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Journal of Nuclear Medicine : Official... May 2021Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen...
Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting β- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using Ac-PSMA imaging and therapy (I&T). Fourteen patients receiving Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Thirty-four cycles of Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Our first clinical data for TAT using Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on Ac-PSMA-617 TAT.
Topics: Actinium; Antigens, Surface; Beta Particles; Glutamate Carboxypeptidase II; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome
PubMed: 33008928
DOI: 10.2967/jnumed.120.251017 -
Papillomavirus Research (Amsterdam,... Jun 2019Epidemiological and biological studies provide several lines of evidence for the involvement of cutaneous beta human papillomaviruses (HPVs), together with ultraviolet... (Review)
Review
Epidemiological and biological studies provide several lines of evidence for the involvement of cutaneous beta human papillomaviruses (HPVs), together with ultraviolet (UV) radiation, in the development of cutaneous squamous cell carcinoma. These viruses appear to act with a hit-and-run mechanism, being necessary at an early stage of carcinogenesis and being dispensable for the maintenance of the malignant phenotype. Studies in experimental models show that beta HPVs, mainly via the E6 and E7 oncoproteins, are able to promote proliferation and to circumvent cellular stresses induced by UV radiation. These findings support a model of skin carcinogenesis in which beta HPV-infected keratinocytes remain alive despite the accumulation of UV-induced DNA mutations. In this manner, these cells become highly susceptible to progression towards malignancy. Thus, UV radiation is the main driver of skin cancer development, while beta HPVs act as facilitators of the accumulation of UV-induced DNA mutations.
Topics: Betapapillomavirus; Carcinogenesis; Cell Proliferation; Epithelial Cells; Humans; Mutation; Oncogene Proteins; Papillomaviridae; Skin Neoplasms; Ultraviolet Rays
PubMed: 30953864
DOI: 10.1016/j.pvr.2019.04.003 -
Science Advances Dec 2022Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin...
Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. β-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as β-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived β-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma β-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either β-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived β-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.
PubMed: 36525492
DOI: 10.1126/sciadv.abn6025 -
Cancers Aug 2021Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation... (Review)
Review
Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation therapy, the management of advanced hormone resistant metastatic disease (mCRPC) is more challenging. Theranostics is a principle based on the ability to use an organ specific ligand and label it to both a diagnostic and a therapeutic agent. The overexpression of prostate specific membrane antigen (PSMA) on prostate cancer cells creates a unique opportunity for development of targeted radionuclide therapy. The use of both beta and alpha emitting particles has shown great success. Several clinical trials have been initiated assessing the efficacy and safety profile of these radionuclide agents. The results are encouraging with PSMA directed radioligand therapy performing well in patients who have exhausted all other standard treatment options. Future studies need to assess the timing of introduction of these radionuclide therapies in the management schema of mCRPC. Drugs or therapies are not without side effects and targeted radionuclide therapies presents a new set of toxicities including xerostomia and myelosuppression. New therapeutic strategies are being explored to improve outcomes while keeping toxicities to a minimum. This review aims to look at the various PSMA labelled tracers that form part of the theragnostic approach and subsequently delve into the progress made in the area of radionuclide therapy.
PubMed: 34359805
DOI: 10.3390/cancers13153904 -
Frontiers in Medicine 2022According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the... (Review)
Review
According to the 2021 World Health Organization Classification of Tumors of the Central Nervous System, glioblastoma (GB) is a primary brain tumor and presents with the worst prognosis. Due to its infiltrating characteristic, molecular heterogeneity, and only partly preserved function of the blood-brain barrier, the median overall survival time is short (9-15 months), regardless of comprehensive treatment including surgery, radiotherapy, and chemotherapy. Several novel treatment strategies are under investigation. Unfortunately, none of them produced successful results; 90% of patients have a recurrence of the disease within 6 months. Local administration of the drug could be a promising approach to delivering treatment with minimized side effects, due to the recurrence of 95% glioblastomas in a margin of 2 cm at the primary site. Several ligand-receptor systems have been evaluated, such as targeting tenascin, the extracellular matrix protein, or radiolabeled somatostatin analogs, as it is overexpressed with the SSTR-2 receptor system in around 80% of gliomas. Moreover, this study revealed that the NK-1 receptor is overexpressed in GB, suggesting that substance P (SP) may serve as a ligand. A variety of radioisotopes, beta- (I, Y, or Lu) and alpha emitters (Bi, Ac, or At), with different physical properties were tested for treatment. Alpha particles have many advantages over beta radiation such as short range with higher linear energy transfer. According to that characteristic, it is extremely dose delivered to the targeted cells, while reducing harm to nearby healthy tissue. Additionally, the biological effect of alpha radiation is independent of the cell cycle phase, cell oxygenation and O-6-methylguanine-DNA methyltransferase () gene promoter methylation status. In this article, we summarize the experience with local treatment of primary and secondary GBs with locally used radioisotopes such as [Bi]Bi-DOTA-SP or [Ac]Ac-DOTA-SP.
PubMed: 36590948
DOI: 10.3389/fmed.2022.1085245 -
Seminars in Interventional Radiology Oct 2021Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that... (Review)
Review
Transarterial radioembolization with yttrium-90 ( Y) is a mainstay for the treatment of liver cancer. Imaging the distribution following delivery is a concept that dates back to the 1960s. As β particles are created during Y decay, bremsstrahlung radiation is created as the particles interact with tissues, allowing for imaging with a gamma camera. Inherent qualities of bremsstrahlung radiation make its imaging difficult. SPECT and SPECT/CT can be used but suffer from limitations related to low signal-to-noise bremsstrahlung radiation. However, with optimized imaging protocols, clinically adequate images can still be obtained. A finite but detectable number of positrons are also emitted during Y decay, and many studies have demonstrated the ability of commercial PET/CT and PET/MR scanners to image these positrons to understand Y distribution and help quantify dose. PET imaging has been proven to be superior to SPECT for quantitative imaging, and therefore will play an important role going forward as we try and better understand dose/response and dose/toxicity relationships to optimize personalized dosimetry. The availability of PET imaging will likely remain the biggest barrier to its use in routine post- Y imaging; thus, SPECT/CT imaging with optimized protocols should be sufficient for most posttherapy subjective imaging.
PubMed: 34629714
DOI: 10.1055/s-0041-1735569 -
International Journal of Molecular... Apr 2023Transforming growth factor-beta 3 (TGF-β3) is a ubiquitously expressed multifunctional cytokine involved in a range of physiological and pathological conditions,... (Review)
Review
Transforming growth factor-beta 3 (TGF-β3) is a ubiquitously expressed multifunctional cytokine involved in a range of physiological and pathological conditions, including embryogenesis, cell cycle regulation, immunoregulation, and fibrogenesis. The cytotoxic effects of ionizing radiation are employed in cancer radiotherapy, but its actions also influence cellular signaling pathways, including that of TGF-β3. Furthermore, the cell cycle regulating and anti-fibrotic effects of TGF-β3 have identified it as a potential mitigator of radiation- and chemotherapy-induced toxicity in healthy tissue. This review discusses the radiobiology of TGF-β3, its induction in tissue by ionizing radiation, and its potential radioprotective and anti-fibrotic effects.
Topics: Humans; Transforming Growth Factor beta3; Transforming Growth Factor beta; Fibrosis
PubMed: 37108775
DOI: 10.3390/ijms24087614