Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Self-Healing Composite Coating Fabricated with a Cystamine Cross-Linked Cellulose Nanocrystal-Stabilized Pickering Emulsion.

A gelled Pickering emulsion system was fabricated by first stabilizing linseed oil droplets in water with dialdehyde cellulose nanocrystals (DACNCs) and then cross-linking with cystamine. Cross-linking of the DACNCs was shown to occur by a reaction between the amine groups on cystamine and the aldehyde groups on the CNCs, causing gelation of the nanocellulose suspension. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the cystamine-cross-linked CNCs (cysCNCs), demonstrating their presence. Transmission electron microscopy images evidenced that cross-linking between cysCNCs took place. This cross-linking was utilized in a linseed oil-in-water Pickering emulsion system, creating a novel gelled Pickering emulsion system. The rheological properties of both DACNC suspensions and nanocellulose-stabilized Pickering emulsions were monitored during the cross-linking reaction. Dynamic light scattering and confocal laser scanning microscopy (CLSM) of the Pickering emulsion before gelling imaged CNC-stabilized oil droplets along with isolated CNC rods and CNC clusters, which had not been adsorbed to the oil droplet surfaces. Atomic force microscopy imaging of the air-dried gelled Pickering emulsion also demonstrated the presence of free CNCs alongside the oil droplets and the cross-linked CNC network directly at the oil-water interface on the oil droplet surfaces. Finally, these gelled Pickering emulsions were mixed with poly(vinyl alcohol) solutions and fabricated into self-healing composite coating systems. These self-healing composite coatings were then scratched and viewed under both an optical microscope and a scanning electron microscope before and after self-healing. The linseed oil was demonstrated to leak into the scratches, healing the gap automatically and giving a practical approach for a variety of potential applications.

Positron emission tomography derived metrics in relapsed or refractory large B-cell lymphoma with residual disease before autologous stem cell transplant.

Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative treatment for patients with relapsed or refractory large B-cell lymphoma (rrLBCL) with chemosensitive disease. A18 F-fluorodeoxyglucose positron emission tomography (PET) scan after salvage chemotherapy is used to assess response and eligibility for ASCT, but metrics for chemosensitivity in patients with residual disease are not well defined. We performed a single-centre retrospective analysis of 92 patients with a partial response or stable disease after salvage chemotherapy for rrLBCL who received ASCT to investigate PET-derived parameters and their prognostic utility. The Deauville 5-point Scale (D-5PS) score, maximum standardised uptake value (SUVmax ), total metabolic tumour volume (TMTV), and total lesion glycolysis (TLG) were calculated from the post-salvage/pre-ASCT PET scan. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 40% and 54% respectively. A D-5PS score of 5 (p = 0.0082, hazard ratio [HR] 2.09), high SUVmax (p = 0.0015, HR 2.48), TMTV (p = 0.035, HR 1.83) and TLG (p = 0.0036, HR 2.27) were associated with inferior PFS. A D-5PS score of 5 (p = 0.030, HR 1.98) and high SUVmax (p = 0.0025, HR 2.55) were associated with inferior OS. PET-derived parameters may help prognosticate outcomes after ASCT in patients with rrLBCL with residual disease after salvage chemotherapy.

Imaging features of immune checkpoint inhibitor-related nephritis with clinical correlation: a retrospective series of biopsy-proven cases.

OBJECTIVES: Imaging appearances of immune checkpoint inhibitor-related nephritis have not yet been described. The primary objective of this study is to describe the appearances of immunotherapy-related nephritis on computerized tomography (CT) and positron emission tomography (PET). The secondary objectives are to investigate the association of radiologic features with clinical outcomes. METHODS: CT and PET-CT scans before the initiation of immunotherapy (baseline), at nephritis, and after resolution of pathology-proven nephritis cases were reviewed. Total kidney volume, renal parenchymal SUVmax, renal pelvis SUVmax, and blood pool SUVmean were obtained. RESULTS: Thirty-four patients were included. The total kidney volume was significantly higher at nephritis compared to baseline (464.7 ± 96.8 mL vs. 371.7 ± 187.7 mL; p < 0.001). Fifteen patients (44.1%) had > 30% increase in total kidney volume, which was associated with significantly higher renal toxicity grade (p = 0.007), higher peak creatinine level (p = 0.004), and more aggressive medical treatment (p = 0.011). New/increasing perinephric fat stranding was noted in 10 patients (29.4%) at nephritis. Among 8 patients with contrast-enhanced CT at nephritis, one (12.5%) developed bilateral wedge-shaped hypoenhancing cortical. On PET-CT, the renal parenchymal SUVmax-to-blood pool ratio was significantly higher at nephritis compared to baseline (2.13 vs. 1.68; p = 0.035). The renal pelvis SUVmax-to-blood pool SUVmean ratio was significantly lower at nephritis compared to baseline (3.47 vs. 8.22; p = 0.011). CONCLUSIONS: Bilateral increase in kidney size, new/increasing perinephric stranding, and bilateral wedge-shaped hypoenhancing cortical foci can occur in immunotherapy-related nephritis. On PET-CT, a diffuse increase in radiotracer uptake throughout the renal cortex and a decrease in radiotracer activity in the renal pelvis can be seen. KEY POINTS: • CT features of immune checkpoint inhibitor-related nephritis include an increase in kidney volume, new/increasing perinephric stranding, and bilateral ill-defined wedge-shaped hypoenhancing cortical foci. • FDG-PET features of immune checkpoint inhibitor-related nephritis include an increase in FDG uptake throughout the renal cortex and a decrease in FDG activity/excretion in the collecting system. • > 30% increase in total kidney volume is associated with worse toxicity grade and more aggressive medical management.

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

New Directions in Treatment of Metastatic or Advanced Pheochromocytomas and Sympathetic Paragangliomas: an American, Contemporary, Pragmatic Approach.

PURPOSE OF REVIEW: Multiple therapies with novel mechanisms have been explored in clinical trials for the treatment of metastatic pheochromocytomas and paragangliomas. We review current and future therapies for this disease and provide guidance on how and when to prescribe them based on tumor progression, clinical manifestations, molecular features, and social factors. RECENT FINDINGS: Approximately 60-70% of metastatic pheochromocytomas and paragangliomas express the noradrenaline transporter in their cell membranes. High specific activity iodine-131 metaiodobenzylguanidine has been recently approved by the US Food and Drug Administration for the treatment of metastatic pheochromocytomas and paragangliomas that express the noradrenaline transporter, in patients aged ≥ 12 years. More than 90% of patients treated with this medication exhibit clinical benefits. However, other therapies with novel mechanisms of action are needed to help all patients with this disease. Treatment of metastatic pheochromocytomas and paragangliomas is recommended based on the severity of symptoms, the progression of the disease, and the patient's performance status. Currently available therapies include surgery; systemic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, or with temozolomide; high specific activity iodine-131 metaiodobenzylguanidine; peptide receptor radionuclide therapy; immunotherapy; tyrosine kinase inhibitors; and hypoxia-inducible factor 2 alpha inhibitors. Financial and social factors such as health insurance coverage and disparities also impact current clinical practice in the USA.

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.

Semiquantitative Assessment of 18F-FDG Uptake in the Normal Skeleton: Comparison Between PET/CT and Time-of-Flight Simultaneous PET/MRI.

OBJECTIVE: Differences in the attenuation correction methods used in PET/CT scanners versus the newly introduced whole-body simultaneous PET/MRI reportedly result in differences in standardized uptake values (SUVs) in the normal skeleton. The aim of the study was to compare the semiquantitative FDG uptake in the normal skeleton using time-of-flight (TOF) PET/MRI versus PET/CT with and without TOF. SUBJECTS AND METHODS: Participants received a single FDG injection and underwent non-TOF and TOF PET/CT (n = 23) or non-TOF PET/CT and TOF PET/MRI (n = 50). Mean SUV (SUVmean) and maximum SUV (SUVmax) were measured from all PET scans for nine normal regions of the skeleton. Pearson correlation coefficients (r) were used to evaluate the SUVmax and SUVmean of normal skeleton between non-TOF and TOF PET/CT, as well as between non-TOF PET/CT and TOF PET/MRI. In addition, percentage differences in SUVmax and SUVmean of the normal skeleton between non-TOF and TOF PET/CT and between non-TOF PET/CT and TOF PET/MRI were evaluated. RESULTS: The SUVmax and SUVmean in the normal skeleton significantly increased between non-TOF and TOF PET/CT, but they significantly decreased between non-TOF PET/CT and TOF PET/MRI. The SUVmax and SUVmean in normal skeleton showed good correlation between non-TOF PET/CT and TOF PET/MRI (SUVmax, r = 0.88; SUVmean, r = 0.91) and showed a similar trend between non-TOF and TOF PET/CT (SUVmax, r = 0.88; SUVmean, r = 0.94). CONCLUSION: In the normal skeleton, SUVmax and SUVmean showed high correlations between PET/MRI and PET/CT. The MRI attenuation correction used in TOF PET/MRI provides reliable semiquantitative measurements in the normal skeleton.

Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer's disease.

Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.

Midlife measurements of white matter microstructure predict subsequent regional white matter atrophy in healthy adults.

OBJECTIVES: Although age-related brain changes are becoming better understood, midlife patterns of change are still in need of characterization, and longitudinal studies are lacking. The aim of this study was to determine if baseline fractional anisotropy (FA), obtained from diffusion tensor imaging (DTI) predicts volume change over a 4-year interval. EXPERIMENTAL DESIGN: Forty-four cognitively healthy middle-age adults underwent baseline DTI and longitudinal T1-weighted magnetic resonance imaging. Tensor-based morphometry methods were used to evaluate volume change over time. FA values were extracted from regions of interest that included the cingulum, entorhinal white matter, and the genu and splenium of the corpus callosum. Baseline FA was used as a predictor variable, whereas gray and white matter atrophy rates as indexed by Tensor-based morphometry were the dependent variables. PRINCIPAL OBSERVATIONS: Over a 4-year period, participants showed significant contraction of white matter, especially in frontal, temporal, and cerebellar regions (P < 0.05, corrected for multiple comparisons). Baseline FA in entorhinal white matter, genu, and splenium was associated with longitudinal rates of atrophy in regions that included the superior longitudinal fasciculus, anterior corona radiata, temporal stem, and white matter of the inferior temporal gyrus (P < 0.001, uncorrected for multiple comparisons). CONCLUSIONS: Brain change with aging is characterized by extensive shrinkage of white matter. Baseline white matter microstructure as indexed by DTI was associated with some of the observed regional volume loss. The findings suggest that both white matter volume loss and microstructural alterations should be considered more prominently in models of aging and neurodegenerative diseases.

High-Specific-Activity 131 I-MIBG for the Treatment of Advanced Pheochromocytoma and Paraganglioma.

PATIENTS AND METHODS: The primary endpoints were objective response rate (ORR) and disease control rate (DCR). Secondary endpoints were duration of response, blood pressure control, safety, overall and progression-free survival rates, MIBG uptake, and correlations with genetic background. RESULTS: The study included 25 patients. Twenty-four patients had distant metastases, 17 (68%) had hormonally active tumors, and 13 (52%) had previously received antineoplastic treatment. In 24 evaluable patients, the ORR was 38%, including 2 patients with complete response, and the DCR was 83%; median time to response was 12.5 months (95% confidence interval, 4.6-25.1). Twelve patients had sporadic disease, among whom the ORR was 25% and DCR was 83%. Twelve patients had hereditary disease ( SDHB , VHL , RET ); among these, the ORR was 50%, and DCR was 83%. Plasma metanephrines normalized in 30% of patients and improved by greater than 50% in 46%. Sixteen patients had hormonally active tumors and hypertension; in 9 (56%) of these, blood pressure normalized, leading to discontinuation of antihypertensive therapy.The most common adverse events were grades 1-2 nausea/vomiting and transient bone marrow suppression. One patient developed premature ovarian failure. Reversible grades 3-4 myelosuppression were seen in 7 patients (28%). One patient had fatal pneumonitis. CONCLUSIONS: HSA- 131 I-MIBG is associated with a high DCR in patients with MPPGL, regardless of underlying genetic mutation.

A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys.

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n=24, 13 males, 11 females) and standard (n=17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A Diet X Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.

Proposed MIBG Scan-Based Tumor Response Criteria of High-Specific-Activity 131 I-MIBG Therapy in Metastatic Pheochromocytoma/Paraganglioma.

ABSTRACT: High-specific-activity 131 I-MIBG (Azedra) is the only Food and Drug Administration-approved therapy for metastatic pheochromocytomas and paragangliomas, which are rare neuroendocrine tumors with limited treatment options. Based on our experience, we proposed here functional imaging-based tumor response criteria for these patient cohorts. Each response category was illustrated with typical sample cases, and clinical correlation was provided.

Vapocoolant Analgesia for Breast Lymphoscintigraphy: A Prospective Clinical Trial.

Breast lymphoscintigraphy is commonly performed before initial surgical intervention and surgical staging in the setting of breast cancer. Breast lymphoscintigraphy injections can often be quite painful and are routinely performed without any anesthesia or analgesia, thus representing a significant unmet need for the breast cancer population. Although vapocoolants have been previously available, they have typically been used on intact skin and not been recommended for sterile procedures. Methods: Thirty consecutive patients were enrolled in our prospective study of which 29 received vapocoolant analgesia in the setting of breast lymphoscintigraphy. Patients were given a postinjection questionnaire that included a self-reported pain score and boolean question regarding whether they would recommend vapocoolant for future patients. Results: The lymposcintigraphy procedure was successful in 100% of cases with an ipsilateral axillary node identified on average within 2.4 h of injection (median, 1 h; range 1-4.5 h). The average self-reported pain score was 1.98 (median, 1; range, 1-10). Conclusion: Vapocoolant analgesia in the setting of breast lymphoscintigraphy is feasible, does not appear to compromise lymphoscintigraphy, and appears to be associated with generally low self-reported pain scores.

Pitfall of 18 F-PSMA PyL PET/CT Imaging of a Displaced Urinary Bladder as Recurrent Prostate Malignancy.

ABSTRACT: We herein present a potential pitfall in the setting of restaging PSMA PyL PET/CT. In this case, there is large non-PSMA-avid cystic structure in the mid pelvis, probably representing a postprostatectomy lymphocele, which was mistaken for the urinary bladder, resulting in the displaced and somewhat crescentic urinary bladder to be deemed recurrence. Subsequently, biopsy and retrospective review of images confirms displaced urinary bladder containing physiologic excreted activity.

Comparison of PSMA-based 18F-DCFPyL PET/CT and Tc-99m MDP bone scan in detection of bone metastasis in prostate cancer.

While Tc-99m MDP bone scan (BS) remains the conventional standard for detection of bone metastasis in prostate cancer, newly FDA-approved imaging with PSMA-based 18F-DCFPyL PET/CT has shown promise for early detection of metastatic disease. However, a paucity of data remains in the diagnostic accuracy of PSMA PET/CT in detecting bone metastasis compared to BS. This retrospective study included 91 patients who received both BS and PSMA PET/CT within a 3-month interval from August 2021 to February 2022. Separate concurrent primary cancer, interval PSA levels greater than a 2-fold difference (or absolute difference >1 ng/ml) between the two studies were excluded. All abnormal bone lesions on either scan were compared. The findings were verified by pathological findings and/or 6-month clinical follow-up. High concordance (78%) was found between modalities with discordant findings (20/91, 22%) demonstrating more false positives (4/20, 20%) and false negatives (3/20, 15%) on BS compared to PET/CT. Additionally, more bone metastases were detected on PSMA PET/CT (13/20, 65%) with all true positive BS lesions also detected PET/CT. The sensitivity, specificity, PPV and NPV for BS were 89%, 91%, 80%, and 95% respectively; and 100%, 97%, 93%, and 100% for 18F-DCFPyL PET/CT respectively. Our results demonstrate that 18F-DCFPyL PET/CT identified more bone metastases while also identifying all bone metastases identified on BS. With the added diagnostic value of detecting primary tumor and soft tissue metastasis, 18F-DCFPyL PET/CT may render BS unnecessary to investigate bone metastases in patients with prostate cancer.

Tackling the challenge of drying and redispersion of cellulose nanofibrils via membrane-facilitated liquid phase exchange.

It is generally acknowledged that to advance the application of cellulose nanofibrils (CNFs) in product formulations, challenges associated with the drying and redispersion of this material must be addressed. Despite increased research efforts in this area, these interventions still involve the use of additives or conventional drying technologies, which both have the capacity to drive up the cost of the final CNF powders. Herein, we prepared dried and redispersible CNF powders with varying surface functionalities without the use of additives nor conventional drying technologies. Rapid drying in air was achieved after liquid phase exchange from water to isopropyl alcohol. The surface properties, morphology and thermal stabilities were the same for the never-dried and redispersed forms. The rheological properties of the CNFs were also unaffected after drying and redispersion of unmodified and organic acid modified materials. However, for 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-mediated oxidised CNFs with higher surface charge and longer fibrils, the storage modulus could not be recovered to the never-dried state because of the possible non-selective reduction in length upon redispersion. Nevertheless, this method provides an effective and low-cost process for the drying and redispersion of unmodified and surface modified CNFs.

Diagnostic Performance of PSMA-Based 18 F-DCFPyL PET/CT in Prostate Cancer Patients After Definitive Treatment With PSA Level ≤0.2 ng/mL.

PURPOSE: The aim of this study was to investigate the role of 18 F-DCFPyL PET/CT in the evaluation of prostate cancer (PC) patients after definitive treatment and with low-level prostate-specific antigen (PSA) level of ≤0.2 ng/mL. PATIENTS AND METHODS: This retrospective study was conducted in PC patients who received definitive treatments with PSA level of ≤0.2 ng/mL and underwent 18 F-DCFPyL PET/CT within a 1-week interval of PSA examination, and without interval treatment change or history of other cancer. Patient and tumor characteristics at initial diagnosis, treatment regimens, and findings on 18 F-DCFPyL PET/CT were collected. Patients with minimal 6-month (median, 11 months; range, 6-21 months) follow-up or definitive biopsy results of the suspected PET/CT findings were included. Imagine findings were reached with consensus among experienced board-certified nuclear medicine physicians. Comprehensive follow-up and/or biopsy results were used as definitive determination of presence or absence of disease. Comparisons between groups of positive and negative 18 F-DCFPyL PET/CT were done by using descriptive statistics. RESULTS: A total of 96 18 F-DCFPyL PET/CTs from 93 patients met the inclusion criteria. The median Gleason score (GS) of positive group is 8 (range, 6-10), whereas negative group is 7 (range, 6-10). The median age of positive group is 71 (range, 50-90), whereas negative group is 69 (range, 45-88). There were 49 positive (51%) and 47 negative 18 F-DCFPyL PET/CTs (49%). Detection rates at PSA level of ≤0.1 and 0.2 ng/mL were 58.7% (27/46) and 44% (22/50), respectively. The scan-based sensitivity, specificity, positive predictive value, and negative predictive value are 100%, 95%, 96%, and 100% in group with PSA level of ≤0.1 ng/mL, and 100%, 97%, 95%, and 100% in group with PSA level of 0.2 ng/mL, respectively. Sites of involvement on positive 18 F-DCFPyL PET/CTs were prostate bed, pelvic lymph nodes, bone, chest and supraclavicular lymph nodes, lung, and adrenal glands. The SUV max value on positive lesions ranged from 1.9 to 141.4; the smallest positive lymph node was 0.4 cm. High GS of 8-10, known metastatic status (M1), presence of extraprostatic extension, presence of seminal vesicle invasion, and very high-risk PC are significantly associated with positive 18 F-DCFPyL PET/CT results ( P < 0.05). Of all analyzed treatment regimes, upfront surgery (radical prostatectomy with or without pelvic lymph node dissection) had strong correlation with negative PET/CT results ( P < 0.001). If patients received ADT only, or ADT plus chemotherapy, the PET/CT results were most likely positive ( P = 0.026). For other treatment regimes, there were no statistical differences between the groups ( P > 0.05). CONCLUSIONS: In the presence of low PSA level in PC patients after definitive treatment, 18 F-DCFPyL PET/CT is most beneficial in detection of disease in patients with GS of 8 or higher at the time of diagnosis, and the ones who have history of ADT only, or ADT plus chemotherapy. There is excellent negative prediction value of 18 F-DCFPyL PET/CT. However, there is no cutoff PSA level for 18 F-DCFPyL PET/CT indication and no correlation between PSA level and SUV max of positive lesions on 18 F-DCFPyL PET/CT.

Obesity Measured via Body Mass Index May Be Associated with Increased Incidence but Not Worse Outcomes of Immune-Mediated Diarrhea and Colitis.

Obesity defined by high body mass index (BMI) has traditionally been associated with gastrointestinal inflammatory processes but has recently been correlated with better survival in patients receiving immune checkpoint inhibitors (ICI). We sought to investigate the association between BMI and immune-mediated diarrhea and colitis (IMDC) outcomes and whether BMI reflects body fat content on abdominal imaging. This retrospective, single-center study included cancer patients with ICI exposure who developed IMDC and had BMI and abdominal computed tomography (CT) obtained within 30 days before initiating ICI from April 2011 to December 2019. BMI was categorized as <25, ≥25 but <30, and ≥30. Visceral fat area (VFA), subcutaneous fat area (SFA), total fat area (TFA: VFA+SFA), and visceral to subcutaneous fat (V/S) ratio were obtained from CT at the umbilical level. Our sample comprised 202 patients; 127 patients (62.9%) received CTLA-4 monotherapy or a combination, and 75 (37.1%) received PD-1/PD-L1 monotherapy. Higher BMIs ≥ 30 were associated with a higher incidence of IMDC than BMIs ≤ 25 (11.4% vs. 7.9%, respectively; p = 0.029). Higher grades of colitis (grade 3-4) correlated with lower BMI (p = 0.03). BMI level was not associated with other IMDC characteristics or did not influence overall survival (p = 0.83). BMI is strongly correlated with VFA, SFA, and TFA (p < 0.0001). Higher BMI at ICI initiation was linked to a higher incidence of IMDC but did not appear to affect outcomes. BMI strongly correlated with body fat parameters measured by abdominal imaging, suggesting its reliability as an obesity index.

Characteristics, treatment, and outcome of diverticulitis after immune checkpoint inhibitor treatment in patients with malignancies.

PURPOSE: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment. METHODS: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups. RESULTS: 77 eligible patients were included: 63 patients developed diverticulitis after ICI exposure (46 had initial episode after ICI exposure, 17 had a history of diverticulitis prior then recurred after ICI exposure), and 14 had diverticulitis before ICI exposure. Diverticulitis occurred after a median of 129 days after ICI initiation. Clinical characteristics overlapped with traditional diverticulitis. 93% of patients had symptom resolution after treatment, while 23.8% experienced complications. These patients exhibited higher rates of hospitalization (87% vs 48%, P = 0.015) and surgery/interventional radiology procedures (27% vs 0, P = 0.002), and worse overall survival (P = 0.022). History of diverticulitis was not associated with a more severe disease course. Immunosuppressants (e.g., corticosteroids) were rarely required unless for concurrent ICI-mediated colitis. CONCLUSION: Colonic diverticulitis can occur after ICI therapy at very low incidence (0.5%). Its clinical presentation, evaluation, and management are similar to traditional diverticulitis, but associated with higher complication rates requiring surgical intervention and has lower overall survival.