Critical steps in hematogenous metastasis: an overview.

Metastasis is responsible for most cancer deaths. A better understanding of the process provides opportunities to develop new treatments to prevent metastasis. This article summarizes findings from experimental in vivo videomicroscopy and quantitative studies on metastatic inefficiency, which indicate that early steps in hematogenous metastasis may be quite efficient, but that regulation of cancer cell growth in secondary sites determines metastatic outcome. The authors have identified three key stages of this growth regulation: survival of a subset of single cells, proliferation of a subset of these cells to form preangiogenic micrometastases, and persistence of growth of a subset of these to form vascularized metastases. Formation of clinically relevant metastases is determined by the proportion of cells that proceeds successfully through each stage, and surviving single cells and preangiogenic micrometastases both represent possible sources of tumor dormancy.

Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency.

Cancer metastasis is an inefficient process. The steps in metastasis responsible for this inefficiency and how metastatic inefficiency can vary in different locations within an organ remain poorly understood. B16F10 cells were injected to target mouse lung, and at sequential times thereafter we quantified in lung the time course of: (a) overall cell survival and metastatic development; and (b) local cell survival and growth with respect to the lung surface and specific interior structures. We found high rates of initial survival of cells trapped in the lung circulation, extravasation into lung tissue, and subsequent survival of extravasated solitary cells (74% at day 3) before metastasis formation. However, at the time of initial replication of metastatic cells a major loss of cells occurred. Although only a small proportion of injected cells started to form metastases, most of these developed into macroscopic tumors. Solitary cells found at later times were dormant. Thus, overall metastatic inefficiency was largely due to postextravasation events affecting solitary cells. Regionally within the lung, cells and metastases were randomly distributed to day 4, but by day 10 preferential tumor growth was found along the lung surface and around arterial and venous vessels. Thus, trapping and early growth of injected cells was unaffected by location within the lung, whereas subsequent metastatic growth was enhanced in specific microenvironments. This study: (a) quantifies early temporal and spatial progression of metastasis in lung; (b) documents persistence of solitary dormant cells; and (c) shows that metastatic inefficiency depends on the initiation of growth in a subset of extravasated cells, whereas continued growth of metastases occurs preferentially in specific tissue environments.

Soft tissue sarcomas: ultrasonographic evaluation of local recurrences.

OBJECTIVE: The diagnosis of early local recurrence of soft tissue sarcomas, especially in those treated with surgery and radiotherapy, is a difficult clinical problem. Financial constraints led us to use ultrasonography instead of CT or MR imaging. The aim of this study was to evaluate the role of ultrasonography (US) in detecting local recurrence. METHODS AND RESULTS: Fifty patients with previous treatment for soft tissue sarcomas were evaluated prospectively for recurrence by US and histopathology. Seven of the 50 patients were clinically suspected to have recurrent tumour. Ultrasonography showed recurrence in 26, no recurrence in 18, benign disease in four and was indeterminate in two cases. Ultrasonography was instrumental in guiding fine needle aspiration biopsies of small local recurrences and indeterminate lesions in 17 patients. In the sonographically tumour positive patients, histopathology confirmed recurrence in 24; one case had benign disease and one patient refused surgery. Thirteen of the 18 sonographically tumour negative patients were operated upon; all were negative for tumour on histopathology. Both the indeterminate cases showed recurrence on histopathology. The benign cases were confirmed by histopathology correlation. Ultrasound guided fine needle aspiration cytology (FNAC) was positive in 14 out of 17 patients (88%). The sensitivity and specificity of US was 92.30% and 94.4% respectively. CONCLUSION: Our study concludes that US is an extremely useful and cost effective method in the detection of early local recurrences of soft tissue sarcomas and should therefore be used for initial routine follow-up and guided biopsies.

Filtration and agar embedding applied to fine needle aspirates for tumor diagnosis by electron microscopy. A combined technique.

OBJECTIVE: To develop a novel method for processing of fine needle aspirates subjected to electron microscopic (EM) study. STUDY DESIGN: Included 70 cases of poorly differentiated malignant tumors in which a definitive diagnosis was not possible on light microscopic (LM) examination and that thus required application of an ancillary technique such as FNA/EM, for diagnosis. We have established a novel method of processing, a technique of filtration through nylon mesh filters to eliminate red blood cells (RBCs) and necrotic debris, followed by agar well embedding to avoid loss of diagnostic material during processing without centrifugation at later steps after agar embedding, thus minimizing the time required for processing. It was successfully carried out in 70 cases. RESULTS: The combined technique was extremely effective in eliminating RBCs and necrotic debris. It also avoided further loss of valuable diagnostic material. An accurate diagnosis was rendered in 70 cases; that was not possible by LM alone. The whole procedure saves two to three hours of processing as centrifugation is not required after the agar embedding step. CONCLUSION: This technique was found to be cost- and time-effective, particularly suitable for developing countries, where financial resources are limited.

Sezary cells with hairy projections.

A case of sezary syndrome where the sezary cells showed cytoplasmic hairy projections is reported. The patient had typical exfoliative erythematous dermatitis, high white cell count, atypical lymphocytes of T-phenotype with folded nuclei and bone marrow involvement. The ultra structure study showed cerebriform nucleus and cytoplasmic projections.

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.

Cost effective treatment of osteogenic sarcoma of the extremities.

In an ongoing trial at our institute 10 patients of high grade osteogenic sarcoma of the extremities have been treated with preoperative chemotherapy including ifosfamide 2 mg/M2/day i.v. for 5 days, doxorubicin 20 mg/M2/day i.v. for 3 days and cisplatinum 120 mg/M2 i.v. on day 1 at 3-4 weeks interval for 2 courses followed by surgery. One patient refused surgery and further treatment. Pathological study of the 9 surgical specimens showed grade IV necrosis in 5, grade III necrosis in 2 and grade I & II necrosis in 2. Overall response rate (Grade III & IV) was 87.5%. The patients showing Grade III/IV response received a further 3 cycles of the same chemotherapy postoperatively. The patient who refused surgery is still alive at 30 months. Our followup ranges from 4-34 months. All patients developed myelosuppression and one patient died after 4th course of chemotherapy due to septicemia. We expect grade IV response to preoperative chemotherapy will be translated into longer disease free survival. Protocols followed in western countries are not practicable in Asian countries. Hence this new combination has been developed without compromising response rate.

Adult acute lymphoblastic leukemia: results of an aggressive regimen in India.

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.

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.

High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia.

Fifteen patients with lymphoid blast crisis of chronic myelogenous leukemia (LyBC-CML) and five patients with acute lymphoblastic leukemia converting to Philadelphia-positive (Ph+) chronic myeloid leukemia (ALL Ph + CML) were followed. Seven of 15 (46.7%) LyBC-CML patients developed meningeal leukemia within a median period of 6 months (range 2-11 months), while there was no medullary relapse. Five of these responded well to triple intrathecal therapy. In the ALL Ph + CML patients, in spite of central nervous system (CNS) prophylaxis with IT MTX and 18 Gy cranial radiation, two of five patients (40%) experienced meningeal leukemia, one isolated and the other with medullary relapse. The data confirm that LyBC-CML patients experience a high incidence of meningeal leukemia. The role of CNS prophylaxis is not very clear, but its use may delay development and reduce morbidity due to CNS disease.

Adjuvant chemotherapy for osteogenic sarcoma of the extremity with sequential adriamycin and cisplatin.

Twenty-nine patients with high-grade nonmetastatic osteogenic sarcoma of the extremities were treated with adjuvant chemotherapy following definitive surgery. Chemotherapy consisted of systemic intravenous Adriamycin and cisplatin in a sequential fashion given for six courses. Nineteen out of 29 patients are alive and continuously disease free over a follow-up period ranging from 9+ to 30+ months. The relapse-free survival was 72%, and overall survival for the entire group was 69%. Median survival is not reached yet. Six out of 29 patients relapsed, of which 1 patient is alive for 6+ months after relapse. Three patients died of chemotherapy toxicity. The results were superior to historical controls treated with surgery alone. The need for more aggressive treatment approaches is discussed.

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)

Characterization of lymphokine-activated killer cells from peripheral blood and lymph nodes of non-Hodgkin's lymphoma patients.

Peripheral blood lymphocytes (PBL) and lymph node lymphocytes (LNL) from non-Hodgkin's lymphoma patients were tested for LAK cell cytotoxicity using appropriate targets in a short-term 51chromium-release assay. The results showed a significant depression in LNL-LAK activity suggesting the reduced capacity of LNL to generate LAK cells. LNL-LAK cells demonstrated significantly low percentages of cells expressing CD16, CD56 and CD25 as compared to PBL-LAK of patients and healthy donors. The reduced capacity to generate LAK cells in lymph nodes could be due to the presence of low numbers of NK cells which are thought to be the main precursors of LAK cells. The IL-2 producing ability of lymph node mononuclear cells was found to be significantly higher than that of peripheral blood mononuclear cells from both healthy donors and NHL patients.

Urinary bladder cancer following cyclophosphamide therapy for Hodgkin's disease.

Urinary bladder cancers following prolonged cyclophosphamide therapy are being increasingly reported. We report a case of transitional cell carcinoma of the urinary bladder occurring 12 years after pulse intravenous therapy with cyclophosphamide for Hodgkin's disease. The mechanism of bladder carcinogenesis and the possible role of the uroprotector MESNA in preventing cyclophosphamide induced bladder cancer are discussed.

Hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in hospital births in Bahrain.

In view of the high prevalence of clinical cases of sickle cell anemia, hemoglobin-H-disease and glucose-6-phosphate dehydrogenase deficiency in the archipelago of the State of Bahrain, a cord blood screening study was undertaken over a 15 month period (October 1984 to December 1985) to determine the gene frequency of these diseases. All the state hospitals participated in this study and a total of 10,327 cord blood samples obtained from babies born to Bahraini parents were analyzed. These presented over 80% of all neonates born in the country during the study period. The phenotypes detected included: AF, AF-Barts, SFA and SFA-Barts. Homozygous sickle cell disease was detected in 2.1%, and in 11.2%, the sickle cell trait was present. The incidence of alpha-thalassemia gene based on elevated Bart's hemoglobin was 24.3% in these neonates. The incidence of G6PD-deficiency was as high as 20.9%. Availability of these statistics has enabled the authorities in the Ministry of Health in collaboration with the National Hereditary Anemia Society to plan a comprehensive health care program for patients with hereditary diseases and their families.

Pure red cell aplasia and non-Hodgkin's lymphoma: a case report and brief literature review.

Pure red cell aplasia associated with lymphoproliferative malignancies other than thymoma is an uncommon occurrence. In the present paper we report a rare case of nodular non-Hodgkin's lymphoma with pure red cell aplasia who presented with symptoms related to anemia rather than the lymphoma and responded well to combination chemotherapy.

Ifosfamide in plasma cell leukemia: a report of two cases and review of the literature.

We report two patients with primary plasma cell leukemia (PLC) treated with a single agent, ifosfamide. One patient had a total disappearance of plasma cells (PC) from the peripheral blood and the bone marrow and disappearance of the myeloma protein, is disease free 8 months after completion of treatment, and alive 14 months after diagnosis. The second patient had a partial response with persistence of plasma cells in the bone marrow lasting 7 months, after which she had a frank relapse of the disease. We suggest that ifosfamide may be an active agent in plasma cell malignancies and needs further evaluation in multiple myeloma.

Pneumocystis carinii pneumonia in untreated acute non-lymphoblastic leukaemia.

Mixed opportunistic infection with Pneumocystis carinii and Candida prior to cytotoxic therapy in a young male diagnosed as having acute non-lymphoblastic leukaemia resulted in early catastrophe. The role of awareness of this complication and its prompt management is discussed.

Four-agent induction/consolidation therapy for childhood acute lymphoblastic leukemia: an Indian experience.

During 1984-1986, a total of 128 children with acute lymphoblastic leukemia (ALL) were treated with an induction-consolidation regimen consisting of doxorubicin, vincristine, cytosine-arabinoside, and prednisolone. One hundred two (80%) patients belonged to high-risk group. The complete remission rate for all the patients was 91%. The event-free survival at 5 years was 32.0% +/- 23%. On multivariate analysis the event-free survival and disease-free survival was not altered by age, sex, WBC count, platelet count, LDH level, and surface phenotype. Infection due to prolonged marrow aplasia was a common complication, leading to mortality of 8 patients during induction and 33 patients during first remission. The relapse rate has been 36% (42 patients). The predominance of high-risk ALL in the Indian population underscores the need for intensive therapy. Improved supportive care during induction and remission seems essential to decrease therapy-related mortality, leading to improved survival.

Alpha-interferon in hairy cell leukemia: an initial Indian experience.

In the last decade, 14 patients were diagnosed as having hairy cell leukemia (HCL) at our hospital; five of these were treated with the biological response modifier, recombinant alpha-interferon (IFN), as their initial treatment. Four of these cases showed a complete remission of the disease while one had a good partial response after a few months of therapy. One case is in unmaintained remission while one has relapsed with a just palpable spleen on stopping the drug; two are still on intermittent IFN therapy while one has been lost to follow up. Fever and skin rash were the most common side effects observed but did not warrant reduction of dose or stoppage of treatment. We conclude that IFN is highly effective and well tolerated as initial treatment of HCL in a country like India. Splenectomy will continue to be the first line therapy in the majority of cases but, in certain selected situations, IFN can be an extremely useful alternative.