Platelet enzyme abnormalities in leukemias.

Aim of the Study: The aim of this study was to evaluate platelet enzyme activity in cases of leukemia. Materials and Methods: Platelet enzymes glucose-6-phosphate dehydrogenase (G6PD), pyruvate kinase (PK) and hexokinase (HK) were studied in 47 patients of acute and chronic leukemia patients, 16 patients with acute myeloid leukemia (AML)(13 relapse, three in remission), 12 patients with acute lymphocytic leukemia (ALL) (five in relapse, seven in remission), 19 patients with chronic myeloid leukemia (CML). Results: The platelet G6PD activity was significantly low in cases of AML, ALL and also in CML. G6PD activity was normalized during AML remission. G6PD activity, although persistently low during ALL remission, increased significantly to near-normal during remission (P < 0.05) as compared with relapse (P < 0.01). Platelet PK activity was high during AML relapse (P < 0.05), which was normalized during remission. Platelet HK however was found to be decreased during all remission (P < 0.05). There was a significant positive correlation between G6PD and PK in cases of AML (P < 0.001) but not in ALL and CML. G6PD activity did not correlate with HK activity in any of the leukemic groups. A significant positive correlation was however seen between PK and HK activity in cases of ALL remission (P < 0.01) and CML (P < 0.05). Conclusions: Both red cell and platelet enzymes were studied in 36 leukemic patients and there was no statistically significant correlation between red cell and platelet enzymes. Platelet enzyme defect in leukemias suggests the inherent abnormality in megakaryopoiesis and would explain the functional platelet defects in leukemias.

Acute promyelocytic leukemia: An experience from a tertiary care centre in north India.

Background: There are very limited data reported about acute promyelocytic leukemia (APL) from developing countries. We reviewed the clinical course and treatment outcome of APL patients treated at our center. Materials and Methods: Between January 1997 and December 2007, 33 patients with APL received induction therapy using ATRA + daunorubicin (n = 26), As = 26), As2O3 (n = 4) or daunorubicin + cytosar ( n = 3). Results: Median age was 30 years with a male to female ratio of 1.68. Twenty seven patients (82%) achieved CR. Complications during induction therapy were febrile neutropenia (33%), ATRA syndrome (30%), bleeding (58%), and diarrhea in (6%) patients. During induction and follow up, 8 (24.24%) patients died, 6 (18.18%) during induction, 1 (3%) during maintenance, and 1 (3%) after relapse. Median OS is 128 months while median EFS is 61 months. Four patients relapsed at a median time of 61 months. At the time of censoring, 25 patients were alive at a median follow up of 13 months (range 0.6 -127 months); 21 in CR1, 3 in CR2, 1 in CR3. Comparisons among the risk groups (CR and relapse rate and survival statistics) were not statistically significant. Conclusions: APL is a highly curable malignancy. Our results confirm the findings of the published literature from larger cooperative studies from the West. We may further improve outcome with quicker diagnosis and more efficient supportive care system.

Recent advances in the mangement of multiple myeloma.

The management of multiple myeloma has undergone a major change during the past decade. Currently, patients < 65 years of age with advanced disease (stage II-III) are best treated with initial chemotherapy (3-4 cycles of vincristine, adriamycin and dexamethasone, or vincristine, adriamycin and methyl prednisolone, or thalidomide and dexamethasone followed by high dose chemotherapy with autologous peripheral blood stem cell transplantation. More than 50% of patients achieve complete response following this approach. The results of a number of nonrandomized and randomized studies indicate that treatment with high dose chemotherapy followed by autologous peripheral blood stem cell transplantation is associated with improved overall and event-free survival compared with conventional chemotherapy. The absence of chromosome 13 abnormalities, serum albumin levels > 3.5 g/dl and low serum b-2 microglobulin are associated with a better outcome. Almost all patients with significant bone disease or osteoporosis are candidates for therapy with bisphosphonates. About one-third of patients with relapsed or refractory myeloma benefit from therapy with thalidomide or bortezomib (a proteosome inhibitor). Recent work in the immunotherapy of myeloma suggests that some novel immune-based approaches might be useful in the management. The application of cytogenetics and molecular genetics, especially gene expression profiling, are likely to be areas of active research in future studies.

Quality of life measures in lung cancer.

Lung cancer is one of the leading causes of cancer death worldwide. Survival has not improved significantly in spite of newer therapies. In view of the high-symptom burden and severe morbidity, evaluation of quality of life (QOL) becomes important in these patients. Several instruments are now available for this purpose, and have demonstrated good correlation with performance status, symptoms, and survival. Quality of life assessments also help in comparing different therapeutic regimes, thus allowing selection of the appropriate modality. Problems of inconsistent interpretability and high-patient dropout rate poses a challenging problem that needs to be tackled. In spite of these drawbacks, QOL is now considered to be an essential component of lung cancer management and should be performed routinely. Such a practice will help the physician plan appropriate treatment strategies and set practical therapeutic goals.

Non small cell lung cancer (NSCLC): current status and future prospects.

The incidence of lung cancer is rising dramatically and it is now the commonest cause of mortality and morbidity not only in the industrialised countries, but in developing nations like India as well. Tobacco smoking has consistently been demonstrated to be an important aetiological factor, though lung cancer occurs in non-smokers also. In spite of great advances in radiological and molecular diagnostic techniques, the ideal screening marker for early detection of lung cancer has still not been found. Histological diagnosis and staging is essential for selecting the mode of therapy in patients with lung cancer. Stages I and II are amenable to surgery. However, advanced stage III and IV need an individualised combination of surgery, chemotherapy and radiotherapy. With a better understanding of the cellular mechanisms operating in carcinogenesis, newer target specific modalities are being developed and tested in order to stem this disease, which threatens to assume epidemic proportions.

Autologous peripheral blood stem cell transplantation: predictors for haematopoietic reconstitution.

Autologous peripheral blood stem cell transplantation is currently used in the treatment of various haematological and non-haematological cancers. Until recently, colony forming unit-granulocyte-macrophage (CFU-GM) assay and mononuclear cell (MNC) count were the indices commonly used to determine the quality of stem cell grafts and the haematopoietic reconstitutive capacity of transplanted stem cells. However, the discovery of CD34 as a stem cell marker has revolutionized the assessment of progenitor cells present in the peripheral blood stem cell graft. Many studies have included enumeration of CD34+ cells, MNCs and CFU-GM assay in stem cell grafts, and their correlation with engraftment has also been studied. However, there is no consensus regarding the optimum dose of each parameter that ensures haematopoietic recovery in all patients. We discuss the stem cell biology and review the literature on stem cell characteristics influencing successful haemopoietic reconstitution.

Electrophysiologic evaluation of Sudarshan Kriya: an EEG, BAER, P300 study.

To compare the resting Electroencephalogram (EEG), Brainstem Auditory Evoked Responses (BAER) and P300 amongst trained and regular practitioners of Sudarshan Kriya (SK) GP-I and Controls (GP-II).

High dose chemotherapy followed by autologous haemopoietic stem cell transplant in multiple myeloma.

BACKGROUND: High dose chemotherapy followed by autologous stem cell transplant is currently used for the treatment of patients with advanced multiple myeloma. However, there are no reports of the results of this treatment modality in Indian patients. METHODS: Fifty patients with advanced multiple myeloma underwent treatment with high dose melphalan followed by autologous stem cell transplant (bone marrow: 7; peripheral blood stem cells: 43). The patients' ages ranged from 26 to 65 years (median: 52 years) and 35 were men. All patients had received chemotherapy initially with a mean of 9.4 cycles (range: 1-36). Thirty patients had evidence of chemosensitive disease at the time of transplant. The mean interval from diagnosis to transplant was 17.5 months (range: 3-129 months) and the median number of mononuclear cells infused was 4.86 x 10(8) per kg (range: 2-10.48). RESULTS: Post-transplant, 43 of 50 patients engrafted. The median number of days to engraftment (absolute neutrophil count > 500/cmm) was 12 (range: 9-24) and to achieve platelet transfusion independence (> 20,000/cmm) was 13 (range: 8-36). Seven patients died prior to engraftment. Grade III-IV oral mucositis was the major non-haematological toxicity. Excluding the 4 patients who had complete response prior to the transplant and continued in the same status post-transplant, 31/46 patients (67%) responded; complete response was achieved in 25 (54%) and partial response in 6 (13%). Patients with chemosensitive disease had higher rates of complete response; 20 of 26 patients with partial response at transplant achieved complete response compared to 5 of 20 patients with persistent/refractory disease (p < 0.01). Currently, 34 of 50 (68%) patients are alive, 17 (34%) disease-free, 6 with disease are on salvage therapy, 11 (22%) with positive monoclonal protein but asymptomatic are under observation. Nine (18%) patients have died; 8 due to progressive disease and 1 of an unrelated cause. The median follow up for the entire group is 26 months (range: 1-144 months). The Kaplan-Meier probability of overall and progression-free survival for the whole group at 30 months is 62% +/- 8.11% (SE) and 42% +/- 9.54% (SE), respectively. A haemoglobin level < or = 10 g/dl (p < 0.003) affected the survival adversely. Chemosensitive disease (p < 0.008) at transplant and complete response post-transplant (p < 0.0001) were associated with significantly longer survival. CONCLUSION: High dose melphalan followed by autologous stem cell transplantation is an effective treatment for patients with advanced multiple myeloma and achievement of complete response is associated with improved survival.

Germ cell tumours of the testis: clinical features, treatment outcome and prognostic factors.

BACKGROUND: The prognosis of patients with germ cell tumours of the testis has Improved over the past two decades following cisplatinum-based chemotherapy. Currently, staging and risk assessment of the disease is crucial in order to provide curative therapy for patients with poor risk features and not over-treat good risk patients. METHODS: We reviewed the case records of 71 men diagnosed to have germ cell tumours between January 1993 and October 1999. Their clinical characteristics, staging, treatment outcome and prognostic factors for response and survival were analysed. RESULTS: The median age of the patients was 30 years (range: 3-65 years); 69% were in the third and fourth decades. Sixty-one patients (86%) had a primary testicular tumour while in 10 (14%) the tumour was extragonadal. Histopathologically, 53 patients (75%) had non-seminomatous germ cell tumours and 15 (21%) had a seminoma. Twenty-seven patients (62%) had evidence of metastatic disease at the time of diagnosis. On prognostication, non-seminomatous germ cell tumour patients could be divded into good, intemediate and poor prognostic groups comprising 41%, 17% and 40% of patients, respectively. All patients with a seminoma were in the good prognostic subgroup. Fifty-eight patients were evaluable for response. Overall, 91% of patients responded: complete response 71% and partial response 20%. Complete response rates were signiflcantly higher for the good risk (95%) compared to the intermediate (49%) and poor risk (47%) categories (p< 0.003). At a median follow up of 26 months, the 2-year overall and progression-free survival for all patients was 70% and 57%, respectively. The predictors for decreased overall and progression-free survival were age >35 years, presence of poor risk features and mediastinal primary disease. CONCLUSION: The outcome for germ cell tumours in men with good risk is excellent. A protocol consisting of bleomycin, etoposide and cisplatin is effective. Tailoring of chemotherapy In good risk patients to minimize toxicity and Improving results in poor risk patients are areas that need further work.

Autologous bone marrow/stem cell transplantation: initial experience at a north Indian referral centre.

BACKGROUND: High-dose chemotherapy and/or radiation therapy rescued by autologous bone marrow or peripheral blood stem cells is being increasingly used for the treatment of haematological and solid malignancies. While few centres in India use this modality of therapy, the worldwide experience is encouraging. We, therefore, analysed the results of our initial experience with this therapeutic modality. METHODS: Forty-two patients [multiple myeloma (17), Hodgkin's disease (4), non-Hodgkin's lymphoma (3), chronic myeloid leukaemia (2), acute myeloid leukaemia (2), acute lymphoblastic leukaemia (2), epithelial ovarian cancer (6), breast cancer (4), primitive neuroectodermal tumour and testicular germ cell tumour (1 each)] underwent high-dose chemotherapy followed by either autologous bone marrow transplant (n = 9), peripheral blood stem cell transplant (n = 30) or both (n = 3). The indications for transplant included either advanced stage at diagnosis, other adverse prognostic indicators during the course of their disease, or relapse. The data were analysed retrospectively in December 1998 using hospital records. Follow up data of all the patients were available. RESULTS: Thirty-four of the 42 patients (81%) showed stable engraftment. Eight patients (19%) died in the early post-transplant period (day 5 to day 52 post-transplant). Seven patients died due to neutropenic infections and one due to acute renal failure. Of the 34 surviving patients, 20 were alive at the time of analysis and 14 had died. All but one death in this group were due to progressive primary malignancy. The median overall survival for all patients was 17 months and for the 34 engrafted patients it was 27 months. An analysis of factors affecting survival revealed that patients with chemosensitive disease had a longer overall survival (20.9 v. 6.1 months, p = 0.04) compared to those with chemoresistant disease. CONCLUSION: Autologous bone marrow or peripheral stem cell transplantation is a feasible procedure in India with an acceptable morbidity and mortality. It should be offered more frequently to properly selected patients.

Hodgkin's disease: a retrospective analysis of 15 years experience at a large referral centre.

BACKGROUND: The prognosis of patients with Hodgkin's disease has improved significantly over the past two decades, primarily as a result of the development of curative combination chemotherapy. However, data on the presentation and results of treatment in Indian patients are scarce. We reviewed the clinical and pathological data and the treatment outcome of patients with Hodgkin's disease seen at our centre over the last 15 years. METHODS: The case records of 289 patients diagnosed to have Hodgkin's disease at our centre between 1977 and 1992 were reviewed. Their clinical characteristics, treatment outcome and prognostic factors for survival were analysed. RESULTS: The median age of the patients was 26 years with 30% being in the third decade. The male:female ratio was 4:1. The mixed cellularity histological subtype was the most common (68.5%), followed by nodular sclerosis (8.9%). 'B' symptoms were present in 73% of patients and 9.4% had bone marrow involvement. At the time of presentation, 70% of patients had advanced disease (stage III: 36%, stage IV: 34%). Complete response to treatment was obtained in 65.7% of patients while 17.3% had partial response. The predictors of decreased overall survival were age > 40 years, presence of 'B' symptoms, lymphocyte depletion histological subtype and stage IV disease. Disease-free survival was influenced by the presence of 'B' symptoms, bone marrow involvement and stage IV disease. CONCLUSION: Hodgkin's disease in Indian patients has a distinct clinico-pathological profile. Combination chemotherapy has high response rates even in patients with advanced disease at presentation.

Blood stem cell transplantation: current concepts.

Mobilized peripheral blood haematopoietic progenitor cells are increasingly being used as against bone marrow (BM) transplants, following high dose chemotherapy and/or radiotherapy for the management of chemosensitive malignancies. Rapid haematopoietic reconstitution as evidenced by reduced duration of neutropaenia, fewer donor platelet infusions, shorter hospital stay and reduced cost of treatment are the advantages of this procedure. Reduced tumour cell contamination of mobilized blood compared to bone marrow however, has not been substantiated. Mobilization of lymphokine activated killer cells (LAK), use of blood stem cells (BSC) for allogeneic transplants and ex vivo expansion of the mobilized cells are emerging as the future areas for research. Addition of interleukin-3 (IL-3), stem cell factor (c-kit ligand) and PIXY-321 appear to open-up new vistas by enforcing trilineage and multilineage haematopoietic reconstitution.

Infections in the immunocompromised host: a prospective multicenter survey in patients receiving chemotherapy for acute leukemia.

Patients receiving chemotherapy for acute leukemia were prospectively followed up to determine the frequency, nature and outcome, of episodes of infection during a 6 or 12 month period at each of the participating centres. A total of 605 cycles of chemotherapy were surveyed. Of these, 490 cycles were received by patients with acute lymphoblastic leukemia (ALL) and 115 by patients with acute non-lymphoblastic leukemia (ANLL). 241 episodes of infection were recorded during the survey: 179 among ALL patients and 62 among patients of ANLL. Infections were more common during chemotherapy for ANLL than for ALL, occurring in 54% (62/115) and 36% (179/490) of chemotherapeutic cycle respectively. A favorable response to empiric antibacterial agents was seen in 39% (23/59) of episodes in ANLL patients and 77% (134/174) of episodes among ALL patients. Infection presented as fever of unidentified origin in an overwhelming majority (63%) of episodes. Gastroenteritis and pneumonia occurred with a frequency of 11% and 10% while the frequency of all other diagnoses was 3% or less. Overall, E coli and Candida were the most frequently isolated organisms while Staphylococcus aureus and Group A Streptococci were the most frequent isolates from blood and throat swabs, respectively. A high degree of resistance to commonly used antimicrobial agents was seen among the most frequently isolated organisms. About 75% of episodes of infection which did not respond to antibacterial agents responded to empiric systemic antifungal therapy; although fungi were mycologically isolated in only a quarter of these instances. Oropharyngeal candidiasis occurred in association with 3% of chemotherapeutic cycles.

Storage of haemopoietic stem cells for autologous bone marrow transplantation.

For reinfusing autologous bone marrow cells after high-dose chemotherapy and/or radiotherapy it is necessary that an effective technique for their storage is available. The traditional method uses 10% dimethyl sulphoxide as cryoprotectant, a rate-controlled computerized freezer programmed to cool the cells at a constant rate of 1 degrees C per minute and liquid nitrogen as the storage system. The method is time-consuming, expensive and requires technical expertise. Moreover, it is often associated with varying levels of clinical toxicity following infusion of the preserved cells. Processing the harvest to reduce the initial volume and the mature cells has been shown to be beneficial in reducing the volume of the cryoprotectant and the incidence of toxicity. An alternative, cost-effective method using a cryoprotectant mixture of 5% dimethyl sulphoxide, 6% hydroxyethyl starch and 4% albumin has been found to be effective even when the cells are stored at -80 degrees C without rate-controlled freezing. However, its efficacy needs to be evaluated for extended periods. The current use of purging and cell sorting methods seems to be promising.

Biological therapies in bone marrow transplantation.

Biological materials are increasingly being utilized in bone marrow transplants. Alpha interferon is given post autotransplants, in an attempt to eradicate residual cancer cells. Colony stimulating factors (granulocyte macrophage colony stimulating factor: GM-CSF and granulocyte colony stimulating factor: G-CSF) are widely used after bone marrow transplants to accelerate bone marrow recovery. Their use has been associated with fewer infections, shorter hospital stay and lower procedural costs. Both these factors benefit some patients with graft failure as well. The recent demonstration that both GM-CSF and G-CSF can mobilize large numbers of haematopoietic stem cells into the peripheral blood has resulted in the widespread use of peripheral blood stem cell transplantation as an alternative to autologous bone marrow transplantation. Identification of tumour cells in the mobilized peripheral blood stem cells, however, has raised some concern.

Role of serum ferritin in assessment of disease activity in acute & chronic leukemia.

Serum ferritin (SF) was estimated using double antibody sandwich ELISA in 83 patients of acute and chronic leukemia at various stages of the disease. In 35 patients of acute lymphoblastic leukemia (ALL) in remission, the SF levels fell significantly from 550.63 ng/ml at presentation to 319.56 ng/ml but remained significantly higher than the control values of 46.14 ng/ml. In 28 patients of acute myeloid leukemia (AML), the SF values at 775.0 ng/ml were much higher than those in ALL patients and showed no decline with remission. This pattern was also seen in patients of chronic myeloid leukemia in blast crisis (CML-BC) with SF levels of 804.03 ng/ml at presentation and 717.43 ng/ml at partial remission. The values of SF were lowest in patients of CML in chronic phase ranging from 271.5 ng/ml to 332.12 ng/ml and showed no relationship with variation in total leucocyte count. No correlation was found between SF values and various clinical and laboratory parameters such as age, sex, fever, organomegaly, haemoglobin and total leucocyte count. Thus, while there appeared to be a correlation between remission and SF values in ALL, no such correlation existed between the activity of the disease and SF in other types of leukemia.

Effect of gamma interferon on the expression of class I MHC antigens on fresh leukemic cells and their susceptibility to lysis by lymphokine activated killer cells.

Relationship between MHC class I antigen expression on PBLs from leukemia patients and their susceptibility to lysis by LAK cells was investigated. LAK cells induced small yet significant lysis of leukemic cells. In nine out of 14 cases studied, treatment with Interferon gamma (200 U/ml for 48 hours) resulted in a decrease in the LAK susceptibility of leukemic cells. In six of these cases, there was a concomitant increase in the expression of class I MHC antigen expression. In three samples, the increase in MHC class I antigen expression was not accompanied by a decrease in LAK susceptibility. IFN treatment had no effect on the binding of leukemic cells to LAK effector cells.

Emerging concepts in the management of acute lymphoblastic leukaemia.

Modern chemotherapy can cure more than 70 per cent of children with standard risk acute lymphoblastic leukaemia (ALL). Encouraging results are also reported in children with high risk ALL receiving intensive chemotherapy. Results in adults with ALL are less satisfactory, the long term survival is less than 35 per cent. Further dose intensification as possible in the setting of bone marrow transplantation (BMT) has increased the cure rate to 50 per cent in adult ALL. Allogeneic BMT has, however, besides the enhanced antileukaemia activity related to high dose therapy, additional antileukaemia effect related to immune mechanisms. Immune effects may be separated into three elements viz., an antileukaemia effect of graft vs host disease (GvHD), a separate antileukaemia effect of T cells and possibly a specific graft vs leukemia effect (GvL). These immune mediated antileukaemic effects offer a new potential therapeutic modality. For instance, the T cell antileukaemic effect of transplant could be achieved by transfusing radiated T cells or administering lymphokines. Alternatively autologous bone marrow could be manipulated in vitro prior to reinfusion. Manipulation might include activation of natural killer (NK) cells or lymphokine activated killer (LAK) activity. Another newer approach to treat ALL is the use of hemopoietic growth factors. Use of these factors prior to chemotherapy may increase the proportion of proliferating leukaemic stem cells. This would increase the efficacy of many drugs since most are active against proliferating cells. Hemopoietic regulatory factors could also be used to directly inhibit leukemic cell growth or to promote differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Management of malignant germ cell tumours of ovary.

Ten patients of the advanced malignant germ cell tumours of the ovary were treated by cisplatin based combination chemotherapy after initial conservation surgery. Eight patients completed course containing cisplatinum, vinblastine and bleomycin. Five patients (62.5%) achieved CR while 2 (25%) attained PR. One patient died due to tumour lysis and respiratory infection. Rest two patients did not turn up in follow up. Long term follow up indicates above regimen to be highly effective. However poor performance status, advanced stage of disease and post operative gross residual disease were poor prognostic factors in our patients.