Activity and toxicity of 2-CDA in Langerhans cell histiocytosis: a single institutional experience.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of immature and abnormal bone marrow derived langerhans cells. Treatment is usually multimodal. Potent anti-monocyte as well as immunomodulatory activity of 2-CDA and its proven efficacy in many lymphoproliferative disorders has made 2-CDA a rational choice in treatment of LCH. AIM: To evaluate the efficacy and toxicity profile of 2-CDA in children with relapsed or refractory LCH. SETTING AND DESIGN: This is a pilot study and we present the initial data of the first seven patients treated at our institution. MATERIALS AND METHODS: Seven patients of relapsed and refractory LCH were enrolled from July 2000 to June 2004. The cohort of seven patients included six males and one female with a median age at initiation of cladribine was 2.25 years (range, 1.67 to 7.0 years). Three patients had received one prior chemotherapy regimen while the rest were heavily pretreated. Cladribine was administered over two hours IV daily for five days and repeated every four weeks. RESULTS: After a median of six courses of cladribine (range, 2 to 9), two (33%) patients achieved PR and two (33%) patients have SD on imaging but are clinically better. None experienced grade 3 or 4 hematologic toxicity. At a median follow-up of 19 months (range, 8 to 52 months), five patients remain alive and one patient has died. CONCLUSION: Our study shows that single agent 2-CDA is active and well-tolerated in children with relapsed or refractory LCH.

Constitutional and somatic RB1 mutation spectrum in nonfamilial unilateral and bilateral retinoblastoma in India.

An epidemiologic survey has indicated a comparatively high prevalence of retinoblastoma (Rb) in Asian countries. Recently, the development of preventive strategies in nonfamilial Rb has become a major goal. The present studies were designed for identification and characterization of constitutional and somatic RB1 gene mutations by conventional cytogenetics, fluorescent in situ hybridization (FISH) and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-DNA sequencing. Of 34 patients 32 were nonfamilial and 2 were familial Rb. Maternal inheritance of del (13q14) was common. FISH was sensitive in detecting monoallelic RB1 deletion/deletion mosaicism as a first genetic hit in 20% of cases. Somatic and germline RB1 point mutations affected exons 3, 17, 20, and 21 and these were identified as novel mutations. Involvement of exon 20 as a predisposing mutation in sporadic unilateral retinoblastoma (URB) probably suggests the susceptibility of exon 20 to unknown etiologic factors in our population. A de novo RB1 deletion along with transmitted RB1 point mutation from an asymptomatic parent was identified as a unique predisposing RB1 mutation chimerism in a URB case that later evolved to bilateral retinoblastoma (BRB). The predisposing mutations such as del (13q), RB1 mono-allelic deletion and RB1 point mutation in sporadic Rb were de novo as well as transmitted mutations from asymptomatic/symptomatic parents. The RB1 mutation incidence was comparatively higher (25%) in nonfamilial Rb with emphasis on high prevalence in sporadic URB (18% versus 0%-9% in the literature series). The present studies demonstrated the efficacy of a multitechnique approach to detect various types of constitutional RB1 mutations such as RB1 deletion, deletion mosaicism, point mutation, mutation chimerism in patients of symptomatic/asymptomatic parents.

Desmoplastic small round cell tumor: extra abdominal and abdominal presentations and the results of treatment.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare malignant neoplasm of adolescent males. Current multimodality treatment prolongs life and rarely achieves cure. AIM: To review the presenting features, histopathology and outcome of 18 patients with DSRCT treated at a single institution. SETTING AND DESIGN: This is a retrospective observational study of patients with DSRCT who presented at the Tata Memorial Hospital between January 1994 to January 2005. MATERIALS AND METHODS: Eighteen patients of DSRCT seen during this period were evaluated for their clinical presentation, response to chemotherapy and other multimodality treatment and overall survival. The cohort of 18 patients included 11 males (61%) and 7 females (39%) with a mean age of 16 years (Range 1(1/2)--30 years). Majority (83%) presented with abdomino-pelvic disease. The others, involving chest wall and extremities. There were 6 patients (33%) with metastatic disease at presentation. RESULTS: The treatment primarily included a multimodality approach using a combination of multiagent chemotherapy with adjuvant surgery and radiotherapy as applicable. A response rate of 39% (CR-1, PR-6), with chemotherapy was observed. The overall response rate after multimodality treatment was 39% (CR-5, PR-2). The overall survival was poor except in patients who had complete excision of the tumor. CONCLUSION: 0 Abdomino-pelvic site was the commonest presentation, the disease can occur at other non-serosal surfaces also. Despite aggressive treatment the outcome was poor. However, complete surgical excision seems to provide a better survival.

Brain tumors following cure of acute lymphoblastic leukemia.

The majority of children with acute lymphoblastic leukemia can be cured with effective modern day therapy. However, more and more long term sequelae including carcinogenic potential of the treatment are being recognised. We report two children who developed acute lymphoblastic leukemia at the age of 4 and 5 years respectively and were successfully treated. They developed meningioma and astrocytoma at 9 and 3 years respectively after completion of therapy. Both were treated surgically and the patient with astrocytoma also received radiotherapy. Both are now free of disease 19 months after diagnosis of second neoplasm.

Survival of childhood acute lymphoblastic leukemia: results of therapy at Tata Memorial Hospital, Bombay, India.

The purpose of this study was to analyze the outcome of patients who completed therapy for acute lymphoblastic leukemia (ALL) and to study the role of an aggressive induction regimen in preventing post therapy relapses. Four hundred and twenty-two patients with ALL who completed therapy during the period 1975-1991 were followed. Two hundred and sixty patients received the aggressive MCP 841 protocol and 162 patients received various other less aggressive treatment regimens. Patients were followed with periodic examination and complete blood counts. The incidence of post therapy relapse was 27% in the less aggressive protocols and 15% in the MCP 841 protocol (p = 0.001). An higher percentage of relapses was seen in males (p = 0.05) and 89% relapses occurred within two years of stopping therapy. The relapse rate after 5 years of cessation of therapy was 0.59%. In conclusion, aggressive induction therapy is the most crucial factor in predicting relapses following cessation of therapy in ALL patients. However, relapses are unlikely to occur five years post therapy.

Epidemic iatrogenic Acinetobacter spp. meningitis following administration of intrathecal methotrexate.

We report the first outbreak of Acinetobacter species meningitis in a group of children with acute leukaemia following the administration of intrathecal chemotherapy. Eight of twenty patients receiving methotrexate injections on a single day developed signs and symptoms of meningitis within 18 h of treatment, and cases were clustered by time of administration. A cohort study comparing case and non-case patients did not identify any specific host factor associated with meningitis. Acinetobacter calcoaceticus var anitratus was isolated from the cerebrospinal fluid (CSF) of five patients; three patients died. Our investigation determined that the methotrexate was extrinsically contaminated by reused needles, used for reconstitution and administration, which had been inadequately sterilized. Acinetobacter calcoaceticus var anitratus was isolated from an autoclaved needle and a vial of methotrexate used for chemotherapy; these and the clinical isolates had similar antibiograms. After introduction of single-use disposable needles no subsequent cases occurred.

Limitations of the therapeutic regimens for myelodysplastic syndrome.

Thirty patients of myelodysplastic syndrome (MDS) were treated over a period of 2 yr using 3 different treatment regimens. Twelve patients received hydroxyurea, 4 were given low dose cytosine arabinoside and 14 others were treated with an aggressive acute myeloid leukaemia (AML) induction regimen. A low complete remission was obtained in the first 2 groups (17 and 25% respectively), whereas 9 (64%) patients attained complete remission with the AML induction regimen. Remission in the latter group was associated with prolonged and severe pancytopenia requiring intensive support. Patients in all the 3 groups had a short duration of remission culminating in death with progressive marrow failure or evolution to AML, indicating the limitations of the current treatment strategies for MDS and highlighting the need for exploring newer therapeutic approaches.

Prognostic significance of myeloperoxidase containing blast cells in acute myelogenous leukaemia.

Fifty three newly diagnosed patients of de novo acute myelogenous leukaemia (AML) received treatment consisting of remission induction with daunorubicin 60 mg/m2 on day one and continuous infusion of cytosine arabinoside 200 mg/m2/day over 24 h from day one to 7. Thereafter patients in complete remission received consolidation chemotherapy with two identical courses. Complete remission (CR) could be achieved in 40 patients (75.5%). Seven patients (13.2%) died with complications during aplasia phase following remission induction therapy while six patients (11.3%) had resistant disease. Twenty seven patients (67.5%) developed relapse while eight patients (15.1%) continue to remain in complete remission ranging from 51 to 68 months (median 62.5). The projected event free survival and disease free survival at 60 months is 15 per cent (SE + 11.9%) and 21 per cent (+6%) respectively. Evaluation of the prognostic significance of pretherapy characteristics showed that infection at presentation and low number of myeloperoxidase (MPO) containing blasts affected the achievement of complete remission adversely on univariate analysis. Similarly age at diagnosis, of more than 45 yr, total leucocyte count of 50,000/cumm or more and low number of MPO containing blasts affected the remission duration (disease free survival) adversely on univariate analysis. On multivariate analysis, MPO positivity of blast cells, remained the only significant independent characteristic. High MPO positivity affected the remission duration favourably (P < 0.01). Patients with high MPO positivity also achieved CR with one induction cycle in 32 out of 40 instances while only 2 out of 5 patients with low MPO positivity, achieved CR with one chemotherapy cycle (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydroxyurea on foetal haemoglobin in myeloproliferative & myelodysplastic syndromes.

The effect of hydroxyurea on foetal haemoglobin (HbF) levels was evaluated in 36 patients of myeloproliferative and myelodysplastic disorders. In 17 (47.2%) patients, HbF levels increased from 1.40 +/- 1.17 to 3.03 +/- 1.97 per cent after 4 wk therapy with hydroxyurea. In the responders this increase was highly significant (P less than 0.001). The rise in the HbF levels after hydroxyurea therapy was significant in patients with chronic myeloid leukaemia but not in the other groups.

Infantile neuroblastoma: 10 year TMH experience.

The results of 19 children with neuroblastoma under one year of age treated at the Tata Memorial Hospital between 1981-1990 were analysed. Biologically, neuroblastomas in children under the age of 12 months have an entirely different prognosis as compared to older children. There were four children less than six months of age and 15 children between six and 12 months. All patients with stage II (2/2) disease are alive; 3/4 patients with stage IV-S disease are disease free; 3/5 stage III patients are disease free and 2/8 patients with stage IV disease are disease free. The survival of infants with stage II and IV-S is better than for those with stage III and IV disease.

Aniridia--Wilms' tumour association--a case with 11p 13-14.1 deletion and ventricular septal defect.

A two year old female child with bilateral wilms tumor (WT) along with multiple congenital anomalies like bilateral aniridia with congenital cataracts and nystagmus, microcephaly, mental retardation and ventricular septal defect has been described. The karyotype analysis revealed 46 xx, del 11p 13-14.1. Association of ventricular septal defect with the classical features of 'Aniridia-Wilms' tumor association' is an unusual feature in this case.

131I-MIBG scintigraphy in neural crest tumours.

Radioiodinated meta-iodobenzylguanidine (131I-MIBG) has been widely used for the diagnosis of neuroblastomas, pheochromocytomas, paragangliomas and medullary carcinomas of thyroid. We have developed a procedure for preparation of 131I-MIBG and studied its utility in diagnosis of primary and metastatic neural crest tumours. Studies were carried out in 54 patients. Of them 39 cases were of neuroblastomas, 1 pheochromocytoma; 6 operated medullary carcinomas; 5 paragangliomas; 2 Ewing's sarcoma and 1 Rhabdomyosarcoma; The sensitivity for the detection of primary tumours of neuroblastomas was 94% and for the detection of metastasis was 83%; while in the case of paragangliomas and medullary carcinoma, the sensitivity was 75% and 70% respectively. Our experience in the present study shows that 131I-MIBG scintigraphy is a sensitive and specific diagnostic tool to localise primary and metastatic disease of neural crest tumours.

Acute lymphoblastic leukemia in childhood: treatment, results and prognostic factors.

Two hundred and nine children (20 years and below) diagnosed as acute lymphoblastic leukemia between January 1980 and December 1983 were retrospectively analysed to evaluate the clinical features, prognostic factors and the results of therapy. One hundred and eighty one evaluable patients were treated with three different chemotherapy regimens consisting of vincristine and prednisolone (Group-A), vincristine, prednisolone and L-asparaginase (Group B-60 patients), and vincristine, prednisolone and adriamycin (Group C-81 patients). Complete remission was achieved in 152 (84%) patients, remission induction being 75 percent, 85 percent and 88 percent in Group A, B and C respectively. At a median follow-up of 36 months the disease free survival for complete responders was 35.5 patient. The disease-free survival for Group A, B and C was 20 percent, 47 percent 34 percent respectively indicating the superiority of a three drug regimen over the conventional two drug regimen. Patients at standard risk in each group had significantly better survival when compared to those at high risk. A 3-drug treatment regimen was superior to the 2-drug regimen and a low initial leucocyte count was an important favourable prognostic factor.

Myelodysplastic syndrome. A clinical and pathological analysis of 88 patients.

Eighty eight patients with myelodysplastic syndromes were studied to determine the clinical and pathological features and the prognosis. All the patients had anemia. Neutropenia was seen in 44% and thrombocytopenia in 78% patients. The subtypes included refractory anemia in six, refractory anemia with ringed sideroblasts in three, refractory anemia with excess blasts in 30, refractory anemia with excess blasts in transformation in 32 and chronic myelomonocytic anemia in 17 patients. Forty four patients who received chemotherapy were evaluable for response. Three of the 15 patients treated with hydroxyurea achieved partial remission. Eighteen patients were treated with low dose cytosine arabinoside and complete remission was achieved in five and partial response in six patients. Aggressive chemotherapy was given to 11 patients at the onset of the illness resulting in complete remission in six and partial response in two patients. Nineteen of the 88 patients transformed to acute myeloid leukemia. The crude survival of all the patients ranged from 15 days to 22.5 months. The mortality was due to hemorrhage in 15% and septicemia in 85%. Our data reveals ineffectiveness of the current therapy and emphasizes on the need to develop newer therapeutic approaches.

Evaluating efficiency of bone marrow harvest and its manipulation--role of CD 34 positivity.

We evaluated harvested marrow cells for total nucleated cells (27.49 x 10(9)), absolute 'lymphocyte' count (6.29 x 10(9)) and CD 34 positive cells (3.57 x 10(9)). The same parameters were studied after in vitro manipulation to remove RBCs and plasma. Reinfused WBCs contained 12.87 x 10(9) nucleated cells, 4.25 x 10(9) absolute 'lymphocyutes' and 3.34 x 10(9) CD 34 positive cells. The corresponding figures for loss during in vitro manipulation (tubing, RBCs and plasma) are 14.62 (53.18%), 2.04 (32.43%) and 0.23 x 10(9) (6.44%) cells respectively. Therefore CD 34 positivity may be a better indicator of total yield, loss during manipulation and reinfusion of hemopoietic progenitor cells in bone marrow transplantation.

Multiple myeloma. Analysis of fifty cases.

Fifty patients of multiple myeloma have been studied. Seventy eight per cent of the patients were in the 5th, 6th and 7th decades of life. Commonest presenting feature was bone pains (76%). 8%, 20% belonged to stage I, II and III respectively. Skull (58%), ribs (52%) and pelvis (24%) were most commonly involved. Immunoelectrophoresis revealed IgG type of myeloma in 76% and IgA type in 10% cases. Bence-Jones proteinuria was seen in 60% of patients; Kappa specificity was commoner than lambda. Overall survival at 30 months was 50%. The survival was adversely influenced by advanced stage, higher plasma cell count in the bone marrow, low haemoglobin and high serum creatinine values.

Preliminary experience with allogeneic bone marrow transplantation in haematological disorders in India.

Between March 1983 and December 1985, six patients with haematological disorders (four acute nonlymphocytic leukaemias, one chronic phase chronic myeloid leukaemia and one severe aplastic anaemia have undergone allogeneic bone marrow transplantation. Four of the 6 patients are alive and free from disease between 33+ and 55+ months; two patients died due to grade IV acute graft versus host disease (GVHD).

Cytotoxic therapy. Role of durable venous access.

Aggressive chemotherapy regimens and supportive measures in haemato-oncology patients demand reliable venous access. Experience with this method in India has been limited. During a period of six months, we have used 42 subclavian indwelling catheters and 31 cubital Cavafix long lines. The mean age of patients in the two groups was 32 years and 7 years respectively. Subclavian catheters had a median duration of catheter placement of 46 days (range 4-145) and total 1494 catheter days, while cubital longlines yielded a median duration of insertion of 14 days (range 4-27) and total 508 catheter days. Catheter related complications were infection in 25% of patients, thrombophlebitis in 22%, blockade in 12% and misplacement in 17% in both groups taken together. The patients and families were extremely satisfied with the devices. Our experience supports further use of durable venous access in cancer patients. Implanted central venous catheters should be preferred whenever feasible.

Childhood myelodysplastic syndromes: clinical features, cytogenetics and prognosis.

Sixteen children with myelodysplastic syndrome as defined by the French-American-British co-operative group are presented. The mean age was 10.5 (2.5 to 16) years, with a male predominance. All patients belonged to the more aggressive subtypes of myelodysplastic syndromes. Seven patients presented with refractory anaemia with excess blasts, six had refractory anemia with excess blasts in transformation, and three had chronic myelomonocytic leukemia. Cytogenetic analysis done in 7 of the 16 patients, revealed karyotype abnormalities involving chromosomes 7, 8 and 17. One patient with Down's syndrome had karyotype of 47, XY, +21 (major clone) and 46, XY (minor clone). Five of these patients evolved to acute leukemia. The mean duration of survival was 5.5 months. Aggressive chemotherapy as a primary line of treatment induced remission in five out of six patients. Predominance of aggressive types of myelodysplastic syndromes in children and their good but short-lived response to aggressive chemotherapy suggests the need for early bone marrow transplantation following chemotherapy.

Low incidence of CNS relapse with cranial radiotherapy and intrathecal methotrexate in acute lymphoblastic leukemia.

OBJECTIVES: To assess the incidence of isolated central nervous system (CNS) relapses in patients of acute lymphoblastic leukemia (ALL) treated with a protocol containing cranial irradiation and intrathecal methotrexate as CNS directed therapy. DESIGN: Prospective non randomized study. SETTING: Department of Medical Oncology, Tata Memorial Hospital. SUBJECTS: 623 children of ALL on MCP 841. METHODS: CNS relapse was diagnosed, if upon examination of the CSF, more than 50 cells/microliter were observed, or a count of 5 cells which were unequivocally lymphoblasts. RESULTS: The incidence of isolated CNS relapse was 1.75% with the use of this treatment. Age, sex, white blood cell count, platelet count, lactic dehydrogenase and immunophenotyping were not significantly related to isolated CNS relapse. CONCLUSION: A low incidence of isolated CNS relapse demonstrates the adequacy of the presymptomatic CNS therapy.