Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia.

PURPOSE: The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management. METHODS: A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning. RESULTS: The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649. CONCLUSIONS: TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

Epedimiologic, clinical profile and factors affecting the outcome in febrile neutropenia.

BACKGROUND: Febrile neutropenia (FN) is common in cancer patients particularly hematologic malignancies due to intensive cytotoxic chemotherapy. It is an important cause of morbidity, mortality and treatment delays. The risk is greater in patients with ANC < 500/ mm3 and increases dramatically in those with ANC < 100/ mm3 and duration of neutropenia more than 1 week. AIMS AND OBJECTIVES: The purpose of this study was to evaluate the incidence, demographic characteristics, clinical profile, mortality, outcome and factors affecting the outcome in patients with febrile neutropenia (FN) admitted at our Center between January 2011 and November 2012. MATERIALS AND METHODS: All cases of FN admitted in our Institute between January 2011 and November 2012 were analyzed. Data was analyzed using IBM statistic SPSS version 19. RESULTS: A total of 333 episodes of FN were reviewed. Hematologic malignancies accounted for 299 (89.7%) episodes and 88% of all the episodes had grade 4 neutropenia. There was a significant association noted between high serum bilirubin, creatinine and outcome. Isolation of an organism from blood culture, positive findings on chest X-ray and fungal infection was associated with higher mortality. Association between transfusion requirements and outcome was analyzed and it was observed that patients who had multiple component transfusions vs single component ones were at a significantly higher risk of death. There were only 7 deaths noted among the patient population. CONCLUSION: Leukemias are the leading cause of FN at our Institute. Higher bilirubin, creatinine, chest imaging favoring pneumonia, positive isolates and multiple transfusions had significant association with mortality. Large scale prospective studies are needed to determine the association of preemptive therapy with higher mortality. The outcome of high risk FN in this study is favorable.

Incidence and spectrum of paraneoplastic neurological syndromes: single center study.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. They are much less common, but are nevertheless important because they cause severe neurological morbidity and mortality. The present cases were studied to characterize the clinical features of patients of suspected PNS and to study their association with different types of tumors. In this study conducted from a super speciality teaching institute from South India, forty five (incidence-0.25%) patients were diagnosed with PNS based on the clinical data. They were subdivided into two groups patients with central nervous system (CNS) manifestations and those with neuromuscular manifestations. Immunological markers were assessed in a subset of patients. Majority of them (75.6%) were above 40 years. There was no sex predilection and a chronic presentation was common (42.2%). While more than half had involvement of peripheral nervous system (64.4%), CNS manifestations were present in 16 (35.6%) cases. Immunological markers were present in 10 out of 14 (58.8%) patients. Classic PNS was seen 22 cases (48.9%), while 23 (51.1%) were non classical. Most common tumor was lung cancer followed by myeloma and breast carcinoma. Present study construed that, in patients with neurological syndromes of unknown cause, search should be focused for occult malignancy based on the phenotype and onconeural antibodies, targeting the lung and breast in particular.

Plasma cell leukaemia masquerading as hairy cell leukaemia: a case report.

Plasma cell leukaemia is a rare and aggressive neoplasm with survival of less than one year with conventional treatment. It can rarely present with morphology mimicking hairy cell leukaemia. We present a case of plasma cell leukaemia with hairy cell morphology for its rarity, diagnostic difficulty and aggressive course.

Primary Ewing's sarcoma of the cranium: case series and review of literature.

Primary Ewing's sarcoma (EWS) of the cranium is extremely rare. It accounts for <1% of cases. We retrospectively analyzed our EWS cases to determine those which had a primary cranial involvement. Out of a total of 332 cases of EWS registered between the years 2000 and 2011, 7 were of the primary cranial involvement. Treatment modalities included surgery, chemotherapy, and radiotherapy (RT), as indicated. The follow-up ranged from 8 months to 7.5 years. In our study, parieto-occipital region was the commonest site. Most patients presented with localized disease and swelling of the scalp. Excision followed by chemotherapy or RT appears to have good survival rates. At a median follow-up of 32.2 months, only one patient had a recurrence, and was successfully salvaged with second line chemotherapy. These cases illustrate that a multi-disciplinary approach in patients with EWS of the cranium results in a good outcome.

A multicenter phase II randomized study of Cremophor-free polymeric nanoparticle formulation of paclitaxel in women with locally advanced and/or metastatic breast cancer after failure of anthracycline.

AIMS: Paclitaxel is extensively used in the treatment of advanced carcinomas of the breast, ovary and non-small cell lung cancer. In clinical use it is formulated in the non-ionic surfactant polyethoxylated castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility. Cremophor adds to toxic effects of paclitaxel by producing or contributing to the well-described hypersensitivity reactions that commonly occur during its infusion, affecting a large number of patients. This randomized trial was conducted to evaluate efficacy and safety of novel nanoparticle-based paclitaxel in the treatment of patients with advanced breast cancer. METHOD: Patients were randomized to receive either nanoparticle paclitaxel (NP) 300 mg/m(2) , (NP300) or NP220 mg/m(2) or Cremophor paclitaxel 175 mg/m(2) (CP 175). NP was administered as a 1-h infusion without premedication and CP as a 3-h infusion with premedication every 3 weeks. RESULTS: In total, 194 patients who had been administered at least one dose were included for safety analysis and 170 patients who completed at least two cycles of therapy were analyzed for efficacy. NP showed an overall response rate (complete response + partial response) of 40% in the NP220 and NP300 arms as compared to 31% in the CP arm. The incidence of neutropenia (all grades) was lowest in the NP220 arm (39.4%) compared to the NP300 (55%) and CP arm (50%). CONCLUSION: NP is well tolerated and can be safely administered without any premedication in comparison to conventional paclitaxel, which requires the use of premedication before administration. NP demonstrates promising efficacy with a favorable safety profile.

Utility of fine needle aspiration cytology in mediastinal lesions: a clinicopathologic study of 1617 cases from a single institution.

OBJECTIVE: To study the distribution, prevalence and cytomorphologic features of mediastinal lesions and assess the utility of fine needle aspiration cytology (FNAC) in such lesions by correlating with clinical, laboratory and imageologic parameters. STUDY DESIGN: A retrospective study was performed of mediastinal lesions that were referred for ultrasonographic/computed tomography-guided FNAC during the years 2001-2006. Correlation was done wherever possible using the following parameters: histology, bone marrow, imageology, tumor markers, cytology, immunohistochemistry, antecedent history and regression after therapy. RESULTS: A total of 161 patients underwent 182 aspirates. Diagnosis was possible in 130 (80.7%) patients, and, in 31 cases (19.3%), aspirates were unsatisfactory. In 71 (54.6%) correlation was done, and in 70 (98.5%) positive correlation was found. CONCLUSION: FNAC in correlation with clinical, imageologic and hematologic features proved to be an excellent diagnostic tool in diagnosing as well as classifying mediastinal lesions and can be used as a substitute to core biopsy.

Treatment of advanced hormone-sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib.

PURPOSE: Preclinical data showed that the combination of exemestane and celecoxib has synergistic effects. Therefore, a study was undertaken to explore the efficacy and tolerability of this combination in postmenopausal patients with advanced, hormone-sensitive breast cancer. PATIENTS AND METHODS: A randomized phase II study was conducted in postmenopausal patients with hormone-sensitive breast cancer and measurable disease who had progressive disease after treatment with tamoxifen. Patients were randomly assigned to either exemestane 25 mg daily or the combination of exemestane 25 mg daily with celecoxib 400 mg twice daily. Response Evaluation Criteria in Solid Tumors Group criteria were used to determine antitumor efficacy. Primary end point was the rate of clinical benefit. Secondary end points were tolerability, objective response rate, time to progression (TTP), and duration of clinical benefit. A pharmacodynamic and a pharmacokinetic study were conducted in parallel. RESULTS: One hundred eleven patients (exemestane, n = 55; combination, n = 56) were enrolled in 2002. The demographic characteristics and prognostic factors were similar in both arms. In the assessable population, 24 of 51 patients in the combination arm and 24 of 49 patients in the exemestane arm achieved clinical benefit. TTP was similar in both groups. Duration of clinical benefit was longer in the combination group (median, 96.6 v 49.1 weeks). The addition of celecoxib did not change the tolerability profile of exemestane alone. CONCLUSION: Similar rates of clinical benefit were achieved in both groups.

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.

BACKGROUND: Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS: We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS: 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION: Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Phase II, randomized, multicenter, comparative study of peginterferon-alpha-2a (40 kD) (Pegasys) versus interferon alpha-2a (Roferon-A) in patients with treatment-naïve, chronic-phase chronic myelogenous leukemia.

The efficacy and safety of peginterferon-alpha-2a (40 kD) (PEG-IFNalpha-2a), 450 microg once weekly, versus IFNalpha-2a, 9 MIU once daily, for 12 months, was evaluated in a Phase II study in IFN-naïve patients with chronic-phase, Philadelphia-chromosome-positive CML. At the end of the treatment, complete hematological response was observed in 66.2% (47/71) and 45.2% (33/73) of the PEG-IFNalpha-2a group and IFNalpha-2a groups, respectively (p = 0.009), and major cytogenetic response occurred in 35.2% and 17.8%, respectively (p = 0.016). PEG-IFNalpha-2a was at least as effective as IFNalpha-2a overall, including progression-free survival at the end of treatment, and overall survival after 30 months of follow-up. Adverse events necessitated fewer withdrawals but more dose adjustments in the PEG-IFNalpha-2a group compared with the IFNalpha-2a group (11%versus 23%, and 84.5%versus 65.8%, respectively). In conclusion, PEG-IFNalpha-2a (40 kD), 450 microg once weekly, compared with IFNalpha-2a, 9 MIU once daily, resulted in higher rates of hematologic and cytogenetic response and greater overall survival.