Eye-Related Adverse Events after I-131 Radioiodine Therapy: A Systematic Review of the Current Literature.

OBJECTIVE: Although I-131 is relatively safe, there is limited focus on probable eye-related side effects after radioactive iodine (RAI) therapy. Thus, we aimed to provide evidence for the adverse outcomes of I-131, exclusively in thyroid cancer patients. METHODS: A systematic review based on the PRISMA guidelines was designed to examine the ocular complications of RAI therapy. Databases including PubMed, Scopus and Web of Science were searched until October 2023 with specific MeSH terms. After thorough screening and review, relevant data were extracted. RESULTS: The database search yielded 3,434 articles, which resulted in the final 28 eligible studies. These studies investigated ophthalmic symptoms following RAI therapy, classifying them as obstructive diseases (e.g., nasolacrimal duct obstruction [NLDO; median incidence rate: 6.8%]), inflammatory symptoms (median incidence rate: 13%), and cataracts (median incidence rate: 2.5 and 5%). The most common time interval between RAI therapy and the onset of symptoms was within the first 12 months and then declined in the preceding years. A strong positive correlation was observed between higher I-131 doses of more than 100-150 mCi (3.7-5.55 GBq) and the risk of symptom development. Ages older than 45 also showed a significant association with NLDO. CONCLUSION: The risk of ophthalmic complications is associated with various factors, including the administration of high I-131 doses, age of more than 45 years, and time to event within the first 12 months. Considering these conditions may help enhance patient care and prevent adverse outcomes that may limit patients' quality of life.

Free TcO4- in 99mTc-PSMA Scan: A Case Report and Review of an Old Pitfall in the New Era of Modern Imaging.

ABSTRACT: In a recent 99mTc-HYNIC-PSMA study conducted at our department, we examined 2 patients with prostate cancer referred for initial staging on the same day. The whole-body scans revealed radiotracer uptake in the gastric mucosa and thyroid glands, alluding to high levels of free TcO4- in the injected vial. The scans were repeated after confirming acceptable radiopharmaceutical purity of 97% (normal range, 95%-100%). Interestingly, 1 patient had liver metastases at presentation, which remained non-PSMA-avid after repeating the scan. We have reviewed this pitfall, which has been reported with many radiotracers, yet not reported with PSMA tracers.

Nonmalignant 68 Ga-FAPI-46 Uptake in 2 Cases of TENIS Syndrome : Comparison With 18 F-FDG.

ABSTRACT: The cancer specificity of fibroblast activation protein inhibitor (FAPI) uptake remains understudied topic, and several cases of false-positive FAPI PET/CT findings have been reported. We present 2 patients of differentiated thyroid cancer with thyroglobulin elevation and negative iodine scintigraphy syndrome who underwent 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT for evaluation of any possible sites for metastatic disease. Although no focus of metastatic disease was found in these patients, remarkable findings were noticed instead. Nonmalignant FAPI uptake was evident in the gallbladder, uterus, and degenerative changes, whereas these uptake were discordant or partially concordant with those in FDG's, also CT images showed no underlying abnormality.

99m Tc-HYNIC-FAPI-46 SPECT/CT Uptake in Lactating Breasts.

ABSTRACT: A 36-year-old woman with a history of medullary thyroid carcinoma was referred for 99m Tc-HYNIC-FAPI-46 scan. Her calcitonin levels gradually increased after external beam radiation therapy, whereas her CEA levels were stable. A few suspicious tumoral lymphadenopathies were localized to the superior mediastinum. Interestingly, bilateral physiologic breast uptake was noticed, which was presumed to be due to lactation in the past 18 months. To our knowledge, physiologic breast uptake in 99m Tc-HYNIC-FAPI imaging has not been previously reported.

Quadruplet Therapy in De Novo High-Volume Mixed Neuroendocrine Prostate Cancer Using 177Lu-PSMA: A Case Report.

ABSTRACT: We present a case of de novo high-volume metastatic prostate cancer with high PSMA expression, partially PSMA-negative, using quadruplet therapy (PROMISE ver. 2 miTNM; miT4N2M1aM1b(dmi) PRIMARY score: 5, PSMA-expression score: 0-3). Because of our patient's partial PSMA negativity and after a multidisciplinary tumor board discussion, we decided to use a modified protocol involving doublet hormonal therapy along with 177Lu-PSMA and radiation therapy to address the PSMA-negative disease. The patient responded well to this treatment, but recurrence was ultimately inevitable. This case represents a typical example of mixed neuroendocrine prostate carcinoma and highlights its resistant phenotype in response to quadruplet therapy.

The Prognostic Power of Preablation Stimulated Thyroglobulin in Children With Differentiated Thyroid Cancer.

OBJECTIVE: To analyze prognostic factors in children with differentiated thyroid carcinoma (DTC) who have been treated in a single center in the last 27 years. METHODS: We studied 126 children (≤18 years old) who have been treated with near-total thyroidectomy followed by radioiodine therapy and thyroid hormone replacement. Follow-up of the patients was done 2, 6, and 12 months after treatment and then by yearly evaluation. Response to treatment was defined according to the American Thyroid Association guidelines. RESULTS: Papillary thyroid cancer was the main pathology (93.7%), and 52.4% of the patients had lymph node metastasis at presentation, which was extensive (>5) in 30% of the patients. Distant metastasis was seen in 8.8%. The mean initial dose of I-131 was 74 ± 42.2 MBq/kg. The median follow-up was 59 months and the median time to achieve an excellent response was 29 months. The preablation stimulated thyroglobulin (psTg) level was 202.4 ± 301.8 ng/mL in patients with first-year incomplete response compared with 11.2 ± 17.5 ng/mL in others (P =.001). Furthermore, using logistic regression, the psTg level was found to be the only significant predictor of distant metastasis, and psTg ≥ 13.75 ng/mL was the most powerful predictor of first-year incomplete response. Moreover, distant metastasis was more common in boys than in girls, and it took longer time for boys to achieve an excellent response. CONCLUSION: The psTg level was the only significant predictor of distant metastases in children with DTC, and psTg ≥ 13.75 ng/mL was the most powerful predictor of first-year incomplete response.

Bipolar Androgen Therapy: When Excess Fuel Extinguishes the Fire.

Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through "Darwinian" treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.

How did the COVID-19 pandemic affect the referral patterns for SPECT myocardial perfusion? A single center experience.

Objectives: We evaluated the impact of the COVID-19 pandemic on the number of referrals for SPECT myocardial perfusion imaging (SPECT-MPI) as well as changes in the clinical and imaging characteristics. Methods: We respectively reviewed 1042 SPECT-MPI cases performed in a 4-month period during the COVID-19 pandemic (PAN; n=423) and compared their findings with those acquired in the same months before the pandemic (PRE; n=619). Results: The number of stress SPECT-MPI studies performed during the PAN period significantly dropped compared to the number of studies carried out in the PRE period (p = 0.014). In the PRE period, the rates of patients presenting with non-anginal, atypical and typical chest pain were 31%, 25% and 19%, respectively. The figures significantly changed in the PAN period to 19%, 42%, and 11%, respectively (all p-values <0.001). Regarding the pretest probability of coronary artery disease (CAD), a significant decrease and increase were noticed in patients with high and intermediate pretest probability, respectively (PRE: 18% and 55%, PAN: 6% and 65%, p <0.001 and 0.008, respectively). Neither the rates of myocardial ischemia nor infarction differed significantly in the PRE vs. PAN study periods. Conclusion: The number of referrals dropped significantly in the PAN era. While the proportion of patients with intermediate risk for CAD being referred for SPECT-MPI increased, those with high pretest probability were less frequently referred. Image parameters were mostly comparable between the study groups in the PRE and PAN periods.

[68Ga] Ga-Pentixafor diffuse bilateral Adrenal & Breast uptake in a patient with High-grade Glioma: A note of caution on normal variants.

[68Ga] Ga-labeled C-X-C motif receptor4 as a novel radio-ligand using PET/CT has been investigated for tracing various kinds of solid and hematopoietic malignancies in recent years. High-grade Glioma (WHO classification 2016 grade III and IV) shows elevated levels of CXCR4 ligand expression in the affected tumoral cells. Healthy and non-affected organ cells express low-level CXCR4 ligands density. We performed [68Ga] Ga-Pentixafor (Pars-Cixafor™) PET/CT in a patient with high-grade Glioma (anaplastic oligodendroglioma WHO grade III) with no other documented medical condition and history. In addition to the Pentixafor-avid tumor remnant in the PET/CT images, we observed mild symmetrical bilateral uptake in the fibro glandular tissue of the breasts and moderate CXCR4(Pentixafor) avidity in both adrenal glands without any discernable pathology and abnormal density changes in the CT component of the study. Attention should be paid to the interpreting [68Ga] Ga-Pentixafor PET/CT examination and its normal uptakes and variants.

Lung Ventilation-Perfusion Scan in COVID-19: Various Patterns of Perfusion Defects.

ABSTRACT: Although COVID-19 infection is associated with the increased risk of pulmonary thromboembolism (PTE), COVID-19 pulmonary lesions cause ventilation-perfusion (V/Q) patterns other than PTE. Although extensive research has been done to address different anatomical patterns of COVID-19, there is a knowledge gap in terms of V/Q lung scintigraphy in these patients. The purpose of this study is to demonstrate these patterns and to show how important it is to use SPECT/CT in addition to planar images to differentiate between these patterns from PTE. In the current collection, we presented various patterns of V/Q SPECT/CT abnormalities in COVID-19 patients.

Peptide Receptor Radionuclide Therapy in Merkel Cell Carcinoma: A Comprehensive Review.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177Lu- or 90Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world.

Prostatic bed calcification with MDP uptake: Easy to miss on planar images.

A 65 years old man with high-risk prostate adenocarcinoma underwent bone scintigraphy with 99mTc-methylene diphosphate (99mTc-MDP). The scan revealed a focus of radiotracer uptake in the left pubic region, which was suspicious for metastatic involvement. Additional imaging with single photon emission computed tomography (SPECT/CT) confined the uptake to be extra-osseous and contributed to the calcified zone in the prostate bed. Prostatic bed calcification with 99mTc-MDP uptake mimics metastasis and can be easily missed on planar images.

A crying liver: a scan pattern mimicking spontaneous perforation of the biliary ducts.

A 2-month-old infant was referred for hepatobiliary scintigraphy due to ascites of unknown cause. The top differential diagnosis was spontaneous perforation of the biliary ducts. Delayed images up to 4 hours were against this diagnosis showing normal distribution of the radiotracer throughout the bowel. However, on delayed images, the scan showed mild tracer retention in the ascites confirmed by SPECT/CT images. Surprisingly, the exploratory abdominal surgery revealed an intact hepatobiliary system, pointing toward other possible etiologies. Second-review surgery was performed due to uncontrolled progressive ascites showing congestive hepatopathy and biliary leak from the hepatic surface suggestive of the "crying liver".

[18F]FDG-PET/CT Radiomics and Artificial Intelligence in Lung Cancer: Technical Aspects and Potential Clinical Applications.

Lung cancer is the second most common cancer and the leading cause of cancer-related death worldwide. Molecular imaging using [18F]fluorodeoxyglucose Positron Emission Tomography and/or Computed Tomography ([18F]FDG-PET/CT) plays an essential role in the diagnosis, evaluation of response to treatment, and prediction of outcomes. The images are evaluated using qualitative and conventional quantitative indices. However, there is far more information embedded in the images, which can be extracted by sophisticated algorithms. Recently, the concept of uncovering and analyzing the invisible data extracted from medical images, called radiomics, is gaining more attention. Currently, [18F]FDG-PET/CT radiomics is growingly evaluated in lung cancer to discover if it enhances the diagnostic performance or implication of [18F]FDG-PET/CT in the management of lung cancer. In this review, we provide a short overview of the technical aspects, as they are discussed in different articles of this special issue. We mainly focus on the diagnostic performance of the [18F]FDG-PET/CT-based radiomics and the role of artificial intelligence in non-small cell lung cancer, impacting the early detection, staging, prediction of tumor subtypes, biomarkers, and patient's outcomes.

Could Fibroblast Activation Protein (FAP)-Specific Radioligands Be Considered as Pan-Tumor Agents?

Background: Cancer-associated fibroblasts (CAFs) can strongly modulate the response to therapy of malignant tumor cells, facilitating their continuous proliferation and invading behaviors. In this context, several efforts were made in identifying the fibroblast activation protein (FAP) as a CAF recognizer and in designing FAP-specific PET radiotracers (as 68Ga-FAPI) along with FAP-specific therapeutic radioligands. Herein, we review different clinical studies using the various FAP-specific radioligands as novel theranostic agents in a wide range of oncologic and nononcologic indications. Methods: A comprehensive systematic search was conducted on the PubMed and Scopus databases to find relevant published articles concerning the FAP-specific PET imaging as well as the FAP-specific radionuclide therapy in patients with oncologic and nononcologic indications. The enrolled studies were dichotomized into oncologic and nononcologic categories, and the required data were extracted by precisely reviewing the whole text of each eligible study. A meta-analysis was also performed comparing the detection rates of 68Ga-FAPI vs. 18F-FDG PET/CT using odds ratio (OR) and risk difference as outcome measures. Results: Of the initial 364 relevant papers, 49 eligible articles (1479 patients) and 55 case reports were enrolled in our systematic review. These studies observed high radiolabeled FAPI avidity as early as 10 minutes after administration in primary sites of various malignant tumors. Based on the meta-analysis which was done on the reported detection rates of the 68Ga-FAPI and 18F-FDG PET/CT scans, the highest OR belonged to the primary lesion detection rate of gastrointestinal tumors (OR = 32.079, 95% CI: 4.001-257.212; p = 0.001) with low heterogeneity (I2 = 0%). The corresponding value of the nodal metastases belonged to hepatobiliary tumors (OR = 11.609, 95% CI: 1.888-71.365; p = 0.008) with low heterogeneity (I2 = 0%). For distant metastases, the highest estimated OR belonged to nasopharyngeal carcinomas (OR = 77.451, 95% CI: 7.323-819.201; p < 0.001) with low heterogeneity (I2 = 0%). Conclusions: The outperformance of 68Ga-FAPI PET/CT over 18F-FDG PET/CT in identifying certain primary tumors as well as in detecting their metastatic lesions may open indications for evaluation of cases with inconclusive 18F-FDG PET/CT findings. What needs to be emphasized is that the false-positive results might be problematic and must be taken into account in 68Ga-FAPI PET/CT interpretation. More clarification on the role of FAPI radioligands in oncologic imaging, radionuclide therapy, and radiotherapy treatment planning is therefore required.

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.

Efficacy, safety and prognostic factors affecting overall survival among metastatic prostate cancer patients undergoing treatment with 177Lu-PSMA-617: A single center study.

BACKGROUND: Determining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). METHOD: In this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51-88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6-12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. RESULTS: A total of 112 cycles of PRLT with a median of 3 cycles (range: 1-6) and median administered activity per cycle of 6.29 GBq (range: 4.45-7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/µL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥ 115 ng/mL, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS. In multivariable Cox regression analysis, higher baseline platelet count, lower baseline hemoglobin, superscan pattern, and lower cumulative dose of 177Lu-PSMA remained significant predictors of poor OS. CONCLUSION: PRLT with 177Lu-PSMA is well-tolerated and effective in metastatic prostate cancer patients who have no other treatment options available. The novel prognostic markers found in this study (high platelet count, superscan pattern) were associated with poor overall survival.

Prostate Cancer With Neuroendocrine Differentiation Recurring After Treatment With 177Lu-PSMA: A Chance for 177Lu-DOTATATE Therapy?

ABSTRACT: Prostate cancer with NED (neuroendocrine differentiation) may occur in various stages of the disease, which is associated with a poor prognosis and treatment resistance. We present a case of a patient with metastatic castration-resistant prostatic cancer, who was treated with 7 cycles of 177Lu-PSMA and a very good response. Although only few foci with PSMA uptake were remained in the last posttreatment images, PSA levels dramatically began to rise. This raised suspicion for NED, and 68Ga-DOTATATE was done showing sufficient uptake to consider a trial of 177Lu-DOTATATE. The patient reported pain response, and PSA levels dropped after 1 cycle of the treatment.