Quantifying hypoxia in human cancers using static PET imaging.

Compared to FDG, the signal of 18F-labelled hypoxia-sensitive tracers in tumours is low. This means that in addition to the presence of hypoxic cells, transport properties contribute significantly to the uptake signal in static PET images. This sensitivity to transport must be minimized in order for static PET to provide a reliable standard for hypoxia quantification. A dynamic compartmental model based on a reaction-diffusion formalism was developed to interpret tracer pharmacokinetics and applied to static images of FAZA in twenty patients with pancreatic cancer. We use our model to identify tumour properties-well-perfused without substantial necrosis or partitioning-for which static PET images can reliably quantify hypoxia. Normalizing the measured activity in a tumour voxel by the value in blood leads to a reduction in the sensitivity to variations in 'inter-corporal' transport properties-blood volume and clearance rate-as well as imaging study protocols. Normalization thus enhances the correlation between static PET images and the FAZA binding rate K 3, a quantity which quantifies hypoxia in a biologically significant way. The ratio of FAZA uptake in spinal muscle and blood can vary substantially across patients due to long muscle equilibration times. Normalized static PET images of hypoxia-sensitive tracers can reliably quantify hypoxia for homogeneously well-perfused tumours with minimal tissue partitioning. The ideal normalizing reference tissue is blood, either drawn from the patient before PET scanning or imaged using PET. If blood is not available, uniform, homogeneously well-perfused muscle can be used. For tumours that are not homogeneously well-perfused or for which partitioning is significant, only an analysis of dynamic PET scans can reliably quantify hypoxia.

Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome.

BACKGROUND: A patient with Birt-Hogg-Dubé syndrome (BHD) presented with gross hematuria of 6 months' duration. Imaging revealed the presence of a mass in the left prostatic lobe, in addition to a previously observed renal mass. Prostate biopsy and imaging findings indicated an inflammatory etiology, and the patient was discharged. 5 months later, the patient presented once again with urinary retention. During transurethral resection of the prostate, a mass adjacent to the bladder was observed. Postoperative imaging revealed a large pelvic mass, a second mass impinging on the rectum, and extensive lymphadenopathy. The patient died 2 weeks later. INVESTIGATIONS: CT and MRI, physical examination, measurement of serum markers, urinalysis, transrectal prostate biopsy, histopathological and genetic examination of tumor specimens, postmortem immunohistochemical analysis. DIAGNOSIS: Neuroendocrine carcinoma of prostate or bladder origin. MANAGEMENT: The patient died before planned chemotherapy or radiation therapy could be implemented. More-frequent monitoring of the patient might have led to earlier diagnosis and allowed treatment to be started before widespread tumor metastasis and invasion.

Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance.

Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1alpha to a hypoxia-responsive element (positions -8484 to -8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.