Potential Efficacy of 68 Ga-Trivehexin PET/CT and Immunohistochemical Validation of αvß6 Integrin Expression in Patients With Head and Neck Squamous Cell Carcinoma and Pancreatic Ductal Adenocarcinoma.

PURPOSE: αvß6 integrin is exclusively expressed in epithelial cells and is upregulated in many carcinomas, such as pancreatic ductal adenocarcinomas (PDACs) and head and neck squamous cell carcinomas (H&NSCCs). Trivehexin is a recently synthesized trimerized αvß6 integrin selective nonapeptide, which can be labeled with a positron emitter like 68 Ga. This is a pilot study to assess the potential role of 68 Ga-Trivehexin PET/CT in patients with H&NSCC and PDAC and their correlation with αvß6 integrin expression by the tumor tissue on immunohistochemistry (IHC). PATIENTS AND METHODS: Thirty-two patients with suspected H&NSCC (n = 20) or PDAC (n = 12) underwent whole-body 68 Ga-Trivehexin PET/CT and 18 F-FDG PET/CT scans on 2 separate days. All 32 patients underwent biopsy from the tumor site for histopathological diagnosis and IHC for αvß6 integrin expression. The degree of αvß6 integrin expression on IHC was scored using the immunoreactive score and modified 4-point immunoreactive score classification. RESULTS: The 68 Ga-Trivehexin PET images demonstrated increased tracer uptake (mean SUV max 5.9 ± 3.3) in the primary and metastatic lesions with good lesion delineation in 8 out of the 9 cases of PDACs. However, FDG PET showed increased tracer uptake in 7 cases (6.2 ± 2.6). Among various cases of H&NSCC, increased uptakes of 68 Ga-Trivehexin (6.6 ± 4.5) and 18 F-FDG (12.7 ± 6.7) were seen in 17 out of the 18 patients. The 2 cases of inflammatory changes with suspected disease recurrence showed increased tracer uptake in 18 F-FDG PET (7.98 ± 3.1) and no significant uptake in 68 Ga-Trivehexin PET (2.2 ± 0.34).IHC showed higher expression of αvß6 integrins in lesions with higher uptake of 68 Ga-Trivehexin. A higher sensitivity, specificity, and accuracy of 68 Ga-Trivehexin PET over 18 F-FDG PET was seen for detection of primary and metastatic lesions. CONCLUSIONS: 68 Ga-Trivehexin is a promising noninvasive molecular imaging agent for tumors expressing αvß6 integrin, especially in cases where 18 F-FDG PET/CT scan may be suboptimal due to its low uptake, or due to its nonspecific uptake around tumor sites.

The Role of PET-CT-Guided Metabolic Biopsies in Improving Yield of Inconclusive Anatomical Biopsies: A Review of 5 Years in a Teaching Hospital.

Tumour sampling is indispensable to diagnostic and therapeutic decision making. Thus, 18F-FDG PET/CT has the potential to accurately discriminate between viable and non-viable tissues due to its ability to characterise the metabolism of visible tissues. This study's objective was to evaluate the incremental utility of 18F-FDG PET-CT-guided metabolic biopsy in individuals with suspected lesions and a previous negative anatomical biopsy. This study included a total of 190 consecutive patients with probable malignancy and who had experienced a previous unsuccessful anatomical biopsy who underwent PET-CT-guided metabolic biopsy. We retrospectively analysed the patients' medical records and imaging investigations to assess demographics, complications, pathologies, and final clinical diagnoses. Using multivariate logistic regression, correlation between several confounding factors that lead to post-procedural problems was evaluated. Adequate material was obtained in all patients, and 162 (85%) were found to be positive for malignancy with a diagnostic yield of 96.9%. In 25 (13.1%) patients, post-procedural complications were reported, with pneumothorax being the most prevalent issue. In evaluating oncological patients, metabolic biopsy provides a safer alternative therapy with a high diagnostic yield and comparable complications. PET-CT, being an essential component of cancer staging, may serve as a one-stop shop for the management of these patients' conditions.

Validation of In-House Kit-Like Synthesis of 68Ga-Trivehexin and Its Biodistribution for Targeting the Integrin αvß6 Expressing Tumors.

Background: Integrin αvß6 has become an extremely promising theranostic target for precise delineation of fast-growing malignant cells in the recent years. The aim of the study was to validate the in-house kit-like synthesis of 68Ga-Trivehexin (integrin αvß6) and to evaluate its uptake in patients with integrin αvß6 expressing head and neck and pancreatic cancer. Materials and Methods: 68Ga-Trivehexin was synthesized by adding the variable amount of integrin αvß6 (30-50 µg) to full volume (4-5 mL) Ga-68 in 0.05 M HCl and heating the reaction mixture at 90°C for 12 min at pH 3.5-4 to obtain the radiotracer with high radiochemical purity (RCP) and high yield. Quality control procedures were done to assess the RCP, stability, pyrogenicity and sterility of the radiotracer. 68Ga-Trivehexin was then administered in patients who met the eligibility criteria. Whole body PET/CT scans were done at variable time points post intravenous (i.v.) injection of 84-185 MBq of 68Ga-Trivehexin to assess its biodistribution and maximum uptake time. Results: 0.2 mCi of 68Ga/µg of Trivehexin at 90°C for 12 min was the optimal parameter to obtain 85%-88% of noncorrected yield and 99% of RCP. The 68Ga-Trivehexin showed in vitro stability upto 6 h and was also found to be sterile and pyrogen free. Intense radiotracer uptake was noticed in the tumor and no uptake was noticed in healthy tissues. PET/CT imaging at 60 min post injection was found to be the optimal time for imaging the tumors with 68Ga-Trivehexin. Conclusion: The protocol for in-house kit-like labeling of 68Ga-Trivehexin was safe, reproducible, and cost-effective. 68Ga-Trivehexin is an extremely promising agent for noninvasive molecular imaging of integrin αvß6 expressing tumors.

Feasibility of 18F-FDG Labelling of Leucocytes in a Centre Without an On-Site Cyclotron and Monitoring of Radiation Dose to Occupational Worker in the Labelling Procedure.

Objectives: Differentiation of infection from sterile inflammation is still a major concern for clinicians. The 18F-WBC positron emission tomography/computed tomography scan has been considered a promising tool for accurate diagnosis of infection owing to its high specificity, but it renders the availability of a medical cyclotron a necessity. The aim of the present study was to determine the feasibility of labeling leukocytes and establish the protocol in a center without the availability of an on-site medical cyclotron. The secondary aim was to monitor radiation doses to occupational workers involved in labeling of leukocytes with 18F-FDG. Materials and Methods: Leukocyte separation was performed and leukocytes were radiolabeled with 18F-FDG in a sterile environment according to the procedure described by Bhattacharya et al. In vitro leukocyte viability was assessed using the trypan dye exclusion technique. Labeling efficiency and yield were also estimated for all radiolabeling procedures. Whole-body and extremity doses received by the personnel involved in the radiolabeling procedure were also estimated using pocket dosimeters. Results: Leukocyte labeling was carried out in 35 runs, during which there were two failed labeling attempts due to clotting of the blood sample. The total time involved in the whole procedure was around 2.5 h. The average labeling efficiency was 78.01% ± 6.99% (range 63.46%-86.54%), cell viability was 98%, and the cell suspension was stable up to 4 h. The mean dose was measured as 17 µSv at the chest level and 32 µSv at the extremity level, per procedure. Conclusions: Labeling of leukocytes with 18F-FDG is possible at a tertiary nuclear medicine setup without the availability of an on-site medical cyclotron, with reasonable labeling efficiency of 78.01% ± 6.99%. In addition, in-house labeling of leukocytes with 18F-FDG is safe and the radiation doses incurred by the personnel during the labeling procedure are well within the occupational dose limits established by the national regulatory authority.

Incremental Value of 18 F-FDG-Labeled Leukocytes PET/CT Over 18 F-FDG PET/CT Scan in the Detection of Occult Infection.

PURPOSE: Differentiating infection and sterile inflammation is the main clinical concern of clinicians as they are closely related to each other. Although 18 F-FDG PET/CT imaging is widely used, its main disadvantage is its lack of specificity to discriminate aseptic from septic inflammation. 18 F-WBC PET/CT scan is a promising tool for the accurate diagnosis of infection owing to its high specificity. The aim of the present study is to determine the utility of 18 F-WBC PET/CT in the diagnosis of occult infections and to assess its incremental value over routine 18 F-FDG PET/CT scan. PATIENTS AND METHODS: This prospective observational diagnostic accuracy study included 33 patients with fever of unknown origin or suspected periprosthetic infection and raised C-reactive protein and total leukocyte count. All the patients underwent both 18 F-WBC PET/CT scan and 18 F-FDG PET/CT scan using a standard protocol on 2 different days. Images of both the scans were evaluated by both visual analyses based on uptake intensity and quantitative grading based on lesion-to-background SUV max values. For interpretation of FDG PET/CT images, visual scoring of grade 0 (undetectable or no uptake), grade 1a (less than liver uptake), grade 1b (equivalent to liver uptake), grade 2 (higher than liver uptake), and grade 3 (higher than cerebellum uptake) was used. 18 F-WBC PET/CT images were also interpreted visually as grade 0 (undetectable or no uptake), grade 1a (significantly less than lumbar vertebrae or liver uptake for truncal lesions, and in case of extremity lesion slightly higher than neighboring soft tissue uptake or less than neighboring bone marrow uptake), grade 1b (equivalent to liver or lumbar vertebrae uptake for truncal lesions, and in case of extremity lesion significantly higher than neighboring soft tissue uptake or higher than neighboring bone marrow uptake), grade 2 (higher than liver or bone marrow uptake), and grade 3 (higher than twice the liver or bone marrow uptake). Similarly, a quantitative grading was also done based on lesion-to-background SUV max using a circular region of interest manually drawn. For both 18 F-FDG and 18 F-WBC PET/CT, the lesion-to-background ratio of <1.5 was recorded as grade 0, 1.5-2.5 as grade 1a, 2.5-3.5 as grade 1b, 3.5-4.5 as grade 2, and >4.5 as grade 3. Final diagnosis was made by histopathological, microbiological analysis, or clinical-radiological workup. RESULTS: Twenty-nine foci of suspected infection were found in 25/33 patients by either 18 F-FDG PET/CT or 18 F-WBC PET/CT scan. No abnormal uptake of either 18 F-FDG or 18 F-FDG WBC scan was seen in 8 patients. There was a concordance of 18 F-FDG PET/CT and 18 F-WBC PET/CT in 28 sites each using grade 1b of visual and quantitative analysis, respectively. Of the 29 suspicious infected foci, 18 were proven positive for infection (14/18 sites by the histopathological/microbiological culture and the rest 4/18 sites by clinical/radiological workup). Culture of aspirates or biopsy from 11/29 suspicious sites was proven noninfective. Seven of 11 suspicious sites were proven noninfective by clinical/radiological workup. The mean clinical follow-up was 8 months (1-15 months).Overall significantly higher diagnostic accuracy was demonstrated with 18 F-WBC PET/CT in comparison to 18 F-FDG PET/CT for the detection of infection ( P < 0.05). The highest diagnostic accuracy of 18 F-WBC PET/CT scan was reported with both grade 1b of visual as well as of quantitative analysis (lesion-to-background SUV max , 2.5-3.5) and grade 2 for both visual and quantitative analysis for 18 F FDG PET/CT. CONCLUSIONS: 18 F-WBC PET/CT has a higher diagnostic accuracy over 18 F-FDG PET/CT for the diagnosis of occult infection.

18F-Labeled WBC PET/CT Scan in a Case of Recurrent Glioblastoma Multiforme, Presented as Pyrexia of Unknown Origin.

ABSTRACT: Neoplastic causes account for approximately 10% to 20% cases of PUO (pyrexia of unknown origin). The mechanisms by which malignancies induce fever are not fully understood. The release of pyrogenic cytokines either directly from tumor cells or from macrophages responding to tumor are likely to play a major role, which acts on the hypothalamus, causing a change in the thermostatic set point. We present a case of recurrent glioblastoma multiforme, who presented with PUO. 18F-FDG-labeled leukocyte PET/CT scan done for localization of infective focus demonstrated significant tracer accumulation at the periphery of the recurrent brain lesion. Subsequent excisional biopsy from the lesion was suggestive of noninfected recurrent glioblastoma multiforme.

Invasive Fungal Infection in COVID-19-Recovered Patient Detected on 18F-FDG-Labeled Leukocytes PET/CT Scan.

ABSTRACT: Occurrence of invasive fungal infections has gained significant attention during recent times in patients with COVID-19. Patients with severe form of COVID-19, such as those treated in the intensive care unit with prolonged steroid use, are particularly vulnerable to secondary bacterial and fungal infections. Disseminated systemic mycosis is a life-threatening condition, especially in immunocompromised patients. Here, we report a case of a recovered severe COVID-19 patient, who presented with persistent fever. 18F-FDG-labeled leukocyte scan revealed focal accumulation of radiotracer in the small intestine and right lung lower lobe. Subsequently, performed biopsy revealed mucormycosis.

Upfront Use of 177Lu-Labeled PSMA Radioligand Therapy and Treatment Response Assessment in Treatment-Naive Prostate Cancer.

ABSTRACT: Prostatic malignancy is the most common type of nonskin cancer and associated with significant morbidity and mortality. Early androgen deprivation therapy (ADT) is the treatment of choice in metastatic prostate cancer, whereas ADT delays progression of disease, but it is associated with significant adverse effects and frequently impairs the quality of life. Therefore, there is growing interest in treatments to postpone ADT while achieving a good progression-free survival. We present a case of oligometastatic prostate cancer, who was treated upfront with 177Lu-labeled PSMA radioligand therapy and demonstrated excellent response to a single dose of 177Lu-PSMA-617.

Radioguided Surgery in Insulinoma Using 68Ga Labeled Exendin-4: a Case Report.

Laparoscopic resection of tumor is often performed for benign and small insulinomas, or for those located in the body or tail of the pancreas. The precise preoperative and intraoperative localization of the insulinoma is critical to minimize the surgical intervention. Conventional imaging studies, i.e., MRI, CT, and endoscopic ultrasound have limited sensitivity due to the small size of the insulinomas. Angiography, intraarterial calcium stimulation, and venous sampling are invasive procedures with concomitant risk for complications. Exendin-4 PET/CT scan has shown to be of great value in preoperative localization of insulinomas. In the absence of the traditional gold standard, i.e., intraoperative ultrasound with manual palpation, in laparoscopic surgery, a simple enucleation procedure might not be possible. Gamma probe-assisted surgery is a new method of diagnosis and treatment which allows a small area of tissue to be identified and removed, while a large area of the organ or the system remains unaffected. We present a case of a 34-year-old man with clinical suspicion of insulinoma with negative conventional imaging and successful lesion localization with 68Ga-Exendin-4 PET/CT scan in the pancreatic body, who underwent laparoscopic enucleation of the lesion with the aid of a hand-held gamma detecting probe.

Dosimetric analyses of intra-arterial versus standard intravenous administration of 177Lu-DOTATATE in patients of well differentiated neuroendocrine tumor with liver-dominant metastatic disease.

OBJECTIVE: The aim of the present study was to perform calculation of the absorbed doses to organs at risk and to neuroendocrine tumors and to determine whether hepatic intra-arterial (IA) injection of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) would achieve higher intratumoral concentrations than standard intravenous administration of 177Lu-DOTATATE. METHODS: 29 patients with Grade I-II, inoperable, metastatic gastro-entero-pancreatic neuroendocrine tumor (GEPNET) were prospectively identified and enrolled for the study. 15 patients of GEPNETs with liver-dominant metastatic disease and less than 3 sites of extrahepatic metastatic disease were administered a single dose of 177Lu-DOTATATE therapy through the selective catheterization of the hepatic artery (IA group). The other 14 patients received a single dose of 177 Lu- DOTATATE through standard intravenous route (IV group). For dosimetry, whole-body γ (anterior and posterior planar acquisitions) and SPECT/CT scans of the abdomen at 2, 24 and 96 h post 177Lu-DOTATATE administration were acquired. Dosimetric calculations were done using the HERMES software. RESULTS: The mean dose per unit activity (DpA) in the liver and tumor lesions in the IA group differed significantly (p < 0.05) but differed insignificantly in spleen and kidneys (p > 05) with the IV group. The mean tumor/non-tumor concentration at 96 h was 76.83 ± 7.9 (range 10.2-251.3) in the IA group whereas it was 25.6 ± 5.9 (Range: 12-55) in the IV group. There was an average threefold increase in tumoral concentration over the standard intravenous group. CONCLUSION: IA administration of 177Lu-DOTATATE results in higher concentration and absorbed dose in hepatic metastases in patients of GEPNETs as compared to a single dose of PRRT administered through standard IV route, and thus seems to be a powerful tool to improve the efficacy of PRRT. ADVANCES IN KNOWLEDGE: Measurement of the dose received by the tumor lesions and the critical organs is of paramount importance for the prognostication of a radionuclide therapy. Scant data exist on the dosimetric impact of IA administration of the therapy with 177Lu-DOTATATE on the tumors and other organs, and this study would add an impact towards the better treatment outcome in patients of neuroendocrine tumor with liver-dominant metastatic disease.

Therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy in patients of metastatic castrate resistant prostate cancer after taxane-based chemotherapy.

OBJECTIVES: 225Ac-PSMA-617 therapy has shown good response in many recent studies. We report our experience of targeted alpha therapy with 225Ac-PSMA-617 in mCRPC patients who have failed therapy with taxanes. MATERIALS AND METHODS: Thirty-eight patients with CRPC with progressive disease following at least one taxane-based chemotherapy received 225Ac-PSMA-617 between July 2017 and Nov 2019. Primary end point was a composite 50% PSA and radiological response. Secondary endpoints were PFS, OS, and changes in QOL. The differences in outcomes between patients with skeletal and lymph-node metastases versus those with visceral metastases were also studied. RESULTS: A composite response by predetermined criteria was observed in 25 (66%) of 38 patients. The median PFS was 8 months (95% CI 5.3-10.6 months). Median overall survival was 12 months (95% CI 9.1-14.9) with 16 patients alive at the time of censorship. There was no difference in response rates or survival statistics between patients with visceral metastases versus those with only bone and lymph-node metastases (Chi-square 1.51, df 1, Sig 0.218). The most common adverse effect was xerostomia. On the QOL Symptom score, Pain, Fatigue Insomnia, and constipation showed a significant improvement as compared to baseline. CONCLUSIONS: 225Ac-PSMA-617 is a safe and tolerable treatment option for mCRPC that demonstrates marked anti-tumour activity with improvement in quality of life even in patients of metastatic CRPC who have been previously treated with taxane-based chemotherapy.

Incremental Value of Ga-68 Prostate-Specific Membrane Antigen-11 Positron-Emission Tomography/Computed Tomography Scan for Preoperative Risk Stratification of Prostate Cancer.

BACKGROUND: Prostate cancer (PC) is the second-most common cause of cancer.68Ga-prostate-specific membrane antigen (PSMA)-11 positron-emission tomography/computed tomography (PET/CT) scan help in accurate staging of PC owing to its high PSMA avidity and specificity. The aim of this prospective observational study was to determine the incremental value of Ga-68 PSMA-11 PET/CT over multiparametric magnetic resonance imaging (mpMRI) in the locoregional staging of intermediate- and high-risk PC using histopathology from radical prostatectomy specimens as a gold standard. MATERIALS AND METHODS: This was a prospective study, including 35 patients with biopsy-proven prostate carcinoma. All the patients underwent whole-body Ga-68 PSMA-11 PET/CT scans along with mpMRI including a dedicated pelvic imaging protocol within a time window of ± 10 days. The reference standard was based on histopathological results, postprostatectomy. RESULTS: All 35 patients showed Ga-68 PSMA-11-avid disease, of which 29 underwent radical prostatectomy, one underwent radiation therapy, and five did not undergo surgery owing to metastases. A total of 52 PC lesions were detected in 29 patients on histopathology. Of 52 lesions, 29 lesions were identified in prostate parenchyma and 23 were extraprostatic lesions on histopathology. Ga-68 PSMA-11 PET/CT detected a total of 45 lesions, of which 29 lesions were located within the prostate parenchyma and 16 were representative of extraprostatic lesions. mpMRI detected a total of 36 lesions, of which 29 lesions were located within the prostate parenchyma and seven were representative of extraprostatic lesions. The overall sensitivity of 68Ga-PSMA PET/CT and mpMRI in the detection of lesions was 86.2% and 68.6%, respectively. However, the overall specificity was 94.7% and 89.1% for 68Ga-PSMA and mpMRI, respectively. CONCLUSION: Ga-68 PSMA-11 PET/CT provided superior locoregional preoperative staging of PC as compared to mpMRI in intermediate- and high-risk PC patients.