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Cancer cells acquire abnormalities in energy metabolism, collectively known as the Warburg effect, affecting substrate availability of thiamine-dependent enzymes. To investigate a strategy to exploit abnormal cancer-associated metabolism related to thiamine, we tested the cytotoxicity of native Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, in the NCI60 cell line drug cytotoxicity screening program and found that leukemia cell lines were among the most sensitive to thiaminase I. We obtained additional lymphoid leukemia cell lines and confirmed that native thiaminase I and linear chain PEGylated thiaminase I enzyme (LCPTE) have cytotoxic activity in these cell lines. In addition, the IC(50) of 3 of the 5 leukemia cell lines (Reh, RS4, and Jurkat) were at least 1,000-fold more sensitive than Molt-4 cells, which in turn, were among the most sensitive in the NCI60 panel. The 3 LCPTE-sensitive leukemia cell lines were also sensitive to removal of thiamine from the medium, thus suggesting the mechanism of action of LCPTE involves extracellular thiamine starvation. Surprisingly, rapamycin showed a protective effect against LCPTE toxicity in the 3 LCPTE-sensitive cell lines but not in the other 2 cell lines, suggesting involvement of an mTOR-dependent pathway. Immunoblot analysis of the LCPTE-sensitive cell lines after LCPTE exposure revealed changes in mTOR pathway phosphorylation. Nude mice bearing RS4 leukemia xenografts showed both tumor growth delay and prolonged survival after a single dose of LCPTE. Therefore, disruption of thiamine-dependent metabolism may be a novel therapeutic approach to target altered energy metabolism in leukemia and other cancers.

Thirty eight patients with acute lymphoblastic leukemia were treated protocol 0171 (VCR, PRED, MTX, cyclophosphamide +/- +/- 6-MP) and protocol 0276/A (VRC, PRED, L-ASP, MTX, 6-MP, cyclophosphamide). Overall complete remission rate in both studies was 84--85%, and additional treatment in protocol 0171 resulted in complete remission rate of 92%. Median duration of complete remission in protocol 0171 was 23 months and median survival of all patients was 33 months. Six patients randomized to regimen "A" (without 6-MP in intensification) had median duration of complete remission 8 months and media survival was 13 months. Seventeen patients treated with regimen "B" (with 6-MP in intensification) had median duration of complete remission 25 months and median survival was 39 months. Median survival of patients allocated on protocol 0276/A in 21+ months and median duration of complete remission is 23 months at present. Twelve percent of patients treated with the best regimen have survived more than 66 months in continuous complete remission. The incidence of drug related death in complete responders was 6%. The relapses were most frequent during the first two years of remission. Extramedullary leukemia as the initial site of relapse was observed in 9% of patients.

The clinical and haematological characters and the response to therapy of 32 consecutive patients with acute lymphoblastic leukaemia, aged more than 12 years, were reviewed. All patients were given vincristine (V) and (6-methyl) prednisolone (P) for 6 weeks; daunomycin (D) was added in 9 cases, and cyclophosphamide (C) + D in another 10 cases. 3 patients died during induction. 4 patients failed to achieve remission. 25 patients (78%) achieved complete remission (CR). All of them but one received 'prophylactic' central nervous system (CNS) therapy with cranial irradiation and i.t. methotrexate (MTX) and arabinosyl cytosine. CR was maintained with daily 6-mercaptopurine and weekly MTX. Median duration of CR was of 22 months. 2 patients are currently disease-free and off-therapy, 78 and 53 months after diagnosis, respectively. Blast cell membrane markers were studied in 21 consecutive cases: 3 patients had T-cell leukaemia and 2 patients B-cell leukaemia. Prognostic factors were evaluated basing on the present series of 32 patients, and on further 106 cases reported by others. Age (under and above 40) influenced significantly both the CR rate and the length of survival. In patients aged under 40, a circulating blast cell count higher than 25,000/microliter, or a platelet count lower than 50,000/microliter, negatively affected the survival.

Discriminant and regression analyses were employed to determine the influence of a large number of clinical and laboratory indices on outcome of treatment in a series of 158 adults presenting with acute leukaemia between 1970 and 1977. Induction therapy had been most commonly cytosine arabinoside plus daunorubicin, vincristine and prednisolone. This induced complete remission in 42% of non-lymphoblastic, and in 58% of lymphoblastic plus undifferentiated leukaemias. Some induction failures who had non-lymphoblastic leukaemia were treated with cytosine arabinoside plus 6-thioguanine, which induced remissions in 46%. Advanced age was the factor most strongly associated with failure either to achieve or to sustain complete remission. Thrombocytopenia, promyelocytic leukaemia, high percentage of marrow blasts, and absence of metaphases in marrow cytogenetic preparations were also associated with poor survival. A number of other factors which appeared to be associated with poor prognosis were found by the analysis to lack significance as independent variables.

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.

Long-term second remissions were seen in 5/66 patients with all. Relapse was extramedullary in 2/5. Persistent, progressive marrow lymphocytosis preceded relapse in 4/5 patients and persistent marrow eosinophilia in 1/5. All 5 patients had had an unmaintained remission of at least 6 months prior to relapse, and responded the second time to drugs which were essentially the same as those used initially. We conclude that long-term second remissions may occur in all. Patients who relapse after 6 months or more of unmaintained remission should be treated with the drugs used in current initial induction regimens in hope of cure.

Forty-one previously untreated children with Stage IV non-Hodgkin's lymphoma were studied from January 1971 to April 1979. All patients had bulky disease histologically proven to be non-Hodgkin's lymphoma with bone marrow involvement. They were separated into two groups according to the extent of bone marrow involvement. Group IVA included 14 patients with 25% or less lymphoblasts in the bone marrow. Group IVB included 27 patients with more than 25% blasts in the marrow. Their clinical characteristics with regard to age, sex, hemogram, histology, primary site, and blast morphology are compared. All were treated with the LSA2-L2 protocol with radiation therapy to one or more bulky sites of involvement. The disease-free actuarial survival for Group IVA was 64% with a median observation time of 49 months while that for Group IVB was 65% with a median observation time of 66 months. There was no statistical difference in the survival rates between the two groups. Hence, we conclude that the extent of bone marrow involvement does not affect the prognosis in Stage IV non-Hodgkin's lymphoma. It appears that radiation therapy may have contributed to the improved survival in our series. Furthermore, a subset of patients in Group IVB (24/27) who could be considered as high-risk acute lymphoblastic leukemia on the basis of age, initial leukocyte count, hemoglobin, mediastinal mass or T- or B-cell markers showed an improved survival (73% versus 43%) when compared to patients treated with conventional leukemia regimens.

Evidence that the first human neoplasm systematically explored with chemotherapeutic treatments has apparently been cured in a palpable segment of affected patients evokes optimism for other types of cancer. The application of similar effort, similar logic, and quantitative experimental therapeutic approaches to the common cancers augurs well for cancer research and clinical medicine.

A clinical study was performed to 80 children with ALL; the patients were classified into three groups. Group I, consisting of 20 patients treated before the GLATHEM cooperative study was initiated in our institution and of Groups II and III, consisting of 30 patients each included in the cooperative study. The probability of surviving 5 years is 40% for all patients with ALL entered on the study, and more than 50% for those included in the GLATHEM. The probability of remaining in complete remission for more than 6 years is significantly higher in "standard risk" patients than in "high risk" patients. The proportion of patients that may remain in complete remission 4 years or more, is greater in children who received levamisole than in those who did not.

Unlabelled: Sixty-one children with ALL were treated between 1970 an 1973 according to a scheme including: a) Remission induction with vincristine-prednisolone-daunorubicine. b) Cytoreduction therapy with 4 drugs (6-MP, MTX,Ara-C and CYCLO) combined two by two in 3 types of associations given at three months cycles. Every three months, two-week "reinductions" with vincristine and prednisolone plus one dose of i.t. MTX. c) Early therapy on CNS, according to two patterns: one group received one dose of i.t. MTX after induction, repeated every 3 months; the other group was given cranial irradiation [2,400 r] plus 5 doses of i.t. MTX. d) After three years of chemotherapy, patients were treated for two more years with BCG by scarification., Results: Complete remission was achieved in 93%. After three years of chemotherapy, 37% of the first group (not irradiated) and 55% of the second (irradiated) persisted in C.R. Twenty-five patients initiated BCG-therapy; eighteen of these (72%) persisted, after 2 years, in C.R.; then all treatment was suppressed. Initial relapses in the 5 years period were hematological in 13, CNS in 13, both hematological and CNS in 2, and testicular in 3. Mortality of patients in C.R. was 4 (7.7%). Survival rates were 33% after 5 years for the non-irradiated group and 50% in the irradiated one. At present, 30% of all evaluable patients who attained remission continue in C.R. after an average time of 102 months-40% in the irradiated group and 20% in the not irradiated-. This difference, statistically significant, is due to the number of CNS relapses: 13 of 30 (43%) in the first group and 3 of 22 (13.1%) in the second. The 24% relapses occurring during immunotherapy do not permit to assess the efficacy of this form of therapy.

Sixty-two adult patients with acute lymphoblastic leukemia (ALL) were treated with an induction regimen including vincristine, daunorubicin and prednisone (VDP) followed by CNS prophylaxis. Forty-five patients (72.5%) achieved complete remission (CR). The CR were maintained with daily 6-MP and weekly MTX. Monthly reinduction cycles with vincristine and prednisone (plus daunorubicin every three courses) were also given. Median duration of CR was 10.4 months. Overall survival was 17.4 months. The remission rate and length of CR were studied in relation to the clinical and hematological features present at diagnosis. CR rate was adversely influenced by age only over 40 and by tumoral presentation. The length of remission was negatively influenced by tumoral presentation, CNS involvement, high circulating blast count, L2 and L3 cytology, and T or B immunological phenotype. Multiple regression analysis confirmed the weight of FAB morphology in determining the length of remission. Among L2 adult patients, tumoral presentation appears to be the major unfavourable prognostic factor.

This paper reports late effects and health status of 198 children who had cancer or leukemia diagnosed under 2 years of age and their therapies electively withdrawn. This series (92 neuroblastoma [NBL], 57 Wilms' tumor [WT], 46 acute lymphoblastic leukemia [ALL], and 3 non-Hodgkin's lymphoma) was followed for 1-12 years after discontinuation of therapy. Thirty-three children were diagnosed before 1973, 92 between 1973 and 1977, and 73 after 1977 in 16 Italian Pediatric Oncology Centers. As of December 1983, 176 children were reported to be alive and without evidence of primary cancer by physicians responsible for their care. One child died from a second primary tumor, two from late recurrences of the primary cancer, and three from other causes; eight were alive with evidence of primary cancer; and eight were lost to follow-up. Kyphoscoliosis was found in 22 children and other musculoskeletal anomalies in 8. Neurological sequelae were observed in 8 out 35 children with ALL treated with radiotherapy (RT) and intrathecal methotrexate. All but one were in continuous complete remission when they developed seizures (three cases), leukoencephalopathy (three cases), or intracerebral calcifications (two cases). One child had cardiomyopathy and subsequently died from cardiac failure: he had received doxorubicin (400 mg/m2) and mediastinal RT (13 Gy) for NBL. Growth impairments were observed in children with NBL and WT.

Eighty-eight children younger than 15 years with acute lymphoblastic leukemia were treated with two similar protocols. Both regimens consist of multidrug combinations, with CNS prophylaxis. Sixty-four patients were enrolled on first protocol 0171 with vincristine and prednisone induction therapy. After remission induction patients were randomized on two arms: regimen A which consists of intensive courses of methotrexate with vincristine and prednisone reinductions and administration of cyclophosphamide. Regimen B is similar to regimen A, only courses of methotrexate are alternated with courses of 6-mercaptopurine during consolidation and intensification therapy. In maintenance phase both regimens have daily administration of 6-mercaptopurine and twice weekly administration of methotrexate, with vincristine and prednisone reinductions. The second protocol 0276/A is similar to regimen B of protocol 0171, but L-asparaginase is administered in the end of induction phase and total duration of therapy since induction of complete remission is prolonged from 2.5 to 4 years. Complete remission rate ranged from 92 to 96% in the patients achieving complete remission. In protocol 0171 actuarial proportion of children alive in complete remission for more than 10 years is 60% at present. The actual median survival of all children treated with protocol 0171 is 46+ months and actual median duration of complete remission is 43+ months. There was no significant difference between patients treated with methotrexate alone and those treated with combination of methotrexate and 6-mercaptopurine during consolidation and intensification phase. In protocol 0171 the relapse rate was 28% and the death rate in complete remission was 15%. More than 70% of complete responders in protocol 0276 is in continuous complete remission from 2+ to 57+ months, relapse rate is only 4% at present and the death rate in complete remission is 9% in this protocol.