Development of a combined microPET-MR system.

As evidenced by the success of PET-CT, there are many benefits from combining imaging modalities into a single scanner. The combination of PET and MR offers potential advantages over PET-CT, including improved soft tissue contrast, access to the multiplicity of contrast mechanisms available to MR, simultaneous imaging and fast MR sequences for motion correction. In addition, PET-MR is more suitable than PET-CT for cancer screening due to the elimination of the radiation dose from CT. A key issue associated with combining PET and MR is the fact that the performance of the photomultiplier tubes (PMTs) used in conventional PET detectors is degraded in the magnetic field required for MR. Two approaches have been adopted to circumvent that issue: retention of conventional, magnetic field-sensitive PMT-based PET detectors by modification of other features of the MR or PET system, or the use of new, magnetic field-insensitive devices in the PET detectors including avalanche photo-diodes (APDs) and silicon photomultipliers (SiPMs). Taking the former approach, we are assembling a modified microPET Focus 120 within a gap in a novel, 1T superconducting magnet. The PMTs are located in a low magnetic field (approximately 30mT) through a combination of magnet design and the use of fiber optic 'bundles'. Two main features of the modified PET system have been tested, namely the effect of using long fiber optic bundles in the PET detector, and the impact of magnetic field upon the performance of the position sensitive PMTs. The design of a modified microPET-MR system for small animal imaging is completed, and assembly and testing is underway.

Lutetium oxyorthosilicate block detector readout by avalanche photodiode arrays for high resolution animal PET.

Avalanche photodiodes (APDs) have proven to be useful as light detectors for high resolution positron emission tomography (PET). Their compactness makes these devices excellent candidates for replacing bulky photomultiplier tubes (PMTs) in PET systems where space limitations are an issue. The readout of densely packed, 10 x 10 lutetium oxyorthosilicate (LSO) block detectors (crystal size 2.0 x 2.0 x 12 mm3) with custom-built monolithic 3 x 3 APD arrays was investigated. The APDs had a 5 x 5 mm2 active surface and were arranged on a 6.25 mm pitch. The dead space on the edges of the array was 1.25 mm. The APDs were operated at a bias voltage of approximately 380 V for a gain of 100 and a dark current of 10 nA per APD. The standard deviation in gain between the APDs in the array ranged from 1.8 to 6.5% as the gain was varied from 50 to 108. A fast, low-noise, multi-channel charge sensitive preamplifier application-specific integrated circuit (ASIC) was developed for the APD readout. The amplifier had a rise time of 8 ns, a noise floor of 515 e- rms and a 9 e- pF(-1) noise slope. An acquired flood image showed that all 100 crystals from the block detector could be resolved. Timing measurements with single-channel LSO-APD detectors, as well as with the array, against a plastic scintillator and PMT assembly showed a time resolution of 1.2 ns and 2.5 ns, respectively. The energy resolution measured with a single 4.0 x 4.0 x 10 mm3 LSO crystal, wrapped in four-layer polytetrafluoroethylene (PTFE) tape and coupled with optical grease on a single APD of the array, yielded 15% (full width at half maximum, FWHM) at 511 keV. Stability tests over 9 months of operation showed that the APD arrays do not degrade appreciably. These results demonstrate the ability to decode densely packed LSO scintillation blocks with compact APD arrays. The good timing and energy resolution makes these detectors suitable for high resolution PET.

Performance evaluation of the microPET P4: a PET system dedicated to animal imaging.

The microPET Primate 4-ring system (P4) is an animal PET tomograph with a 7.8 cm axial extent, a 19 cm diameter transaxial field of view (FOV) and a 22 cm animal port. The system is composed of 168 detector modules, each with an 8 x 8 array of 2.2 x 2.2 x 10 mm3 lutetium oxyorthosilicate crystals, arranged as 32 crystal rings 26 cm in diameter. The detector crystals are coupled to a Hamamatsu R5900-C8 PS-PMT via a 10 cm long optical fibre bundle. The detectors have a timing resolution of 3.2 ns, an average energy resolution of 26%, and an average intrinsic spatial resolution of 1.75 mm. The system operates in 3D mode without inter-plane septa, acquiring data in list mode. The reconstructed image spatial resolution ranges from 1.8 mm at the centre to 3 mm at 4 cm radial offset. The tomograph has a peak system sensitivity of 2.25% at the centre of the FOV with a 250-750 keV energy window. The noise equivalent count rate peaks at 100-290 kcps for representative object sizes. Images from two phantoms and three different types of laboratory animal demonstrate the advantage of the P4 system over the original prototype microPET. including its threefold improvement in sensitivity and a large axial FOV sufficient to image an entire mouse in a single bed position.

A tumor-secreted protein associated with human hypercalcemia of malignancy. Biology and molecular biology.

This investigation addresses a theoretical concept of tumor pathogenesis proposed over 40 years ago, namely that malignancy-associated hypercalcemia can result from endocrine secretion by tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or tumor-secreted cofactors or hormones, can produce hypercalcemia and other biochemical abnormalities associated with HHM. The hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other tumor-secreted peptide displays this biological profile. These studies establish one (PTH-like) mechanism by which human tumors could produce hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of hormone analogs. A broad spectrum of biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted proteins. Although some structural homology is shared by the two hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both hormones, is more pronounced. The similarity in biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]bPTH-(7-34)NH2 against the tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two hormones. In any case, these studies establish a promising new approach to therapy of tumor-associated hypercalcemia.

100 patient-years of ambulatory home total parenteral nutrition.

More than 100 patient-years' experience has been acquired in the treatment of 133 patients with ambulatory home total parenteral nutrition (TPN) between May 1974 and December 1983. Indications for chronic or permanent home TPN include short bowel syndrome, malabsorption, scleroderma, and vasoactive intestinal polypeptide syndrome. Indications for acute or temporary home TPN include Crohn's disease, malignancies, gastrointestinal fistulas, ulcerative colitis, anorexia nervosa, and numerous other disorders. Eighty-two patients in the acute group were treated primarily with percutaneously placed standard subclavian catheters and 51 patients in the chronic group have been treated thus far with implanted silicone rubber, Dacron-cuffed catheters for a cumulative total of 38,939 patient days. Of the 125 implanted catheters, 115 were placed in the superior vena cava and ten in the inferior vena cava for an average duration of 250 catheter-days, the longest single catheter remaining in situ for more than 8 1/2 years. Catheter-related sepsis occurred 33 times with the implanted catheters, or once every 2.6 catheter-years. One hundred and fourteen temporary catheters were placed percutaneously in the superior vena cava via a subclavian vein for an average duration of 68 days, the longest single catheter remaining in situ for 213 days. Catheter-related sepsis occurred seven times, equivalent to one episode per 3 catheter-years. Total catheter-related complications were quite infrequent and were directly related to duration of catheterization. They included venous thrombosis (12), clotted catheter (11), catheter failure or rupture (8), catheter compression (5) and inadvertent catheter removal (4). Twenty-six catheters were repaired or spliced in situ when the external segment was accidentally damaged or deteriorated secondary to long-term material fatigue. One remarkable patient has been maintained exclusively by TPN originally as an inpatient and subsequently as an outpatient for the entire 13 years of his life.

Comparison of two methods for detecting microbial contamination in intravenous fluids.

An aliquot sampling method and a qualitative membrane filltration method of microbial detection in intravenous infusion solutions were compared. One-liter plastic bags of total parenteral nutrition solutions were contaminated at approximately 1000, 100, 10, and 1 organisms per liter using clinically isolated strains of Escheichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Candida albicans. Ten-milliliter aliquots of the solutions were injected into blood culture bottles to test the aliquot method. All remaining fluid was filtered through the Addi-Chek system to test the filtration method. Samples were incubated at 30 degrees C for 10 days and inspected daily for turbidity. The aliquot sampling method consistently detected each of the four organisms at levels of 100 organisms/liter and above. The membrane filtration method consistently detected all levels of contamination (as few as four organisms/liter). The aliquot sampling method is inexpensive and easy to use but may fail to detect some contaminated solutions. The qualitative membrane filtration system will detect all levels of contamination but is more costly in both time and money, and its reliability has not been assessed objectively.