[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.

Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate (177 Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.

Salvaging donated kidneys from prolonged warm ischemia during ex vivo hypothermic oxygenated perfusion.

Prolonged warm ischemic is the main cause discarding donated organs after cardiac death. Here, we identified that prolonged warm ischemic time induced disseminated intravascular coagulation and severe capillary vasospasm after cardiac death of rat kidneys. Additionally, we found a significant accumulation of fibrinogen in a hypoxic cell culture of human umbilical vein epithelial cells and in isolated kidneys exposed to prolonged warm ischemic following flushing out of blood. However, pre-flushing the kidney with snake venom plasmin in a 90-minute warm ischemic model maximized removal of micro thrombi and facilitated the delivery of oxygen and therapeutic agents. Application of carbon monoxide-releasing CORM-401 during ex vivo hypothermic oxygenated perfusion achieved multipath protective effects in prolonged warm ischemic kidneys. This led to significant improvements in perfusion parameters, restoration of the microcirculation, amelioration of mitochondrial injury, oxidative stress, and apoptosis. This benefit resulted in significantly prolonged warm ischemic kidney recipient survival rates of 70%, compared with none in those receiving ex vivo hypothermic oxygenated perfusion alone. Significantly, ex vivo hypothermic oxygenated perfusion combined with cytoprotective carbon monoxide releasing CORM-401 treatment meaningfully protected the donated kidney after cardiac death from ischemia-reperfusion injury by reducing inflammation, oxidative stress, apoptosis, and pathological damage. Thus, our study suggests a new combination treatment strategy to potentially expand the donor pool by increasing use of organs after cardiac death and salvaging prolonged warm ischemic kidneys.

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.

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.

A randomized prospective study comparing the effect of low-volume bowel preparations for colonoscopy preparation in China.

AIM: To evaluate the effect of sodium picosulfate/magnesium citrate (SPMC) and 3 L split-dose polyethylene glycol (PEG) with or without dimethicone on bowel preparation before colonoscopy. METHODS: In this multicenter, prospective, randomized, controlled study conducted from April 2021 to December 2021, consecutive adult patients scheduled for colonoscopy were prospectively randomized into four groups: SPMC, SPMC plus dimethicone, 3 L PEG, and 3 L PEG plus dimethicone. Primary endpoint was colon cleansing based on Boston Bowel Preparation Scale (BBPS). Secondary endpoints were bubble score, time to cecal intubation, adenoma detection rate (ADR), patient safety and compliance, and adverse events. RESULTS: We enrolled 223 and 291 patients in SPMC and 3 L PEG group, respectively. The proportion with acceptable bowel cleansing, total BBPS score and cecal intubation time were similar in all four subgroups (p > 0.05). Patient-reported acceptability and tolerability was significantly greater in SPMC than 3 L PEG group (p < 0.001); adverse events were significantly lower in SPMC than latter group (p < 0.001). ADR in both groups was greater than 30%. CONCLUSION: SPMC had significantly higher acceptability and tolerability than 3 L PEG, however, was similar in terms of bowel-cleansing effect and cecal intubation time and hence can be used before colonoscopy preparation.

Efficacy and safety of same-day preparation with sodium picosulfate plus magnesium citrate on the day of colonoscopy for bowel preparation: Multicenter, single-arm, open-label study.

BACKGROUND AND AIM: Sodium picosulfate plus magnesium citrate (SP + MC) is a well-tolerated bowel preparation agent. However, Japan currently approves only two methods of taking SP + MC: the day-before and split-dose preparation, without approval of same-day preparations. This study aimed to evaluate the efficacy and safety of same-day SP + MC preparations. METHODS: This was a multicenter, single-arm, nonrandomized, open-label study. We enrolled 145 Japanese patients between June and December 2023. The patients received two sachets of SP + MC dissolved in 300 ml of water and 1200 mL or more of clear liquid on the day of colonoscopy. Bowel cleansing efficacy, adverse events (AEs), and patient satisfaction were evaluated. RESULTS: Of the enrolled patients, 137 underwent colonoscopy according to our protocol. Bowel preparation was adequate in 133 patients (97.1%). The mean total Boston Bowel Preparation Score was 8.3 ± 1.2. Five patients experienced AEs (3.6%): two (1.5%), abdominal pain; one (0.73%), ischemic enteritis; one (0.73%), vomiting or nausea; and one (0.73%), headache. All AEs were treated conservatively. None of the patients exhibited abnormal blood test results or clinical symptoms after receiving SP + MC. Regarding patient satisfaction, all patients were able to take SP + MC as directed; 136 (99.2%) expressed a preference for this bowel preparation for future colonoscopies. CONCLUSION: The same-day SP + MC preparation showed high bowel-cleansing efficacy and satisfaction in Japanese patients without serious AEs.

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.

Neurobehavioral assessment of BMEDA by modified Irwin test in Sprague-Dawley rats.

The neurobehavioral assessment of N,N-bis(2-mercapatoethly)-N',N'-diethylenediamine (BMEDA), which can form a chelate with rhenium-188 (188Re) to produce the 188Re-BMEDA-liposome, was evaluated. The purpose of this study was to evaluate the potential neurobehavioral changes by using the functional observational battery observation procedures when intravenous injection of BMEDA to Sprague-Dawley rats. Rats were administered BMEDA at dose levels of 1, 2, and 5 mg/kg. No mortalities were observed. There are some observations related to BMEDA treatment found in the 5 mg/kg dose group at 10 min post-dose. Tremor was observed in one male rat and seven female rats. The increased respiration, vocalization, not easy to handle and/or loss of tone in the limb were observed in both males and females, and increased body temperature was observed in male animals. Based on the results, a single intravenous dose of BMEDA administered to rats resulted in increased respiration, vocalization, not easy to handle and/or loss of tone in the limb increasing at the dose level of 5 mg/kg. No neurobehavioral effects were noted after BMEDA administration up to the dose level of 2 mg/kg. The information of this study will provides a point of reference to design appropriately therapeutic studies for future human use.

Antitumor effect of nanophotothermolysis mediated by zinc phthalocyanine particles.

Nanophotothermolysis (NPhT) effect is considered to be an approach for the development of highly selective modalities for anticancer treatment. Herein, we evaluated an antitumor efficacy of NPhT with intravenously injected zinc phthalocyanine particles (ZnPcPs) in murine subcutaneous syngeneic tumor models. In S37 sarcoma-bearing mice a biodistribution of ZnPcPs was studied and the high antitumor efficacy of ZnPcPs-mediated NPhT was shown, including a response of metastatic lesions. The morphological investigation showed the main role of a local NPhT-induced vascular damage in the tumor growth and tumor spread inhibition. Murine tumors of different histological origin were not equally sensitive to the treatment. The results demonstrate a potential of ZnPcPs-mediated NPhT for treatment of surface tumors.

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.

CXCR4-Binding Positron Emission Tomography Tracers Link Monocyte Recruitment and Endothelial Injury in Murine Atherosclerosis.

OBJECTIVE: vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 (viral chemotactic cytokine ligand 2) binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer (64Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe-/- mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64Cu-DOTA-vMIP-II at Apoe-/- plaque sites was strong but declined with AAV-mApoE-induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. CONCLUSIONS: Endothelial injury status of plaques is marked by CXCR4 expression and this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.

Near-infrared-traceable DNA nano-hydrolase: specific eradication of telomeric G-overhang in vivo.

Telomeric DNA, whose length homeostasis is closely correlated with immortality of cancer cells, is regarded as a molecular clock for cellular lifespan. Regarding the capacity in forming G-quadruplex, G-rich 3'-overhang (G-overhang) has been considered as an attractive anticancer target. However, it is still challenging to precisely target telomeric G-overhang with current ligands because of the polymorphism of G-quadruplexes in cells. Herein, we construct a telomeric G-overhang-specific near-infrared-traceable DNA nano-hydrolase, which is composed of four parts: (i) dexamethasone for targeting cell nuclei; (ii) complementary DNA for hybridizing with G-overhang; (iii) multinuclear Ce(IV) complexes for hydrolyzing G-overhang; and (iv) upconversion nanoparticles for real-time tracking. The multivalent targeted DNA nano-hydrolase can be traced to precisely digest telomeric G-overhang, which contributes to telomeric DNA shortening and thereby causes cell aging and apoptosis. The anticancer treatment is further proved by in vivo studies. In this way, this design provides a telomeric G-overhang-specific eradication strategy based on a non-G-quadruplex targeting manner.

Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi-institutional randomized controlled trial.

Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.

Effects of zinc porphyrin and zinc phthalocyanine derivatives in photodynamic anticancer therapy under different partial pressures of oxygen in vitro.

Photodynamic therapy (PDT) is gradually becoming an alternative method in the treatment of several diseases. Here, we investigated the role of oxygen in photodynamically treated cervical cancer cells (HeLa). The effect of PDT on HeLa cells was assessed by exposing cultured cells to disulphonated zinc phthalocyanine (ZnPcS2) and tetrasulphonated zinc tetraphenylporphyrin (ZnTPPS4). Fluorescence microscopy revealed their different localizations within the cells. ZnTPPS4 seems to be mostly limited to the cytosol and lysosomes, whereas ZnPcS2 is most likely predominantly attached to membrane structures, including plasmalemma and the mitochondrial membrane. Phototoxicity assays of PDT-treated cells carried out under different partial pressures of oxygen showed dose-dependent responses. Interestingly, ZnPcS2 was also photodynamically effective at a minimal level of oxygen, under a nitrogen atmosphere. On the other hand, hyperbaric oxygenation did not lead to a higher PDT efficiency of either photosensitizer. Although both photosensitizers can induce a significant drop in mitochondrial membrane potential, ZnPcS2 has a markedly higher effect on mitochondrial respiration that was completely blocked after two short light cycles. In conclusion, our observations suggest that PDT can be effective even in hypoxic conditions if a suitable sensitizer is chosen, such as ZnPcS2, which can inhibit mitochondrial respiration.

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 .

177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants.

OBJECTIVE: To retrospectively analyze toxicity, progression-free survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe-r-apy, undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. METHODS: A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6- to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached. RESULTS: A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden >50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow. CONCLUSION: 177Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS.

Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.

INTRODUCTION: The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment. OBJECTIVE: To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity. METHODS: 68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time. RESULTS: A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes. CONCLUSIONS: No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.