Effect of hormonal therapy on 18F-fluciclovine PET/CT in the detection of prostate cancer recurrence, localization of metastatic disease, and correlation with prostate-specific antigen.

INTRODUCTION: 18F-Fluciclovine, is a positron emission tomography (PET) radiotracer approved for the localization of sites of prostate cancer recurrence in men with a rising prostate-specific antigen (PSA) after definitive treatment. To explore the impact of androgen deprivation therapy (ADT) on the performance of 18F-fluciclovine, we conducted a retrospective analysis to compare the 18F-fluciclovine PET/CT positivity rate in patients receiving ADT at the time of the scan with the rate achieved in patients not receiving ADT. METHODS: A retrospective review of data from patients who underwent 18F-fluciclovine PET/CT for biochemical recurrence of prostate cancer between December 2016 to March 2020 was performed. The cohort was divided into an ADT group (patient reportedly on ADT) and a non-ADT group (not currently receiving ADT). Patients with unknown ADT status or undetectable/unknown PSA were excluded. For each group, the number of positive 18F-fluciclovine PET/CT scans (positivity rate) was evaluated for the whole body, prostate/bed, and extraprostatic regions and rates were correlated with PSA. The Fisher's Exact test was applied to establish the significance between the ADT and non-ADT positivity groups. Mantel-Haenszel trend test was performed to assess linearity between the positivity rate and PSA level. RESULTS: In 320 patients, the status of ADT was known. At the time of the 18F-fluciclovine scan, 68/320 (21%) patients were on ADT, while 252/320 (79%) were not. The median Gleason score was 8 (range of 6-10) in the ADT group vs. 7 (range of 6-10) in the non-ADT group (P < 0.001). Overall, positivity rates demonstrated no statistical significance between the ADT and non-ADT groups; Positivity rates (ADT vs. non-ADT) were 82% (56/68) vs. 82% (206/252) for the whole body, 57% (39/68) vs. 60% (152/252) for prostate/bed, and 60% (41/68) vs. 53% (133/252) for extraprostatic regions (P > 0.05). A positive linear correlation was noted between PSA and each group's positivity rate (P < 0.01). However, no significant difference was observed between ADT and non-ADT groups at different PSA levels (P > 0.05). CONCLUSIONS: Detection of prostate cancer recurrence with 18F-fluciclovine PET/CT is not significantly influenced by ADT, suggesting that localization of disease in patients with detectable PSA who are receiving ADT is feasible with 18F-fluciclovine.

Positivity Rate of [18F]Fluciclovine PET/CT in Patients with Suspected Prostate Cancer Recurrence at PSA Levels Below 1 ng/mL.

PURPOSE: Early and precise localization of recurrent prostate cancer lesions after local therapy facilitates optimal disease management. Here, we present results from a single-center study to evaluate the utility of [18F]fluciclovine PET/CT to localize prostate cancer recurrence in patients with PSA <1 ng/mL. PROCEDURES: Data from men who underwent [18F]fluciclovine PET/CT (August 2016-March 2020) for suspected recurrent prostate cancer and who had a PSA value <1ng/mL were retrospectively reviewed. The number of positive scans (positivity rates, PR) was calculated for the whole body, prostate/bed, and extraprostatic regions (pelvic or extrapelvic lymph nodes, bones, and soft tissue). PR were stratified by pre-scan PSA. RESULTS: Data from 113 patients were included. In total, 98 (87%) were post-prostatectomy and 15 (13%) had received non-surgical primary therapy. Twenty patients (18%) were receiving ADT at the time of the scan, 91 (81%) were not, and ADT status was not known for 2 (1.8%) patients. The overall PR at PSA <1ng/mL was 59% (67/113). For the prostate/bed, it was 35% (40/113), and for extraprostatic locations, it was 37% (42/113). At PSA >0-<0.2, 0.2-<0.5, and 0.5-<1 ng/mL, the overall PR was 43% (10/23), 70% (35/50), and 55% (22/40), respectively. In the prostate/bed, these were 13% (3/23), 50% (25/50), and 30% (12/40), respectively, and in extraprostatic lesions were 30% (7/23), 44% (22/50), and 33% (13/40), respectively. Pelvic lymph nodes were the most common site for extraprostatic lesions (29/113, 26%). PR in extrapelvic lymph nodes, bone, and soft tissue were 8.0%, 12%, and 3.5%, respectively. Soft tissue lesions comprised lung nodules (n=3) and a perirectal mass implant (n=1). CONCLUSIONS: Despite low PSA values, more than half of patients had positive [18F]fluciclovine PET/CT findings. Patients with low PSA levels may demonstrate suspicious findings outside of the pelvis, including abdominal lymph nodes and metastatic disease to bones and lungs.

Pain resolution and glucose control in pediatric patients with chronic pancreatitis after total pancreatectomy with islet auto-transplantation.

BACKGROUND: Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) in pediatric patients are strongly associated with genetic mutations and lead to pan-parenchymal disease refractory to medical and endoscopic treatment. Our aim was to assess pain resolution and glucose control in patients with CP and ARP following total pancreatectomy with islet auto-transplantation (TPIAT). METHODS: We retrospectively analyzed prospectively collected clinical data of 12 children who developed CP and ARP and underwent TPIAT when 21 years old or younger at the University of Chicago between December 2009 and June 2020. Patients with recurrent or persistent abdominal pain attributed to acute or chronic pancreatic inflammation and a history of medical interventions attempted for the relief of pancreatic pain were selected by a multi-disciplinary team for TPIAT. We followed patients post-operatively and reported data for pre-TPIAT, post-operative day 75, and yearly post-TPIAT. RESULTS: All 12 patients experienced complete resolution of pancreatic pain. The overall insulin-independence rate after 1 year was 66% (8/12) and 50% (3/6) at 4 years. Shorter duration of CP/ARP pre-TPIAT, higher mass of islets infused, and lower BMI, BMI percentile, and BSA were associated with insulin-independence post-TPIAT. CONCLUSIONS: TPIAT is a viable treatment option for pediatric patients with CP and ARP. Pediatric patients undergoing TPIAT for CP achieved resolution of pancreatic-type pain and reduced opioid requirements. The majority were able to achieve insulin-independence which was associated with lower pre-TPIAT BMI and higher islet mass transplanted (i.e., over 2000 IEQ/kg), the latter of which can be achieved by earlier TPIAT. LEVEL OF EVIDENCE: Treatment study, Level IV.

Interplay of stromal tumor-infiltrating lymphocytes, normal colonic mucosa, cancer-associated fibroblasts, clinicopathological data and the immunoregulatory molecules of patients diagnosed with colorectal cancer.

A total of 94 patients with colorectal cancer (CRC) were included in this study. Lymphocytic infiltration of CD45+ cells in the normal colon was more pronounced than that in the paired tumor stroma (p = 0.0008). The mean immunoscore of CD45+TILs was decreased in CRC compared with the controls (p = 0.0010). The percentage of CD3+ cells was higher in stage II than in stage IV (p = 0.0218) and showed a negative correlation with the TNM classification (r = -0.2867, p = 0.0109). The number of stromal CD4+TILs was higher in stage I than in stage III (p = 0.0116) and IV (p = 0.0104), and there was a negative correlation between this number and the stage (r = -0.3708, p = 0.0008). There was a positive correlation between the Ki-67 and CD45+ (r = 0.2468, p = 0.0294), CD3+ (r = 0.3822, p = 0.0006), and CD4+ cells (r = 0.5465, p < 0.0001). The levels of cancer-associated fibroblast (CAF) markers such as α-SMA, thrombin and fibronectin were significantly higher in CRC than in normal colonic mucosa. The immunohistochemical expression of α-SMA was negatively correlated with TILs, while fibronectin showed positive coexpression. A higher number of cells expressing IL-2Rα, PD-L1, CD33 and CD14 were found in colorectal adenocarcinomas than in controls. The number of CD14+ cells was also dependent on the TNM stage (p = 0.0444) and tumor budding (p = 0.0324). These findings suggest a suppressive impact of CRC on the adaptive immune response and emphasize the importance of CAFs in regulating tumor immunity.

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance.

BACKGROUND: Tumor initiation and subsequent progression are usually long-term processes, spread over time and conditioned by diverse aspects. Many cancers develop on the basis of chronic inflammation; however, despite dozens of years of research, little is known about the factors triggering neoplastic transformation under these conditions. Molecular characterization of both pathogenetic states, i.e., similarities and differences between chronic inflammation and cancer, is also poorly defined. The secretory activity of tumor cells may change the immunophenotype of immune cells and modify the extracellular microenvironment, which allows the bypass of host defense mechanisms and seems to have diagnostic and prognostic value. The phenomenon of immunosuppression is also present during chronic inflammation, and the development of cancer, due to its duration, predisposes patients to the promotion of chronic inflammation. The aim of our work was to discuss the above issues based on the latest scientific insights. A theoretical mechanism of cancer immunosuppression is also proposed. CONCLUSIONS: Development of solid tumors may occur both during acute and chronic phases of inflammation. Differences in the regulation of immune responses between precancerous states and the cancers resulting from them emphasize the importance of immunosuppressive factors in oncogenesis. Cancer cells may, through their secretory activity and extracellular transport mechanisms, enhance deterioration of the immune system which, in turn, may have prognostic implications.

Comparative analysis of exosome markers and extracellular vesicles between colorectal cancer and cancer-associated normal colonic mucosa.

INTRODUCTION: Exosomes are currently considered as the new biomarkers of colorectal cancer (CRC). Tetraspanins (CD9, CD63) belong to the well­known exosome markers, but can also be found on other subtypes of extracellular vesicles (EVs). OBJECTIVES: The aim of this study was to estimate the expression level of exosome markers and EVs in CRC. PATIENTS AND METHODS: The expression level of CD9 and CD63 antigens was evaluated by immunohistochemical staining in 109 patients diagnosed with CRC. Immunohistochemistry results were verified by nanoparticle tracking analysis (NTA), as well as the Western blot analysis and transmission electron microscopy. Exosomes isolation was performed on solid tissues. The immunohistochemical expression of both tetraspanins was compared with expression of cellular p roliferation marker, Ki­67. RESULTS: A higher expression level of exosome markers was observed in CRC compared with the normal colonic mucosa. The NTA revealed higher concentrations of nanoparticles in CRC tissues than in controls. There was a strong positive correlation between exosome markers and the Ki­67 antigen. The expression levels of both tetraspanins were different for lymph node stagi ng (N stage). CONCLUSIONS: Exosome markers and EVs were more pronounced in the CRC samples compared with controls. Immunohistochemical evaluation of tetraspanins reflects the results obtained by the NTA. Exocytosis appears to play an important role in the pathogenesis of CRC. To the best of our knowledge, such analysis was carried out for the first time.

Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration.

INTRODUCTION: Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. METHODS: Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. RESULTS: On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. DISCUSSION: Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018.