Ian Magrath

Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen.

PURPOSE We have used identical treatment protocols for adults and children with small non-cleaved-cell lymphoma (SNCL) for many years and report here the results of two successive treatment regimens in these age groups. PATIENTS AND METHODS Seventy-two patients (39 adults and 33 children) were treated with protocol 77-04 between 1977 and 1985. All patients, except those with resected abdominal disease, received 15 cycles of a combination of cyclophosphamide (CTX), doxorubicin (ADR), prednisone (PRED), vincristine (VCR), high-dose methotrexate (MTX), and intrathecal (IT) therapy. Forty-one patients (20 adults and 21 children) were treated with protocol 89-C-41, which has been used since 1989. High-risk patients received four alternating cycles (with a total duration of 12 to 15 weeks) of an intensified version of protocol 77-04 without PRED (CODOX-M), and a new drug combination consisting of ifosfamide, etoposide, high-dose cytarabine (ara-C), and IT MTX (IVAC). Low-risk patients received three cycles of the CODOX-M regimen. High-risk patients were randomized to either receive or not receive granulocyte-macrophage colony-stimulating factor (GM-CSF). RESULTS Event-free survival (EFS) in protocol 77-04 was 56% at 2 years and beyond. EFS in protocol 89-C-41 was 92% at 2 years and beyond. GM-CSF was associated with increased thrombocytopenia. CONCLUSION Adults and children with SNCL have a similar prognosis when treated with the same chemotherapy. EFS in high-risk patients has been markedly improved by including IVAC in protocol 89-C-41, and excellent results can be achieved with only four cycles of therapy. In protocol 89-C-41, GM-CSF was not beneficial.

Acute tumor lysis syndrome: A review of 37 patients with Burkitt's lymphoma

Renal and metabolic complications of tumor lysis during 46 episodes of remission induction chemotherapy were reviewed in 37 patients with American Burkitts lymphoma. Azotemia occurred in 14 patients, preceding chemotherapy in eight. All of these patients had abdominal tumors. Pretreatment azotemia was associated with elevated lactic dehydrogenase (LDH) and uric acid levels, and sometimes extrinsic ureteral obstruction by tumor. Two patients required dialysis for uric acid nephropathy before chemotherapy was initiated. Following chemotherapy, major complications of tumor lysis (hyperuricemia, hyperkalemia and hyperphosphatemia) were associated with very large tumors, high LDH levels and inadequate urinary output. In patients undergoing diuresis and receiving allopurinol, hyperkalemia or hyperuricemia developed infrequently unless concomitant renal failure ensued. Hyperphosphatemia, which occurred only after chemotherapy, developed in 10 of 32 (31 per cent) nonazotemic and in all azotemic patients. Hemodialysis was required in three post-treatment patients for control of azotemia, hyperuricemia, hyperphosphatemia and/or hyperkalemia. Because of the potential for renal failure caused by precipitation of phosphate, severe hyperphosphatemia is an additional criterion for dialysis in patients with acute tumor lysis syndrome.

Activation of Suppressor T Cells during Epstein-Barr-Virus-Induced Infectious Mononucleosis

Infectious mononucleosis is caused by the Epstein-Barr virus (EBV), an unusual human pathogen because it preferentially infects B lymphocytes and consequently activates them to produce immunoglobulins. When cultures of lymphocytes from patients with infectious mononucleosis were stimulated with polyclonal activators, unseparated cells failed to produce immunoglobulins, whereas purified B cells responded normally. Cocultures demonstrated profound suppressor T-cell activity in blood from patients with infectious mononucleosis. Early in this disease, circulating immunoglobulin-secreting cells were elevated, but during the second week their number was strikingly depressed. These data indicate that during infectious mononucleosis, EBV causes polyclonal activation of B cells, reflected by hypergammaglobulinemia and increased circulating immunoglobulin-secreting cells. Next, suppressor T cells become activated and inhibit further B-cell activation. Thus, activation of suppressor T cells in infectious mononucleosis provides a unique additional mechanism of host defense because these T cells inhibit the activation and proliferation of an important target of the causative virus.

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer

Abstract Early initiation of empiric antibiotic therapy in febrile cancer patients has become established practice, but the appropriate duration of antibiotic therapy when no infectious source can be identified is unknown. The complications of broad-spectrum antibiotics argue for brief treatment, but the risk of an inadequately treated infection in the granulocytopenic patient favors longer therapy. We prospectively studied 306 episodes of fever and granulocytopenia in 143 patients with leukemia or solid tumor (age one to 33 years) with respect to the duration of empiric antibiotic treatment. Eligible patients (fever > 38 °C three times/24 hours or > 38.5 °C once, plus polymorphonuclear leukocytes 3 ) had an extensive diagnostic evaluation, including at least two preantibiotic blood cultures, and therapy was then started with a broad-spectrum antibiotic regimen— Keflin ® , gentamicin and carbenicillin (KGC). Initial evaluation failed to identify an infectious etiology for the fever in 142 of 306 (46 per cent) episodes. Fifty-six of 142 (39 per cent) of these fevers of unknown origin were associated with persistent granulocytopenia for more than seven days; in 33 of these, defervescence occurred while the patients received KGC. After seven days of empiric KGC therapy, the 33 patients with fevers of unknown origin who had become afebrile with empiric antibiotics but whose polymorphonuclear leukocytes remained less than 500/mm 3 were randomized to either continue or discontinue (dc) to receive KGC. The patients who continued to receive KGC until their polymorphonuclear leukocytes were more than 500/mm 3 had no infectious sequelae. However, in seven of 17 (41 per cent) of the patients randomized to dc KGC infectious sequelae developed (p = 0.007) within a median of two days of discontinuing KGC (two with fever which again responded to KGC therapy, and five with a documented infection [two ultimately fatal]). In none of the patients did a resistant microbial flora or superinfection develop. These data suggest that the patient with a fever of unknown origin who becomes afebrile during empiric antibiotic therapy may profit from continued therapy while granulocytopenia persists.

The American Burkitt's Lymphoma Registry: eight years' experience.

Four‐hundred‐twenty‐one Americans diagnosed as having Burkitts lymphoma (BL), 409 from the United States, were studied by the American BL Registry to obtain information about the cause and control of this disease. Of these 421 cases, 256 were confirmed by our pathologists as being morphologically indistinguishable from African BL. A relationship between age and organ involvement was observed; cervical lymph nodes, ileum, and nasopharynx were initial sites of involvement primarily in younger patients. Although the Epstein‐Barr virus (EBV) was less frequently associated with American BL than African, a high antibody titer to the EBV capsid antigen was associated with a more favorable prognosis.

Renal and Metabolic Complications of Undifferentiated and Lymphoblastic Lymphomas

The early metabolic events in 33 patients with non-Hodgkin lymphoma were analyzed in the present study. Twenty-three patients had Burkitt lymphoma, 3 had non-Burkitt undifferentiated lymphoma and 7 had lymphoblastic lymphoma. Eight patients developed azotemia prior to starting chemotherapy while five did so during the first treatment week. All the patients but two who developed azotemia had stage C or D disease. Serum LDH prior to chemotherapy correlated well with the stage of disease and predicted the serum levels of creatinine, uric acid and phosphorus in the post-treatment period. Surgical excision of the main tumor mass was associated with a low incidence of azotemia and other metabolic derangements. Hyperuricemia and occasionally obstruction were encountered as the causes of azotemia in the pre-treatment period. Hyperuricemia and/or hyperphosphatemia were presumed responsible for the development of azotemia in the post-chemotherapy period. Two patients were dialyzed for renal failure due to hyperuricemia and one for renal failure due to hyperphosphatemia which developed shortly after starting chemotherapy. The patterns of renal and metabolic disturbances observed during treatment of these patients were characterized by the following profiles: 1. Azotemia due to hyperuricemia prior to treatment. 2. Hyperuricemia without azotemia in the pre-treatment period with azotemia due to hyperphosphatemia in the post-treatment period. 3. Azotemia due to combined hyperphosphatemia and hyperuricemia developing gradually in post-treatment period. 4. Increased urine phosphorus excretion in both non-azotemic and azotemic patients.

African Burkitt's lymphoma. History, biology, clinical features, and treatment.

Dennis Burkitts first description of the African tumor that is now known by his name appeared in 1958. In the brief intervening span of 32 years, this lymphoma has provided an extraordinarily valuable paradigm that has afforded insights into topics that encompass the entire discipline of oncology. These include the origins of lymphoid neoplasms at epidemiological, cellular, and molecular levels, and the efficacy of chemotherapy in rapidly progressive, widely disseminated lymphomas. In addition, epidemiological considerations led to the discovery of a new virus, the Epstein-Barr virus, which has proved to be an important human pathogen. This virus probably plays a pathogenetic role in several neoplastic diseases, including the lymphoproliferative syndromes associated with inherited and acquired immunodeficiency. Small, noncleaved cell lymphoma is the latest histological designation of the category of lymphomas that includes Burkitts lymphoma. This tumor, which is biologically heterogeneous, has become notorious because of its high incidence in individuals infected with the human immunodeficiency virus, which is providing a second, potentially fertile model for the exploration of the pathogenesis of lymphoid neoplasms. Already, enough is known of the pathogenesis of Burkitts lymphoma to permit the first tentative steps toward the development of novel therapeutic approaches directed toward the molecular genetic abnormalities associated with the neoplasm. In this article, the history, biology, clinical features, and treatment of African Burkitts lymphoma are reviewed.

Prolonged complete remission following high dose chemotherapy of burkitt's lymphoma in relapse

Fourteen patients with American Burkitts lymphoma resistant to conventional chemotherapy were treated with high‐dose combination chemotherapy and intensive supportive care. Four patients died shortly after chemotherapy, 3 of an acute carditis. All ten remaining patients demonstrated tumor regression and 3 remain in prolonged complete unmaintained remission 29+, 19+, and 9+ months after treatment. These findings demonstrate that high‐dose chemotherapy will benefit some patients with Burkitts lymphoma unresponsive to conventional chemotherapy, but the medullary and extramedullary toxicity of this treatment strategy remains a formidable obstacle.

Baseline status of paediatric oncology care in ten low-income or mid-income countries receiving My Child Matters support: a descriptive study.

BACKGROUND Childhood-cancer survival is dismal in most low-income countries, but initiatives for treating paediatric cancer have substantially improved care in some of these countries. The My Child Matters programme was launched to fund projects aimed at controlling paediatric cancer in low-income and mid-income countries. We aimed to assess baseline status of paediatric cancer care in ten countries that were receiving support (Bangladesh, Egypt, Honduras, Morocco, the Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam). METHODS Between Sept 5, 2005, and May 26, 2006, qualitative face-to-face interviews with clinicians, hospital managers, health officials, and other health-care professionals were done by a multidisciplinary public-health research company as a field survey. Estimates of expected numbers of patients with paediatric cancer from population-based data were used to project the number of current and future patients for comparison with survey-based data. 5-year survival was postulated on the basis of the findings of the interviews. Data from the field survey were statistically compared with demographic, health, and socioeconomic data from global health organisations. The main outcomes were to assess baseline status of paediatric cancer care in the countries and postulated 5-year survival. FINDINGS The baseline status of paediatric oncology care varied substantially between the surveyed countries. The number of patients reportedly receiving medical care (obtained from survey data) differed markedly from that predicted by population-based incidence data. Management of paediatric cancer and access to care were poor or deficient (ie, nonexistent, unavailable, or inconsistent access for most children with cancer) in seven of the ten countries surveyed, and accurate baseline data on incidence and outcome were very sparse. Postulated 5-year survival were: 5-10% in Bangladesh, the Philippines, Senegal, Tanzania, and Vietnam; 30% in Morocco; and 40-60% in Egypt, Honduras, Ukraine, and Venezuela. Postulated 5-year survival was directly proportional to several health indicators (per capita annual total health-care expenditure [Pearsons r(2)=0.760, p=0.001], per capita gross domestic product [r(2)=0.603, p=0.008], per capita gross national income [r(2)=0.572, p=0.011], number of physicians [r(2)=0.560, p=0.013] and nurses [r(2)=0.506, p=0.032] per 1000 population, and most significantly, annual government health-care expenditure per capita [r(2)=0.882, p<0.0001]). INTERPRETATION Detailed surveys can provide useful data for baseline assessment of the status of paediatric oncology, but cannot substitute for national cancer registration. Alliances between public, private, and international agencies might rapidly improve the outcome of children with cancer in these countries.

Paediatric cancer in low-income and middle-income countries

Patterns of cancer incidence across the world have undergone substantial changes as a result of industrialisation and economic development. However, the economies of most countries remain at an early or intermediate stage of development-these stages are characterised by poverty, too few health-care providers, weak health systems, and poor access to education, modern technology, and health care because of scattered rural populations. Low-income and middle-income countries also have younger populations and therefore a larger proportion of children with cancer than high-income countries. Most of these children die from the disease. Chronic infections, which remain the most common causes of disease-related death in all except high-income countries, can also be major risk factors for childhood cancer in poorer regions. We discuss childhood cancer in relation to global development and propose strategies that could result in improved survival. Education of the public, more and better-trained health professionals, strengthened cancer services, locally relevant research, regional hospital networks, international collaboration, and health insurance are all essential components of an enhanced model of care.