Therapeutic potential of [177Lu]Lu-DOTAGA-FAPi dimers in metastatic breast cancer patients with limited treatment options: efficacy and safety assessment.

PURPOSE: The upregulation of fibroblast activation protein (FAP) expression has been observed in various cancers, including metastatic breast carcinoma, prompting research into small molecule inhibitors for both diagnostic and therapeutic purposes. While the diagnostic value of PET/CT imaging using 68 Ga- or 18F-labelled FAPi-monomers in breast cancer diagnosis is well-established, there is a significant need for therapeutic analogs. This retrospective study aimed to assess the safety and effectiveness of [177Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy in patients with advanced-stage breast cancer who had previously undergone [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans to confirm the expression of FAP. MATERIALS AND METHODS: Between November 2020 and March 2023, a compassionate treatment approach was utilized to administer [177Lu]Lu-DOTAGA.FAPi dimer radionuclide therapy to heavily pretreated patients with advanced breast cancer. Nineteen patients (18 females, 1 male) with metastatic breast cancer participated in the study, with an average age of 44.6 ± 10.7 years. The therapy was administered at intervals of 8 to 12 weeks, and the median follow-up duration was 14 months. The primary objective of the study was to assess molecular response using [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans, with response evaluation based on the PERCIST criteria. Secondary endpoints included overall survival (OS), progression-free survival (PFS), clinical response assessment, and safety evaluation using CTCAE v5.0 guidelines. RESULTS: A total of 65 cycles were administered, with a mean cumulative activity of 19 ± 5.7 GBq (510 ± 154 mCi) ranging from 11 to 33.3 GBq (300 to 900 mCi) of [177Lu]Lu-DOTAGA.FAPi dimer. The number of cycles ranged from 2 to 6, with a median of 3 cycles. The treatment protocol consisted of different numbers of cycles administered to the patients: specifically, two cycles were given to five patients, three cycles to nine patients, four cycles to one patient, and six cycles to four patients. Most patients had invasive/infiltrative ductal carcinoma (94.7%), while a small percentage had invasive lobular carcinoma (5.3%). All patients had bone metastases, and five of them also had liver involvement, while seven had brain metastases. Response assessment using [68 Ga]Ga-DOTA.SA.FAPi PET/CT scans showed that 25% of the 16 patients evaluated had partial remission, while 37.5% exhibited disease progression. According to the VAS response criteria, 26.3% achieved complete response, 15.7% had partial response, 42% showed minimal response, 11% had stable disease, and 5% had no response. The clinical disease control rate was promising, with 95% of patients achieving disease control. The clinical objective response rate was 84%. The median follow-up period was 14 months. At the time of analysis, the median overall survival was 12 months, and the median progression-free survival was 8.5 months. Notably, no severe hematological, renal, or hepatic toxicities, electrolyte imbalances, or adverse events of grade 3 or 4 were observed during the study. CONCLUSION: The findings suggest that [177Lu]Lu-DOTAGA.FAPi dimer therapy is well-tolerated, safe, and effective for treating end-stage metastatic breast cancer patients. [177Lu]Lu-DOTAGA.FAPi dimer treatment demonstrated promising efficacy in patients with advanced breast cancer, as indicated by high disease control rates, favorable response outcomes, and acceptable safety profile. Further research and longer follow-up are warranted to assess long-term outcomes and validate these findings.

Neuropsychological Rehabilitation for Epilepsy in India: Looking Beyond the Basics.

BACKGROUND: Neuropsychological Rehabilitation (NR) helps manage cognitive deficits in epilepsy. As internationally developed programs have limited applicability to resource-limited countries, we developed a program to bridge this gap. This 6-week caregiver-assisted, culturally suitable program has components of (1) psychoeducation, (2) compensatory training, and, (3) cognitive retraining and is called EMPOWER (Indigenized Home Based Attention and Memory Rehabilitation Program for Adult Patients with Drug Refractory Epilepsy). Its efficacy needs to be determined. METHODS: We carried out an open-label parallel randomized controlled trial. Adults aged 18-45 years with Drug Refractory Epilepsy (DRE), fluency in Hindi and or English, with impaired attention or memory (n = 28) were randomized to Intervention Group (IG) and Control Group (CG). The primary outcomes were objective memory (Auditory Verbal Learning Test), patient and caregiver reported everyday memory difficulties (Everyday Memory Questionnaire-Revised), number of memory aids in use, depression (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) and quality of life (Quality of Life in Epilepsy-31). Intention to treat was carried out for group analysis. In the absence of norms necessary for computing Reliable Change Indices (RCIs), a cut-off of +1.0 Standard Deviation (SD) was utilized to identify clinically meaningful changes in the individual analysis of objective memory. A cut-off of 11.8 points was used for quality of life. Feedback and program evaluation responses were noted. RESULTS: The majority of the sample comprised DRE patients with temporal lobe epilepsy who had undergone epilepsy surgery. Group analysis indicated improved learning (p = 0.013), immediate recall (p = 0.001), delayed recall (p < 0.001), long-term retention (p = 0.031), patient-reported everyday memory (p < 0.001), caregiver-reported everyday memory (p < 0.001), anxiety (p = 0.039) and total quality of life (p < 0.001). Individual analysis showed improvement in 50 %, 64 %, 71 %, 57 %, and 64 % of patients on learning, immediate recall, delayed recall, long-term retention, and total quality of life respectively. Despite improvements, themes indicative of a lack of awareness and understanding of cognitive deficits were identified. Overall, the program was rated favorably by patients and caregivers alike. CONCLUSION: NR shows promise for patients with DRE, however larger studies are warranted. The role of cognition in epilepsy needs to be introduced at the time of diagnosis to help lay the foundation for education and acceptance.

Fluorescence-tagged salivary small extracellular vesicles as a nanotool in early diagnosis of Parkinson's disease.

BACKGROUND: Parkinson's disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery. METHODS: In our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson's disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography. RESULTS: We observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112). CONCLUSIONS: In this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study.

PURPOSE: Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. METHODS: The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. RESULTS: Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). CONCLUSION: [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.

Head-to-head comparison of [68Ga]Ga-DOTA.SA.FAPi with [18F]F-FDG PET/CT in radioiodine-resistant follicular-cell derived thyroid cancers.

PURPOSE: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [18F]F-FDG PET/CT serves as a widely used and valuable diagnostic imaging method. However, there is growing interest in utilizing molecular imaging probes that target cancer-associated fibroblasts (CAFs) as an alternative approach. This study sought to compare the diagnostic capabilities of [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT in patients with RAI-R-FCTC. METHODS: In this retrospective study, a total of 117 patients with RAI-R-FCTC were included. The study population consisted of 68 females and 49 males, with a mean age of 53.2 ± 11.7 years. The aim of the study was to perform a comprehensive qualitative and quantitative assessment of [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT scans in RAI-R-FCTC patients. The qualitative assessment involved comparing patient-based and lesion-based visual interpretations of both scans, while the quantitative assessment included analyzing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings obtained from the scans were validated by correlating them with morphological findings from diagnostic computed tomography and/or histopathological examination. RESULTS: Among the 117 RAI-R-FCTC patients, 60 had unilateral local disease, and 9 had bilateral lesions with complete concordance in the detection rate on both PET scans. [68Ga]Ga-DOTA.SA.FAPi had a higher detection rate for lymph nodes (95.4% vs 86.6%, p<0.0001), liver metastases (100% vs. 81.3%, p<0.0001), and brain metastases (100% vs. 39%, p<0.0001) compared to [18F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [68Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [18F]F-FDG had a detection rate of 64.6%. Remarkably, [68Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [18F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [68Ga]Ga-DOTA.SA.FAPi exhibited higher uptake. CONCLUSION: The study results demonstrate the superior performance of [68Ga]Ga-DOTA.SA.FAPi compared to [18F]F-FDG PET/CT in detecting lymph nodal, liver, bowel, and brain metastases in patients with RAI-R-FCTC. These findings highlight the potential of [68Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [18F]F-FDG PET/CT in the imaging of RAI-R-FCTC.

Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are most commonly associated with typical and atypical antipsychotics. However, other drugs such as antidepressants, antihistamines, antiepileptics, antiarrhythmics, and gastrointestinal drugs can also cause abnormal involuntary movements. Different types of movement disorders can also occur because of adverse drug reactions. Therefore, the important key to diagnosing DIMDs is a causal relationship between potential offending drugs and the occurrence of abnormal movements. The pathophysiology of DIMDs is not clearly understood; however, many cases of DIMDs are thought to exert adverse mechanisms of action in the basal ganglia. The treatment of some DIMDs is quite challenging, and removing the offending drugs may not be possible in some conditions such as withdrawing antipsychotics in the patient with partially or uncontrollable neuropsychiatric conditions. Future research is needed to understand the mechanism of DIMDs and the development of drugs with better side-effect profiles. This article reviews the phenomenology, diagnostic criteria, pathophysiology, and management of DIMDs.

Assessment of myocardial sympathetic innervation with 18F-FDOPA-PET/CT in patients with autonomic dysfunction: feasibility study in IPD patients.

BACKGROUND: Dysfunction and denervation of myocardial nor-adrenergic sympathetic neurons has been documented in IPD patients with dysautonomia. The aim of this study was to evaluate the feasibility of single tracer imaging of myocardial sympathetic and cerebral striatal involvement in these patients. METHODS: Twenty-two controls (mean-age 59.09 ± 12.39 years, 15 men) with no clinical autonomic-dysfunction and normal striatal-uptake in 18F-FDOPA-PET/CT; and 28 patients (mean-age 58.18 ± 8.25 years, 18 men) with autonomic-dysfunction (in Autonomic Function Tests) and striatal dopaminergic-dysfunction were enrolled. Both cardiac-PET/CT (40 minutes post IV-injection of 185-259MBq 18F-FDOPA) and Brain-PET/CT (60 minutes post-IV) were acquired in same session. ROIs were drawn over the entire left ventricular myocardium, individual walls and mediastinum for quantification. Patients and controls were followed-up for 26.93 ± 5.43 months and 37.91 ± 8.63 months, respectively. RESULTS: Striatal and myocardial-parameters were significantly lower in patients compared to controls; with Myocardium/mediastinal ratio (MwMR) yielding the area-under-the-curve of .941 (P < .001). MwMR correlated negatively with the drop in systolic blood pressure (SBP) during AFTs {Pearson-coefficient (-).565, P = .002}. Mean MwMR in patients with abnormal-AFTs was significantly lower than patients with borderline-AFTs (1.39 ± .12 vs 1.55 ± .10; P = .002). 9/20 patients with abnormal-AFTs showed functional worsening during follow-up, compared to 2/8 with borderline-AFTs. CONCLUSION: Single tracer, single session imaging of striatal and cardiac sympathetic dysfunction in patients with advanced IPD is feasible with use of 18F-FDOPA. Significantly reduced 18F-FDOPA uptake is seen in the myocardium of the IPD patients with sympathetic dysfunction.

Ga-68 PSMA PET/CT in recurrent high-grade gliomas: evaluating PSMA expression in vivo.

PURPOSE: We planned this prospective study to evaluate PSMA expression in recurrent high-grade gliomas (rHGG), including anaplastic astrocytoma and glioblastoma using Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68 (HBED-CC)]- (Ga-68 PSMA) positron emission tomography (PET), with its theranostic potential in mind. METHODS: This was a prospective study enrolling patients with clinical and MRI evidence of rHGG on follow-up. Three treated cases of HGG with RN on MRI were also included as negative controls. Abnormal tracer accumulation in the brain parenchyma, more than the contralateral hemisphere was interpreted as positive study. For semiquantitative analysis, a 3D spherical region of interest (ROI) was drawn around the site of the abnormal Ga-68 PSMA uptake, and the ratio of SUVmax of tumor (T) to SUVmax of the contralateral corresponding area (TBR) was calculated. Each patients' PSMA brain PET was fused to the corresponding MRI and reviewed for concordance. RESULTS: Thirty patients were included in the study, a total of 49 lesions were detected on MRI, and fused PET/MR images showed increased Ga-68 PSMA uptake in all these lesions. Multifocal lesions were better appreciated on fused PET-MR images, and concordance between MRI and PET was 100 % for patient and lesion-wise detection. Recurrent glioma lesions showed SUVmax and SUVmean values (median and IQR) 6.0 (4.4-8.2) and 3.3 (2.8-3.7), respectively. Lesions labeled as radiation necrosis on MRI did not show tracer accumulation. CONCLUSION: Ga-68 PSMA has potential utility for evaluating recurrence in HGG and its potential for theranostics would encourage its use in the evaluation of these patients.

Serum Matrix Metalloproteinase 7 as a Diagnostic and Prognostic Biomarker for Extrahepatic Biliary Atresia.

Background: Differentiation of neonatal cholestasis into neonatal hepatitis (NH) and extrahepatic biliary atresia (EHBA) is essential to formulate the treatment plan; promptness is indispensable for optimal outcomes. The clinical and nonoperative algorithms lack precision; the gold standard investigations (liver biopsy or per-operative cholangiogram) are invasive. There is a need for a noninvasive test which is both, sensitive and specific and has a high likelihood ratio. Aim: To study the (diagnostic) role of matrix metalloproteinase 7 (MMP-7) as a serum biomarker to differentiate between EHBA and NH and evaluate the prognostic significance in EHBA based on its correlation with liver histopathology and serological predictors of liver fibrosis - Aspartate-to-Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). Materials and Methods: This was a prospective study conducted upon patients of neonatal cholestasis presenting with acholic stools (n = 46) with equal number of controls (n = 45) with no liver pathology. Observational parametric included disease-specific workup and serum MMP-7 levels (all participants); liver biopsyl and APRI-FIB-4 (EHBA). Results: (Diagnostic) Serum MMP-7 levels were significantly elevated in EHBA (n = 25; 28 ng/mL) as compared to those in NH (n = 21; 1.88 ng/mL) and normal infants (n = 45; 1.2 ng/mL) (P < 0.001 for both). Serum cutoff at 4.99 ng/mL differentiated EHBA-NH with a high sensitivity (96%), specificity (90.5%), and a negative predictive value (95%), with the number needed to misdiagnose being 23. (Prognostic) Inflammatory activity and fibrosis-stage on liver histopathology (METAVIR-and-Ishak scores) correlated with MMP-7 levels. APRI and FIB-4 scores also depicted a strong correlation with each other, age of the patient, and liver fibrosis. Conclusions: MMP-7 has a diagnostic value in differentiating EHBA from NH and may also be used as a prognostic biomarker in the follow-up of these patients. MMP-7 levels in controls may be used as a baseline for future studies.

Retrospective analysis of IgG4-related disease cases at a tertiary care centre in India.

Objectives: IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder with prominent fibrosis. This retrospective analysis was undertaken to study the clinical, laboratory, and radiological characteristics of patients with extra-pancreatic IgG4-RD and their response to treatment at a tertiary care centre located in northern India. Material and methods: Patient data from our centre between January 2017 and January 2021 were reviewed. Probable/definite IgG4-RD cases were included in the analysis. Results: A total of 14 cases were identified with a median age of 39 years (range 19-56 years). There were 10 males and 4 females. All patients presented with slowly progressive soft tissue swellings with pain/discomfort related to local mass effect. The median delay in diagnosis was 9.5 months (range 2-72 months). Cross-sectional imaging showed soft tissue masses in all cases. All contrast-enhanced studies (n = 7) showed enhancement on computed tomography and magnetic resonance imaging scan. F-18 fluorodeoxyglucose-avidity was observed in 8 of 9 (88.9%) cases. Biopsies performed in 12 of these were classified as definite in 8 and possible IgG4-RD in 4 cases. Patients were treated with a median dose of 1 mg/kg/day (range 0.5-1 mg/kg/day) prednisolone. Steroids were successfully tapered in all 12 cases with 41.6% (5 of 12) being off corticosteroids at a median follow-up of 10 months (range 0-18 months). Two patients were lost to follow-up. Conclusions: IgG4-related disease is a chronic illness with a wide spectrum of manifestations, in which the diagnosis is often delayed, but it shows an excellent response to treatment. Efforts must be made to increase awareness among physicians about this disease to institute appropriate treatment as early as possible.

225 Ac-PSMA-617-targeted alpha therapy for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to present an overview of the role of 225 Ac-PSMA (prostate-specific membrane antigen)-targeted alpha therapy (TAT) as a salvage treatment option in metastatic castration-resistant prostate cancer. METHODS: A systematic literature review was performed in databases such as Medline, Embase, PubMed, Cochrane Central Register of Controlled Clinical Trials, and the website; www.ClinicalTrials.gov until December 2020. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. All original articles, including retrospective, prospective, hand-searched articles, and clinical trials, were searched, and appropriate data were included for the analysis. The study's primary endpoint assessed therapeutic efficacy by biochemical response assessment criteria (any prostate-specific antigen [PSA] decline and >50% PSA decline from the baseline) after 225 Ac-PSMA-TAT. The secondary endpoints included assessing overall survival (OS), progression-free survival (PFS), molecular response, and therapy-related adverse events across all the studies. The values were expressed as pooled proportions and demonstrated graphically by forest plots using the random-effects model. RESULTS: After the data extraction and filtration process, a total of three publications, including 141 patients, were included for the final analysis. The pooled proportion of patients demonstrating any PSA decline and greater than 50% PSA decline were 83% (95% confidence interval [CI]: 77%-89%) and 59% (95% CI: 42%-76%), respectively. The pooled proportions for OS was 81% (95% CI: 74%-89%). The pooled proportion of patients who have shown complete molecular response are 17% (95% CI: 5%-29%). The median PFS was 12 months (interquartile range: 8.2-14.4 months). Across the studies, the most common side effects from 225 Ac-PSMA-617 TAT were xerostomia/dry mouth, which pertained to Gr I-II in 63.1% (89 of 141), followed by fatigue in 44.5% (45 of 101) of patients. Grade I-II and III anemia was noted in 48.5% (49 of 101) and 6% (6 of 101), respectively. Grade III leukopenia and thrombocytopenia were negligible: 0.9% (1 of 101) and 0.9% (1 of 101), respectively. Similarly, grade III nephrotoxicity was also observed only in 5 of 101 (5%) patients. CONCLUSION: Treatment with 225 Ac-PSMA-617 TAT demonstrated biochemical response, improved survival, caused low treatment-related toxicity proving a promising salvage treatment option in mCRPC patients.

Biodistribution, pharmacokinetics, dosimetry of [68Ga]Ga-DOTA.SA.FAPi, and the head-to-head comparison with [18F]F-FDG PET/CT in patients with various cancers.

PURPOSE: [68Ga]Ga-labeled fibroblast activation protein inhibitors ([68Ga]Ga-FAPi) have shown promising preclinical and clinical results in PET imaging. The present study aimed to evaluate the biodistribution, pharmacokinetics, and dosimetry of [68Ga]Ga-DOTA.SA.FAPi, another modified FAPi tracer, and performed a head-to-head comparison with [18F]F-FDG PET/CT scans in patients with various cancers. METHODS: In this prospective study, patients underwent both [18F]F-FDG and [68Ga]Ga-DOTA.SA.FAPi PET/CT scans 60 min post-injection (p.i.). Dosimetry studies were conducted in three patients using [68Ga]Ga-DOTA.SA.FAPi serial time-point imaging. The absorbed dose was calculated using OLINDA/EXM 2.2 software. Quantification of the uptake of the tracers was assessed using standardized uptake values corrected for lean body mass (SUL). RESULTS: Fifty-four patients (mean age; 48.4 years) with 14 types of cancers involving 37% breast, 24% lung, 7.4% head and neck (H&N), and remaining 31.6% patients with other histologies were evaluated prospectively. Physiological uptake of [68Ga]Ga-DOTA.SA.FAPi was observed in the liver, kidneys, pancreas, heart contents, and to a lesser extent in the lacrimals, oral mucosa, salivary glands, and thyroid glands. Uptake in the target lesions on [68Ga]Ga-DOTA.SA.FAPi scan was initiated at 10 min, and no additional lesions were detected in the delayed acquisition time points. The pancreas was the organ with the highest absorbed dose (5.46E-02 mSv/MBq). While the patient-based comparison between the radiotracers revealed complete concordance in the detection of primary, pleural thickening, bone and liver metastases, and second primary malignancy, discordant findings were observed in the detection of lymph node (7.5%), lung nodules (5.6%), and brain metastases (2%). According to the site of primary disease, patients with H&N cancers demonstrated the highest SULpeak and average (avg) values on [68Ga]Ga-DOTA.SA-FAPi which was similar to the values of [18F]F-FDG [(SULpeak: 15.4 vs. 14.2; P-0.680) (SULavg: 8.3 vs. 7.9; P-0.783)]. The lowest uptake was observed in lung cancers with both the radiotracers [(SULpeak: 5.8 vs. 7.4; P-0.238) (SULavg: 4.9 vs. 5.3; P-0.313)]. A significantly higher SULpeak and SULavg for brain metastases to normal brain parenchyma ratios were observed on [68Ga]Ga-DOTA.SA.FAPi in contrast to the [18F]F-FDG values {SULpeak: median: 59.3 (IQR: 33.5-130.8) versus 1.5 (1-2.3); P-0.028}. Except for brain metastases, comparable SULpeak and average values were noted between the radiotracers in all other regions of metastases with no significant difference. CONCLUSION: [68Ga]Ga-DOTA.SA.FAPi is a promising alternative among the FAPI class of molecules and performed well as compared to standard-of-care radiotracer [18F]F-FDG in the diagnosis of various cancers.

Diagnostic added value of interictal magnetic source imaging in presurgical evaluation of persons with epilepsy: A prospective blinded study.

BACKGROUND AND PURPOSE: In presurgical evaluation for epilepsy surgery, information is sourced from various imaging modalities to accurately localize the epileptogenic zone. Magnetoencephalography (MEG) is a newer noninvasive technique for localization. However, there is limited literature to evaluate if MEG provides additional advantage over the conventional imaging modalities in clinical decision making. The objective of this study was to assess the diagnostic added value of MEG in decision making before epilepsy surgery. METHOD: This was a prospective observational study. Patients underwent 3 h of recording in a MEG scanner, and the resulting localizations were compared with other complimentary investigations. Added value of MEG (considered separately from high-density electroencephalography) was defined as the frequency of cases in which (i) the information provided by magnetic source imaging (MSI) avoided implantation of intracranial electrodes and the patient was directly cleared for surgery, and (ii) MSI indicated additional substrates for implantation of intracranial electrodes. Postoperative seizure freedom was used as the diagnostic reference by which to measure the localizing accuracy of MSI. RESULTS: A total of 102 patients underwent epilepsy surgery. MEG provided nonredundant information, which contributed to deciding the course of surgery in 33% of the patients, and prevented intracranial recordings in 19%. A total of 76% of the patients underwent surgical resection in sublobes concordant with MSI localization, and the diagnostic odds ratio for good (Engel I) outcome in these patients was 2.3 (95% confidence interval 0.68, 7.86; p = 0.183) after long-term follow-up of 36 months. CONCLUSION: Magnetic source imaging yields additional useful information which can significantly alter as well as improve the surgical strategy for persons with epilepsy.

Metabolic scoring in autoimmune epilepsy-Should APE scores be modified?

OBJECTIVE: We evaluate the potential utility of F-18 FDG-PET in addition to MRI in the diagnostic work-up of patients with autoimmune epilepsy (AE) and propose the inclusion of functional imaging in the antibody prevalence in epilepsy (APE) scoring system. METHODS: This was a retrospective analysis in 60 patients, diagnosed and treated for AE, of whom 40 were antibody negative (presumed AE) and 20 were antibody positive (definitive AE). All patients had undergone a dedicated brain and whole body FDG-PET in the department of Nuclear Medicine. RESULTS: In the antibody negative group, MRI supported a diagnosis of AE in 23 patients. Both MRI and PET were indicative in 12 cases, and standalone PET was positive in 8. While MRI alone was diagnostic in 57% (23/40), the combined yield of both modalities was 77% (31/40). When PET scores were added to assign the APE score in MRI negative cases, average APE score was 5.4. In the antibody positive group, MRI supported the diagnosis of AE in 7 patients. Both MRI and PET were positive in 4 patients and standalone PET was positive in 5 patients. While MRI alone was diagnostic in 35% (7/20), the combined yield of both modalities was 60% (12/20). When PET scores were added to assign the APE score in MRI negative cases, average APE score was 6.1. CONCLUSION: The inclusion of metabolic information from PET distinctly improved (the sensitivity of) APE scores to predict autoimmune origin even in antibody negative cases. A larger prospective study of similar type could justify adoption of FDG-PET into the standard diagnostic procedure.

Surgery for Drug-Resistant Epilepsy in Children.

BACKGROUND: Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. METHODS: In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory. RESULTS: At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet-Kamat intelligence quotient (difference, 2.5; 95% CI, -0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%). CONCLUSIONS: In this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).

Broadening horizons with 225Ac-DOTATATE targeted alpha therapy for gastroenteropancreatic neuroendocrine tumour patients stable or refractory to 177Lu-DOTATATE PRRT: first clinical experience on the efficacy and safety.

PURPOSE: The objective of this study was to investigate and present the early results on the efficacy, safety, and quality of life of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced, progressive, 177Lu-DOTATATE refractory, and somatostatin receptor (SSTR) expressing metastatic GEP-NETs. METHODS: In this prospective study, we recruited patients with metastatic GEP-NETs who were stable or progressive disease on 177Lu-DOTATATE therapy. Systemic TAT using 225Ac-DOTATATE was performed in all the patients with 225Ac-DOTATATE (100 kBq/kg body weight) at an interval of 8 weeks. The primary end point was to assess the objective response (measured by RECIST 1.1 and functional M.D. Anderson criteria). The secondary end points included biochemical response assessment as per the Italian Trials in Medical Oncology (ITMO), adverse event profile as per CTCAE v5.0, and clinical response assessment by the quality of life (assessed with EORTC QLQ-GI.NET21 patient-based questionnaire). RESULTS: Between April 2018 and March 2019, 32 patients (17 females, 15 males, mean age 52 ± 9.2 years, 35-72 years) with either stable disease after completing 177Lu-DOTATATE therapy (14, 44%) or progressive disease on 177Lu-DOTATATE therapy (18, 56%) were included in the study. The morphological response was assessed in 24/32 patients that revealed partial remission in 15 and stable disease in 9. There was no documented disease progression or deaths in the median follow-up of 8 months (range 2-13 months). There was a significant decrease in the plasma chromogranin level post-225Ac-DOTATATE therapy (P < 0.0001). CONCLUSION: Our short-term clinical results indicate 225Ac-DOTATATE TAT as a promising treatment option which adds a new dimension in patients who are refractory to 177Lu-DOTATATE therapy or have reached the maximum prescribed cycles of 177Lu-DOTATATE therapy.

Evaluation of [68Ga]Ga-DATA-TOC for imaging of neuroendocrine tumours: comparison with [68Ga]Ga-DOTA-NOC PET/CT.

PURPOSE: Recently, the new hybrid chelator DATA (6-amino-1,4-diazepine-triacetate) has been introduced, which has the advantage of high yield and radiolabelling of DATA-based octreotide derivative (TOC) at room temperature in contrast to tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA) that needs 95 °C for effective labelling. However, the diagnostic potential of DATA-TOC has not been studied with other chelators in humans. The aim of this study was to compare the diagnostic efficacy of [68Ga]Ga-DATA-TOC with [68Ga]Ga-DOTA-NOC (which is the current standard for imaging neuroendocrine tumours (NET)) in patients of gastroenteropancreatic neuroendocrine tumours (GEP-NETs). METHODS: Fifty patients (thirty-one males and nineteen females) with biopsy-proven GEP-NETs were included in the study. Patients age ranged from 14 to 75 years (mean 46.11 years). All patients underwent two PET studies with [68Ga]Ga-DATA-TOC and [68Ga]Ga-DOTA-NOC. Images were evaluated visually and semi-quantitatively using maximum standardized uptake values (SUVmax) of tumour, mediastinum and liver. Tumour-to-liver (T/L) and tumour-to-mediastinum (T/M) SUVmax ratios were computed. For the purpose of comparison, patient-wise as well as lesion-wise analysis was carried out. The nonparametric-related samples Wilcoxon signed-rank test was used for comparison of the SUVmax values and ratios. RESULTS: On visual evaluation, the biodistribution and image quality of [68Ga]Ga-DATA-TOC was similar to [68Ga]Ga-DOTA-NOC. Physiological liver uptake was lower in [68Ga]Ga-DATA-TOC as compared with [68Ga]Ga-DOTA-NOC, 7.65 ± 5.37 vs 8.94 ± 5.95 (p = 0.009), respectively. On a patient-wise analysis, both [68Ga]Ga-DATA-TOC and [68Ga]Ga-DOTA-NOC were lesion-positive in the 44 patients (88%) and were negative in the 6 patients (12%). On a lesion-based analysis, [68Ga]Ga-DATA-TOC had 98.6% concordance with [68Ga]Ga-DOTA-NOC (232 out of 235 lesions detected). The target tumour SUVmax on [68Ga]Ga-DATA-TOC and [68Ga]Ga-DOTA-NOC were 36.63 ± 32.24 and 40.82 ± 36.89, respectively (p = 0.097). The T/L SUVmax ratios were not significantly different (5.99 ± 5.52 vs 5.67 ± 4.96, p = 0.77). CONCLUSION: [68Ga]Ga-DATA-TOC PET/CT imaging produced results that were comparable with [68Ga]Ga-DOTA-NOC. It, thus, has potential utility as an effective and safe alternative to 68Ga-DOTA-NOC with the added benefit of ease, cost-effective and improved yield of instant kit-type synthesis.

A prospective study of non-tuberculous mycobacterial disease among tuberculosis suspects at a tertiary care centre in north India.

Background & objectives: The burden of non-tuberculous mycobacterial (NTM) disease is increasing worldwide. The disease shares clinicoradiological features with tuberculosis (TB), Nocardia and several fungal diseases, and its diagnosis is frequently delayed. The present study was performed to determine the frequency of NTM disease among TB suspects in a tertiary care centre in north India. Methods: In this prospective study, mycobacterial culture isolates from pulmonary and extrapulmonary specimens among TB suspects were tested with immunochromatographic assay (ICA). All ICA-negative isolates were considered as NTM suspects and further subjected to 16S-23S rRNA internal transcribed spacer gene sequencing for confirmation and species identification. Patients with active disease were treated with drug regimen as per the identified NTM species. Follow up of patients was done to determine clinical, radiological and microbiological outcomes. Results: Of the 5409 TB suspects, 42 (0.77%) were diagnosed with NTM disease. Patients with active disease consenting for treatment were treated and followed up. Thirty four patients had NTM pulmonary disease (NTM-PD) and the remaining eight had extrapulmonary NTM (EP-NTM) disease. Mycobacterium intracellulare and M. abscessus, respectively, were most frequently isolated from NTM-PD and EP-NTM patients. Fifteen NTM-PD and seven EP-NTM patients successfully completed the treatment. Ten patients died due to unrelated causes, five were lost to follow up and another four declined the treatment. Interpretation & conclusions: Our study showed that the frequency of NTM disease was low among TB suspects at a large tertiary care centre in north India and this finding was similar to other Indian studies. More studies need to be done in other parts of the country to know the geographical variation in NTM disease, if any.

Undiagnosed Fever in a TB Contact Patient: An Unusual Cause.

IgG4-Related Disease(IgG4-RD) is a rare disease that can present with myriad clinical features. We report a tuberculosis contact case who presented with fever and constitutional complaints with imaging evidence of paravertebral and retroperitoneal soft tissue thickening. Further workup, including tissue biopsy ruled out tuberculosis and revealed diagnosis to be IgG4-related disease. Patient was started on oral steroids, which led to symptomatic improvement. In a TB endemic country such as ours, for a patient presenting with pleural and/or peritoneal fibrosis, a differential diagnosis of IgG4-RD must be kept.

Bowel Excretion of Technetium-99mL, L-Ethylene Dicysteine Masquerading as a Dilated Ureter in a Case of Pelvi-Ureteric Junction Obstruction: Case Report and Review.

The treatment plan and the decision for surgery in a significant proportion of patients with pelvi-ureteric junction (PUJ) obstruction type of hydronephrosis are dependent on the findings of renal scintigraphy. We report a case of a 3.5-year-old girl with right-sided PUJ obstruction, wherein the tracer excretion into the cecum and ascending colon complicated the clinical picture thereby misleading the final diagnosis or treatment plan and blurring the distinction between hydronephrosis and hydroureteronephrosis. Additional investigations may be required in such cases to reach a conclusion. The authors considered reporting this case in view of the deep-rooted clinical implications toward making a correct diagnosis. Besides, the possible mechanisms to explain the presence of the tracer inside the bowel have been discussed.