Evaluating the biodistribution for [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007 PET/CT with an inter- and intrapatient based analysis.

BACKGROUND: Liver uptake in [68Ga]Ga-PSMA-11 PET is used as an internal reference in addition to clinical parameters to select patients for [177Lu]Lu-PSMA-617 radioligand therapy (RLT). Due to increased demand, [68Ga]Ga-PSMA-11 was replaced by [18F]F-PSMA-1007, a more lipophilic tracer with different biodistribution and splenic uptake was suggested as a new internal reference. We compared the intra-patient tracer distribution between [68Ga]Ga-PSMA-11 and [18F]F-PSMA-1007. METHODS: Fifty patients who underwent PET examinations in two centers with both [18F]F-PSMA-1007 and [68Ga]Ga-PSMA-11 within one year were included. Mean standardized uptake values (SUVmean) were obtained for liver, spleen, salivary glands, blood pool, and bone. Primary tumor, local recurrence, lymph node, bone or visceral metastasis were also assessed for intra- and inter-individual comparison. RESULTS: Liver SUVmean was significantly higher with [18F]F-PSMA-1007 (11.7 ± 3.9) compared to [68Ga]Ga-PSMA-11 (5.4 ± 1.7, p < .05) as well as splenic SUVmean (11.2 ± 3.5 vs.8.1 ± 3.5, p < .05). The blood pool was comparable between the two scans. Malignant lesions did not show higher SUVmean on [18F]F-PSMA-1007. Intra-individual comparison of liver uptake between the two scans showed a linear association for liver uptake with SUVmean [68Ga]Ga-PSMA-11 = 0.33 x SUVmean [18F]F-PSMA-1007 + 1.52 (r = .78, p < .001). CONCLUSION: Comparing biodistribution of [68Ga]Ga and [18F]F tracers, liver uptake on [68Ga]Ga-PSMA-11 PET is the most robust internal reference value. Liver uptake of [18F]F-PSMA-1007 was significantly higher, but so was the splenic uptake. The strong intra-individual association of hepatic accumulation between the two scans may allow using of a conversion factor for [18F]F-PSMA-1007 as a basis for RLT selection.

Prognostic and diagnostic value of [18F]FDG-PET/CT in restaging patients with small cell lung carcinoma: an Italian multicenter study.

BACKGROUND: The presence of residual disease after initial treatment in small cell lung cancer (SCLC) influences prognosis and impacts patient management. To date, few data exist on the value of fluorine-18-fluorodeoxyglucose ([F]FDG)-PET/computed tomography (CT) in SCLC at restaging. Therefore, in restaging patients with SCLC, we aimed to (a) evaluate the prognostic value yielded by [F]FDG-PET/CT and (b) assess the diagnostic agreement between [F]FDG-PET/CT and contrast-enhanced computed tomography (ceCT). PATIENTS AND METHODS: From a multicenter database, we evaluated 164 patients with SCLC who underwent [F]FDG-PET/CT for restaging purposes. PET scans were evaluated visually to identify the presence of recurrence. For each patient, the maximum and the mean standardized uptake value (SUVmax and SUVmean, respectively), metabolic tumor volume, and total lesion glycolysis were calculated, taking into account the lesion with the highest [F]FDG uptake (namely, the index lesion) in the local recurrences, lymph node involvement, and distant metastasis categories. Kaplan-Meier curves were computed to assess the effects of [F]FDG-PET/CT findings on overall survival (OS) and progression-free survival. Furthermore, the agreement between PET/CT and ceCT in detecting metastases was evaluated in 119 patients on a patient-based analysis (Cohen's κ; P < 0.05). RESULTS: The presence of metastatic lesions at [F]FDG-PET/CT was associated with a significantly shorter OS (P = 0.039) and progression-free survival (P < 0.001). Higher SUVmax showed a trend toward a shorter OS (P = 0.065). The K-agreement between ceCT and PET/CT in recurrent SCLC was 0.37 (P < 0.001). PET/CT and ceCT showed the same number of lesions in 52 (43.7%) patients, whereas PET/CT detected additional lesions in 35 (29.4%) patients. CONCLUSION: Detection of metastatic lesions at restaging by [F]FDG-PET/CT can predict a higher rate of progression and negatively influence OS in patients with SCLC. [F]FDG-PET/CT and ceCT seem to be complementary imaging modalities in patients with metastatic SCLC.

Predictive and prognostic value of left ventricular mechanical dyssynchrony assessed by myocardial perfusion single photon emission computed tomography in asymptomatic patients under hemodialysis.

BACKGROUND: Patients under hemodialysis (HD) have an increased risk of major adverse cardiac events (MACEs). In these patients, myocardial perfusion scintigraphy (MPS) provides useful prognostic information. Left ventricular mechanical dyssynchrony (LVD) has been proven to predict all-cause death in patients under HD. It remains unclear, whether the same prognostic value pertains also to the prediction of MACEs. PATIENTS AND METHODS: Ninety patients under HD (duration range: 2-216 months) with neither history nor symptoms of coronary artery disease at the time of MPS were retrospectively evaluated. All underwent clinical evaluation and MPS with dipyridamole stress test. MPS was reprocessed to derive left ventricular ejection fraction (EF), perfusion scores [summed stress score (SSS) and summed difference score (SDS)] and LVD (phase histogram bandwidth and phase SD).ResultsMACEs were reported in 10 (11.1%) patients as assessed at more than 2 years of follow-up (median 29 months). At univariate analysis, a correlation was demonstrated between MACEs and LVD (P<0.001), BMI (P=0.04), ECG changes during stress (P=0.03), dyspnea (P=0.02), SSS (P=0.04) and SDS (P=0.02). At stepwise multivariate analysis, only LVD (P<0.001), SSS (P=0.01) and SDS (P=0.001) were independent predictors of MACEs. No thresholds of SSS or SDS showed predictive value (P=0.79 for SSS ≥4, P=0.10 for SSS >8 and P=0.66 for SDS ≥2). At survival analysis, patients with LVD had a significantly shorter MACE-free survival (P<0.001). This predictive value held true even in patients with an unremarkable pattern of perfusion. CONCLUSION: In asymptomatic patients without known coronary artery disease under HD, LVD is highly predictive of the onset of MACEs at more than 2 years of follow-up and provides incremental value over perfusion scores alone. A phase analysis on gated MPS should be routinely performed in these patients to yield useful prognostic information.

Predictive value of (18)F-FDG PET/CT in restaging patients affected by ovarian carcinoma: a multicentre study.

PURPOSE: Ovarian cancer is the eighth most common malignancy among women and has a high mortality rate. Prognostic factors able to drive an effective therapy are essential. (18)F-Fluoro-2-deoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has been investigated in patients with epithelial ovarian cancer and showed promise in diagnosing, staging, detecting recurrent lesions and monitoring treatment response. Conversely, its prognostic role remains unclear. We aimed at assessing the prognostic value of (18)F-FDG PET/CT performed in the restaging process in a multicentre study. METHODS: We evaluated 168 patients affected by ovarian carcinoma, who underwent a restaging (18)F-FDG PET/CT. The presence of local recurrences, lymph node involvement and distant metastasis was recorded as well as lesion dimensions, maximum and mean standardized uptake values (SUVmax and SUVmean, respectively). Progression-free survival (PFS) and overall survival (OS) at 3 and 4 years were computed by using Kaplan-Meier curves. Increased odds ratio was assessed using Cox regression analysis testing all lesion parameters measured by PET/CT. RESULTS: PFS was significantly longer in patients with a negative than a positive restaging PET/CT study (3- and 4-year PFS 64 and 53% vs 23 and 12%, respectively; p < 0.001). Similarly, a negative study was associated with a significantly higher OS rate after 4 years of follow-up (67 vs 25% in negative and positive groups, respectively; p < 0.001). Lymph node or distant involvement were also independently associated with an increased risk of disease progression [hazard ratio (HR) 1.6 and 2.2, respectively; p = 0.003]. Moreover, PET/CT showed an incremental prognostic value compared to the International Federation of Gynecology and Obstetrics (FIGO) staging system. In the analysis of patient subsets, individuals with the same FIGO stage I-II but with negative PET had a significantly better 4-year OS than patients with low FIGO stage but positive PET. This implies that patients with the same FIGO stage can be further prognostically stratified using PET (p = 0.01). At receiver-operating characteristic (ROC) analysis, no thresholds for semiquantitative parameters were predictive of a worse outcome. CONCLUSION: (18)F-FDG PET/CT has an important prognostic value in assessing the risk of disease progression and mortality rate. An efficacious therapy planning might therefore effectively rely on (18)F-FDG PET/CT findings. Semiquantitative data were not proven to be an effective tool to predict disease progression.

Mitochondrial genome sequence evolution in Chlamydomonas.

The mitochondrial genomes of the Chlorophyta exhibit significant diversity with respect to gene content and genome compactness; however, quantitative data on the rates of nucleotide substitution in mitochondrial DNA, which might help explain the origin of this diversity, are lacking. To gain insight into the evolutionary forces responsible for mitochondrial genome diversification, we sequenced to near completion the mitochondrial genome of the chlorophyte Chlamydomonas incerta, estimated the evolutionary divergence between Chlamydomonas reinhardtii and C. incerta mitochondrial protein-coding genes and rRNA-coding regions, and compared the relative evolutionary rates in mitochondrial and nuclear genes. Synonymous and nonsynonymous substitution rates do not differ significantly between the mitochondrial and nuclear protein-coding genes. The mitochondrial rRNA-coding regions, however, are evolving much faster than their nuclear counterparts, and this difference might be explained by relaxed functional constraints on the mitochondrial translational apparatus due to the small number of proteins synthesized in Chlamydomonas mitochondria. Substitution rates at synonymous sites in a nonstandard mitochondrial gene (rtl) and at intronic and synonymous sites in nuclear genes expressed at low levels suggest that the mutation rate is similar in these two genetic compartments. Potential evolutionary forces shaping mitochondrial genome evolution in Chlamydomonas are discussed.

Evolutionary rates and expression level in Chlamydomonas.

In many biological systems, especially bacteria and unicellular eukaryotes, rates of synonymous and nonsynonymous nucleotide divergence are negatively correlated with the level of gene expression, a phenomenon that has been attributed to natural selection. Surprisingly, this relationship has not been examined in many important groups, including the unicellular model organism Chlamydomonas reinhardtii. Prior to this study, comparative data on protein-coding sequences from C. reinhardtii and its close noninterfertile relative C. incerta were very limited. We compiled and analyzed protein-coding sequences for 67 nuclear genes from these taxa; the sequences were mostly obtained from the C. reinhardtii EST database and our C. incerta EST data. Compositional and synonymous codon usage biases varied among genes within each species but were highly correlated between the orthologous genes of the two species. Relative rates of synonymous and nonsynonymous substitution across genes varied widely and showed a strong negative correlation with the level of gene expression estimated by the codon adaptation index. Our comparative analysis of substitution rates in introns of lowly and highly expressed genes suggests that natural selection has a larger contribution than mutation to the observed correlation between evolutionary rates and gene expression level in Chlamydomonas.

Multiple metabolic roles for the nonphotosynthetic plastid of the green alga Prototheca wickerhamii.

The presence of plastids in diverse eukaryotic lineages that have lost the capacity for photosynthesis is well documented. The metabolic functions of such organelles, however, are poorly understood except in the case of the apicoplast in the Apicomplexa, a group of intracellular parasites including Plasmodium falciparum, and the plastid of the green alga Helicosporidium sp., a parasite for which the only host-free stage identified in nature so far is represented by cysts. As a first step in the reconstruction of plastid functions in a nonphotosynthetic, predominantly free-living organism, we searched for expressed sequence tags (ESTs) that correspond to nucleus-encoded plastid-targeted polypeptides in the green alga Prototheca wickerhamii. From 3,856 ESTs, we found that 71 unique sequences (235 ESTs) correspond to different nucleus-encoded putatively plastid-targeted polypeptides. The identified proteins predict that carbohydrate, amino acid, lipid, tetrapyrrole, and isoprenoid metabolism as well as de novo purine biosynthesis and oxidoreductive processes take place in the plastid of P. wickerhamii. Mg-protoporphyrin accumulation and, therefore, plastid-to-nucleus signaling might also occur in this nonphotosynthetic organism, as we identified a transcript which encodes subunit I of Mg-chelatase, the enzyme which catalyzes the first committed step in chlorophyll synthesis. Our data indicate a far more complex metabolism in P. wickerhamii's plastid compared with the metabolic pathways predicted to be located in the apicoplast of P. falciparum and the plastid of Helicosporidium sp.