Complete Resolution of Locally Advanced Prostate Cancer After Molecular Endoradiotherapy With 177 Lu-PSMA.

ABSTRACT: A 76-year-old man with castration-resistant prostate cancer underwent 68 Ga-prostate-specific membrane antigen (PSMA) PET/CT for restaging. A large PSMA-avid tumor with invasion to adjacent organs was noted causing gross hematuria and symptomatic anemia. Two cycles of 177 Lu-PSMA were administered, and the patient showed significant reduction of hematuria as well as declining in PSA levels. 177 Lu-PSMA therapy can be a good treatment option in patients with locally invasive tumors.

[68Ga]Ga-FAP-2286, a novel promising theragnostic approach for PET/CT imaging in patients with various type of metastatic cancers.

BACKGROUND: Fibroblast activation protein (FAP) has emerged as a promising target for diagnosis and therapeutic intervention due to high expression and accumulation in the stromal compartments of a variety of malignant tumors. FAP-2286 utilizes cyclic peptides with FAP-binding characteristics to enhance the retention of the imaging agent within tumors, in contrast to the small-molecule FAP inhibitors (FAPI) like FAPI-04/46. The aim of this study was to quantify the tumor uptake of [68Ga] Gallium-FAP-2286 within primary solid tumors, adjacent excised tissues, and metastatic lesions. METHODS: In this prospective study, 21 patients (average age 51.9) with various diagnoses of remaining and metastatic cancers participated. Among them, six had metastatic sarcoma, and 14 had adenocarcinoma, including eight breast, two rectum, two lung, two pancreas, and one thyroid cases. The patients underwent a [68Ga]Ga-FAP-2286 PET/CT scan. An hour post-administration of [68Ga]Ga-FAP-2286, a visual assessment of whole body scans and semi-quantification of the PET/CT results were carried out. The standardized uptake values (SUV)max of [68Ga]Ga-FAP-2286 in tumor lesions and the tumor-to-background ratio (TBR) were then calculated. RESULTS: The vital signs of the patients, such as heart rate, blood pressure, and temperature, were observed before, during, and after the diagnostic procedure during the 4-h follow-up. All individuals underwent the [68Ga]Ga-FAP-2286 PET/CT scans without any signs of drug-associated pharmacological effects. The PET/CT scans displayed substantial absorption of [68Ga]Ga-FAP-2286 in tumor lesions in all patients (100% (21/21)). Irrespective of the tumors' origins (epithelial or mesothelium) and whether they exhibited local recurrence, distant recurrence, or metastatic lesions, the PET/CT scans revealed the uptake of [68Ga]Ga-FAP-2286 in these lesions. CONCLUSION: Overall, these data suggest that [68Ga]Ga-FAP-2286 is a promising FAP derivative for efficient metastatic cancer diagnosis and being considered as a potential compound for therapeutic application in patients with advanced metastatic cancers.

Spermatogenesis regeneration by transfected spermatogonial stem cells in infertile roosters through testicular transplantation.

Investigations pertaining to spermatogonial stem cells (SSCs) have led to the use of these cells in a variety of fields including infertility treatments, production of transgenic animals, and genome editing. The aim of the present study was to investigate the plausibility of regenerating spermatogenesis in infertile roosters by transplanting transfected SSCs into testes. Spermatogonial stem cells were isolated and cultured for seven days. Afterward, pDB2, a plasmid vector carrying a reporter gene, GFP, was transfected into the SSCs. Transfected SSCs were transplanted into the left testis of infertile roosters. Tissue samples from the recipients' testes were obtained six weeks after the transplantation and transplanted SSCs were observed in the basement membrane. After eight weeks, GFP-positive spermatozoa were observed in collected semen from the recipient roosters and GFP gene in spermatozoa was confirmed using PCR. The recipient roosters were mated with hens. Hatchlings were visually checked and their tissue samples were tested by PCR to identify transgenesis but both of them were negative. Overall, it seems that regeneration of spermatogenesis in roosters via transfected SSCs is possible but more studies are need to produce recombinant proteins by this way.

68 Ga-FAPI-46 PET/CT in a Metastatic Castration-Resistant Prostate Cancer Patient With Low PSMA Expression.

ABSTRACT: A 70-year-old man with mCRPC (metastatic castration-resistant prostate cancer) was referred for 68 Ga-PSMA PET/CT for restaging and the possibility of targeted molecular radioligand therapy with 177 Lu-PSMA. Numerous 68 Ga-PSMA-avid skeletal metastases with low SUVs were noted. Because of low PSMA expression, a 68 Ga-FAPI-46 PET/CT was performed to evaluate the eligibility for FAPI-based radioligand therapy. There were some discordant findings between 68 Ga-PSMA and 68 Ga-FAPI PET/CT scans regarding the detectability of lesions and SUVs. Our case signifies that 68 Ga-FAPI theragnostic may have a potential role in the treatment of mCRPC patients with insignificant PSMA expression or in cases after the failure of 177 Lu-PSMA therapy.

68 Ga-FAPI-46 and 18 F-FDG in Advanced Metastatic Pancreatic Cancer.

ABSTRACT: Recently imaging with new PET radiotracers that act as fibroblast activation protein inhibitors (FAPIs) showed promising results in oncology and even nononcology imaging. Here we report a case of advanced pancreatic adenocarcinoma, imaged with both 18 F-FDG and 68 Ga-FAPI-46 PET/CT scans. The result indicated that imaging with 68 Ga-FAPI-46 showed significant improvement in detection of metastases as well as local malignancy recurrence. Moreover, the intensity and SUVs of the lesions were higher in 68 Ga-FAPI-46 scan compared with 18 F-FDG.

Fibroblast Activation Protein Inhibitor Imaging and Therapy in a Patient With Multiple Endocrine Neoplasia Type 2A Syndrome.

ABSTRACT: A patient with multiple endocrine neoplasia type 2A syndrome who had exhausted several surgeries and radiotherapy was referred to nuclear medicine department for theranostic approaches. [68Ga]-DOTATATE PET/CT and [131I]I-mIBG SPECT/CT were performed, but the degree of uptake was insufficient for using the treatment companion of these tracers. Finally, 1 year later, [68Ga]-FAPI-46 PET/CT showed progressive disease with metastases to the lung, liver, bone, and lymph nodes with intense [68Ga]-FAPI-46 uptake. Treatment with [177Lu]Lu-FAPI-46 was done, and the patient tolerated treatment and showed evidence of clinical improvement following therapy.

68Ga-PSMA PET/CT Scan Leading to Diagnosis of PSMA-Positive Rectal Adenocarcinoma in a Patient With Prostate Cancer.

ABSTRACT: A 59-year-old prostate cancer patient, status post radical prostatectomy, was referred to our department for restaging with 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scan. Aside multiple metastatic lesions involving pelvic lymph nodes as well as the right femoral trochanter, a PSMA-positive rectal wall thickening was detected. Colonoscopy correlation and tissue diagnosis, recommended to rule out accompanying primary malignancy, confirmed the presence of rectal adenocarcinoma. This case signifies the importance of requesting pathological correlation for unexplained PSMA-positive lesions, emphasizing the potential role PSMA ligands may play in detecting occult second primary malignancies, especially synchronous/metachronous colorectal cancers.

Feasibility and Therapeutic Potential of 177Lu-Fibroblast Activation Protein Inhibitor-46 for Patients With Relapsed or Refractory Cancers: A Preliminary Study.

INTRODUCTION: Fibroblast activation protein (FAP) is a member of the serine protease family and has a high expression in the stroma of approximately 90% of epithelial malignancies. The present investigation aimed to assess the feasibility, safety, and dosimetry data of 177Lu-FAPI-46 in diverse malignancies. PATIENTS AND METHODS: Patients with advanced cancers with nonoperable tumors, or tumors refractory to conventional therapies, were enrolled. Treatment included escalating doses of 177Lu-FAPI-46 (1.85-4.44 GBq) per cycle using a combination of clinical and statistical expertise design, and intervals of 4 to 6 weeks were considered between the cycles. Biodistribution and dosimetry were examined by whole-body scans. We applied the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 to measure peptide-targeted radionuclide therapy (PTRT)-associated toxicity. RESULTS: A total of 21 patients (11 females and 10 males) with a median age of 50 years (range, 6-79 years) were investigated. Of 21 participants, 18 cases were selected for PTRT. Overall, 36 PTRT cycles were performed. The median number of PTRT cycles and the median injected amount of activity in each cycle were 2 and 3.7 GBq, respectively. The dosimetric analysis revealed median absorbed doses of 0.026, 0.136, 0.886, and 0.02 with ranges of 0.023-0.034, 0.001-0.2, 0.076-1.39, and 0.002-0.2 mGy/MBq for the whole body, liver, kidneys, and spleen, respectively. The therapy was well tolerated in almost all patients. CONCLUSIONS: The findings of this preliminary investigation might indicate the potential feasibility and safety of PTRT using 177Lu-FAPI-46 for different aggressive tumors. Moreover, the current study could be beneficial in determining the suitable amount of activity for a phase 2 study.

Robust DNase activity of the ooplasm can act as a gametic transfection barrier in rainbow trout.

In this study, we evaluated DNase activity of rainbow trout oocyte using an in vitro and in vivo study. First, synthetic single strand and natural double strand DNA from Eukaryotic and prokaryotic sources as well as naked DNA were in vitro incubated with the oocyte cytoplasm. Results showed that the DNase activity of rainbow trout oocyte is strong enough to degrade any type of DNA at the onset of the incubation. Then, we evaluated if similar to the mammalian species, dead spermatozoa from rainbow trout can protect exogenous DNA from oocyte DNases. A series of dead spermatozoa was incubated with pDB2, carrying EGFP transgene, for 30 min followed by the ooplasm treatment for an additional 30 min. Not only did oocyte DNases completely degrade the exogenous DNA, but also it degraded the compact genome of spermatozoa. In conclusion, in vitro results clearly showed that strong DNase activity of ooplasm could degrade any types of foreign DNAs including oligonucleotides and intensively compact sperm genome. The strong DNase activity of rainbow trout ooplasm could be a stumbling block for genetic modification using plasmids in salmonids.

False-positive elevated CEA during colon cancer surveillance: a cholecystitis case report diagnosed by PET-CT scan.

A 53-year-old man with previous history of sigmoid colon adenocarcinoma who had undergone surgical resection and adjuvant chemotherapy presented with slightly rising carcinoembryonic antigen (CEA), while anatomical imaging modalities were unremarkable. FDG PET-CT study did not identify residual tumoral disease; however, there were abnormalities in the gallbladder most likely suggestive of cholecystitis. Eight weeks after cholecystectomy, serum CEA concentration reached normal values. Final histopathology of the gallbladder was also consistent with acute on chronic cholecystitis.

Developing a puncture-free in ovo chicken transfection strategy based on bypassing albumen nucleases.

Chicken is a dual-purpose animal important from both agricultural and medical aspects. Even though significant improvements have been made in chicken transgenesis technologies, chicken genome manipulation has not been widely used in developmental biology. This study was aimed to evaluate chicken egg white nuclease properties and thereof plausibility of devising an in vivo transfection technology without causing physical damage to the embryo. First, the nuclease activity of egg albumen was assessed. The egg white nucleases were strongly active in degrading DNA and RNA. The egg white DNase activity was comparable to commercially available DNase-I. Nuclease activities were also assessed after heating, proteinase K, or EDTA treatment. Unlike proteinase K, both heating and EDTA were noticeably effective for the nuclease inactivation. Simultaneous application of lipoplex form of DNA (1 µg pDB2: 3 µl Lipofectamine2000) and EDTA showed a synergistic effect in protection against egg white nucleases. Finally, we injected the lipoplexes with or without EDTA close to the embryo at day0, but outside the embryonic epiblast. Implementation of a scrutinized PCR assay indicated that transfection took place only when EDTA was complemented to the lipoplexes. The transfection rate of day4 embryos and the hatched chicks were 54.5 and 30.0%, respectively. EGFP expression was detected in two out of three transgenic chicks. In conclusion, this study provided a detail analysis of chicken egg albumen nuclease properties and suggested the feasibility of developing a puncture-free handmade technology for transfection of the chicken embryo.

A SNP in the 3'-untranslated region of AMPKγ1 may associate with serum ketone body and milk production of Holstein dairy cows.

AMPK is the key switch for providing the energy balance between cellular anabolic and catabolic processes. In this study, we aimed to screen the PRKAG1 (AMPKγ1) gene in high, moderate, and low producing Holstein dairy cows. A sample of 100 pregnant dairy cows, comprising 41 high, 33 moderate, and 26 low milk yields were selected from three large dairy herds in Isfahan province of Iran. Body condition score (BCS) was estimated before parturition while beta hydroxyl butyric acid (BHBA) as a measure of ketone bodies was measured at the fifth day postpartum. In addition, using three primer pairs covering exons 2-11 and 3'-UTR of the PRKAG1 gene, a random sample of 10 high milk yield dairy cows were amplified and sequenced. The sequencing results showed the presence of a T12571C mutation in intron 6 and a T14280C mutation in the 3'-untranslated region (UTR) of the PRKAG1 gene. Following a PCR reaction for amplification of the 3'-UTR amplicons, single strand conformation polymorphism (SSCP) assay was implemented for discrimination of the mutation in the studied population. Then, we evaluated if the mutation associates with the BCS, serum BHBA level, and production traits. The experimental analysis showed that the mutated allele significantly increased the BHBA level, BCS, as well as milk and protein yield. Bioinformatic study revealed that this 3'-UTR mutation distorts the target site of mir-423-5p microRNA which is one of the most highly expressed microRNAs in the bovine mammary gland, liver, and kidney. Given the role of AMPK in energy metabolism, the newly identified 3'-UTR mutation highlights the importance of AMPK and suggests a role of miRNAs for regulation of cellular metabolism, metabolism disorders, and production traits in Holstein dairy cows.

Presence of SNPs in GDF9 mRNA of Iranian Afshari Sheep.

BACKGROUND: Multiple births occur frequently in some Iranian sheep breeds, while infertility scarcely occurs. Mutation detection in major fecundity genes has been explored in most of Iranian sheep flocks over the last decade. However, previously reported single nucleotide polymorphisms (SNPs) for bone morphogenetic protein receptor-(BMPR)-1B and growth differentiation factor ) GDF9( known to affect fertility have not been detected. This study was conducted to assess whether any significant mutations in GDF9 were extracted from slaughtered ewe ovaries of Iranian Afshari sheep breed. MATERIALS AND METHODS: Ovaries defined as poor, fair, and excellent quality based on external visual appearance of follicles were used for histology and RNA extraction processes. High quality RNAs underwent reverse transcriptase-polymerase chain reaction (RT-PCR) from GDF9 mRNA, and the products sequenced. RESULTS: No streak ovaries, which are considered indicators of infertility due to homozygocity for some mutations in GDF9 and BMP15, were found. Sequencing results from GDF9 cDNA showed that G2 (C471T), G3 (G477A), and G4 (G721A) mutations were observed from 1, 4, and 1 out of 12 ewes, respectively. Though all 3 mutations were previously reported, this is the first report on their presence in Iranian breeds. The first and second mutations do not alter the amino acids, while G4 is a non-conservative mutation leading to E241K in the prohormone. CONCLUSION: As the G4 mutation was observed only in ovaries defined superficially as top quality, it could be considered as one of reasons for higher ovulation rate in some sheep. Furthermore since multiple mutations were observed in some cases, it might be possible that combinations of minor mutations in GDF9 and BMP15 interact to affect fecundity in some Iranian sheep breeds.