Synthesis of 68Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68Ga as exemplified by [68Ga]Ga-PSMA-11 for prostate cancer PET imaging.

[68Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [68Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [177Lu]Lu-PSMA-617, [225Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [68Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [68Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [68Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04-1.57 GBq (28-42 mCi); cyclotron method (single target), 1.47-1.89 GBq (40-51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [68Ga]Ga-PSMA-11 prepared using the two production methods.

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target.

PURPOSE: To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module. METHODS: Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2-0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50-75 min) and beam currents (27-40 µA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use. RESULTS: The decay corrected yield of 68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined 66/67Ga) for a practical clinical product shelf-life. The activity yield of [68Ga]GaCl3 was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). CONCLUSION: Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.

Lung density associates with survival in alpha 1 antitrypsin deficient patients.

INTRODUCTION: CT density correlates with quality of life (QOL) scores and impaired upper zone lung density associates with higher mortality in alpha one antitrypsin deficiency (A1ATD). We hypothesised that decline in CT densitometry would relate to survival or deterioration in QOL in A1ATD. METHODS: All augmentation naïve PiZZ patients in the UK A1ATD registry with ≥ two successive quantitative CT scans were selected. Patients were divided into groups based on CT density decline and the relationship to survival and change in QOL compared by univariate analyses and multivariate Cox regression. Analyses were performed for whole lung, upper zone and lower zone density separately. Exploratory analyses of FEV1 subgroups were conducted. RESULTS: 110 patients were identified; 77 had whole lung and lung zone density recorded on two CT scans, 33 patients had upper zone data only on four scans. Decline in lower zone density associated with survival, even after adjustment for baseline lung density (p = 0.048), however upper zone density and whole lung density decline did not. This difference appeared to be driven by those with FEV1 >30% predicted. CONCLUSION: Rate of change in lung densitometry could predict survival in A1ATD.

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.

Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end-point was change in CT lung density, and an exploratory approach was adopted to identify optimal methodology, including two methods of adjustment for lung volume variability and two statistical approaches. Other end-points were exacerbations, health status and physiological indices. CT was more sensitive than other measures of emphysema progression, and the changes in CT and forced expiratory volume in 1 s were correlated. All methods of densitometric analysis concordantly showed a trend suggestive of treatment benefit (p-values for Prolastin versus placebo ranged 0.049-0.084). Exacerbation frequency was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation.

Outcomes for COPD pharmacological trials: from lung function to biomarkers.

The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Validation of computed tomographic lung densitometry for monitoring emphysema in alpha1-antitrypsin deficiency.

BACKGROUND: Lung densitometry derived from computed tomographic images offers an opportunity to quantify emphysema non-invasively, but a pathological standard cannot be applied to validate its use in longitudinal monitoring studies. Consequently, forced expiratory volume in 1 second (FEV1) remains the standard against which new methods must be judged. We related progression of densitometry (15th percentile point and voxel index, threshold -950 Hounsfield units) to disease stage and FEV1 decline in two studies of subjects with alpha1-antitrypsin deficiency (PiZ). METHODS: Consistency of progression, measured using densitometry and FEV1, was assessed in relation to disease stage in a 2 year study of 74 subjects grouped according to the FEV1 criteria employed in the GOLD guidelines. In the second study of a subgroup of subjects with extended data (n=34), summary statistics were applied to measurements performed annually over 3 years and the rate of progression of densitometry was related to FEV1 decline. RESULTS: The progression of percentile point was consistent across a wide spectrum of disease severity, but voxel index progression varied in association with disease stage (p=0.004). In the second study, FEV1 decline correlated with progression of lung densitometry (percentile point: rS=0.527, p=0.001; voxel index: rS=-0.398, p=0.012). CONCLUSIONS: 15th percentile point is a more consistent measure of lung density loss across a wide range of physiological impairment than voxel index. However, both methods are valid for use in longitudinal and interventional studies in which emphysema is the major outcome target.

Panniculitis secondary to extravasation of clarithromycin in a patient with alpha 1-antitrypsin deficiency (phenotype PiZ).

alpha 1-Antitrypsin deficiency (AATD) is known to be associated with panniculitis. Although reports of this association are rare, the true incidence may be unappreciated because of underdiagnosis of AATD. We report a case of panniculitis occurring in a 34-year-old woman with severe AATD following the extravasation of clarithromycin infused intravenously for treatment of community-acquired pneumonia. Resolution occurred with conservative management. The histopathology and management of this unusual condition are discussed, with a review of the literature.

Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group.

A prospective population-based study was conducted in Australia and New Zealand during 1994-1997 to elucidate the epidemiology of cryptococcosis due to Cryptococcus neoformans var. neoformans (CNVN) and C. neoformans var. gattii (CNVG) and to relate clinical manifestations to host immune status and cryptococcal variety. The mean annual incidence per 10(6) population was 6.6 in Australia and 2.2 in New Zealand. Of 312 episodes, CNVN caused 265 (85%; 98% of the episodes in immunocompromised hosts) and CNVG caused 47 (15%; 44% of the episodes in immunocompetent hosts). The incidence of AIDS-associated cases in Australia declined annually (P<.001). Aborigines in rural or semirural locations (P<.001) and immunocompetent males (P<.001) were at increased risk of CNVG infection. Cryptococcomas in lung or brain were more common in immunocompetent hosts (P< or =.03) in whom there was an association only between lung cryptococcomas and CNVG. An AIDS-associated genetic profile of CNVN serotype A was confirmed by random amplification of polymorphic DNA analysis. Resistance to antifungal drugs was uncommon. The epidemiology of CNVN infection has changed substantially. Clinical manifestations of disease are influenced more strongly by host immune status than by cryptococcal variety.

Maxillary sinusitis caused by medusoid form of Schizophyllum commune.

We present a case of maxillary sinusitis in a diabetic female caused by the basidiomycete fungus Schizophyllum commune. Identification of the isolate was hampered by its atypical features. Subcultures formed sterile medusoid structures from nonclamped mycelia until spontaneous dikaryotization resulted in the development of characteristic fan-shaped fruiting bodies. Identification was confirmed by the presence of spicules formed on the hyphae and by vegetative compatibility with known isolates.

Psychophysiological stress responses, muscle tension, and neck and shoulder pain among supermarket cashiers.

This study examined psychological and physiological stress, as well as muscle tension and musculoskeletal symptoms, among 72 female supermarket cashiers. Stress levels were found to be significantly elevated at work, as reflected in the catecholamines, blood pressure, heart rate, electromyographic (EMG) activity, and self-reports. Fifty cashiers (70%) suffering from neck-shoulder pain (trapezius myalgia) were found to have higher EMG activity at work and reported more tension after work. Women who kept a diary for 1 week and reported more musculoskeletal pain (above the median) were older, had higher blood pressure, and reported more work stress and psychosomatic symptoms. The elevated stress levels at work are consistent with data from workers involved in other types of repetitive tasks and can be important for the high prevalence of neck and shoulder symptoms among the cashiers.

Acanthamoeba keratitis in New Zealand, including two cases with in vivo resistance to polyhexamethylene biguanide.

BACKGROUND: Acanthamoeba keratitis is an uncommon corneal infection that can run a protracted course with, at times, serious visual results. Eighty-five per cent of cases occur in soft contact lens wearers. The first New Zealand case occurred in 1990 and only seven cases have been identified in New Zealand to the end of 1996. METHODS: We surveyed the ophthalmologists looking after these seven cases of acanthamoeba keratitis as to time to diagnosis, treatment and outcome. RESULTS: New Zealand has a low incidence of this disease. All cases were soft contact lens wearers with defective care in every instance. After an initial two late-diagnosed cases, the time to diagnosis for four of the five other cases has been within 2 weeks. Medical treatment has varied over this series, but since the introduction of the cationic antiseptics polyhexamethylene biguanide (PHMB) and chlorhexidine in 1992, the last five cases were all treated with PHMB. One case diagnosed within 2 weeks ran a devastating course, despite intensive PHMB, and a second case remained culture positive after 1 year of PHMB and the late addition of chlorhexidine. Debridement, 0.1% PHMB and hexamidine eventually settled this eye. CONCLUSIONS: For treatment PHMB, hexamidine rather than propamidine and surgical debridement are favoured. While all Acanthamoeba isolates show good in vitro sensitivity to PHMB, the in vivo response is not always proportionate. A bacterial endosymbiont may have been a factor in the favourable outcome of one protracted case.

Pythium insidiosum keratitis.

A case of Pythium insidiosum keratitis is described. It is an unusual organism that is difficult to isolate. Cases in animals and humans have been reported from tropical and subtropical parts of the world but this is the first case from a temperate region and was acquired from a hot pool. Although resembling a fungus, it is insensitive to all antifungals and requires wide surgical excision for cure.

Percutaneous balloon-assisted aspiration thrombectomy of clotted hemodialysis access grafts.

PURPOSE: To present experience with percutaneous balloon-assisted aspiration thrombectomy (BAT) for the treatment of patients with clotted hemodialysis access grafts. MATERIALS AND METHODS: BAT was performed with use of 7-F intravascular sheaths and a Fogarty balloon catheter. It was tested with an in vitro flow-circuit model. Twenty consecutive BAT procedures were performed in 15 patients with clotted grafts. The balloon catheter was advanced through the sheath to the arterial anastomosis. The balloon was inflated and withdrawn while suction was applied from the sideport to recover thrombus. The procedure was repeated for the venous limb. BAT was used alone in 12 procedures and in combination with urokinase in eight procedures. RESULTS: Almost complete thrombectomy was achieved in all tubes (in vitro), with very low venous and arterial embolic fractions. Technical success (restored graft thrill and almost complete thrombectomy) was achieved in 18 cases (90%). Clinical success (patency after 1 week of dialysis) was achieved in 17 cases (85%). CONCLUSION: Percutaneous BAT is feasible in recently clotted dialysis grafts.

Evidence for nosocomial transmission of Candida albicans obtained by Ca3 fingerprinting.

The moderately repetitive sequence Ca3 was used to fingerprint Candida albicans isolates from 32 patients hospitalized for more than 3 days, 17 recent admissions or outpatients, and 8 recently readmitted patients and 10 commensal isolates from the community in Wellington, New Zealand, plus isolates from 21 hospitalized patients, 26 outpatients or recent admissions, 4 recently readmitted patients, and 10 healthy individuals in the community in Auckland, New Zealand. In Wellington, isolates from patients hospitalized in Wellington Hospital for more than 3 days were genetically significantly less diverse than were isolates from outpatients or recent admissions or isolates from healthy individuals in the community. In addition, two clusters of genetically similar strains were isolated from hospitalized patients significantly more often than from other individuals. These observations provide evidence (albeit indirectly) for nosocomial transmission of hospital-specific C. albicans strains. In contrast, no indication of hospital-specific transmission of C. albicans was found in Auckland Hospital. Since these results were obtained under conditions in which no candidiasis outbreak occurred in either hospital, they also suggest that Ca3 fingerprinting may be a useful tool in preventive nosocomial infection control programs, allowing assessment of the extent of C. albicans transmission occurring in a hospital.

High-molecular-weight hydroxypropylmethylcellulose. A cholesterol-lowering agent.

BACKGROUND: We assessed the efficacy of a high-molecular-weight hydroxypropylmethylcellulose (K8515) as a cholesterol-lowering agent, the dose-response profile of its action, and the ability of adult subjects to tolerate its ingestion at effective doses. METHODS: These studies were conducted at the Clinical Research Center of The University of Michigan Hospitals, Ann Arbor. Efficacy was assessed in 10 normal and 12 mildly hyperlipidemic subjects in double-blind, randomized crossover trials of 1 and 2 weeks' duration, respectively. The dose-response profile was studied in 12 mildly hypercholesterolemic subjects in a nonrandomized control trial with doses given in escalating order. Tolerance was assessed by a questionnaire of adverse effects and bowel movement habits in all subjects. RESULTS: We found that 10 g of K8515 ingested in a prehydrated form three times a day with meals lowered total cholesterol levels by an average of 1.45 mmol/L (56 mg/dL) (32%) in normal subjects within 1 week. In two studies in subjects with mildly elevated cholesterol levels (with entry levels ranging from 5.35 mmol/L [207 mg/dL] to 6.70 mmol/L [260 mg/dL]), average reductions of 1.00 mmol/L (39 mg/dL) (18%) and 1.15 mmol/L (45 mg/dL) (20%) were observed within the same period. The effect was primarily due to a reduction in low-density lipoprotein cholesterol levels. Low-density lipoprotein levels in normal subjects were an average of 1.10 mmol/L (42 mg/dL) (38%) lower after a week of 10 g of K8515 three times a day with meals, and in the two studies in subjects with mild hyperlipidemia, the reductions in low-density lipoprotein levels after 1 week were 0.95 mmol/L (37 mg/dL) (23%) and 1.05 mmol/L (40 mg/dL) (25%). Although there was a tendency for high-density lipoprotein cholesterol levels to decrease, this was significant only in normal subjects. Decreases in cholesterol levels were not accompanied by any rise in triglyceride levels. Dose-response studies in those with mildly elevated cholesterol levels indicated that it is possible to achieve a 15% decrease in low-density lipoprotein cholesterol levels within 1 week at a dose of 6.7 g three times a day, with minimal adverse effects. CONCLUSION: These results suggest a role for high-molecular-weight hydroxypropylmethylcellulose in the clinical treatment of mild hypercholesterolemia.