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The hypoxia-inducible transcription factor HIF1α drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1α transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1α signaling. Negative regulation of HIF1α by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1α transcriptional coactivator p300. Notably, of the HIF1α-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small-molecule inhibitor of aldolase A was sufficient to increase overall survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis-HIF-1α feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid tumors. Cancer Res; 76(14); 4259-69. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: Limited information is available on the use of positron emission tomography (PET) in paediatric oncology. The aim of this study was to review the impact of PET on the management of paediatric patients scanned over a 10-year period., Methods: One hundred and sixty-five consecutive oncology patients aged 11 months to 17 years were included. Two hundred and thirty-seven scans were performed. Diagnoses included lymphoma (60 patients), central nervous system (CNS) tumour (59), sarcoma (19), plexiform neurofibroma with suspected malignant change (13) and other tumours (14). A questionnaire was sent to the referring clinician to determine whether the PET scan had altered management and whether overall the PET scan was thought to be helpful., Results: One hundred and eighty-nine (80%) questionnaires for 126 patients were returned (63 relating to lymphoma, 62 to CNS tumours, 30 to sarcoma, 16 to plexiform neurofibroma and 18 to other tumours). PET changed disease management in 46 (24%) cases and was helpful in 141 (75%) cases. PET findings were verified by histology, clinical follow-up or other investigations in 141 cases (75%). The returned questionnaires indicated that PET had led to a management change in 20 (32%) lymphoma cases, nine (15%) CNS tumours, four (13%) sarcomas, nine (56%) plexiform neurofibromas and four (22%) cases of other tumours. PET was thought to be helpful in 47 (75%) lymphoma cases, 48 (77%) CNS tumours, 24 (80%) sarcomas, 11 (69%) neurofibromas and 11 (61%) cases of other tumours. PET findings were verified in 44 (70%) lymphoma cases, 53 (85%) CNS tumours, 21 (70%) sarcomas, 12 (75%) neurofibromas and 11 (61%) other tumour cases., Conclusion: PET imaging of children with cancer is accurate and practical. PET alters management and is deemed helpful (with or without management change) in a significant number of patients, and the results are comparable with the figures published for the adult oncology population.

The nutritional status of a child on cancer therapy influences both tolerance of and response to treatment. However, it is difficult to assess nutritional status on a daily basis because an accurate quantitation of the calorie intake is difficult. Anthropometric and biochemical parameters are prone to error and often reflect past rather than current nutritional status. In practice, a subjective clinical assessment is usually relied upon. This study objectively appraises the value of such an assessment. Based on clinical symptoms that alter oral intake and absorption of food, a scoring system was designed to assess nutritional status on a day to day basis. A symptom score (SS) of 10 implied "normality"; 0 indicated maximum debility. Over a 2-year period 511 daily scores were recorded in 30 patients aged 0.7-17.5 years. Patients were studied at presentation and during treatment for acute lymphoblastic leukemia (ALL, n = 14; solid tumors receiving megatherapy with autologous bone marrow rescue (ABMR, n = 8), and chemotherapy for different tumors (miscellaneous, n = 8). The SS was compared with other nutritional parameters, including sequential anthropometric indices, serum albumin, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), and whole-body protein turnover (WBPT) using [1-(13) C]leucine. The mean SS was reduced at diagnosis for all leukemic patients (median score = 8), improved during first remission (p < 0.002), fell to a minimum during febrile neutropenia (p = 0.0009), and improved with clinical and hematological recovery (p = 0.0009). A reduction in SS was related to fever (p < 0.001) and a fall in neutrophil count (p < 0.001). There was no correlation with anthropometric indices or IGF-I and IGFBP-3 levels. Paired WBPT studies in 9 patients showed that SS correlated well with protein breakdown (p = 0.026). The results suggest that the ongoing nutritional status of children with malignancy undergoing chemotherapy is best assessed using simple clinical parameters.

Little is known about Clostridium difficile infection in children with cancer but a presumed outbreak has previously been described. The carriage rate before admission to hospital and morbidity is reported to be high, especially in younger children. The prevalence of C difficile infection on a paediatric oncology ward was monitored from June 1991 to May 1992. Twenty eight (13%) of 214 children were found to be infected. Though the temporal distribution suggested an outbreak, polyacrylamide gel electrophoresis identified several different types. Unlike previous reports, infection appeared to be possibly endogenous or possibly environmental in origin rather than due to cross infection; the morbidity was low and age was not a determinant for infection. The duration of hospital stay and the primary diagnosis were found to be determinants for infections, those with lymphoid malignancies being at the highest risk. The diagnostic category at greatest risk were those most intensively treated, with protracted neutropenia and prolonged antibiotic exposure. Early identification of cases and prompt institution of simple control measures will prevent cross infection. It is therefore important that diarrhoea is not accepted as a normal symptom of cancer chemotherapy and stool specimens are sent for full bacteriological and viral investigation.

A questionnaire study was carried out in a group of survivors of childhood cancer to assess their quality of life. The questionnaire was sent to 30 survivors who had completed treatment with megatherapy followed by autologous bone marrow rescue at St Bartholomew's Hospital, London. Of the 28 respondents (93%), in 27 (96%) the quality of life was judged to be good, with 11 of these 27 (40%) having no disability whatsoever and a further 9 (33%) reporting only minimal disability. The other 7 patients had moderate to severe disabilities, with pain and depression remaining ongoing problems, and some adolescents felt that they were unable to cope with everyday life alongside their peers. Nine parents and 14 of the children themselves expressed anxiety about the previous illness. The study shows that, by using a postal method, a satisfactory assessment of quality of life in survivors of childhood cancer can be made.

Objectives: To investigate causes of death and survival in subjects who had survived at least five years after diagnosis of childhood cancer; to compare observed mortality with that expected in the general population; and to compare results with a corresponding cohort diagnosed earlier., Design: Retrospective cohort study., Setting: Population based National Register of Childhood Tumours., Subjects: 9080 five year survivors of childhood cancer diagnosed in Britain during 1971-85, of whom 793 had died. Comparison with corresponding cohort diagnosed during 1940-70., Main Outcome Measures: Cause of death established from all available sources of information (including hospital and general practitioner records and postmortem reports) and underlying cause of death coded on death certificate., Results: Of the 781 deaths for which sufficient information was available, death was attributed to recurrent tumour in 578 (74%) cases, treatment related effect in 121 (15%), second primary tumour in 52 (7%), and other causes in 30 (4%). Comparison of observed mortality with that expected in the general population indicated a fourfold excess of deaths from non-neoplastic causes. The risk of dying of recurrent tumour in the next 10 years after surviving five years from diagnosis during 1940-70 and 1971-85 fell from 12% to 8%. The risk of dying from a treatment related effect increased slightly from 1% to 2%., Conclusion: Improvements in five year survival after childhood cancer have been accompanied by a reduction in risk of dying from recurrent tumour during the subsequent 10 years and by a slight increase in risk of dying from treatment related effects. The results provide information relevant to decisions concerning balance between effective treatments and their potentially harmful effects.

An investigation of 749 deaths occurring among 4082 patients surviving at least five years after the diagnosis of childhood cancer in Britain before 1971 has been undertaken. Of the 738 with sufficient information the numbers of deaths attributable to the following causes were: recurrent tumour, 550 (74%), a second primary tumour, 61 (8%), a medical condition related to treatment of the tumour, 49 (7%), an traumatic death unrelated to the tumour or its treatment, 34 (5%), finally, any other cause unrelated to the tumour or its treatment, 44 (6%). Less than 10% of five year survivors of non-Hodgkin lymphomas, neuroblastoma, retinoblastoma, Wilms' tumour, or a soft tissue sarcoma died of recurrent tumour during the next 15 years, while more than 25% of five year survivors of Hodgkin's disease, ependymoma, medulloblastoma, and Ewing's tumour died of recurrent tumour during the corresponding period. Almost 50% of five year survivors of acute lymphoblastic leukaemia died of recurrent disease during the corresponding 15 years, a large proportion of deaths being due to central nervous system relapse in an era before central nervous system prophylaxis was routinely given. Comparison of the mortality observed with that expected from mortality rates in the general population indicated three times the expected number of deaths from non-neoplastic causes. Five times the expected number of deaths from cardiovascular causes were observed, these were predominantly myocardial infarction and cerebrovascular accidents. There was no evidence of an excess in the number of suicides observed, but there were three times the expected number of deaths from accidents observed after central nervous system tumours. Two groups of patients were identified whose deaths were potentially avoidable. Seven patients with craniopharyngioma and panhypopituitarism presented with addisonian crises during periods of stress not adequately covered by exogenous corticosteroids. In the other group were children who received radiotherapy and later developed problems related to radiation fibrosis. We emphasize that our investigation relates to patients diagnosed with childhood cancer before 1971. The pattern of mortality that will emerge after recent treatment regimens, in which chemotherapy is being used more extensively, is likely to be different from that observed in our study.

The educational achievement of 37 long-term survivors of childhood cancer were matched with the sibling closest in age. Analysis of the sibling pairs revealed no significant difference in educational achievement between the study group and controls. A subset, who were treated with cranial prophylaxis, also showed no difference, but their numbers were small.

Thirty nine children with malignant disease and without antibodies to varicella zoster virus were immunised with a live Oka strain varicella vaccine. Seroconversion was shown in 24 of those who were vaccinated but five of 18 who responded to the vaccine who were followed up for over six months subsequently lost their antibodies. Of 10 children who were revaccinated, nine responded to the second dose but three lost their antibodies within six months to two years. Four children developed reactions related to the vaccine, one local and three generalised, but all these were transitory and of no clinical concern. Nine of those who were vaccinated, including four who did not respond to the vaccine, have subsequently had close exposure to varicella but none has developed the disease.

During a 5 year period, 64 children with advanced stage malignant solid tumours have been treated with high dose melphalan (140-220 mg/m2) combined with non-cryopreserved autologous marrow transplantation. All children developed a profound neutropenia and thrombocytopenia following high dose melphalan. Both the duration of neutropenia (median 11 d) and the duration of thrombocytopenia (median 18 d) were related to the nucleated cell count of the reinfused marrow but neither appeared to be affected by the dose of melphalan. This suggests that the initial recovery of the peripheral blood count results from the engrafted autologous marrow. We conclude that autologous marrow transplantation accelerates haemopoietic recovery in children with solid tumours treated with high dose melphalan.