Cumulative Activity Research Articles

Biological Effects Associated with Internal and External Contamination of Diagnostic Nuclear Medicine Sources: An In vitro Study.

Aim:In a Nuclear Medicine department, the risk of external and internal contamination in radiation workers is much higher than in other medical radiation facilities. The risk associated with both types of contaminations should be quantified to estimate the radiation dose received by the personal. Here, we designed an in vitro model to see the impact of internal and external contamination of F-18 and Technetium-99 m (Tc-99 m) on DNA damages.Methodology:Chinese hamster lung fibroblast V79 was used for all of the experiments. Irradiation was performed internally and externally (scenarios activity is mixed with the cell line [Internal] and activity kept at 1 cm distance from cell line [external]) using two different diagnostic radioactive sources (Tc-99 m and F-18) of known quantity 37 MBq. Total cumulated activity (MBq-min) was calculated up to one half-life of sources for both internal and external setups. An alkaline single gel electrophoresis technique (comet assay) was used for DNA damage analysis. Olive tail moment (OTM) was used to characterize DNA damage.Results:We have not observed any significant difference (P > 0.05) in OTM between internal and external irradiation for cumulated activity presented before one half-life of both diagnostic isotopes. However, a significant difference in OTM was noted between internal and external irradiation for cumulated activity presented at one half-life of radioactive sources (P < 0.05). DNA damage with internal exposure was found to be 17.28% higher for F-18 and 23% higher for Tc-99 m than external exposure at one half-life of radioactive sources. Overall, we noted greater DNA damage in F-18 as compared to Tc-99 m.Conclusions:Our in vitro study practically demonstrated that internal contamination is more hazardous than external exposure.

Hematological Markers as Predictors of Treatment Outcomes with Lutetium 177 (177Lu)-DOTATATE in Patients with Advanced Neuroendocrine Tumors.

Background: Chronic inflammation has been linked to the development and prognosis of neuroendocrine tumors (NETs). The current study intended to evaluate the role of peripheral hematological inflammatory markers, viz. the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio, and monocyte-lymphocyte ratio, as predictors of treatment outcomes in patients with advanced NETs after Lutetium-177(177Lu)-DOTATATE therapy. Materials and Methods: Data of consecutive patients with advanced metastatic and/or inoperable NETs treated with 177Lu-DOTATATE from the year 2012 to 2019 at the authors' center were retrospectively analyzed. Results: Forty-two NET patients (median age: 49.5 years) received a median cumulative activity of 29.6 GBq of 177Lu-DOTATATE over 2-5 cycles at 8-12-week intervals. The median progression-free survival (PFS) of the study cohort was 30 months (95% confidence interval, CI: 18.2-41.9 months). A baseline PLR ≥173.1 was found to be a significant predictor of poor PFS with a univariate hazard ratio of 3.82 (95% CI: 1.21-12.03); however, the association was not significant on multivariate analysis. The median overall survival was not reached and none of the parameters were significantly associated with it. Conclusions: A higher baseline PLR was shown to be associated with a negative outcome on PFS after 177Lu-DOTATATE therapy and is a promising marker for future larger studies.

Assessment of absorbed dose for Zr-89, Sm-153 and Lu-177 medical radioisotopes: IDAC-Dose2.1 and OLINDA experience

ObjectiveIn this article, IDAC-Dose2.1 and OLINDA computer codes are compared as they are the most widely used software tools for internal dosimetry assessment at the present time. OLINDA/EXM personal computer code was created as a replacement for the widely used MIRDOSE3.1 code. IDAC-Dose2.1 was developed based on the ICRP specific absorbed fractions and computational framework of internal dose assessment given for reference adults in ICRP Publication 133. IDAC uses cumulated activities per administered activity in hours and calculates the absorbed dose and the effective dose. The program calculates the dose in the Eckerman stylized family phantoms. It is useful in standardizing and automating internal dose calculations, assessing doses in clinical trials with radiopharmaceuticals, making theoretic calculations for existing pharmaceuticals, teaching, and other purposes. MethodsTo produce such a comparison, the results of this work were compared with available published data in the literature on radiopharmaceuticals. Radiopharmaceuticals with 89Zr, 153Sm, 177Lu radionuclides are used as the basis for the comparison. 89Zr, 153Sm, 177Lu radionuclides are regarded as the future of radiopharmaceutical treatment. For 89Zr, two different labelled carriers, Zr-89_cMAb U36 and Zr-89 Panitumumab, were used on patients. ResultsThe results show a clear difference in terms of absorbed dose of the Zr-89 radiopharmaceuticals for red bone marrow when calculated by IDAC-Dose2.1 (0.76 mGy/MBq), while the estimated absorbed dose in literature results is 0.07 mGy/MBq and 0.14 mGy/MBq when the calculation is done by OLINDA program. In the case of 177Lu-EDTMP, the absorbed dose in red bone marrow is in reasonable agreement (0.63 mGy/MBq and 0.8 mGy/MBq for IDAC-Dose2.1 and OLINDA, respectively). A significant difference was found for the absorbed dose in the bone surface, which was almost twice as high for OLINDA (2.1 mGy/MBq for IDAC-Dose2.1 and 5.4 mGy/MBq for OLINDA). In some direct cases, the calculated absorbed dose in the urinary bladder wall with OLINDA is ten times higher compared to WinAct (which was utilized to calculate the total activity in the organs and tissues) and IDAC 2.1. These results are considered key to greater accuracy in internal dose calculation.

RELATIONSHIP BETWEEN COGNITIVE RESERVE, MOTOR RESERVE AND THALAMUS VOLUMETRY IN OLDER ADULTS

With the increasing worldwide population, an ongoing escalation in mild cognitive impairment and dementia is predicted. Motor reserve – the cumulative physical activity experience gained throughout life, as well as cognitive reserve – the brain’s ability to overcome a pathology, such as neurodegenerative disorders, - has been identified as protective factors in cognitive decline. Thus, this study aimed to investigate the relationship between cognitive reserve, motor reserve, and brain volumetry in older adults. 44 older adults (M = 70, SD = 5.18, 77.3% female) with no self-reported significant neurological, ongoing oncological etc. disorders that might limit their participation in the study were involved in the study. All participants underwent a thorough life-style and psychological assessment, as well as structural brain MRI analysis. Overall, our study indicated the significance of a combination of lifestyle factors in predicting thalamic volume. The results of this study indicate that life-long participation in physical, intellectual, and social activities could be beneficial for preserving the volume of thalamus, which is among the first to decline due to aging.

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study.

The purpose of this study was to assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Efficacy and safety of 177Lu-DOTATATE in patients (pts) with advanced pancreatic neuroendocrine tumors (pNETs): Data from the NETTER-R international, retrospective registry.

4116 Background: Peptide receptor radionuclide therapy with 177Lu-DOTATATE is indicated in somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumours. The NETTER-R registry builds upon the existing evidence for pts with advanced pNETs, who have limited therapeutic options. Methods: NETTER-R is a retrospective registry of pts with unresectable or metastatic, well-differentiated, SSTR-positive, progressive pNETs treated with 177Lu-DOTATATE in the UK, France and Spain. Pts who received ≥1 administration of 177Lu-DOTATATE were included. The primary endpoint was progression-free survival (PFS) based on RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tumour response. Results: A total of 110 pts with pNETs were identified. Median age was 58.0 years (range 28–89) and 52.7% were male. At baseline, 96.4% of pts had progressive disease. The Ki-67 index was ≤2% in 23.6%, 3–20% in 66.4% and &gt;20% in 2.7% of pts (7.3% missing). Metastases were present in the liver in 95.5% and bone in 29.1% of pts. Nearly all pts (90.9%) had received at least one prior anticancer therapy (somatostatin analogues: 70.0%, chemotherapy: 61.8%, protein kinase inhibitors: 38.2%). The majority of pts (70.0%) received all four scheduled cycles of 177Lu-DOTATATE. The cumulative activity was 26.6–32.6 GBq in 65.5% of pts (&lt;26.6 GBq: 31.8%, ≥32.6 GBq: 2.7%). 12 pts were re-treated after disease progression and received 1–4 additional cycles of 177Lu-DOTATATE. By RECIST v1.1, evaluable in 62 pts, median PFS was 24.8 months (95% CI 17.5–34.5) and objective response rate was 40.3% (95% CI 28.1–53.6); all responses were partial. The response rate, including radiological, clinical, metabolic and biomarker assessments, evaluable in 100 pts, was 54.0% (95% CI 43.7–64.0), including 2 pts with complete response. Over a median follow-up of 24.5 months (range 2.0–123.4), median OS in 110 pts was 41.4 months (95% CI 28.6–50.2). 71.8% (n=79/110) of pts had at least one treatment-emergent adverse event (TEAE). The most frequent were nausea (28.2%) and fatigue (22.7%), predominantly grade 1/2 in severity. No TEAEs led to treatment discontinuation. Grade 3 anaemia and lymphopenia occurred in 1 (0.9%) and 4 (3.6%) pts, respectively. No grade ≥3 thrombocytopenia or neutropenia were reported. Renal TEAEs occurred in 6 pts (5.5%; grade 1: n=1, grade 2: n=2, grade 3: n=3). Grade 3 renal events were transient (≤24 days) and did not lead to treatment modification. No acute leukaemia or myelodysplastic syndrome were reported within the follow-up. Conclusions: In a real-world population of pts with advanced pNETs, 177Lu-DOTATATE was well tolerated with a safety profile consistent with the NETTER-1 trial. With limited follow-up, the OS and PFS compared favourably with cohorts of progressive pNET patients treated with other systemic agents.

Prospective evaluation of organ-specific dose and lesional doses following therapeutic [177Lu]Lu-EDTMP administration in patients with multiple skeletal metastases and its correlation with clinical hematological toxicity.

In patients with multiple skeletal metastases, accurate estimation of absorbed doses to radiosensitive bone marrow in bone-directed systemic radionuclide therapies (RNT) is critically important from clinical dose determination standpoint. The primary aim of the present study was to estimate the radiation absorbed doses of therapeutic [177Lu]Lu-EDTMP to bone marrow by two methods viz. Medical Internal Radiation Dose (MIRD) schema and using OLINDA software and correlate with hematological toxicity. A total of 15 patients diagnosed to have multiple painful skeletal metastases being treated with [177Lu]Lu-EDTMP for palliation of pain, were enrolled for this prospective study. For all patients, urine was collected immediately after infusion of [177Lu]Lu-EDTMP up to 24 h post-administration and cumulative activity excreted from body via urine was calculated. For dosimetry, patients underwent post-administration whole-body scintigraphy at five-time points: 0.5 (pre-void), 2, 24, 48 and 120 h (post-void). From the time-activity curves generated by drawing regions of interest (ROIs) on the images, number of disintegrations was determined. Absorbed doses for organs and bone lesions were calculated using OLINDA 2.2.0 software. For bone marrow dose estimates, in addition to OLINDA 2.2.0 software, MIRD schema was also adopted. Hematological profile was monitored in all patients during the treatment and post-treatment follow-up (estimating complete blood counts, every 15 d for 3 months after therapy). The mean ± standard deviation activity of [177Lu]Lu-EDTMP administered per patient per cycle was 2.08 ± 0.45 GBq. The results demonstrated higher uptake of [177Lu]Lu-EDTMP in bone metastases compared to normal bones. Within 2 and 24 h of administration of [177Lu]Lu-EDTMP, [177Lu]Lu activity excreted from the body was 24 ± 9% and 39 ± 14%, respectively. The mean absorbed organ doses (mean ± SD) in Gy/GBq were as follows: osteogenic cells 3.15 ± 1.85, bone marrow 0.57 ± 0.31, kidneys 0.08 ± 0.05, urinary bladder 0.32 ± 0.04, and bone lesions 2.91 ± 1.88. Strong correlation was found between (a) MIRD schema and OLINDA 2.2.0 software method for estimation of bone marrow doses (r = 0.96; P = <0.0001) and (b) Bone marrow absorbed dose and hematological toxicity (r = 0.81, P = 0.0027). Radiation absorbed doses to the bone marrow and skeletal metastatic lesions, following therapeutic [177Lu]Lu-EDTMP were estimated using a convenient and non-invasive quantitative imaging method. The estimated bone marrow absorbed dose, either by MIRD schema or the OLINDA 2.2.0 software method, demonstrated strong correlation. Strong correlation was also observed between bone marrow absorbed dose and hematological toxicity.

Structural analogues in herbal medicine ginseng hit a shared target to achieve cumulative bioactivity

By a pilot trial on investigating immunomodulatory activity and target of ginsenosides, the major bioactive components of ginseng, here we report that structural analogues in herbal medicines hit a shared target to achieve cumulative bioactivity. A ginsenoside analogues combination with definite immunomodulatory activity in vivo was designed by integrating pharmacodynamics, serum pharmacochemistry and pharmacokinetics approaches. The cumulative bioactivity of the ginsenoside analogues was validated on LPS/ATP-induced RAW264.7 macrophages. The potentially shared target NLRP3 involved in this immunomodulatory activity was predicted by systems pharmacology. The steady binding affinity between each ginsenoside and NLRP3 was defined by molecular docking and bio-layer interferometry assay. The activation of NLRP3 inflammasomes in LPS/ATP-induced RAW264.7 was significantly suppressed by the combination, but not by any individual, and the overexpression of NLRP3 counteracted the immunomodulatory activity of the combination. All these results demonstrate that the ginsenoside analogues jointly hit NLRP3 to achieve cumulative immunomodulatory activity.

Long-term outcome of 177Lu-PSMA-617 radioligand therapy in heavily pre-treated metastatic castration-resistant prostate cancer patients.

ObjectiveInvestigators have extensively explored the short-term safety and efficacy data on 177Lu-PSMA-617 radioligand therapy (RLT) in mCRPC patients. However, scarce literature is reported on the long-term outcome of these patients. The current goal of this study is focused on the long-term outcome of mCRPC patients treated with 177Lu-PSMA-617 RLT.MethodsAmong 135 patients, 121 mCRPC patients fulfilled the eligibility criteria and were included in the final analysis. Patients received a median of 3 cycles of 177Lu-PSMA-617 RLT at 6 to 12-week intervals. Primary endpoint included overall survival (OS) and secondary endpoints involved progression-free survival (PFS), predictive factors of OS and PFS, PSA response rate, molecular response, clinical response, and toxicity assessment.ResultsThe median administered cumulative activity was 20 GBq (3.7–37 GBq). The median follow-up duration was 36 months (6–72 months). The estimated median PFS and OS were 12 months (mo) (95% CI: 10.3–13 mo) and 16 mo (95% CI: 13–17 mo), respectively. Any PSA decline and PSA decline >50% was achieved in 73% and 61% of the patients, respectively. Multivariate analysis revealed only failure to achieve >50% PSA decline as a significant factor associated with a poor PFS. Prognostic factors associated with reduced OS included, failure to experience >50% PSA decline, heavily pre-treated patient cohort who received >2 lines of prior treatment options, and patient sub-group treated with ≥2 lines of chemotherapy. Patients re-treated with additional treatment options after attaining 177Lu-PSMA refractory disease showed a remarkably prolonged OS. A significant clinical benefit was achieved post 177Lu-PSMA-617 RLT. The most common toxicities observed were fatigue (34.7%), followed by nausea (33%), and dry mouth (24.7%).ConclusionThe current study supports the short-term safety and efficacy results of high response rates, prolonged PFS and OS, improved quality of life, and low treatment-related toxicities in patients treated with 177Lu-PSMA-617 radioligand therapy.

Pedogeomorphology and paleoenvironmental implications of large termite mounds at the Brazilian semiarid landscape

Large termite mounds, regionally called Murundus, forming hillocks throughout the Brazilian territory, occur, with different names, across the entire tropical belt. Little is known about the genesis and age of these large biogenic structures in the semiarid zone, where termites have a limited range due to water deficit. We aimed to understand the process of mounds building on different types of soils at the ecotonal semiarid region of Minas Gerais state. In addition, we tested the hypothesis that these mounds have been produced by termites during the Holocene, and that the paleoenvironmental conditions during mound formation were different from today, helping to enhance the understanding of vegetation dynamics in the semiarid Caatinga Biome. For this, five mounds with and without living termites (M1, M2, M3, M4 and M5) and five adjacent soil profiles (P1, P2, P3, P4 and P5) were selected for morphological description, followed by physical, chemical, mineralogical and micromorphological analysis, as well as δ13C and 14C dating analysis. The occurrence of these large termite mounds in the semiarid landscape is unrelated to soils or parent material, and represent the products of cumulative termite activity in the edge of the semiarid domain. Mounds and adjacent soils formed after the mid Holocene (younger than 4000 years), based on 14C dating, and may be even older. The calculated rates of termite accretion (based on 14C dating) are consistent with previous reports of tropical soils, in the range of 0.027 to 0.066 cm soil/Ha/y. A comparative estimate based on mound volume and density was 0.188 cm soil/Ha/y, up to 3.5 times greater than the previous approach based on 14C dating. These figures suggest the production of a soil mantle in the range of 270–660 cm in 10,000 years, accounting for erosion. The mounds and adjacent soils have differences in micropedological features, notably related to bioturbation (excremental infillings), and contrasting textural variations with depth, with higher and more uniform clay and silt contents in mounds, and a kaolinitic/illitic mineralogical composition throughout. The chemical fertility of murundus depends on the type of underlying soil from which it was built, and does not increase in all cases. In the murundus studied, the microgranular structure typical of oxic materials is welded and massive, indicating that the natural compaction of soils dominated by kaolinite/illite under the semi-arid climate prevents the stability of loose aggregates formed by termite bioturbation, reorganizing the termitic microaggregate groundmass. This clearly shows the polycyclic (polyphasic) biogenic nature of mounds and adjacent soils, corroborated by carbon isotopes studies. Soils and mounds are younger than mid Holocene in the first 100 cm, and experienced alternations of dry and wet climate spells from the mid-Holocene onwards, resulting in apparent changes in vegetation at the ecotonal, southern limit of semi-arid Caatinga, over the last 5000 years. Since we did not reach the base of mounds, they should be even older; mounds represent fine proxies for Holocene paleoclimate reconstructions, if a more detailed pedostratigraphic study is carried out. A general model of termite mounds formation in relation to the interconnected pedological, geomorphological and vegetational evolution is presented, summarizing all present knowledge on these outstanding biogenic landforms.

Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning — A retrospective analysis

PurposeNephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. MethodsFrom our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10–12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to CTCAE. Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. ResultseGFR grade 1–2 dropped from 87/102 at the baseline to 71 cases at follow-up (p < 0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p < 0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p = 0.006). ConclusionIn roughly 20% of cases an increase in grading of nephro- or hematotoxicity is observed. In those patients, except in one, toxicity findings were mild or moderate one year after completion of four cycles of PRRT with either Y-90- or Lu-177-SST-analogues. In terms of safety, PRRT has no critical impact on further oncologic treatment options in the case of disease progression.

Growing Cumulative Activity of Major Tropical Cyclones

Here, we show that from 1980 onward, the global annual cu- mulative count of major tropical cyclones (TC), category 3 and above, exhibit an upward trend (at 98% con dence level). We attribute this trend to a global sea surface warming. Identi cation and attribution of the growing cumulative frequency of major TC provides the empir- ical foundation for modeling of this phenomenon. Our ndings lead to the stable and ecient data-driven stochastic model of the underlying utmost complex process, which enables estimates of the impact of pro- jected changes in the global radiative balance on the temporal behavior of major TC.

Eficacia de lutecio-177 DOTATATE/TOC en pacientes con tumores neuroendocrinos bien diferenciados en estado avanzado. Ensayo clínico fase II

Introducción: En 2009, el Instituto Nacional de Cancerología (INC) elaboró el 177Lu-DOTATATE/TOC. El propósito del estudio fue demostrar la eficacia de estos radiopéptidos en el tratamiento paliativo de pacientes con tumores neuroendocrinos (TNE) avanzados inoperables (metastásicos o localmente avanzados) y en progresión. Métodos: Ensayo clínico abierto fase II de un solo brazo en 13 pacientes adultos con TNE grado 1 o 2, con expresión de receptores de somatostatina en lesiones blanco demostrada por captación Krenning 3 o 4 en 99mTc-HYNIC TOC. Los pacientes fueron tratados con 177Lu-DOTATATE o 177Lu-DOTATOC (según disponibilidad) a una actividad acumulativa proyectada de 600-800 mCi dividida en 3-4 dosis cada 6-9 semanas comenzando siempre con una actividad fija de 200 mCi y dosimetría con la primera dosis. El desenlace primario fue la respuesta objetiva calculada 6 y 12 meses después de la última dosis del tratamiento. Resultados: Se incluyeron 13 pacientes (7 mujeres) de 63 ± 11,6 años con TNE avanzado inoperable y en progresión. La actividad final administrada fue de 800 mCi, 600 mCi, 400 mCi y 200 mCi en 4, 7, 1 y 1 pacientes, respectivamente. La tasa de control de enfermedad a 6 y 12 meses fue de 69,2% y 45,5%, respectivamente, logrando únicamente enfermedad estable. Fallecieron 7 pacientes, 2 de ellos en los primeros 6 meses. La mediana de supervivencia global a partir de la última dosis del radiopéptido fue de 15,7 meses. Conclusiones: Se corroboró la eficacia y la seguridad del tratamiento con los radiopéptidos en NETs avanzados.

Signal-To-Noise Ratio Calculations to Validate Sensor Positioning for Facial Muscle Assessment Using Noninvasive Facial Electromyography.

The evaluation of neuromodulator treatment outcomes can be performed by noninvasive surface-derived facial electromyography (fEMG) which can detect cumulative muscle fiber activity deep to the skin. The objective of the present study is to identify the most reliable facial locations where the motor unit action potentials (MUAPs) of various facial muscles can be quantified during fEMG measurements. The study population consisted of five males and seven females (31.0 [12.9] years, body mass index of 22.15 [1.6] kg/m2). Facial muscle activity was assessed in several facial regions in each patient for their respective muscle activity utilizing noninvasive surface-derived fEMG. Variables of interest were the average root mean square of three performed muscle contractions (= signal) (µV), mean root mean square between those contraction with the face in a relaxed facial expression (= baseline noise) (µV), and the signal to noise ratio (SNR). A total of 1,709 processed fEMG signals revealed one specific reliable location in each investigated region based on each muscle's anatomy, on the highest value of the SNR, on the lowest value for the baseline noise, and on the practicability to position the sensor while performing a facial expression. The results of this exploratory study may help guiding future researchers and practitioners in designing study protocols and measuring individual facial MUAP when utilizing fEMG. The locations presented herein were selected based on the measured parameters (SNR, signal, baseline noise) and on the practicability and reproducibility of sensor placement.

Insight into chain scission and release profiles from photodegradation of polycarbonate microplastics

Bisphenol A polycarbonate (BPA-PC) is a kind of widely used engineering plastics. However, excessive usage causes the production of plastic wastes, following property changes of polymers and high risks of released chemicals during outdoor weathering. In this study, we systematically investigated the photoaging behavior of PC microplastics (MPs) in aquatic environment and evaluated the potential risk of released intermediates. Light irradiation along with mechanical abrasion facilitated the fragmentation of PC MPs and stimulated photooxidative modification during 640 h of ultraviolet (UV) exposure. Continuous degradation of the polymer was accompanied with dramatic decline of molecular weight. Also, BPA was released from irradiated PC MPs with a trend of an initial rapid increase followed by a decrease versus the irradiation time, and the maximum concentration of dropped BPA was detected up to 652.80 ± 72.89 μg/g (43.39% and 56.61% respectively in particles and leachates). However, the releasing amount of BPA in the leachate merely occupied 2.7% of the total organic carbon (TOC) leached out, suggesting that a great number of unknown organic products were produced other than BPA. Liquid chromatography-time-of-flight-mass spectrometry (LC-TOF-MS) analysis showed that these organic compounds forming MPs-derived dissolved organic matter (MPs DOM) were partly composed of 4,4’-dihydroxybenzophenone (DHB), p-hydroxybenzoic acid (p-HBA) and methyparaben (MeP), which would also contribute to the estrogenic activity. The degradation pathway of PC MPs was elaborated with the photolysis process of PC dimer and BPA, and the remarkable photoaging of PC MPs was mainly dominated by the generated reactive oxygen species (ROS). The findings of this study indicated that understanding the photoaging process of PC MPs was vital to evaluate their integral cumulative estrogenic activity in aquatic environment, and further highlighted the notable possible risks of plastic leachates to exposed biota.

RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer

PurposeThis is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer.MethodsRADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by 18F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by 18F-FDG PET/CT, 99mTc-HMDP bone scan and 18FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety.ResultsTen patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4–35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). 18F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, 99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; 18FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3–4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related.ConclusionThe trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation.Trial registration numberNCT02390934. Registration date 18.03.2015.

Cumulative inflammatory burden and obesity as determinants of insulin resistance in patients with established rheumatoid arthritis: cross-sectional study

ObjectivesTo describe the prevalence of insulin resistance (IR) in patients with established rheumatoid arthritis (RA) and to analyse the contribution of cumulative inflammatory burden and other factors to its development.DesignObservational...

Is There Any Need for Adjusting 131I Activity for the Treatment of High Turnover Graves' Disease Compared to Normal Turnover Patients? Results from a Retrospective Cohort Study Validated by Propensity Score Analysis.

To compare 131I-therapy outcomes in high turnover and normal turnover Graves' disease patients and predict optimal first 131I activity for high turnover patients. Retrospective cohort design (1:2) validated by propensity score analysis. Cohort 1, high turnover (2-h RAIU/24-h RAIU ≥ 1), n = 104, and cohort 2, normal turnover (ratio < 1), n = 208, patients were compared for post 131I outcome. The cure was defined as a combined euthyroid and stable hypothyroid state following 131I treatment. Logistic regression analysis was used for identifying prognostic factors. The propensity score was applied; 77 matched pairs (1:1 ratio) of high and normal turnover patients were selected as a validation set. First 131I cure rates of 28% in high turnover and 66% in normal turnover groups (p = 0.001) were noted. The therapy cycles (median, 2 vs. 1) and cumulative 131I activity (median, 15 vs. 7mCi) were required to cure hyperthyroidism in cohort 1 and cohort 2, respectively. Age (> 44years), higher grade of goitre, and 2-h RAIU (> 37%) were associated with 131I therapy failure. The high turnover patients needed a factor of 1.5-2 times more 131I activity to achieve a similar cure rate compared to the normal turnover patients. The first-dose cure rate was 31% vs. 60% by propensity score analysis (n = 154), no way different (28% vs.66%) from the whole group of 312 patients. High turnover Graves' disease patients, if administered standard 131I activity, the outcomes shall be poor. To improve the success rate, 131I activity should be increased by 1.5 to 2 times in the high turnover patients. The online version contains supplementary material available at 10.1007/s13139-020-00674-3.

Safety and efficacy of repeat Y90 radioembolization to the same hepatic arterial territory.

To study the efficacy and safety of repeat transarterial radioembolization (TARE) to similar hepatic arterial territories. Between 3/2011 and 4/2019, 26 patients (25 males and 1 Female, Mean Age: 65 yo, SD: 11.7 yo, Range: 18-83.0 yo) received TARE with Y90 glass microspheres to treat recurrent or residual primary disease in similar hepatic arterial lobe or segments. Tumor response was evaluated by imaging using the modified-RECIST criteria. Incidence of RILD and adverse events were categorized by a standardized scale using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Mean cumulative activity after the first treatment was 2.50 GBq (SD:1.04 GBq, Range:0.61-4.93 GBq) and second treatment was 2.27 GBq (SD:1.01 GBq, Range:0.92-5.46 GBq). Mean interval time between initial and repeat treatments was 9.6 months (Range: 1-53 months). Tumor responses were complete, partial, or progression in 73% (n = 19/26), 23% (n = 6/26), and 4% (n = 1/26) in repeat treatment patients, respectively. The incidence of RILD was 0%. Toxicity after first and second treatment was seen in 19% (n = 5/26) & 23% (n = 6/26) patients, respectively, and were all of CTCAE Grade 2. No significant predictors of treatment toxicity for repeat treatment were identified except increased MELD score (p = 0.04). Kaplan-Meier survival analysis in patients with repeat treatment showed a median survival of 15.0 months (95% CI 8.8-21.1 months) and 19.0 months (95% CI 8.1-29.9 months) in patients who only received one treatment with a p value of 0.485. Repeat TARE with glass microspheres was an effective and safe treatment strategy for disease management in patients with residual or recurrent disease to the similar hepatic arterial territories without any major treatment related toxicity. Although safety and efficacy of repeat radioembolism has been studied, no study has focused on repeat treatment to similar hepatic arterial territories. The current study shows that repeat treatment to the same hepatic arterial territory is as safe as single treatment to the same territory.

Forager age and foraging state, but not cumulative foraging activity, affect biogenic amine receptor gene expression in the honeybee mushroom bodies.

Foraging behavior is crucial for the development of a honeybee colony. Biogenic amines are key mediators of learning and the transition from in-hive tasks to foraging. Foragers vary considerably in their behavior, but whether and how this behavioral diversity depends on biogenic amines is not yet well understood. For example, forager age, cumulative foraging activity or foraging state may all be linked to biogenic amine signaling. Furthermore, expression levels may fluctuate depending on daytime. We tested if these intrinsic and extrinsic factors are linked to biogenic amine signaling by quantifying the expression of octopamine, dopamine and tyramine receptor genes in the mushroom bodies, important tissues for learning and memory. We found that older foragers had a significantly higher expression of Amdop1, Amdop2, AmoctαR1, and AmoctβR1 compared to younger foragers, whereas Amtar1 showed the opposite pattern. Surprisingly, our measures of cumulative foraging activity were not related to the expression of the same receptor genes in the mushroom bodies. Furthermore, we trained foragers to collect sucrose solution at a specific time of day and tested if the foraging state of time-trained foragers affected receptor gene expression. Bees engaged in foraging had a higher expression of Amdop1 and AmoctβR3/4 than inactive foragers. Finally, the expression of Amdop1, Amdop3, AmoctαR1, and Amtar1 also varied with daytime. Our results show that receptor gene expression in forager mushroom bodies is complex and depends on both intrinsic and extrinsic factors.