[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high­dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.

BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.

Safety and efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors: A single center experience.

Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.

Evaluation of the effects of different photosensitizers used in antimicrobial photodynamic therapy on tooth discoloration: spectrophotometric analysis.

BACKGROUND: Tooth discoloration is a common concern in antimicrobial photodynamic therapy (aPDT) using various photosensitizers (PS). Toluidine Blue (TB), Methylene Blue (MB), Phthalocyanine (Pc), and 2-mercaptopyridine-substituted zinc phthalocyanine (TM-ZnPc) are among those studied, but their relative impacts on tooth discoloration remain unclear. AIM: This study aimed to compare the effects of TB, MB, Pc, and TM-ZnPc in aPDT on tooth discoloration, utilizing a controlled experimental setup. MATERIALS AND METHODS: The study comprised seventy-five single-rooted incisors with root canals. Following meticulous preparation, a standardized area on the crown surface was designated for examination, and precise measurements of the initial tooth colors were recorded. Samples were randomly divided into five groups: Negative control, MB, TM, Pc, and TM-ZnPc. Photoactivation was performed using LED light, and color measurements were taken at multiple time points up to 90 days. Data were converted to Lab* color values of the CIE Lab* color system (International Commission on Illumination, Vienna, Austria), and ΔE values were calculated. Statistical analysis was performed using Two-way ANOVA and Post-Hoc Tukey tests (p < 0.05). RESULTS: At day 7 and 30, TM-ZnPc and Pc caused less discoloration compared to MB and TB. TM-ZnPc caused more tooth discoloration compared to Pc (p < 0.05). Compared to baseline, MB and TM-ZnPc caused more tooth discoloration at 30 days and TB caused more tooth discoloration at 90 days (p < 0.05). No significant difference was observed in terms of tooth discoloration at all periods evaluated after Pc application (p > 0.05). All photosensitizers tested in the study caused tooth coloration. CONCLUSION: All PS induced clinically detectable tooth discoloration, with TB and MB causing more significant discoloration compared to Pc and TM-ZnPc at certain time points. TM-ZnPc and Pc demonstrated more stable coloration levels over time, suggesting their potential reliability in aPDT applications. This study highlights the importance of selecting appropriate PS to minimize tooth discoloration in aPDT, with Pc showing promise in this regard.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

Inversion recovery and saturation recovery pulmonary vein MR angiography using an image based navigator fluoro trigger and variable-density 3D cartesian sampling with spiral-like order.

Contrast enhanced pulmonary vein magnetic resonance angiography (PV CE-MRA) has value in atrial ablation pre-procedural planning. We aimed to provide high fidelity, ECG gated PV CE-MRA accelerated by variable density Cartesian sampling (VD-CASPR) with image navigator (iNAV) respiratory motion correction acquired in under 4 min. We describe its use in part during the global iodinated contrast shortage. VD-CASPR/iNAV framework was applied to ECG-gated inversion and saturation recovery gradient recalled echo PV CE-MRA in 65 patients (66 exams) using .15 mmol/kg Gadobutrol. Image quality was assessed by three physicians, and anatomical segmentation quality by two technologists. Left atrial SNR and left atrial/myocardial CNR were measured. 12 patients had CTA within 6 months of MRA. Two readers assessed PV ostial measurements versus CTA for intermodality/interobserver agreement. Inter-rater/intermodality reliability, reproducibility of ostial measurements, SNR/CNR, image, and anatomical segmentation quality was compared. The mean acquisition time was 3.58 ± 0.60 min. Of 35 PV pre-ablation datasets (34 patients), mean anatomical segmentation quality score was 3.66 ± 0.54 and 3.63 ± 0.55 as rated by technologists 1 and 2, respectively (p = 0.7113). Good/excellent anatomical segmentation quality (grade 3/4) was seen in 97% of exams. Each rated one exam as moderate quality (grade 2). 95% received a majority image quality score of good/excellent by three physicians. Ostial PV measurements correlated moderate to excellently with CTA (ICCs range 0.52-0.86). No difference in SNR was observed between IR and SR. High quality PV CE-MRA is possible in under 4 min using iNAV bolus timing/motion correction and VD-CASPR.

Site-selective antibody-lipid conjugates for surface functionalization of red blood cells and targeted drug delivery.

Displaying antibodies on carrier surfaces facilitates precise targeting and delivery of drugs to diseased cells. Here, we report the synthesis of antibody-lipid conjugates (ALCs) through site-selective acetylation of Lys 248 in human Immunoglobulin G (IgG) and the development of antibody-functionalized red blood cells (immunoRBC) for targeted drug delivery. ImmunoRBC with the HER2-selective antibody trastuzumab displayed on the surface (called Tras-RBC) was constructed following a three-step procedure. First, a peptide-guided, proximity-induced reaction transferred an azidoacetyl group to the ε-amino group of Lys 248 in the Fc domain. Second, the azide-modified IgG was subsequently conjugated with dibenzocyclooctyne (DBCO)-functionalized lipids via strain-promoted azide-alkyne cycloaddition (SPAAC) to result in ALCs. Third, the lipid portion of ALCs was then inserted into the cell membranes, and IgGs were displayed on red blood cells (RBCs) to construct immunoRBCs. We then loaded Tras-RBC with a photosensitizer (PS), Zinc phthalocyanine (ZnPc), to selectively target HER2-overexpressing cells, release ZnPc into cancer cells following photolysis, and induce photodynamic cytotoxicity in the cancer cells. This work showcases assembling immunoRBCs following site-selective lipid conjugation on therapeutic antibodies and the targeted introduction of PS into cancer cells. This method could apply to the surface functionalization of other membrane-bound vesicles or lipid nanoparticles for antibody-directed drug delivery.

Comparison of Intralesional Sodium Stibogluconate versus Intralesional Meglumine Antimoniate for the Treatment of Leishmania major Cutaneous Leishmaniasis.

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.

Magnetic resonance lymphangiography: Establishing normal.

BACKGROUND: Despite an increased interest in visualizing the lymphatic vessels with magnetic resonance lymphangiography (MRL), little literature is available describing their appearance in nonlymphedematous individuals. To determine lymphatic abnormalities, an understanding of how healthy lymphatic vessels appear and behave needs to be established. Therefore, in this study, MRL of individuals without a history of lymphatic disease was performed. METHODS: A total of 25 individuals (15 women) underwent MRL of their lower limbs using a 3.0 T Philips magnetic resonance imaging scanner (Philips Medical Systems). The first nine participants were recruited to establish the concentration of gadolinium-based contrast agent (GBCA) to administer, with the remainder imaged before and after interdigital forefoot GBCA injections at the optimized dose. Outcomes, including lymphatic vessel diameter, tortuosity, and frequency of drainage via particular drainage routes, were recorded. RESULTS: Healthy lymphatic vessels following the anteromedial pathway were routinely observed in post-contrast T1-weighted images (average tortuosity, 1.09 ± 0.03), with an average of 2.16 ± 0.93 lymphatic vessels with a diameter of 2.47 ± 0.50 mm crossing the anterior ankle. In six limbs, vessels following the anterolateral pathways were observed. No vessels traversing the posterior of the legs were seen. In a subset of 10 vessels, the lymphatic signal, measured at the ankle, peaked 29 minutes, 50 seconds ± 9 minutes, 29 seconds after GBCA administration. No lymphatic vessels were observed in T2-weighted images. CONCLUSIONS: Contrast-enhanced MRL reliably depicts the lymphatic vessels in the legs of healthy controls. Following interdigital contrast injection, anteromedial drainage appears dominant. Quantitative measures related to lymphatic vessel size, tortuosity, and drainage rate are readily obtainable and could be beneficial for detecting even subtle lymphatic impairment.

Impact of late gadolinium enhancement image acquisition resolution on neural network based automatic scar segmentation.

BACKGROUND: Automatic myocardial scar segmentation from late gadolinium enhancement (LGE) images using neural networks promises an alternative to time-consuming and observer-dependent semi-automatic approaches. However, alterations in data acquisition, reconstruction as well as post-processing may compromise network performance. The objective of the present work was to systematically assess network performance degradation due to a mismatch of point-spread function between training and testing data. METHODS: Thirty-six high-resolution (0.7×0.7×2.0 mm3) LGE k-space datasets were acquired post-mortem in porcine models of myocardial infarction. The in-plane point-spread function and hence in-plane resolution Δx was retrospectively degraded using k-space lowpass filtering, while field-of-view and matrix size were kept constant. Manual segmentation of the left ventricle (LV) and healthy remote myocardium was performed to quantify location and area (% of myocardium) of scar by thresholding (≥ SD5 above remote). Three standard U-Nets were trained on training resolutions Δxtrain = 0.7, 1.2 and 1.7 mm to predict endo- and epicardial borders of LV myocardium and scar. The scar prediction of the three networks for varying test resolutions (Δxtest = 0.7 to 1.7 mm) was compared against the reference SD5 thresholding at 0.7 mm. Finally, a fourth network trained on a combination of resolutions (Δxtrain = 0.7 to 1.7 mm) was tested. RESULTS: The prediction of relative scar areas showed the highest precision when the resolution of the test data was identical to or close to the resolution used during training. The median fractional scar errors and precisions (IQR) from networks trained and tested on the same resolution were 0.0 percentage points (p.p.) (1.24 - 1.45), and - 0.5 - 0.0 p.p. (2.00 - 3.25) for networks trained and tested on the most differing resolutions, respectively. Deploying the network trained on multiple resolutions resulted in reduced resolution dependency with median scar errors and IQRs of 0.0 p.p. (1.24 - 1.69) for all investigated test resolutions. CONCLUSION: A mismatch of the imaging point-spread function between training and test data can lead to degradation of scar segmentation when using current U-Net architectures as demonstrated on LGE porcine myocardial infarction data. Training networks on multi-resolution data can alleviate the resolution dependency.

Unrecognized myocardial scar by late-gadolinium-enhancement cardiovascular magnetic resonance: Insights from the population-based Hamburg City Health Study.

BACKGROUND: The presence of myocardial scar is associated with poor prognosis in several underlying diseases. Late-gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging reveals clinically silent "unrecognized myocardial scar" (UMS), but the etiology of UMS often remains unclear. This population-based CMR study evaluated prevalence, localization, patterns, and risk factors of UMS. METHODS: The study population consisted of 1064 consecutive Hamburg City Health Study participants without a history of coronary heart disease or myocarditis. UMS was assessed by standard-phase-sensitive-inversion-recovery LGE CMR. RESULTS: Median age was 66 [quartiles 59, 71] years and 37% (388/1064) were females. UMS was detected in 244 (23%) participants. Twenty-five participants (10%) had ischemic, and 217 participants (89%) had non-ischemic scar patterns, predominantly involving the basal inferolateral left-ventricular (LV) myocardium (75%). Two participants (1%) had coincident ischemic and non-ischemic scar. The presence of any UMS was independently associated with LV ejection fraction (odds ratios (OR) per standard deviation (SD) 0.77 (confidence interval (CI) 0.65-0.90), p = 0.002) and LV mass (OR per SD 1.54 (CI 1.31-1.82), p < 0.001). Ischemic UMS was independently associated with LV ejection fraction (OR per SD 0.58 (CI 0.39-0.86), p = 0.007), LV mass (OR per SD 1.74 (CI 1.25-2.45), p = 0.001), and diabetes (OR 4.91 (CI 1.66-13.03), p = 0.002). Non-ischemic UMS was only independently associated with LV mass (OR per SD 1.44 (CI 1.24-1.69), p < 0.001). CONCLUSION: UMS, in particular with a non-ischemic pattern, is frequent in individuals without known cardiac disease and predominantly involves the basal inferolateral LV myocardium. Presence of UMS is independently associated with a lower LVEF, a higher LV mass, and a history of diabetes.

Spectral computed tomography angiography using a gadolinium-based contrast agent for imaging of pathologies of the aorta.

OBJECTIVES: Especially patients with aortic aneurysms and multiple computed tomography angiographies (CTA) might show medical conditions which oppose the use of iodine-based contrast agents. CTA using monoenergetic reconstructions from dual layer CT and gadolinium (Gd-)based contrast agents might be a feasible alternative in these patients. Therefore, the purpose of this study was to evaluate the feasibility of clinical spectral CTA with a Gd-based contrast agent in patients with aortic aneurysms. METHODS: Twenty-one consecutive scans in 15 patients with and without endovascular aneurysm repair showing contraindications for iodine-based contrast agents were examined using clinical routine doses (0.2 mmol/kg) of Gd-based contrast agent with spectral CT. Monoenergetic reconstructions of the spectral data set were computed. RESULTS: There was a significant increase in the intravascular attenuation of the aorta between pre- and post-contrast images for the MonoE40 images in the thoracic and the abdominal aorta (p < 0.001 for both). Additionally, the ratio between pre- and post-contrast images was significantly higher in the MonoE40 images as compared to the conventional images with a factor of 6.5 ± 4.5 vs. 2.4 ± 0.5 in the thoracic aorta (p = 0.003) and 4.1 ± 1.8 vs. 1.9 ± 0.5 in the abdominal aorta (p < 0.001). CONCLUSIONS: To conclude, our study showed that Gd-CTA is a valid and reliable alternative for diagnostic imaging of the aorta for clinical applications. Monoenergetic reconstructions of computed tomography angiographies using gadolinium based contrast agents may be a useful alternative in patients with aortic aneurysms and contraindications for iodine based contrast agents.

A pilot study evaluating high dose esomeprazole, bismuth subcitrate and amoxicillin for eradicating Helicobacter pylori infection in Iran.

BACKGROUND: Helicobacter pylori (H. pylori) is strongly associated with peptic ulcer disease and gastric cancer. We evaluated two triple therapy regimens comprising esomeprazole, high dose bismuth, and different doses of amoxicillin for first-line H. pylori eradication. MATERIALS AND METHODS: Two hundred patients with dyspepsia and naive H. pylori infection were randomly assigned into two groups (n = 100). Both groups were treated for 14 days similarly with esomeprazole (40 mg, twice daily) and bismuth subcitrate (240 mg, three times daily), but the dose of amoxicillin was varied between Groups A (750 mg) and B (1000 mg) three times daily. Treatment compliance and side effect were evaluated following the therapies and after 8 weeks, a negative test of stool H. pylori antigen confirmed eradication. RESULTS: The two groups were comparable with respect to sex and age. According to intention to treat analysis, eradication rates were 80% (95% CI: 77.2%-82.8%) and 90% (95% CI: 84.1%-95.9%) in A and B groups, respectively (p = 0.22). Per-protocol eradication rates were 87% (95% CI: 80.4%-93.6%) and 92.8% (95% CI: 87.7%-97.9%), respectively (p = 0.23). Severe adverse effects were 3% and 2%, respectively (p = 0.34). CONCLUSION: High dose esomeprazole, amoxicillin and bismuth achieved 92.8% cure rates per protocol in a country with a high background rate of resistance. Additional studies are needed to ascertain whether this therapy can be further improved. Until then, it can be recommended as a first-line H. pylori eradication in north of Iran.

Translating a radiolabeled imaging agent to the clinic.

Molecular Imaging is entering the most fruitful, exciting period in its history with many new agents under development, and several reaching the clinic in recent years. While it is unusual for just one laboratory to take an agent from initial discovery through to full clinical approval the steps along the way are important to understand for all interested participants even if one is not involved in the entire process. Here, we provide an overview of these processes beginning at discovery and preclinical validation of a new molecular imaging agent and using as an exemplar a low molecular weight disease-specific targeted positron emission tomography (PET) agent. Compared to standard drug development requirements, molecular imaging agents may benefit from a regulatory standpoint from their low mass administered doses, they nonetheless still need to go through a series of well-defined steps before they can be considered for Phase 1 human testing. After outlining the discovery and preclinical validation approaches, we will also discuss the nuances of Phase 1, Phase 2 and Phase 3 studies that may culminate in an FDA general use approval. Finally, some post-approval aspects of novel molecular imaging agents are considered.

Sodium picosulfate/magnesium citrate versus 4L split-dose polyethylene glycol for bowel cleansing prior to colonoscopy in high fibre diet African patients.

INTRODUCTION: an adequate bowel preparation is essential for good mucosal inspection during colonoscopy. This study aims to compare the efficacy of two validated oral lavage solutions for colonoscopy preparation in African patients. METHODS: a prospective observational study of patients undergoing colonoscopy in a referral endoscopy facility in Port Harcourt, Nigeria, using sodium picosulfate magnesium citrate (SPMC) and 4L split-dose polyethylene glycol (PEG). Variables collated were sociodemographic, primary indication, comorbidities, Aronchick bowel preparation scale, polyp/adenoma detection, caecal intubation and outcome. Statistical analysis was performed using IBM SPSS version 20. RESULTS: one hundred and twenty-four patients received PEG prior to colonoscopy and SPMC in 175 patients. The age range was from 22 to 92 years; mean age of 53.8 ± 14.2 years for PEG group and 55.3 ± 13.2 years for SPMC group (p=0.361). There were 215 males and 84 females. An excellent/good bowel preparation scale was recorded in 77 (62%) PEG group and 130 (74.3%) for SPMC group (p=0.592). PEG was predominantly used in the early years of endoscopists practice with the odds ratio (OR) of no polyp detection in the PEG vs SPMC groups as 1.64 (confidence interval CI 1.06-2.55) versus 0.76 (CI 0.62-0.92), respectively (p=0.016). For no adenoma detection, OR was 4.18 (CI 1.12-15.60) versus OR 0.63 (CI 0.52-0.75), respectively (p=0.012). CONCLUSION: there is similar efficacy profile using either split volume PEG or SPMC prior to colonoscopy in these African patients. Polyp and adenoma detection rates are highly dependent on the expertise of the endoscopist.

Functional and histologic imaging of urinary bladder wall after exposure to psychological stress and protamine sulfate.

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Magnetic resonance imaging with intravenous gadoteridol injection based on 3D-real IR sequence of the inner ear in Meniere's disease patient: feasibility in 3.5-h time interval.

BACKGROUND: Intravenous gadoteridol injection can be applied to visualize endolymphatic hydrops (EH). AIMS/OBJECTIVES: To explore whether 3.5-h time interval was feasible for clinical practice. MATERIALS AND METHODS: We collected 70 unilateral Meniere's disease (MD) patients who were divided into two groups randomly (group A: 3.5-h time interval; group B: 4-h time interval). Among the two groups, the signal intensity (SI) in perilymphatic area of the basal turn of cochlea, the results of visual evaluations in the vestibule, cochlea and semicircular canal and the detection results of EH were compared. RESULTS: Regarding the SI, no difference was found between A-affected ears and B-affected ears (p=.499), and no difference was found between A-unaffected ears and B-unaffected ears (p=.111). However, a difference was found between A-affected ears and A-unaffected ears (p=.005), and a difference was found between B-affected ears and B-unaffected ears (p=.012). Besides, no difference was found between the visual evaluations in the vestibule, cochlea, and semicircular canal of the two groups. Regarding the detection results of EH, no difference was found between the two groups (all p>.05). CONCLUSIONS AND SIGNIFICANCE: In the clinical application of gadoteridol for the inner ear, 3.5-h delayed MR imaging is feasible.

Targeted Delivery of Zinc Pyrithione to Skin Epithelia.

Zinc pyrithione (ZnPT) is an anti-fungal drug delivered as a microparticle to skin epithelia. It is one of the most widely used ingredients worldwide in medicated shampoo for treating dandruff and seborrheic dermatitis (SD), a disorder with symptoms that include skin flaking, erythema and pruritus. SD is a multi-factorial disease driven by microbiol dysbiosis, primarily involving Malassezia yeast. Anti-fungal activity of ZnPT depends on the cutaneous availability of bioactive monomeric molecular species, occurring upon particle dissolution. The success of ZnPT as a topical therapeutic is underscored by the way it balances treatment efficacy with formulation safety. This review demonstrates how ZnPT achieves this balance, by integrating the current understanding of SD pathogenesis with an up-to-date analysis of ZnPT pharmacology, therapeutics and toxicology. ZnPT has anti-fungal activity with an average in vitro minimum inhibitory concentration of 10-15 ppm against the most abundant scalp skin Malassezia species (Malassezia globosa and Malassezia restrica). Efficacy is dependent on the targeted delivery of ZnPT to the skin sites where these yeasts reside, including the scalp surface and hair follicle infundibulum. Imaging and quantitative analysis tools have been fundamental for critically evaluating the therapeutic performance and safety of topical ZnPT formulations. Toxicologic investigations have focused on understanding the risk of local and systemic adverse effects following exposure from percutaneous penetration. Future research is expected to yield further advances in ZnPT formulations for SD and also include re-purposing towards a range of other dermatologic applications, which is likely to have significant clinical impact.

An automated synthesis of 177Lu-EDTMP as an efficient bone-seeking therapeutic radiopharmaceutical.

OBJECTIVE: Radiolabeled bisphosphonates have found wide clinical use in nuclear medicine for palliative therapy of bone metastases. 177Lu-EDTMP was used to relieve metastatic bone pain in patients with breast or prostate cancer. The therapeutic efficacy of 177Lu-EDTMP at 1-, 3-, 6-, and 8-weeks post-therapy was evaluated using Standard Pain Scoring Assessment Criteria. In addition, toxicity was evaluated in terms of hematological parameters using the Common Terminology Criteria for Adverse Events V4.0. PATIENTS AND METHODS: A fully automated synthesis of 177Lu-EDTMP was achieved in this study with high radiochemical efficiency and high radiochemical purity. During the study, 75 patients (57 M: 18 F, mean age: 68.0 ± 11.1 years) of breast/prostate cancer with documented skeletal metastases were included. Patients were administered intravenously with 177Lu-EDTMP at a dose rate of 22.2-37.0 MBq/kg following a fully automated synthesis of 177Lu-EDTMP using a disposable cassette system. RESULTS: Among the 75 patients all treated with 177Lu-EDTMP, 59 patients were responsive and the remaining 16 patients did not respond to the therapy. Mean pain score values in the responder group were 5.60 ± 0.5, 4.3 ± 0.1, 2.6 ± 0.4 and 1.4 ± 0.7 at weeks 1, 3, 6, and 8, respectively. Also, the mean pain score decreased from a baseline score of 7.6 ± 1.6 to 1.4 ± 0.7 at week 8 in the responder group. Statistical analysis of the pain score data showed a significant decrease in pain score after each radiopharmaceutical treatment, compared to the baseline scores (p <0.0001). Mild to severe toxicity was observed in two patients each treated with 177Lu-EDTMP. CONCLUSIONS: These findings demonstrated that the 177Lu-EDTMP radiopharmaceutical could be used safely to achieve considerable therapeutic efficacy, in metastatic bone pain palliation together with the safe clinical application and low radiation exposure during preparation.

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.

Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer.

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.