Abbreviations used in this paper: FRET, fl uorescence resonance energy transfer; hpf, hours postfertilization; MO, morpholino oligonucleotide; RR, ruthenium red; TRP, transient receptor potential.The online version of this paper contains supplemental material.

Ga-PSMA PET outperforms planar BS for the detection of affected bone regions as well as determination of overall bone involvement in PC patients. Our results indicate that BS in patients who have received PSMA PET for staging only rarely offers additional information; however, prospective studies, including a standardized integrated x-ray computed tomography (SPECT/CT) protocol, should be performed in order to confirm the presented results.

The trafficking of ion channels to the plasma membrane is tightly controlled to ensure the proper regulation of intracellular ion homeostasis and signal transduction. Mutations of polycystin-2, a member of the TRP family of cation channels, cause autosomal dominant polycystic kidney disease, a disorder characterized by renal cysts and progressive renal failure. Polycystin-2 functions as a calcium-permeable nonselective cation channel; however, it is disputed whether polycystin-2 resides and acts at the plasma membrane or endoplasmic reticulum (ER). We show that the subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting protein (PACS)-1 and PACS-2, two adaptor proteins that recognize an acidic cluster in the carboxy-terminal domain of polycystin-2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin-2 by the protein kinase casein kinase 2, required for the routing of polycystin-2 between ER, Golgi and plasma membrane compartments. Our paradigm that polycystin-2 is sorted to and active at both ER and plasma membrane reconciles the previously incongruent views of its localization and function. Furthermore, PACS proteins may represent a novel molecular mechanism for ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments

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Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is increasingly used in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed doses for normal organs and tumor lesions using 177 Lu-PSMA I&T (I&T is imaging and therapy) in patients undergoing up to 4 cycles of radioligand therapy. Results were compared with pretherapeutic Glu-NH-CO-NH-Lys-(Ahx)-[ 68 Ga(HBEDCC)] ( 68 Ga-PSMA-HBED-CC) PET. Methods: A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third, and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30-120 min, 24 h, and 6-8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pretherapeutic 68 Ga-PSMA-HBED-CC PET/CT. Absorbed doses for individual cycles were calculated using OLINDA/EXM. SUVs from pretherapeutic PET were compared with absorbed doses and with change of SUV. Results: The mean whole-body effective dose for all cycles was 0.06 6 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 6 0.21 Gy/GBq for the kidneys; 0.12 6 0.06 Gy/GBq for the liver; and 0.55 6 0.14 Gy/GBq for the parotid, 0.64 6 0.40 Gy/ GBq for the submandibular, and 3.8 6 1.4 Gy/GBq for the lacrimal glands. Absorbed organ doses were relatively constant among the 4 different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2 6 2.6 Gy/GBq (range, 0.22-12 Gy/GBq). Doses to tumor lesions gradually decreased, with 3.5 6 2.9 Gy/GBq for the first, 3.3 6 2.5 Gy/GBq for the second, 2.7 6 2.3 Gy/GBq for the third, and 2.4 6 2.2 Gy/GBq for the fourth cycle. SUVs of pretherapeutic PET moderately correlated with absorbed dose (r 5 0.44, P , 0.001 for SUV max ; r 5 0.43, P , 0.001 for SUV mean ) and moderately correlated with the change of SUV (r 5 0.478, P , 0.001 for SUV max , and r 5 0.50, P , 0.001 for SUV mean ). Conclusion: Organ-and tumorabsorbed doses for 177 Lu-PSMA I&T are comparable to recent reports and complement these with information on an excellent correlation between the 4 therapy cycles. With the kidneys representing the critical organ, a cumulative activity of 40 GBq of 177 Lu-PSMA I&T appears to be safe and justifiable. The correlation between pretherapeutic SUV and absorbed tumor dose emphasizes the need for PSMA-ligand PET imaging for patient selection.

Radioligand therapy with (177)Lu-PSMA-I&T appears to be safe and active in heavily pretreated patients with metastatic castration resistant prostate cancer.

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Abbreviations used in this paper: FRET, fl uorescence resonance energy transfer; hpf, hours postfertilization; MO, morpholino oligonucleotide; RR, ruthenium red; TRP, transient receptor potential.The online version of this paper contains supplemental material.