Intra-arterial PRRT with Lu-177 DOTATATE in Liver-dominant Metastatic Neuroendocrine Tumors: Early Assessment of Efficacy and Toxicity.

Purpose: We proposed to administer Lu-177-DOTATATE in intra-arterial (IA) mode for higher first-pass localization to somatostatin receptors, higher residence time in liver metastases, and more radiation to tumor. This study aimed at assessing early hematological, renal and hepatotoxicity; and objective response to IA peptide receptor radionuclide therapy (PRRT). Materials and Methods: Fourteen patients (4 females and 10 males) were prospectively assessed. 5/14 patients underwent 2 cycles, whereas 3/14 underwent 3 cycles, and 6/14 received 1 cycle of IA PRRT. 200 mCi of Lu-177-DOTATATE was administered in 15-20 min by IA route under angiographic guidance. Patients were asked to follow-up at 4 and 8 weeks with hematological, liver, and renal functional parameters, and Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT) after 8 weeks. Response was assessed using RECIST 1.1 and EORTC PET criteria. Results: Safety: 2/14 patients had high total and direct bilirubin, which reverted to normal after IA PRRT. Three patients had low albumin, which improved after 1 cycle. Nine patients showed no worsening of liver function. Two patients showed Grade 1 hematotoxicity which reverted to normal. Five patients showed high creatinine, but preserved glomerular filtration rate and EC clearance. On follow-up at 8 weeks, serum creatinine reverted to normal. Efficacy: In five patients who underwent 2 cycles of IA PRRT, 3 showed partial response (PR) on RECIST 1.1 and partial metabolic response (PMR) on EORTC criteria, whereas 2 showed stable disease (SD). In patients who underwent 3 cycles, 1 showed SD, whereas other patient showed PMR on DOTANOC PET/CT, with PR in size. Among the remaining seven patients, 5 showed PMR, whereas the other 2 showed SD. Thus 9/14 patients showed PR, whereas 5 showed SD on metabolic and size criteria. Conclusions: IA PRRT is a safe and efficacious approach for the treatment of liver dominant metastatic neuroendocrine tumors.

Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors.

INTRODUCTION: The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied. MATERIALS AND METHODS: Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS). RESULTS: Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017). CONCLUSION: A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

PRRT with Lu-177 DOTATATE in Treatment-Refractory Progressive Meningioma: Initial Experience from a Tertiary-Care Neuro-Oncology Center.

PURPOSE: Refractory and/or recurrent meningiomas have poor outcomes, and the treatment options are limited. Peptide receptor radionuclide therapy (PRRT) has been used in this setting with promising results. We have documented our experience of using intravenous (IV) and intra-arterial (IA) approaches of Lu-177 DOTATATE PRRT. METHODS: Eight patients with relapsed/refractory high-grade meningioma received PRRT with Lu-177 DOTATATE by IV and an IA route. At least 2 cycles were administered. Time to progression was calculated from the first PRRT session to progression. The response was assessed on MRI using RANO criteria, and visual analysis of uptake was done on Ga-68 DOTANOC PET/CT. Post-therapy dosimetry calculations for estimating the absorbed dose were performed. RESULTS: Median time to progression was 8.9 months. One patient showed disease progression, whereas seven patients showed stable disease at 4 weeks following 2 cycles of PRRT. Dosimetric analysis showed higher dose and retention time by IA approach. No significant peri-procedural or PRRT associated toxicity was seen. CONCLUSION: PRRT is a safe and effective therapeutic option for relapsed/refractory meningioma. The IA approach yields better dose delivery and should be routinely practised.

Can 18 F FDG PET/CT metabolic parameters be used to noninvasively differentiate between different histopathological subtypes and Fuhrman grades of renal cell cancer?

AIM: To evaluate relationship between metabolic PET metabolic parameters and size of the primary tumor, various histopathological subtypes of renal cell carcinoma (RCC) and Fuhrman grade of the tumors. MATERIAL AND METHODS: Retrospective analysis of 93 biopsy-proven RCC patients who underwent pretreatment flourine 18 flourodeoxyglucose PET/computed tomography ( 18 F FDG PET/CT) was performed. Quantitative PET parameters, size of the primary tumor, histopathological subtypes and Fuhrman grades of the tumor were extracted. We tried to assess if there was any significant difference in the metabolic patterns of various histopathological subtypes of RCCs, Fuhrman grade of the tumors and size of the primary tumor. RESULTS: A significant correlation was noted between the size of primary tumor and maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) ( P  < 0.01, P  < 0.001 and P  < 0.001, respectively). SUV max values correlated significantly with the histopathological subtype ( P  < 0.001). Further sub-analyses was also done by segregating the patients into Low grade (Fuhrman grade 1 and 2) vs. High grade (Fuhrman grade 3 and 4). SUV max , MTV and TLG were significantly different between high grade vs. low grade tumors. ROC analysis yielded cut off values for SUV max , MTV and TLG to differentiate between high grade from low grade tumors. CONCLUSION: FDG PET/CT with the use of metabolic PET parameters can differentiate between different histopathological subtypes of RCC. Incorporation of metabolic parameters into clinical practice can potentially noninvasively identify patients with low-grade vs. high-grade RCC.

Tata Memorial Centre Evidence Based Use of Nuclear medicine diagnostic and treatment modalities in cancer.

ABSTRACT: PET/CT and radioisotope therapy are diagnostic and therapeutic arms of Nuclear Medicine, respectively. With the emergence of better technology, PET/CT has become an accessible modality. Diagnostic tracers exploring disease-specific targets has led the clinicians to look beyond FDG PET. Moreover, with the emergence of theranostic pairs of radiopharmaceuticals, radioisotope therapy is gradually making it's way into treatment algorithm of common cancers in India. We therefore would like to discuss in detail the updates in PET/CT imaging and radionuclide therapy and generate a consensus-driven evidence based document which would guide the practitioners of Oncology.

[90Y]Yttria Alumino Silicate Glass Microspheres: A Biosimilar Formulation to "TheraSphere" for Cost-Effective Treatment of Liver Cancer.

Background: Selective internal radiation therapy (SIRT) using a suitable ß--emitting radionuclide is a promising treatment modality for unresectable liver carcinoma. Yttrium-90 (90Y) [T1/2 = 64.2 h, Eß(max) = 2.28 MeV, no detectable γ-photon] is the most preferred radioisotope for SIRT owing to its favorable decay characteristics. Objective: The present study describes indigenous development and evaluation of intrinsically radiolabeled [90Y]yttria alumino silicate ([90Y]YAS) glass microsphere, a formulation biosimilar to "TheraSphere" (commercially available, U.S. FDA-approved formulation), for SIRT of unresectable liver carcinoma in human patients. Methods: YAS glass microspheres of composition 40Y2O3-20Al2O3-40SiO2 (w/w) and diameter ranging between 20 and 36 µm were synthesized with almost 100% conversion efficiency and >99% sphericity. Intrinsically labeled [90Y]YAS glass microspheres were produced by thermal neutron irradiation of cold YAS glass microspheres in a research reactor. Subsequent to in vitro evaluations and in vivo studies in healthy Wistar rats, customized doses of [90Y]YAS glass microspheres were administered in human patients. Results: [90Y]YAS glass microspheres were produced with 137.7 ± 8.6 MBq/mg YAS glass (∼6800 Bq per microsphere) specific activity and 99.94% ± 0.02% radionuclidic purity at the end of irradiation. The formulation exhibited excellent in vitro stability in human serum and showed >97% retention in the liver up to 7 d post-administration when biodistribution studies were carried out in healthy Wistar rats. Yttrium-90 positron emission tomography scans recorded at different time points post-administration of customized dose of [90Y]YAS glass microspheres in human patients showed near-quantitative retention of the formulation in the injected lobe. Conclusions: The study confirmed the suitability of indigenously prepared [90Y]YAS glass microspheres for clinical use in the treatment of unresectable hepatocellular carcinoma.

Post-ictal changes presenting as late pseudoprogression on MRI and PET in a patient with diffuse glioma: Case report and brief literature review.

Following completion of adjuvant radiation and chemotherapy imaging surveillance forms a major role in the management of diffuse gliomas. The primary role of imaging is to detect recurrences earlier than clinical symptomatology. Magnetic resonance imaging (MRI) is considered the gold standard in follow-up protocols owing to better soft tissue delineation and multiparametric nature. True recurrence can often mimic treatment-related changes, it is of paramount importance to differentiate between the two entities as the clinical course is divergent. Addition of functional sequences like perfusion, spectroscopy and metabolic imaging can provide further details into the microenvironment. In equivocal cases, a follow-up short interval imaging might be obtained to settle the diagnostic dilemma. Here, we present a patient with diagnosis of recurrent oligodendroglioma treated with adjuvant chemoradiation, presenting with seizures five years post-completion of chemotherapy for recurrence. On MRI, subtle new onset gyral thickening of the left frontal region with mild increase in perfusion and patchy areas of raised choline. FET-PET (fluoro-ethyltyrosine) showed an increased tumour-to-white matter (T/Wm) ratio favouring tumour recurrence. Based on discussion in a multi-disciplinary joint clinic, short interval follow-up MRI was undertaken at two months showing decrease in gyral thickening and resolution of enhancing areas in left frontal lobe. Repeat imaging one year later demonstrated stable disease status without further new imaging findings. Given the changes resolving completely without any anti-tumoral intervention, we conclude this to be peri-ictal pseudoprogression, being the second such case described in India.

Evaluation of post-chemotherapy residual seminomatous masses by 18F-fluorodeoxyglucose PET/CT using tumor-to-liver ratio - conundrum or solution?

OBJECTIVE: Assessment of diagnostic accuracy of FDG-PET/CT in the detection of viable disease in post-chemotherapy seminomatous residual masses using visual interpretation, SUVmax, and T/L ratio. METHODS: This is a retrospective study assessing the post-chemotherapy seminomatous residual masses of size >3 cm. The PET/CT scan findings were interpreted visually for presence of residual disease which were validated from histopathology reports or imaging follow-up for a maximum of 3 years. SUVmax and T/L ratios were also determined for all the residual lesions. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value NPV were calculated and compared for all three parameters along with ROC analysis to obtain an optimal cutoff value for SUVmax and T/L ratio, respectively. RESULTS: Sample size was 49. Out of these 49 patients, 8 had validation of PET results with histopathology. Rest was validated with imaging follow-up. FDG-PET was positive in 30 patients and negative in 19 patients by visual interpretation. The sensitivity, specificity, PPV, and NPV by this method were 100%, 62.5%, 73%, and 100%, respectively. The SUVmax and T/L ratios were also calculated for these lesions. The cutoff for these two variables was 4.56 and 1.21, respectively. The sensitivity, specificity, PPV, and NPV at these cutoffs were 76%, 87.5%, 86%, 77.7%, and 92%, 87.5%, 88%, 91%, respectively. CONCLUSION: FDG-PET has a favorable diagnostic value in predicting viable disease in post-chemotherapy seminomatous residual masses and using T/L ratio cutoff of 1.21 will increase the specificity of the test.

Deep learning based automated epidermal growth factor receptor and anaplastic lymphoma kinase status prediction of brain metastasis in non-small cell lung cancer.

Aim: The aim of this study was to investigate the feasibility of developing a deep learning (DL) algorithm for classifying brain metastases from non-small cell lung cancer (NSCLC) into epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement groups and to compare the accuracy with classification based on semantic features on imaging. Methods: Data set of 117 patients was analysed from 2014 to 2018 out of which 33 patients were EGFR positive, 43 patients were ALK positive and 41 patients were negative for either mutation. Convolutional neural network (CNN) architecture efficient net was used to study the accuracy of classification using T1 weighted (T1W) magnetic resonance imaging (MRI) sequence, T2 weighted (T2W) MRI sequence, T1W post contrast (T1post) MRI sequence, fluid attenuated inversion recovery (FLAIR) MRI sequences. The dataset was divided into 80% training and 20% testing. The associations between mutation status and semantic features, specifically sex, smoking history, EGFR mutation and ALK rearrangement status, extracranial metastasis, performance status and imaging variables of brain metastasis were analysed using descriptive analysis [chi-square test (χ2)], univariate and multivariate logistic regression analysis assuming 95% confidence interval (CI). Results: In this study of 117 patients, the analysis by semantic method showed 79.2% of the patients belonged to ALK positive were non-smokers as compared to double negative groups (P = 0.03). There was a 10-fold increase in ALK positivity as compared to EGFR positivity in ring enhancing lesions patients (P = 0.015) and there was also a 6.4-fold increase in ALK positivity as compared to double negative groups in meningeal involvement patients (P = 0.004). Using CNN Efficient Net DL model, the study achieved 76% accuracy in classifying ALK rearrangement and EGFR mutations without manual segmentation of metastatic lesions. Analysis of the manually segmented dataset resulted in improved accuracy of 89% through this model. Conclusions: Both semantic features and DL model showed comparable accuracy in classifying EGFR mutation and ALK rearrangement. Both methods can be clinically used to predict mutation status while biopsy or genetic testing is undertaken.

Primary Neuroendocrine Tumor of Prostate in a Case of Metastatic Adenocarcinoma of Lung: Rare Entity with Histopathological and Gallium 68 DOTANOC Positron Emission Tomography Correlation.

Neuroendocrine tumor (NET) of the prostate is an extremely rare entity which represents <1% of the prostatic cancers, but with increasing incidence. Its spectrum encompasses several histological variants ranging from well-differentiated tumor which are often indolent in nature; to aggressive neuroendocrine carcinoma which portends aggressive management. Hence, such rare entities are to be characterized and treated accordingly. We report an unusual case of well-differentiated NET of prostate which was flagged on fluorodeoxyglucose positron emission tomography computed tomography (PET/CT) performed for other indication and confirmed on Gallium-68 DOTANOC PET/CT. Histopathology and immunohistochemistry confirmed the findings subsequently.

A Rare Case of Plasmablastic Lymphoma of the Ovary with Synchronous Lung Malignancy.

Primary ovarian lymphoma is a rare malignancy with <1% incidence. Plasmablastic lymphoma usually associated with immunocompromised diseases such as HIV rarely involves the ovary; only two case studies are reported in the literature - plasmablastic lymphomatous involvement of an ovarian teratoma and another of plasmablastic variant of B-cell lymphoma involving bilateral ovaries. There are reported case series of synchronous presentation of carcinomas usually including lung, stomach, and colon and nonaggressive lymphomas. Here, we report a rare case of synchronous aggressive primary plasmablastic ovarian lymphoma with adenocarcinoma of the lung, both of which are associated with immune-compromised conditions.

Demonstration of Multiple Metastatic Sites by Positron Emission Tomography/Computed Tomography in a Rare Case of Epithelioid Angiosarcoma of the Scalp.

Epithelioid angiosarcoma is a rare subtype of angiosarcoma, with metastases occurring in more than 50% of cases and the lung is the most organ which is involved. Whole-body fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has demonstrated its clinical utility in the early detection of metastases in angiosarcoma. It is helpful to differentiate between benign lesions with low FDG uptake as compared to malignancies with high FDG avidity. Here, we present a rare case of a young man with epithelioid angiosarcoma, in which FDG PET/CT has demonstrated metastatic sites (especially lung metastases).

Prognostic predictors for recurrence following curative resection in grade I/II pancreatic neuroendocrine tumours.

INTRODUCTION: Pancreatic neuroendocrine tumours (pNETs) have an excellent long-term survival after resection, but are associated with a high recurrence rate. Identification of prognostic factors affecting recurrences would enable identifying subgroup of patients at higher risk of recurrences, who may benefit from more aggressive treatment. METHODS: A retrospective analysis of prospectively maintained database of patients undergoing pancreatectomy with curative intent for grade I and II pNETs between July 2007 and June 2021 was performed. Perioperative and long-term outcomes were analysed. RESULTS: A total of 68 resected patients of pNETs were included in this analysis. Fifty-two patients (76.47%) underwent pancreaticoduodenectomy, 10 (14.7%) patients had distal pancreatectomy, and 2 (2.9%) patients underwent median pancreatectomy, while enucleation was performed in 4 patients (5.8%). The overall major morbidity (Clavien-Dindo III/IV) and mortality rates were 33.82% and 2.94%, respectively. At a median follow-up period of 48 months, 22 (32.35%) patients had disease recurrence. The 5-year overall survival and 5-year recurrence-free survival (RFS) rates were 90.2% and 60.8%, respectively. While OS was unaffected by different prognostic factors, multivariate analysis showed that lymph node involvement, Ki-67 index ≥5%, and presence of perineural invasion (PNI) were independently associated with recurrence. CONCLUSIONS: While surgical resection gives excellent overall survival in grade I/II pNETs, lymph node positivity, higher Ki-67 index, and PNI are associated with a high risk for recurrence. Patients with these characteristics should be stratified as high risk and evaluated for more intensive follow-up and aggressive treatment strategies in future prospective studies.

Imaging-Based Patterns of Failure following Re-Irradiation for Recurrent/Progressive High-Grade Glioma.

BACKGROUND: Re-irradiation (ReRT) is an effective treatment modality in appropriately selected patients with recurrent/progressive high-grade glioma (HGG). The literature is limited regarding recurrence patterns following ReRT, which was investigated in the current study. METHODS: Patients with available radiation (RT) contours, dosimetry, and imaging-based evidence of recurrence were included in the retrospective study. All patients were treated with fractionated focal conformal RT. Recurrence was detected on imaging with magnetic resonance imaging (MRI) and/ or amino-acid positron emission tomography (PET), which was co-registered with the RT planning dataset. Failure patterns were classified as central, marginal, and distant if >80%, 20-80%, or <20% of the recurrence volumes were within 95% isodose lines, respectively. RESULTS: Thirty-seven patients were included in the current analysis. A total of 92% of patients had undergone surgery before ReRT, and 84% received chemotherapy. The median time to recurrence was 9 months. Central, marginal, and distant failures were seen in 27 (73%), 4 (11%), and 6 (16%) patients, respectively. None of the patient-, disease-, or treatment-related factors were significantly different across different recurrence patterns. CONCLUSION: Failures are seen predominantly within the high-dose region following ReRT in recurrent/ progressive HGG.

A dosimetric comparison of systemic peptide receptor radionuclide therapy and intra-arterial peptide receptor radionuclide therapy in patients with liver dominant gastroenteropancreatic neuroendocrine tumours.

OBJECTIVES: Intra-arterial radionuclide therapy (IART) treatment allows direct delivery of 177 Lu-DOTATATE to the overexpressed somatostatin-positive neuroendocrine liver metastases, which led to higher tumour concentration compared with systemic radionuclide therapy (SRT). The aim was to evaluate and compare the absorbed doses of both IART and SRT to organs and hepatic metastatic sites. METHODS: A total of 48 patients received SRT and IART. In SRT, activity was administered intravenously, whereas in IART, activity was administered directly into hepatic arteries. The sequential whole-body images were acquired at 2, 4, 24, 72 and 160 h. The reconstructed whole-body planar and single-photon emission computed tomography-computed tomography images were processed using the Dosimetry Toolkit for the estimation of normalized cumulated activity in the organs and tumour lesions. The absorbed dose was computed using OLINDA EXM 2.0 software. RESULTS: The median absorbed dose (mGy/MBq) of kidneys and spleen in IART was compared with SRT and found to be decreased by 30.7% ( P  = 0.03) and 37.5% ( P  = 0.08), whereas it was found to be increased by 40% ( P  = 0.26) and 8.1% ( P  = 0.28) in the liver and lungs. The median dose (mGy/MBq) of tumours determined in IART was found to be increased by 62.2% ( P  = 0.04). CONCLUSION: IART with 177 Lu-DOTATATE significantly increases tumour dose while reducing overall systemic toxicity in comparison to SRT treatment. After considering the maximum tolerance limit of kidneys in peptide receptor radionuclide therapy, the number of treatment cycles and injected activity can be optimized further with IART for better response and survival.

FAPI PET Positivity in Fibrolamellar Hepatocellular Carcinoma.

ABSTRACT: Fibrolamellar hepatocellular carcinoma (HCC) is a variant of HCC. It is a malignant tumor, but its imaging features often overlap focal nodular hyperplasia, which is a benign entity. FDG PET/CT is also not much help in these cases because both lesions do not concentrate FDG. We present one such case of fibrolamellar HCC with FAPI PET/CT positivity.