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.

Clinical Efficacy of Reduced-Dose Gadobutrol Versus Standard-Dose Gadoterate for Contrast-Enhanced MRI of the CNS: An International Multicenter Prospective Crossover Trial (LEADER-75).

BACKGROUND. Gadobutrol and gadoterate are widely used macrocyclic gadolinium-based contrast agents. Given gadobutrol's higher T1 relaxivity, a reduced gadobutrol dose should achieve essentially equivalent diagnostic efficacy as a standard dose of gadoterate. OBJECTIVE. The purpose of our study was to show efficacy of a 25% reduced dose of gadobutrol is noninferior to 100% standard dose of gadoterate for contrast-enhanced MRI of the CNS. METHODS. In this international prospective multicenter open-label crossover trial (LEADER-75 [Lower Administered Dose With Higher Relaxivity: Gadovist vs Dotarem]), adult patients with known or suspected CNS pathology underwent contrast-enhanced brain MRI with standard-dose gadoterate (0.1 mmol/kg); if an enhancing lesion was identified, a second MRI with reduced-dose gadobutrol (0.075 mmol/kg) was performed within 15 days of the first MRI. Three radiologists independently reviewed images to score three primary efficacy measures: subjective lesion enhancement, lesion border delineation, lesion internal morphology. A noninferiority analysis used readers' mean scores of the primary efficacy measures. Noninferiority of reduced-dose gadobutrol to standard-dose gadoterate for primary efficacy measures was defined as the difference in score between reduced-dose gadobutrol images and unenhanced images achieving at least 80% of the difference in score between standard-dose gadoterate images and unenhanced images. A post hoc analysis was performed to directly compare contrast-enhanced images for equivalence. Secondary efficacy variables included the number of lesions detected, reader confidence, diagnostic performance for malignancy, and reader preference in side-by-side comparison. RESULTS. The efficacy analysis included 141 patients (78 men, 63 women; mean age, 58.5 ± 13.5 [SD] years). Improvement of reduced-dose gadobutrol over unenhanced images was noninferior to improvement of standard-dose gadoterate over unenhanced images using a 20% noninferiority margin for all three primary efficacy measures using mean readings (p ≤ .025). In the post hoc analysis, the mean reading for the three primary efficacy measures differed by less than 1% between reduced-dose gadobutrol and standard-dose gadoterate, supporting equivalence of all measures using a narrow ± 5% margin (p ≤ .025). The total number of lesions detected by mean reading was 301 for reduced-dose gadobutrol versus 291 for standard-dose gadoterate. Mean reader confidence was 3.3 ± 0.6 for reduced-dose gadobutrol versus 3.3 ± 0.6 for standard-dose gadoterate. Sensitivity (58.7%), specificity (91.8%), and accuracy (70.2%) for malignancy from majority reading were identical for reduced-dose gadobutrol and standard-dose gadoterate. Reader preference was not different (95% CI, -0.10 to 0.11). CONCLUSION. A 25% reduced dose of gadobutrol is noninferior to standard-dose gadoterate for contrast-enhanced brain MRI. CLINICAL IMPACT. Use of reduced-dose gadobutrol should be considered for brain MRI, particularly in patients undergoing multiple contrast-enhanced examinations. TRIAL REGISTRATION. ClinicalTrials.gov NCT03602339; EU Clinical Trials Register EudraCT 2018-00690-78.

Patient external dose rate after 177Lu-DOTATATE therapy: factors affecting its decrease and predictive value.

Rationale: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE (oxodotreotide) results in external radiation exposure from the patient. In the PREELU observational prospective study, we determined the equivalent dose rate at 1 m of the patient (EDR-1m) for a period following PRRT. The main objective was to predict which patients could be discharged from the hospital at approximately 3 h after the administration of 177Lu-DOTATATE, i.e. at the end of the infusion of amino-acids according to our PRRT protocol. As presenting no undue risk of radiation exposure for the public, those patients could be treated as outpatients or day patients, rather than inpatients. Methods: We sequentially measured EDR-1m facing the sternum and then the pelvis during 50 PRRT in 24 patients with metastatic neuroendocrine tumours, each 30 minutes after ending administration of Lutathera, over at least 180 minutes. Results: 180 minutes after the administration of ca. 7400 MBq of Lutathera, EDR-1m was <40 µSv/h in all cases, and <25 µSv/h in 32 cases (64%). After an overnight hospital stay, EDR-1m was <25 µSv/h in all cases. The EDR-1m value measured facing the sternum was the greatest in about one-fourth of paired measurements. In patients whose creatinine clearance was >96 mL/min/1.73m2, the EDR-1m was most likely (predictive value=90%) to drop below 25 µSv/h within 180 minutes after the administration of Lutathera. In 16 patients who benefited from several PRRT cycles, the creatinine clearance did not decrease significantly from one cycle to the next, probably due to the kidney protection by the amino-acid infusion. The patients whose EDR-1m dropped below 25 µSv/h at 180 minutes during their first PRRT cycle were unlikely (predictive value= 88%) to decease during the following two years. Conclusion: All patients could have been discharged 3 h after administration according to the criterion EDR-1m <40 µSv/h. Using EDR-1m <25 µSv/h as criterion, an extended hospital stay beyond 3 h would have been necessary in around one-third of the PRRT treatments and could be anticipated based on creatinine clearance ≤96 mL/min/1.73m2. EDR-1m <25 µSv/h at 180 min during the first PRRT yielded a strong predictive value on the patient's survival at two years, a finding that should be confirmed in future studies.

A toxicological evaluation of lithium orotate.

Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless, there have been some concerns in the scientific literature regarding orotic acid, and pharmaceutical lithium salts are known to have a narrow therapeutic window, albeit, at lithium equivalent therapeutic doses 5.5-67 times greater than typically recommended for supplemental lithium orotate. To our knowledge, the potential toxicity of lithium orotate has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test in order to further explore its safety. Lithium orotate was not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 28-day, repeated-dose oral toxicity study, rats were administered 0, 100, 200, or 400 mg/kg body weight/day of lithium orotate by gavage. No toxicity or target organs were identified; therefore, a no observed adverse effect level was determined as 400 mg/kg body weight/day. These results are supportive of the lack of a postmarket safety signal from several decades of human consumption.

Comparison of Nausea and Vomiting Associated With Amino Acid Formulations Coinfused With Peptide Receptor Radionuclide Therapy: Commercial Parenteral Nutrition Formulas Versus Compounded Arginine/Lysine.

OBJECTIVES: Positively charged amino acids (AA) such as arginine/lysine are coinfused with radiolabeled somatostatin analogs to reduce rates of nephrotoxicity. In the phase 3 NETTER-1 trial, commercial AA formulations were used in association with 177Lu-DOTA-0-Tyr3-Octreotate (DOTATATE). These formulations were also used in an early-access program (EAP) before regulatory approval of 177Lu-DOTATATE. Our program transitioned to compounded l-arginine 2.5%/l-lysine 2.5% in 0.9% NaCl after commercial approval of 177Lu-DOTATATE. We sought to compare rates of nausea/vomiting with arginine/lysine versus commercial parenteral AA formulations. METHODS: Rates of nausea/vomiting of all 20 EAP patients who received commercial AAs (15% Clinisol) were compared with the first 29 patients to receive 177Lu-DOTATATE after commercial approval and coinfused with arginine/lysine. Other parameters reviewed included infusion rates, need for PRN nausea medications, and other toxicities. RESULTS: Seventeen percent of patients who received compounded arginine/lysine experienced nausea, compared with 100% of patients in the EAP group (P < 0.0001). Infusion-related reactions occurred in 3% of the arginine/lysine cohort versus 35% in the EAP group. Infusion durations were substantially shorter in the arginine/lysine cohort (reduced by 61%). CONCLUSIONS: Coinfusions of arginine/lysine with radiolabeled somatostatin analogs result in substantially lower rates of nausea/vomiting compared with commercial AA formulations designed for parenteral nutrition.

Delivery of oxaliplatin to colorectal cancer cells by folate-targeted UiO-66-NH2.

Oxaliplatin is being used in different malignancies and several side effects are reported for patients taking Oxaliplatin, including peripheral neuropathy, nausea and vomiting, diarrhea, mouth sores, low blood counts, fatigue, loss of appetite, etc. Here we have developed a targeted anticancer drug delivery system based on folate-conjugated amine-functionalized UiO-66 for the delivery of oxaliplatin (OX). UiO-66-NH2 (U) and UiO-66-NH2-FA(FU) were pre-functionalized by the incorporation of folic acid (FA) into the structure via coordination of the carboxylate group of FA. The FTIR spectra of drug-loaded U and FU showed the presence of new carboxylic and aliphatic groups of OX and FA. Powder X-ray diffraction (PXRD) patterns were matched accordingly with the reference pattern and FESEM results showed semi-spherical particles (115-128 nm). The evaluated amounts of OX in U and FU were calculated 304.5 and 293 mg/g, respectively. The initial burst release of OX was 15.7% per hour for U(OX) and 10.8% per hour for FU(OX). The final release plateau gives 62.9% and 52.3% for U(OX) and FU(OX). To evaluate the application of the prepared delivery platform, they were tested on colorectal cancer cells (CT-26) via MTT assay, cell migration assay, and spheroid model. IC50 values obtained from MTT assay were 21.38, 95.50, and 18.20 µg/mL for OX, U(OX), and FU(OX), respectively. After three days of treatment, the CT26 spheroids at two doses of 500 and 50 µg/mL of U(OX) and FU(OX) showed volume reduction. Moreover, the oxidative behavior of the prepared systems within the cell was assessed by total thiol, malondialdehyde, and superoxide dismutase activity. The results showed that FU(OX) had higher efficacy in preventing the growth of CT-26 spheroid, and was more effective than oxaliplation in cell migration inhibition, and induced higher oxidative stress and apoptosis.

Efficacy and safety of peptide receptor radionuclide therapy in advanced radioiodine-refractory differentiated thyroid cancer and metastatic medullary thyroid cancer: a systematic review.

BACKGROUND: It has been shown that a subgroup of patients with differentiated thyroid cancer (DTC) and medullary thyroid carcinoma (MTC) would progress to advanced stages of thyroid cancer. Therefore, the present study was done to systematically review available evidence in order to investigate efficacy and safety of peptide receptor radionuclide therapy (PRRT) in the patients with advanced radioiodine refractory differentiated thyroid cancer (RR-DTC) and metastatic MTC. METHODS: For this purpose, relevant studies investigated safety and efficacy of PRRT in the patients with advanced RR-DTC and metastatic MTC were identified by searching Medline (Pubmed, Ovid, and Ebsco), Scopus, Embase, Web of Science, and Cochrane Library databases (from database inception to March 24, 2021). The review was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Searching was done independently by two investigators. Two researchers independently extracted the data and any disagreement was adjudicated by consensus. Quality of the studies was assessed using the tool of case reports/series in systematic reviews. RESULTS: Among 2284 related papers, 41 papers met the inclusion criteria. A total of 157 patients with RR-DTC were treated with PPRT. Biochemical and objective responses (partial and complete) were observed in 25.3 and 10.5% of patients, respectively. Among 220 patients with metastatic MTC, biochemical and objective responses were observed in 37.2 and 10.6% of the patients, respectively. Forty-six deaths were reported in 95 patients with advanced RR-DTC. In addition, 63 deaths were observed in 144 patients with metastatic MTC. Major side effects were reported in 124 patients treated with 90Y -based agent. In the patients treated with 177Lu-DOTA-TATE and 111In-Octreotide, mild and transient hematologic or renal complications were reported. CONCLUSION: Findings of the study revealed that in the absence of the established treatment for the patients with RR-DTC and metastatic MTC, PRRT could be effective with few adverse events. TRIAL REGISTRATION: PROSPERO registration number: CRD42019125245 .

A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms.

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Patterns of use, effectiveness and safety of gadolinium contrast agents: a European prospective cross-sectional multicentre observational study.

BACKGROUND: The EU gadolinium-based contrast agents (GBCA) market has changed in recent years due to the European Medicines Agency decision to suspend the marketing authorisation of linear GBCA and the marketing authorisation of new generic macrocyclic GBCA. The study aims to understand the patterns of (GBCA) use, and to study the effectiveness and safety of GBCA in routine practice across Europe. METHODS: Prospective, cross-sectional, multicentre, observational study in patients undergoing contrast-enhanced magnetic resonance. Reported usage patterns included indication, referral and examination details. Assessment of effectiveness included changes in radiological diagnosis, diagnostic confidence and image quality. Safety data were collected by spontaneous patient adverse event (AE) reporting. RESULTS: 2118 patients were included from 8 centres across 5 European countries between December 2018 and November 2019. Clariscan, Dotarem (gadoteric acid), Gadovist (gadobutrol) and ProHance (gadoteridol) were utilised in 1513 (71.4%), 356 (16.8%), 237 (11.2%) and 12 (0.6%) patients, respectively. Most were performed in CNS-related indications (46.2%). Mean GBCA doses were 0.10 mmol/kg body weight, except for Gadovist (mean 0.12 mmol/kg). GBCA use increased confidence in diagnosis in 96.2% of examinations and resulted in a change in radiological diagnosis in 73.9% of patients. Image quality was considered excellent or good in 96.1% of patients and across all GBCA. Four patients reported AEs (0.19%), with only 1 (0.05%) considered serious. CONCLUSIONS: This European study confirmed that GBCAs are used appropriately in Europe for a wide range of indications. The study demonstrated a significant increase in diagnostic confidence after GBCA use and confirmed the good safety profile of GBCAs, with comparable results for all agents used.

Dual-Sensitive PEG-Sheddable Nanodrug Hierarchically Incorporating PD-L1 Antibody and Zinc Phthalocyanine for Improved Immuno-Photodynamic Therapy.

Tumor immunotherapy like immune checkpoint blockade (ICB) shows great success nowadays but is severely limited by low response rates and immune-related adverse events (IRAEs). While photodynamic therapy (PDT) could efficiently eradicate tumor cells and further induce immune responses to promote activating of T lymphocytes. Herein a nanodrug hierarchically incorporating photosensitizer and PD-L1 antibody was developed for synergistic tumor immuno-photodynamic therapy. A pH/enzyme dual-sensitive polymeric micelle with sheddable PEG coating was designed for codelivery of PD-L1 antibody and zinc phthalocyanine (ZnPc) in the tumor. The tumor microenvironment featuring low pH and high matrix metallopeptidase 2 (MMP-2) sequentially triggered the shedding of PEG and the release of PD-L1 antibody to exert local ICB in tumor tissue, after which the remaining nanodrug with ZnPc undergoing charge reversal was readily delivered into tumor cells. With light irradiation, the photodynamic therapy effect of sAMPc induced immunogenic cell death of tumor cells and further promoted intratumor recruitment of CD8+ T cells, thus resulting in a synergistic immuno-photodynamic therapy with ICB. Moreover, the PEG-sheddable strategy endowed the nanodrug with stealth properties in blood circulation, making the IRAEs of PD-L1 antibody significantly reduced. This pH/MMP-2 dual-sensitive PEG sheddable nanodrug provids a promising strategy for well-combined ICB therapy and PDT to achieve improved anticancer immuno-photodynamic therapy with reduced adverse effects.

CORM-3 exerts a neuroprotective effect in a rodent model of traumatic brain injury via the bidirectional gut-brain interactions.

OBJECTIVE: Traumatic brain injury (TBI) induced the gastrointestinal inflammation that is associated with TBI-related morbidity and mortality. Carbon monoxide-releasing molecule (CORM)-3 is a water-soluble exogenous carbon monoxide that exerts protective effects against inflammation-induced pyroptosis. We investigated the gastrointestinal inflammation in a rodent model of traumatic brain injury (TBI) with subsequent hemorrhagic shock and resuscitation (HSR), as well as effects of CORM-3 using an intestinal injection on both gut and brain. METHODS: Following exposure to TBI plus HSR, rats were administrated with CORM-3 (8 mg/kg) through an intestinal injection after resuscitation immediately. The pathological changes and pyroptosis in the gut were measured at 24 h and 30 day post-trauma. We also assessed the intestinal and cortical CO content, as well as IL-1ß and IL-18 levels in the serum within 48 h after trauma. We then explored pathological changes in the ventromedial prefrontal cortex (vmPFC) and neurological behavior deficits on 30 day post-trauma. RESULTS: After TBI + HSR exposure, CORM-3-treated rats presented significantly decreased pyroptosis, more CO content in the jejunum, and lower IL-1ß, IL-18 levels in the serum at 24 h after trauma. Moreover, the rats treated with CORM-3 exerted ameliorated jejunal and vmPFC injury, enhanced learning/memory ability and exploratory activity, improved anxiety-like behaviors than the TBI + HSR-treated rats on 30 day post-trauma. CONCLUSION: These experimental data demonstrated and bidirectional gut-brain interactions after TBI, anti-inflammatory effects of CORM-3, which may improve late outcomes after brain injury.

Prospective study of dynamic whole-body 68Ga-DOTATOC-PET/CT acquisition in patients with well-differentiated neuroendocrine tumors.

To present the feasibility of a dynamic whole-body (DWB) 68Ga-DOTATOC-PET/CT acquisition in patients with well-differentiated neuroendocrine tumors (WD-NETs). Sixty-one patients who underwent a DWB 68Ga-DOTATOC-PET/CT for a histologically proven/highly suspected WD-NET were prospectively included. The acquisition consisted in single-bed dynamic acquisition centered on the heart, followed by the DWB and static acquisitions. For liver, spleen and tumor (1-5/patient), Ki values (in ml/min/100 ml) were calculated according to Patlak's analysis and tumor-to-liver (TLR-Ki) and tumor-to-spleen ratios (TSR-Ki) were recorded. Ki-based parameters were compared to static parameters (SUVmax/SUVmean, TLR/TSRmean, according to liver/spleen SUVmean), in the whole-cohort and according to the PET system (analog/digital). A correlation analysis between SUVmean/Ki was performed using linear and non-linear regressions. Ki-liver was not influenced by the PET system used, unlike SUVmax/SUVmean. The regression analysis showed a non-linear relation between Ki/SUVmean (R2 = 0.55,0.68 and 0.71 for liver, spleen and tumor uptake, respectively) and a linear relation between TLRmean/TLR-Ki (R2 = 0.75). These results were not affected by the PET system, on the contrary of the relation between TSRmean/TSR-Ki (R2 = 0.94 and 0.73 using linear and non-linear regressions in digital and analog systems, respectively). Our study is the first showing the feasibility of a DWB 68Ga-DOTATOC-PET/CT acquisition in WD-NETs.