39.8% of all acute leukemias at this institution. The most common subtype was AML-M2. Myeloperoxidase stain was a useful tool in the diagnosis of myeloid leukemias. CD13 and CD33 were the most diagnostic myeloid markers.

Intra myocardial dissecting hematoma with epicardial rupture - an unusual complication of the Octopus 3 stabilizer.

Stabilizer devices have revolutionized off-pump coronary artery bypass surgery. They stabilize the myocardial wall locally and allow the surgeon to accurately place anastomotic sutures without the need of establishing CPB and without much compromise in patient hemodynamics. We report here an unusual complication of an intramyocardial dissecting hematoma with epicardial rupture caused after using the Octopus 3 stabilizer.

Trisomy 12 in chronic lymphocytic leukemia--geographical variation.

Incidence of trisomy 12 was studied in 60 cases of chronic lymphocytic leukemia (CLL) with chromosome 12 specific alpha-satellite DNA probe by fluorescence in situ hybridization (FISH). Trisomy 12 was observed in 37 (61.8%) patients. Cells with trisomy 12 were detected in a varying proportion, ranging from > 2% to 86%. Patients with trisomy 12 were predominantly observed with total white blood cell (WBC) count > 80 x 10(9) l(-1) (P < 0.001). In addition, the percentage of trisomy 12 positive lymphocytes correlated with the high WBC counts. Trisomy 12 was observed equally in typical and atypical CLL. 90% of our patients were in the intermediate and high risk groups. It was seen that there was significantly higher percentage of trisomy 12 positive lymphocytes ( > 10%) in the high risk groups (P < 0.05). A higher incidence of FMC7 positivity in atypical CLL was seen in our study. However, there was no significant relationship found between trisomy 12 positivity and expression of either FMC7 or CD23 in our cases. It appears that the CLL that we see at our centre is at a different phase of evolution and perhaps biologically different compared to the CLL seen in the West.

Secondary ANLL with t(11;19)(q23;p13) following etoposide and cisplatin for ovarian germ cell tumor.

This is a case report of a ten year old girl with ovarian germ cell tumor who was successfully treated with BEP chemotherapy. She developed acute myloid leukemia, AML-M5 with t(11;19)(q23;p13), 29 months after being off therapy. She received a cumulative dose of 2000 mg/m2 of etoposide and 400 mg/m2 of cisplatin. The association of etoposide and therapy related leukemia is reviewed.

Immunophenotype and ultrastructural studies in blast crisis of chronic myeloid leukemia.

Thirty-four patients with chronic myeloid leukemia in blast crisis (CML-BC) were evaluated for lineage differentiation with immunological markers and the presence of ultrastructural peroxidase. Eighteen (52.9%) were found to have myeloid blast crisis. Cytochemically, myeloperoxidase (MPO) could be detected only in six patients on light microscopy while in the remaining 12 patients, myeloid differentiation was confirmed only by demonstration of MPO either at ultrastructural level or by the reactivity with anti myeloperoxidase (anti MPO) antibody. Six (17.6%) had lymphoid blast crisis as identified by lymphoid specific markers (CD19; CD10; CD7; CD4) along with the absence of myeloid markers. Heterogenous blast cell populations with mixed lineage differentiation were seen in 4 (11.7%) patients. These cases showed both lymphoid (CD19, CD10) and myeloid (anti MPO and ultrastructural MPO) characteristics. A single case of megakaryoblastic blast crisis was identified with positivity for CD41 and CD42 along with the presence of platelet peroxidase at the ultrastructural level. Five cases (14%) of CML blast crisis remained unclassifiable. These results suggest that blast crisis in CML show an arrest of differentiation at an early stage when compared to de novo acute leukemias. This is particularly evident from the fact that MPO could only be demonstrated ultrastructurally or with anti MPO antibody in the majority of patients with myeloid differentiation. It is expected that utilisation of molecular studies including immunoglobulin and T-cell receptor gene rearrangement and m-RNA expression for myeloperoxidase will provide a better insight into the level of differentiation for the presently unclassifiable cases of CML-blast crisis.

Linear quadratic model compared with TDF and TSD concepts for malignancy of cervix uteri treated with twice daily fractionated schedules.

PURPOSE: Various types of fractionation schemes have been tried in recent year with the objective of improving tumor control rate because conventional fractionation schedules do not always produce optimum results. To compare the radiobiological effectiveness and the gain in the therapeutic ratio due to various fractionation schemes, empirical formulae such as NSD, TDF, CRE and TSD were introduced and used despite of many short comings. Recent linear quadratic (LQ) model is claimed to be able to predict the radiobiological responses of tumor as well as normal tissues more accurately. In the present study various empirical models are compared. PATIENTS AND METHOD: We treated malignancy of cervix uteri by twice daily fractionation schedules of 1.2 Gy/fraction, 1.4 Gy/fraction and 1.6 Gy/fraction with interfraction interval of four to six hours. The percentage tumor regression was estimated from weekly clinical observations and the TDFt, TSD and ERDt concepts were applied to the data and the predictions are compared. RESULTS: It was observed that TDFt and TSD concepts predicts equally well (within +/- 3%) the probable tumor regression as predicted by LQ concept. CONCLUSIONS: Till precise values of various parameters of LQ model are known, the TDF and TSD models can be used to predict probable tumor control rates within reasonable accuracy.

Early skin reactions in head and neck malignancy treated by twice-daily fractionated radiotherapy--estimation of alpha/beta of LQ model.

Conventional radiotherapy, the five times a week regime, fails to achieve locoregional control in a large proportion of advanced carcinomas of head and neck and cervix. Different non-conventional fractionation schedules are being investigated to improve the tumour control rate but, during treatment of advanced malignancy with curative intent, it is seldom possible to deliver a radical dose to the tumour because of the constraint of inducing irreparable normal tissue complications. To compare the probability of occurrence of normal tissue damage and gain in therapeutic ratio various empirical models such as NSD, TDF, CRE and TSD have been suggested, and recently the linear quadratic (LQ) model has been gaining popularity and is claimed to be superior to earlier empirical models. We have studied twice-daily fractionated schedules in head and neck malignancy with the aim of estimating the alpha/beta value of the LQ model for early acute skin effects, and found it to be 9.16 Gy, 7.66 Gy and 8.59 Gy for mild erythema, intensive erythema and dry desquamation respectively.

Linear quadratic model--estimation of alpha/beta ratio for mucosal reaction.

In radiotherapy to ensure that appropriate tumor lethal dose is delivered without exceeding normal tissue tolerance, concepts like NSD and its derivatives were used in the past. Due to their short coming these concepts are now replaced by a linear quadratic model. As this model is based on the recent radiobiological data, it is claimed to be able to predict the biological responses of tumors as well as normal tissues more accurately. However, the accuracy of prediction depends on the precise values of various parameters such as alpha/beta, repair constant mu and repopulation factor that are involved in the linear quadratic model. For most of the tumors and normal tissues, values of the parameters are not yet accurately known. We have estimated alpha/beta value for mucosal reactions, i.e. normal tissue early reactions in head neck cases treated with twice daily fractionation schedules and observed it to be 7.90 Gy for slight mucositis whereas it is 7.68 and 8.11 Gy for patchy and confluent mucositis, respectively.

Minimally differentiated acute myeloid leukemia: a morphologic, cytochemical and ultrastructural study.

Seven of 368 cases of acute myeloid leukemia (AML) could not be subclassified by routine morphologic, cytochemical and immunologic analyses during the period January 1989 to December 1990. Further investigations including ultrastructural examination, anti-myeloperoxidase and myeloid specific antigen analysis were carried out in all these patients and they were classified as AML-MO, as per the FAB criteria. Morphologically these blasts resembled ALL-L2/AML-M1. Cytochemically they were negative for Sudan black, myeloperoxidase, periodic acid-Schiff, and non-specific esterase. On initial immunophenotypic analysis, they could not be classified into B, T or myeloid lineages. Further investigations revealed CD13 and CD33 positivity in 4 of 6 patients. Anti-myeloperoxidase was positive in 6 of 6 patients and ultrastructural examination revealed myeloperoxidase-positive blasts in 6 of 7 cases. Cytogenetic analysis done in one patient revealed 60% abnormal metaphases. Six of 7 cases were treated with aggressive chemotherapy. One patient achieved complete remission but relapsed after 6 months, whereas others were resistant to treatment. Hence we conclude that an aggressive investigative and therapeutic approach is required to identify and treat AML-MO.