"Hyper-warburgism," a cause of asymptomatic hypoglycemia with lactic acidosis in a patient with non-Hodgkin's lymphoma.

CONTEXT: In cancer cells, the Warburg effect is defined as the avid consumption of glucose through the glycolytic pathway with concomitant lactate production, even under aerobic conditions. CASE: We report a 64-yr-old woman who was referred to our institution for pancytopenia and hypoglycemia. Physical examination demonstrated hepatosplenomegaly and petechiae. She had no clinical manifestation of neuroglycopenia, despite serum glucose of 26 mg/dl (1.4 mmol/liter) and serum lactate of 28.5 mmol/liter (normal range, 0.5-3.4 mmol/liter). Bone marrow biopsy demonstrated diffuse large B-cell lymphoma. Staging (18)F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography showed increased FDG avidity in an enlarged spleen and absent FDG uptake in the brain. Despite dextrose infusions up to 30 g/h, there was no increase in serum glucose, but there was a paradoxical increase in serum lactate. Immunochemotherapy improved the hematological and metabolic abnormalities. Follow-up FDG-positron emission tomography/computed tomography showed a decrease in splenic avidity and an increase in brain FDG avidity. The patient refused further chemotherapy and died 1 wk after discharge. METHODS: Literature review of cases of lymphoma with lactic acidosis, with and without hypoglycemia, demonstrated that these combinations occurred in multiple categories of B- and T-cell lymphoma. There was no difference in the mortality rate in those with (75%) or without (74%) concomitant hypoglycemia. CONCLUSION: This case represents an exaggerated Warburg effect, or "hyper-warburgism," characterized by excessive lactate production and overwhelming glucose consumption. We speculate that the decreased brain FDG uptake, despite the lack of neuroglycopenic symptoms, supports the hypothesis that lactate served as a fuel for the brain, thus protecting against hypoglycemia.

Follicular lymphoma transformation to dual translocated Burkitt-like lymphoma: improved disease control associated with radiation therapy.

Dual translocated (or "dual hit") lymphomas are highly aggressive B cell neoplasms associated with an extremely poor prognosis. The optimal treatment for these lymphomas remains undefined. We present two cases of follicular lymphoma with transformation to Burkitt-like lymphoma. In both cases dual translocations involving both the bcl-2 and c-myc loci were present. Each patient underwent intensive induction immunochemotherapy followed by autologous stem cell transplantation and radiation therapy. The first patient received post-transplant mediastinal radiation and developed recurrence in multiple areas outside of the radiation field. The second patient received total body irradiation as part of the conditioning regimen, and is without recurrence 18 months after transplant, and 24 months after diagnosis of the dual translocated lymphoma. We review dual translocation B cell lymphoma in the setting of transformation from follicular lymphoma, and suggest a potential role for total body irradiation in the management of this highly aggressive non-Hodgkin lymphoma.

Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells.

We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 microM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.