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Search Results (10,759)

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Keywords = 10-year survival

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11 pages, 2366 KiB  
Article
Ceftazidime–Avibactam Versus Polymyxin-Based Combination Therapies: A Study on 30-Day Mortality in Carbapenem-Resistant Enterobacterales Bloodstream Infections in an OXA-48-Endemic Region
by Rıdvan Dumlu, Meyha Şahin, Okan Derin, Özlem Gül, Sedef Başgönül, Rehile Zengin, Çiğdem Arabacı, Funda Şimşek, Serap Gençer, Ayşe Sesin Kocagöz and Ali Mert
Antibiotics 2024, 13(10), 990; https://doi.org/10.3390/antibiotics13100990 (registering DOI) - 18 Oct 2024
Abstract
Background: Ceftazidime–avibactam (CAZ-AVI) is recommended as first-line treatment for Oxacillinase-48 (OXA-48) β-Lactamase-producing carbapenem-resistant Enterobacterales (CRE) infections, while polymyxin-based combination therapies (PBCTs) are used as a last resort when CAZ-AVI is unavailable. Research comparing the effectiveness of CAZ-AVI and PBCT in CRE blood [...] Read more.
Background: Ceftazidime–avibactam (CAZ-AVI) is recommended as first-line treatment for Oxacillinase-48 (OXA-48) β-Lactamase-producing carbapenem-resistant Enterobacterales (CRE) infections, while polymyxin-based combination therapies (PBCTs) are used as a last resort when CAZ-AVI is unavailable. Research comparing the effectiveness of CAZ-AVI and PBCT in CRE blood stream infections (CRE-BSIs) is limited, mostly focusing on Klebsiella pneumoniae carbapenemase (KPC)-producing isolates. In Turkey, OXA-48 is endemic and OXA-48-Like is common. Therefore, our study aimed to compare the impact of these treatments on 30-day mortality in patients with CRE-BSIs in endemic regions. Methods: Retrospective data from January 2019 to May 2023 were collected from four tertiary healthcare centers in Istanbul. Demographic, clinical, and outcome data of ICU patients treated with CAZ-AVI monotherapy or PBCT for CRE-BSIs were analyzed. The effect on 30-day survival was evaluated using Cox regression analysis post propensity score matching (PSM). Results: Out of 151 patients, 44.4% (n: 67) received CAZ-AVI and 55.6% (n: 84) received PBCT. All-cause mortality rates were 20% (n: 13) with CAZ-AVI and 36.9% (n: 31) with PBCT. Cox regression analysis post PSM indicated CAZ-AVI monotherapy significantly reduced the mortality risk compared to PBCT (HR: 0.16, 95%CI: 0.07–0.37, p < 0.001), while age increased the risk (HR: 1.02 per year, 95% CI 1.0–1.04, p: 0.01). Conclusions: In OXA-48-predominant areas, CAZ-AVI demonstrated significantly lower mortality in patients with CRE-BSIs compared to PBCT. The results were attributed to the pharmacokinetic and pharmacodynamic disadvantages of polymyxins compared to CAZ-AVI, and the impact of age-related physical conditions. Therefore, CAZ-AVI should be the preferred treatment for CRE-BSIs in OXA-48-endemic regions. Full article
(This article belongs to the Section Antibiotic Therapy in Infectious Diseases)
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<p>Effect of targeted therapies on outcomes, according to source of infection in total cohort and propensity score-matched groups.</p>
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<p>Kaplan–Meier survival analysis for patients receiving Ceftazidime-Avibactam and Polymyxin-based combination therapy for 30 days after treatment initiation.</p>
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10 pages, 1502 KiB  
Article
Radiation-Induced Breast Angiosarcoma—A Single-Institution Experience
by Marko Buta, Nada Santrac, Milan Zegarac, Merima Goran, Nikola Jeftic, Nevena Savkovic, Jovan Raketic, Saska Pavlovic, Ognjen Zivkovic, Aleksandar Rankovic and Ivan Markovic
Diagnostics 2024, 14(20), 2326; https://doi.org/10.3390/diagnostics14202326 (registering DOI) - 18 Oct 2024
Abstract
Introduction: Radiation-induced breast angiosarcoma (RIBAS) is a rare adverse event associated with postoperative breast irradiation. The data from the literature indicate that RIBAS occurs in less than 0.3% of patients treated with adjuvant radiotherapy for breast cancer. Given the rarity, diverse clinical [...] Read more.
Introduction: Radiation-induced breast angiosarcoma (RIBAS) is a rare adverse event associated with postoperative breast irradiation. The data from the literature indicate that RIBAS occurs in less than 0.3% of patients treated with adjuvant radiotherapy for breast cancer. Given the rarity, diverse clinical presentation, poor prognosis, and lack of consensus on the management, this study aimed to present experiences of our specialized cancer center with RIBAS, in terms of the incidence, presentation, management, and outcomes. Methods: We reviewed the medical records of 10,834 breast cancer patients treated at the Institute for Oncology and Radiology of Serbia between January 2013 and June 2024 to detect patients that had breast-conserving surgery, followed by postoperative irradiation, and developed angiosarcoma in the irradiated area at least 3 years after radiotherapy, without distant metastases. The incidence, latency period, management, and treatment outcomes were analyzed. Results: A total of nine female patients with RIBAS were identified and included in this study. The median age at RIBAS diagnosis was 64 years (range: 36–68), with a median latency of 64 months (95% CI >57) from irradiation to diagnosis. The mean tumor size was 55 mm (SD 32.78). Patients were followed for a median of 30 months (range: 7–40) after initial RIBAS surgery. Local recurrence occurred in seven patients (77.8%), with five undergoing re-do surgery with curative intent. Three patients developed distant metastases during follow-up. The median overall survival (OS) was 31 months (95% CI >30), with a 3-year survival rate of 15.2% (95% CI 2.5–91.6%). The median local recurrence-free interval was 10 months (95% CI >3). Median OS after RIBAS local recurrence and after breast cancer treatment was 17 months (95% CI >15) and 108 months (95% CI >88), respectively. Conclusions: RIBAS is a rare but increasingly prevalent adverse event associated with BC irradiation, marked by an aggressive disease course and high relapse rates. Awareness, prompt diagnosis, and a radical surgical approach with wide clear margins are critical for improving patients’ outcomes. Full article
(This article belongs to the Special Issue Diagnosis and Precision in Breast Cancer)
42 pages, 7745 KiB  
Opinion
Uncovering Diaphragm Cramp in SIDS and Other Sudden Unexpected Deaths
by Dov Jordan Gebien and Michael Eisenhut
Diagnostics 2024, 14(20), 2324; https://doi.org/10.3390/diagnostics14202324 (registering DOI) - 18 Oct 2024
Abstract
The diaphragm is the primary muscle of respiration. Here, we disclose a fascinating patient’s perspective that led, by clinical reasoning alone, to a novel mechanism of spontaneous respiratory arrests termed diaphragm cramp-contracture (DCC). Although the 7-year-old boy survived its paroxysmal nocturnal “bearhug pain [...] Read more.
The diaphragm is the primary muscle of respiration. Here, we disclose a fascinating patient’s perspective that led, by clinical reasoning alone, to a novel mechanism of spontaneous respiratory arrests termed diaphragm cramp-contracture (DCC). Although the 7-year-old boy survived its paroxysmal nocturnal “bearhug pain apnea” episodes, essentially by breathing out to breathe in, DCC could cause sudden unexpected deaths in children, especially infants. Diaphragm fatigue is central to the DCC hypothesis in SIDS. Most, if not all, SIDS risk factors contribute to it, such as male sex, young infancy, rebreathing, nicotine, overheating and viral infections. A workload surge by a roll to prone position or REM-sleep inactivation of airway dilator or respiratory accessory muscles can trigger pathological diaphragm excitation (e.g., spasms, flutter, cramp). Electromyography studies in preterm infants already show that diaphragm fatigue and sudden temporary failure by transient spasms induce apneas, hypopneas and forced expirations, all leading to hypoxemic episodes. By extension, prolonged spasm as a diaphragm cramp would induce sustained apnea with severe hypoxemia and cardiac arrest if not quickly aborted. This would cause a sudden, rapid, silent death consistent with SIDS. Moreover, a unique airway obstruction could develop where the hypercontracted diaphragm resists terminal inspiratory efforts by the accessory muscles. It would disappear postmortem. SIDS autopsy evidence consistent with DCC includes disrupted myofibers and contraction band necrosis as well as signs of agonal breathing from obstruction. Screening for diaphragm injury from hypoxemia, hyperthermia, viral myositis and excitation include serum CK-MM and skeletal troponin-I. Active excitation could be visualized on ultrasound or fluoroscopy and monitored by respiratory inductive plethysmography or electromyography. Full article
(This article belongs to the Section Pathology and Molecular Diagnostics)
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<p>Muscles of respiration. The primary inspiratory muscles are the diaphragm and paired groups of left and right external intercostal muscles (ICMs, lavender). The latter reduce diaphragmatic workload by their bucket handle movements in adults, which basically widen the ribcage. Theoretically, if the bilateral ICMs were to suddenly fail by cramping, apnea would not occur as long as the diaphragm continued functioning (because it is the main inspiratory muscle). Contrarily, however, if the diaphragm fails, apnea and inspiratory arrest could ensue, but only if the ICMs are unable to independently resume ventilation. Therefore, for apnea to occur, both must fail. With permission by Concept2. Unit C8, Crossgate Drive, Queens Drive Industrial Estate, Nottingham NG2 1LW, UK.</p>
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<p>Respiratory load compensation, REM sleep inhibition and arousal versus apnea in infants with diaphragm fatigue. Normally, under increased physiological demand or diaphragm fatigue, ventilatory workload is shared between the diaphragm and RAM (the latter include the inspiratory ICM). However, sudden RAM inactivation in REM sleep leads to apneas related to the already present and consequently worsening diaphragmatic fatigue (causing peripheral failure). Lack of arousal, with no consequent RAM recruitment, potentiates the apneas [<a href="#B4-diagnostics-14-02324" class="html-bibr">4</a>,<a href="#B5-diagnostics-14-02324" class="html-bibr">5</a>,<a href="#B6-diagnostics-14-02324" class="html-bibr">6</a>].</p>
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<p>Spectrum of diaphragm hyperexcitation disorders (DHDs). Polyonymous clinical descriptors and diagnoses upon literature review made it a challenge categorizing them. However, a pattern emerged: as the frequency of non-physiologic diaphragm contractions increased, respiratory distress became prominent, some with sustained apneas (respiratory arrest). Those to the right presented with severe respiratory distress or frank arrest and could be termed, “unstable diaphragmatic arrhythmias”. DCC could belong to this spectrum.</p>
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<p>Criteria for fatal respiratory arrests by acute diaphragm paralysis, with examples.</p>
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<p>Prolonged expiratory apnea in an infant. The apnea (seen as flatlines in both flow and tidal volume waveforms) was preceded by a big expiration with a decrease in lung volume. Typically, this is followed by a hypoxemic episode (transient oxygen desaturations).</p>
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<p>Partial Sleep polysomnograph demonstrating air trapping (breath stacking), hyperinflation and slowed, reversed respirations after an unidentified apneic event in a spontaneously breathing infant (the full image can be seen in <a href="#app1-diagnostics-14-02324" class="html-app">Figure S1</a>). Normal tidal breathing was interrupted by a brief apnea (arrow) associated with silent squirming. It was followed by a stepwise, breath-to-breath increase in end-expiratory volume consistent with breath stacking (compare broken red line to solid red, tidal breathing baseline). Unusually, these respirations were slowed and reversed, in which expiration preceded inspiration (seen in the airflow tracing). All such changes were associated with persistently increased esophageal pressure for 44 s (not shown), thought secondary to voluntary abdominal muscle contractions (measured by surface EMG). Instead, diaphragm spasm could have been responsible, cross contaminating the EMG. Reprinted with permission of the American Thoracic Society. Copyright © 2024 American Thoracic Society. All rights reserved. The American Journal of Respiratory and Critical Care Medicine (previously known as The American Review of Respiratory Disease) is an official journal of the American Thoracic Society. From: Abu-Osba YK, et al. (1982) [<a href="#B34-diagnostics-14-02324" class="html-bibr">34</a>].</p>
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<p>Periodic breathing is hereby proposed to involve cyclical diaphragm fatigue and spasms alternating with intercostal muscle fatigue and spasms. Due to respiratory load compensation, ventilatory workload shifts from diaphragm to ICM and back as each muscle group fatigues, fails by spasm, and then recovers. Cyclical spikes in D-EMG, thought here to be diaphragm spasms, occur in association with hyperpneic breaths followed by hypopneas and transient apneas. Hypopneas are thought to occur from independent ICM action, whereas apneas are caused by simultaneous failure of both diaphragm and ICM. <span class="html-italic">Insert</span>: Periodic breathing in an infant. Courtesy of Dr. Sadasivam Suresh, Dept. of Paediatric Respiratory and Sleep Medicine, Queensland Children’s Hospital, Brisbane, Australia.</p>
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<p>(<b>A</b>–<b>C</b>). Central versus obstructive sleep apneas measured by airflow and impedance plethysmography. Central and obstructive apneas (pink shading) may in fact have peripheral (diaphragmatic) origins. (<b>A</b>) Central apneas exhibit no airflow and lack of respiratory movements of chest and abdomen. They are presumed to occur by lack of neural stimulation to the ventilatory muscles but could rather be from combined peripheral failure of diaphragm and RAM. (<b>B</b>) Obstructive apneas involve no airflow associated with respiratory movements, here seen as reduced-amplitude hypopneas (middle frame). Supra-glottic muscle collapse is thought responsible but could rather be isolated RAM activity breathing against an immobile diaphragm. (<b>C</b>) “Central” apnea with flutter-like or fibrillatory chest movements (blue line) with brady-hypopneas (red). Although cardiac artifacts could be responsible, so could respiratory flutter.</p>
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<p>Evidence for diaphragm electromechanical dissociation in a sleep apnea (esophageal D-EMG1-5). Blue arrows show the delay in oxygen desaturations after a pathological event involving the diaphragm that exhibited periodicity. The apneic period occurs between the two red lines where there was no airflow or respiratory movements (seen in RIP chest and abdomen). This would therefore be classified as a central apnea. However, there was D-EMG neural activity (albeit attenuated); thus, it is not central. Obstructive sleep apnea would then be presumed; however, that normally involves continued breathing movements, of which there were none. Instead, something else was impairing ventilations associated with reduced D-EMG (i.e., diaphragm spasm). Continued esophageal pressure (P<sub>es</sub>) swings during the apnea could have been caused by independent action of the accessory muscles, while the attenuated D-EMG from continued neural activity during the spasm. It appears a complete novel airway obstruction developed by RAM attempting to inspire against the temporarily inactivated, immobilized diaphragm. Airflow resumed, but with increased D-EMG activity, presumably to overcome airway resistance. Reproduced with permission. Source: Luo et al. [<a href="#B88-diagnostics-14-02324" class="html-bibr">88</a>].</p>
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<p>Spirometry (top, “S”), intercostal EMG (“7,8 RICS”) and diaphragm EMG (“D”) during a generalized spasm in a tetraplegic adult with dyspnea. Continuous tracing from (<b>a</b>) to (<b>b</b>). Breathing stopped in association with coughing (C), straining (St) and a diaphragmatic spasm (SP; red ellipse). This would otherwise have been deemed a central apnea. It persisted longer than the spasm, presumably due to delayed recovery of diaphragm function. 7RICS: seventh right intercostal space. With permission by BMJ Publishing Group Ltd. license (August 2024) [<a href="#B51-diagnostics-14-02324" class="html-bibr">51</a>].</p>
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<p>Tardieu petechiae. <b>Left</b>: Fetal thymus covered with petechiae. <b>Right</b>: Infant thymus showing distinct boundary between the intra- and extrathoracic portions, with and without hemorrhages, respectively (broken line). With permission by source (<b>left</b>): © Prof. Paul Goldwater. Source (<b>right</b>): © Prof. Roger W. Byard.</p>
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<p>Anatomy of the inferior (abdominal) diaphragm. The diaphragm is composed of tendon and muscle, which tightly wrap around three apertures (hiatuses): the inferior vena cava (IVC), aorta, and esophagus. Diaphragm hypertonicity and pathological excitation could effectively clamp these structures, potentially leading to serious hemodynamic and gastrointestinal consequences both above and below the diaphragm. Courtesy of Henry Vandyke Carter. Public domain, Wikimedia Commons, 2008.</p>
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<p>Rapid interval chest X-ray findings in an infant with terminal RSV bronchiolitis. (<b>a</b>) Normal-appearing CXR with some streaky lung infiltrates. (<b>b</b>) Marked changes 2 h later after sudden respiratory distress, with complete bilateral lung field opacification and ectasia of the stomach and proximal bowels. The opacity is probably from bilateral fluid collections (thought to occur by DCC airway obstruction). Creative Commons Attribution 4.0 International License. Source: Bottino et al. [<a href="#B168-diagnostics-14-02324" class="html-bibr">168</a>].</p>
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<p>Postictal diaphragm cramp-contracture hypothesis in seizure deaths. This differs from other SUDEP hypotheses by (1) seizure-induced diaphragm excitation (and fatigue) carried by the phrenic nerve(s), (2) worsened fatigue from postictal tachypnea and (3) sudden excitation by DCC, leading to silent terminal apnea and cardiac arrest.</p>
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<p>Diaphragm anatomy in relation to chest and abdomen (lateral view). The respiratory diaphragm, a hermetic seal like the tympanic membrane of the ear, separates the chest from abdominal cavities. A blunt blow to one cavity is transmitted through the diaphragm to the other. The diaphragm can rupture in high-velocity trauma, but with lesser forces (winding injuries), neuromuscular excitation is thought to occur by diaphragm spasm or persistent cramp. Source: Pearson Scott Foresman, public domain, via Wikimedia Commons, 2008.</p>
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<p>Proposed diaphragm cramp-respiratory arrest pathogenesis in infants. Most, if not all, SIDS risk factors fatigue the diaphragm, increase its workload or delay relaxation. Increased tonicity and excitation develop in skeletal muscles when fatigued, and respiratory muscles like the diaphragm are likely not exempt. Diaphragm cramp is thought to be triggered by ventilatory work overload. A novel airway obstruction would develop where the paralyzed diaphragm resists inspiratory efforts by agonal RAM contractions. Postmortem findings consistent with DCC include disrupted myofibers and anoxic contraction band necrosis (both of which are visible only microscopically) as well as signs of asphyxia by terminal airway obstruction. Respiratory arrest can be reversed by rescue breaths, but the window of opportunity is short given cardiac arrest will ensue within minutes.</p>
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<p>Diaphragm fatigue/excitation factors. These overlap with known SIDS risk factors. Some are modifiable, like giving oral fluids for dehydration, blood transfusions in anemic apnea and avoiding nicotine exposure.</p>
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13 pages, 938 KiB  
Article
Evaluation of Complementary Feeding Indicators Among Children Aged 6–23 Months According to the Health Literacy Status of Their Mothers
by Sevim Gonca Kocagozoglu, Meltem Sengelen and Siddika Songul Yalcin
Nutrients 2024, 16(20), 3537; https://doi.org/10.3390/nu16203537 (registering DOI) - 18 Oct 2024
Abstract
Background/Objectives: Infant and young child feeding (IYCF) practices directly affect child health, development, and survival, especially under 2 years of age and ultimately affect adult life well-being. As the primary caregivers of the children, mothers with higher health literacy may better perceive the [...] Read more.
Background/Objectives: Infant and young child feeding (IYCF) practices directly affect child health, development, and survival, especially under 2 years of age and ultimately affect adult life well-being. As the primary caregivers of the children, mothers with higher health literacy may better perceive the benefits of optimal complementary feeding practices, leading to improved health outcomes for their children. In this study, we aimed to assess complementary feeding practices among children aged 6–23 months in Turkey according to 2021 World Health Organization IYCF indicators [minimum dietary diversity (MDD); minimum meal frequency (MMF); minimum acceptable diet (MAD); egg and/or flesh food consumption (EFF); sweet beverage consumption (SwB); unhealthy food consumption (UFC); zero vegetable or fruit consumption (ZVF); and bottle feeding (BoF)] and investigate their associations with sociodemographic characteristics and mothers’ health literacy. Methods: With a descriptive study design, we reached 572 mothers of children aged 6–23 months from five regions of Turkey. We used the Turkey Health Literacy Scale-32 (TSOY-32) to assess mothers’ health literacy. Results: While maternal and child age are significantly associated with more complementary feeding practices, specifically MDD, MAD, and EFF, having multiple children has negative impacts on several complementary feeding indicators, including MDD, MMF, MAD, UFC, and ZVF. The only indicator associated with mothers’ TSOY-32 scores was zero fruit and vegetable consumption. Conclusion: Raising awareness among mothers about the importance of complementary feeding practices and identification of vulnerable groups will guide practitioners and policymakers to improve child health and nutrition. Full article
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<p>IYC complementary feeding indicators for children 6–23 months of age [<a href="#B4-nutrients-16-03537" class="html-bibr">4</a>].</p>
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13 pages, 851 KiB  
Article
AI Survival Prediction Modeling: The Importance of Considering Treatments and Changes in Health Status over Time
by Nabil Adam and Robert Wieder
Cancers 2024, 16(20), 3527; https://doi.org/10.3390/cancers16203527 (registering DOI) - 18 Oct 2024
Abstract
Background and objectives: Deep learning (DL)-based models for predicting the survival of patients with local stages of breast cancer only use time-fixed covariates, i.e., patient and cancer data at the time of diagnosis. These predictions are inherently error-prone because they do not consider [...] Read more.
Background and objectives: Deep learning (DL)-based models for predicting the survival of patients with local stages of breast cancer only use time-fixed covariates, i.e., patient and cancer data at the time of diagnosis. These predictions are inherently error-prone because they do not consider time-varying events that occur after initial diagnosis. Our objective is to improve the predictive modeling of survival of patients with localized breast cancer to consider both time-fixed and time-varying events; thus, we take into account the progression of a patient’s health status over time. Methods: We extended four DL-based predictive survival models (DeepSurv, DeepHit, Nnet-survival, and Cox-Time) that deal with right-censored time-to-event data to consider not only a patient’s time-fixed covariates (patient and cancer data at diagnosis) but also a patient’s time-varying covariates (e.g., treatments, comorbidities, progressive age, frailty index, adverse events from treatment). We utilized, as our study data, the SEER-Medicare linked dataset from 1991 to 2016 to study a population of women diagnosed with stage I–III breast cancer (BC) enrolled in Medicare at 65 years or older as qualified by age. We delineated time-fixed variables recorded at the time of diagnosis, including age, race, marital status, breast cancer stage, tumor grade, laterality, estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2) status, and comorbidity index. We analyzed six distinct prognostic categories, cancer stages I–III BC, and each stage’s ER/PR+ or ER/PR− status. At each visit, we delineated the time-varying covariates of administered treatments, induced adverse events, comorbidity index, and age. We predicted the survival of three hypothetical patients to demonstrate the model’s utility. Main Outcomes and Measures: The primary outcomes of the modeling were the measures of the model’s prediction error, as measured by the concordance index, the most commonly applied evaluation metric in survival analysis, and the integrated Brier score, a metric of the model’s discrimination and calibration. Results: The proposed extended patients’ covariates that include both time-fixed and time-varying covariates significantly improved the deep learning models’ prediction error and the discrimination and calibration of a model’s estimates. The prediction of the four DL models using time-fixed covariates in six different prognostic categories all resulted in approximately a 30% error in all six categories. When applying the proposed extension to include time-varying covariates, the accuracy of all four predictive models improved significantly, with the error decreasing to approximately 10%. The models’ predictive accuracy was independent of the differing published survival predictions from time-fixed covariates in the six prognostic categories. We demonstrate the utility of the model in three hypothetical patients with unique patient, cancer, and treatment variables. The model predicted survival based on the patient’s individual time-fixed and time-varying features, which varied considerably from Social Security age-based, and stage and race-based breast cancer survival predictions. Conclusions: The predictive modeling of the survival of patients with early-stage breast cancer using DL models has a prediction error of around 30% when considering only time-fixed covariates at the time of diagnosis and decreases to values under 10% when time-varying covariates are added as input to the models, regardless of the prognostic category of the patient groups. These models can be used to predict individual patients’ survival probabilities based on their unique repertoire of time-fixed and time-varying features. They will provide guidance for patients and their caregivers to assist in decision making. Full article
(This article belongs to the Collection Artificial Intelligence in Oncology)
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<p>The C-index vs. the model hyperparameters: n-layers, Ir, batch size, epochs, dropout, n_nodes, alpha, sigma.</p>
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<p>Predicted survival curves for three hypothetical patients. Details of data used to produce these hypothetical predicted survival curves are not permitted by NCI SEER-Medicare because they were derived from individual patient-identifying information.</p>
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27 pages, 4293 KiB  
Article
TGFB2 mRNA Levels Prognostically Interact with Interferon-Alpha Receptor Activation of IRF9 and IFI27, and an Immune Checkpoint LGALS9 to Impact Overall Survival in Pancreatic Ductal Adenocarcinoma
by Sanjive Qazi and Vuong Trieu
Int. J. Mol. Sci. 2024, 25(20), 11221; https://doi.org/10.3390/ijms252011221 - 18 Oct 2024
Abstract
The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies. This study analyzed archived macrophage-associated mRNA expression using datasets deposited in the UCSC Xena [...] Read more.
The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies. This study analyzed archived macrophage-associated mRNA expression using datasets deposited in the UCSC Xena web platform to compare normal pancreatic tissue and PDAC tumor samples. The TGFB2 gene exhibited low mRNA expression levels in normal tissue, with less than one TPM. In contrast, in tumor tissue, TGFB2 expression levels exhibited a 7.9-fold increase in mRNA expression relative to normal tissue (p < 0.0001). Additionally, components of the type-I interferon signaling pathway exhibited significant upregulation of mRNA levels in tumor tissue, including Interferon alpha/beta receptor 1 (IFNAR1; 3.4-fold increase, p < 0.0001), Interferon regulatory factor 9 (IRF9; 4.2-fold increase, p < 0.0001), Signal transducer and activator of transcription 1 (STAT1; 7.1-fold increase, p < 0.0001), and Interferon Alpha Inducible Protein 27 (IFI27; 66.3-fold increase, p < 0.0001). We also utilized TCGA datasets deposited in cBioportal and KMplotter to relate mRNA expression levels to overall survival outcomes. These increased levels of mRNA expression were found to be prognostically significant, whereby patients with high expression levels of either TGFB2, IRF9, or IFI27 showed median OS times ranging from 16 to 20 months (p < 0.01 compared to 72 months for patients with low levels of expression for both TGFB2 and either IRF9 or IFI27). Examination of the KMplotter database determined the prognostic impact of TGFB2 mRNA expression levels by comparing patients expressing high versus low levels of TGFB2 (50th percentile cut-off) in low macrophage TME. In TME with low macrophage levels, patients with high levels of TGFB2 mRNA exhibited significantly shorter OS outcomes than patients with low TGFB2 mRNA levels (Median OS of 15.3 versus 72.7 months, p < 0.0001). Furthermore, multivariate Cox regression models were applied to control for age at diagnosis. Nine genes exhibited significant increases in hazard ratios for TGFB2 mRNA expression, marker gene mRNA expression, and a significant interaction term between TGFB2 and marker gene expression (mRNA for markers: C1QA, CD74, HLA-DQB1, HLA-DRB1, HLA-F, IFI27, IRF9, LGALS9, MARCO). The results of our study suggest that a combination of pharmacological tools can be used in treating PDAC patients, targeting both TGFB2 and the components of the type-I interferon signaling pathway. The significant statistical interaction between TGFB2 and the nine marker genes suggests that TGFB2 is a negative prognostic indicator at low levels of the IFN-I activated genes and TAM marker expression, including the immune checkpoint LGALS9 (upregulated 16.5-fold in tumor tissue; p < 0.0001). Full article
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<p>TGF-β and IFN-I pathway impact cellular components of the TME to affect tumorigenesis in PDAC. Once exposed to polarizing stimuli, the undifferentiated or naive state of macrophage (M0) macrophages differentiate into either M1-like or M2-like Tumor-associated macrophages (TAMs). M1 TAMs can undergo polarization via TGF-β to generate M2 TAMs. Subsequently, these M2 TAMs release TGF-β to promote metastasis, angiogenesis, and fibrosis induction by converting PSCs to CAFs. M2 TAMS releases cytokines such as CCL5 and CCL20 to recruit Tregs and releases IL-6, CCL3, CXCL5, and GM-SF to recruit MDSCs into the TME. MDSCs and Tregs promote EMT via TGF-β production [<a href="#B5-ijms-25-11221" class="html-bibr">5</a>,<a href="#B6-ijms-25-11221" class="html-bibr">6</a>,<a href="#B7-ijms-25-11221" class="html-bibr">7</a>,<a href="#B8-ijms-25-11221" class="html-bibr">8</a>,<a href="#B9-ijms-25-11221" class="html-bibr">9</a>]. IFNβ can be secreted by Neoplastic Epithelial cells and PSCs activate M2 TAMs [<a href="#B8-ijms-25-11221" class="html-bibr">8</a>]. Neoplastic Epithelial cells can produce three isoforms of TGF-β and the receptor for these ligands to form a feed-forward activation loop promoting tumorigenic processes [<a href="#B35-ijms-25-11221" class="html-bibr">35</a>]. TAM: Tumor-associated macrophage; PSC: Pancreatic Stellate Cells; CAF: Cancer-Associated Fibroblasts; MDSC: Myeloid-Derived Suppressor Cell; Treg: Regulatory T cells; EMT: Epithelial-to-Mesenchymal Transition.</p>
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<p>TGFB2 mRNA levels have a significant negative prognostic impact on overall survival (OS) at low macrophage levels in PDAC tumors. OS data correlated with mRNA expression for PDAC patients were depicted as Kaplan–Meier curves to determine the prognostic impact of TGFB2 ligand (TGFB2 median expression cut-off values for high versus low mRNA expression patient sub-groupings) for all PDAC patients ((<b>A</b>) N = 177), PDAC patients with low macrophage populations ((<b>B</b>) N = 68), and PDAC patients with low macrophage and low neoantigen levels ((<b>C</b>) N = 47) (<a href="http://kmplot.com/analysis/index.php?p=service&amp;cancer=pancancer_rnaseq" target="_blank">http://kmplot.com/analysis/index.php?p=service&amp;cancer=pancancer_rnaseq</a>, accessed on 23 May 2024). (<b>A</b>) The median OS time for 88 patients from the TGFB2<sup>low</sup> group (20.5 (95% CI: 17.2–NA, Events = 43) months) was not significantly different from the TGFB2<sup>high</sup> group (N = 89, Median OS = 19.9 (95% CI: 16–24.4, Events = 49) months; Log-rank Chi-Square = 1.91, <span class="html-italic">p</span> = 0.167) of PDAC patients. (<b>B</b>) PDAC patients with low macrophage burden exhibited a significantly improved OS outcome in the TGFB2<sup>low</sup> group of patients (N = 34; Median = 72.7 (95% CI: 17.7–NA, Events = 13) months) compared with the TGFB2<sup>high</sup> group (N = 34; Median = 15.3 (95% CI: 9.3–NA, Events = 21) months; Log-rank Chi-Square = 9.12, <span class="html-italic">p</span> = 0.00252). (<b>C</b>) In PDAC patients with decreased macrophage and neoantigen levels, the TGFB2<sup>low</sup> PDAC group (N = 24, Median = 72.7 (95% CI: 72.7–NA, Events = 5) months) experienced significantly longer OS times than the TGFB2<sup>high</sup> group of patients (Median = 23, Median = 15.3 (95% CI: 9.2–NA, Events = 15) months; Log-rank Chi-Square = 15.66, <span class="html-italic">p</span> &lt; 0.001).</p>
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<p>PDAC patients with low levels of TGFB2 and low levels of IRF9 mRNA expression exhibited improved OS times than patients with high levels of TGFB2 or IRF9 mRNA expression. The median survival times for four different groups of patients are as follows: for 48 patients in group TGFB2<sup>low</sup>/IRF9<sup>low</sup>, the median survival time was 72 months (95% CI: 43.8–NA, Events = 14); for 40 patients in group TGFB2<sup>low</sup>/IRF9<sup>high</sup>, the median survival time was 16 months (95% CI: 12–20.2, Events = 27); for 40 patients in group TGFB2<sup>high</sup>/IRF9<sup>low</sup>, the median survival time was 19 months (95% CI: 13.8–24.3, Events = 25); and, for 49 patients in group TGFB2<sup>high</sup>/IRF9<sup>high</sup>, the median survival time was 20 months (95% CI: 15.1–30, Events = 26). TGFB2<sup>low</sup>/IRF9<sup>low</sup> group of patients exhibited significantly longer survival times compared to all combinations of TGFB2 and IRF9 expression levels (<span class="html-italic">p</span>-value = 0.0003, 0.0004, and 0.0005 for TGFB2<sup>low</sup>/IRF9<sup>high</sup>, TGFB2<sup>high</sup>/IRF9<sup>low</sup> and TGFB2<sup>high</sup>/IRF9<sup>high</sup> respectively).</p>
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<p>PDAC patients with low levels of TGFB2 and low levels of IFI27 mRNA expression exhibited improved OS times than patients with high levels of TGFB2 or IFI27 mRNA expression. Results of the OS examination for each group are as follows: 48 patients from TGFB2<sup>low</sup>/IFI27<sup>low</sup> had a median survival time of 72 months (95% CI: 21.4–NA, Events = 15). 40 patients from TGFB2<sup>low</sup>/IFI27<sup>high</sup> had a median survival time of 16 months (95% CI: 12.9–37.1, Events = 26). 40 patients from TGFB2<sup>high</sup>/IFI27<sup>low</sup> had a median survival time of 19 months (95% CI: 15.1–30, Events = 25). Finally, 49 patients from TGFB2<sup>high</sup>/IFI27<sup>high</sup> had a median survival time of 20 months (95% CI: 15.1–22.8, Events = 26). TGFB2<sup>low</sup>/IFI27<sup>low</sup> group of patients exhibited significantly longer survival times compared to all combinations of TGFB2 and IFI27 expression levels (<span class="html-italic">p</span>-value = 0.004 for all comparisons).</p>
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<p>PDAC patients with high levels of IFNAR1/STAT1/IRF9/IFI27 mRNA expression exhibited significantly increased hazard ratios in the multivariate Cox proportional hazards model considering age and TGFB2 levels. Multivariate analyses of the potential prognostic impact of TGFB2 mRNA expression levels paired with IFNAR1 (<b>A</b>), STAT1 (<b>B</b>), IRF9 (<b>C</b>), and IFI27 (<b>D</b>) mRNA expression levels on OS were determined using the multivariate Cox proportional hazards model to adjust for age, and TGFB2 statistical interaction with IFNAR1/STAT1/IRF9/IFI27. All four models exhibited significant concordant values (0.6–0.66, <span class="html-italic">p</span> &lt; 0.001 for all models), suggesting a good fit of the models to the OS data. High levels of TGFB2 exhibited significant increases in HR for models with IFNAR1 (HR (95% CI range) = 2.27 (1.18–4.36); <span class="html-italic">p</span> = 0.014), IRF9 (HR (95% CI range) = 3.32 (1.71–6.47); <span class="html-italic">p</span> &lt; 0.001) and IFI27 (HR (95% CI range) = 2.74 (1.42–5.28) and <span class="html-italic">p</span> = 0.003). IFNAR1 (HR (95% CI range) = 2.22 (1.17–4.22); <span class="html-italic">p</span> = 0.015), STAT1 (HR (95% CI range) = 2 (1.08–3.71); <span class="html-italic">p</span> = 0.029), IRF9 (HR (95% CI range) = 3.5 (1.82–6.72); <span class="html-italic">p</span> &lt; 0.001) and IFI27 (HR (95% CI range) = 2.56 (1.34–4.87) and <span class="html-italic">p</span> = 0.004) showed significant increases in models that included TGFB2 expression controlling for age at diagnosis and interaction terms. *** indicates <span class="html-italic">p</span> &lt; 0.01, ** indicates <span class="html-italic">p</span> &lt; 0.01, and * indicates <span class="html-italic">p</span> &lt; 0.05. # refers to the number of patients experiencing death events.</p>
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<p>Comparison of normal versus tumor tissue samples for genes exhibiting significant prognostic impacts on OS from the multivariate Cox regression models. Multivariate analyses of the potential effect of TGFB2 in combination with macrophage markers (CD68 (M1), MRC1/CD206 (M2), and 17 identified from single-cell RNA seq experiments), TGFB1, IFNAR1, IFI27, and IRF9 mRNA levels on OS were determined using the multivariate Cox proportional hazards model adjusted for age. (<b>A</b>) This Table shows the calculated HRs for (i) The mRNA expression level for TGFB2 as a categorical variable comparing high (N = 89) versus low (N = 88) TGFB2 mRNA expression levels (50% cut-off for the range of TPM values), (ii) The mRNA expression level for the companion gene, Gene 2, as a categorical variable comparing high (N = 89) versus low (N = 88) Gene 2 mRNA expression levels (50% cut-off for the range of TPM values), (iii) age at diagnosis as a linear covariate and an interaction term (TGFB2 x Gene2) included in the model. This Table is ordered according to the descending order of TGFB2 expression impact on OS. Gene 2 refers to identifying the paired gene mRNA expression with TGFB2 mRNA levels in the leftmost column. The impact on OS hazard ratio (HR) for Gene 2 is indicated in the 3rd column, and the interaction is reported in the 5th column. Nine genes exhibited significant increases in HR for TGFB2 expression, Gene 2 expression, and a significant interaction term (C1QA, CD74, HLA-DQB1, HLA-DRB1, HLA-F, IFI27, IRF9, LGALS9, and MARCO mRNAs). (<b>B</b>) We compared gene expression levels reported for 178 PDAC patients versus 167 pancreatic tissue samples. This resource reports results from the UCSC Toil RNAseq recompute compendium, which is a standardized realigned and recalculated gene and transcript expression dataset for all TCGA and GTEx samples that enables users to contrast gene and transcript expression between TCGA “tumor” samples and corresponding GTEx “normal” samples. Depicted is a cluster figure of the mRNA expression levels for Macrophage markers, TGFB1/2, IFNAR1 activated receptors and the corresponding downstream signaling molecules (IRF9), and the transcriptional product, Interferon Alpha Inducible Protein 27 (IFI27) mean centered to the corresponding mRNA expression levels in normal tissue. The cluster figure shows the log2-transformed fold-change values (blue represents underexpression, and the red color represents overexpression in samples from PDAC patients). Examination of the dendrogram showed that the expression of CCL8 mRNA was distinct from the mRNA expression of other genes and IFNAR1 was co-regulated with ADM, CD40, and IRF9. IFI27 mRNA was coregulated with MARCO, CD68, and APOC1. TGFB2 was co-regulated with TGFB1, MRC1/CD206, TLR8, SPI1, C1QA, HLA-F, and LGALS9 mRNA. LGALS9 presents itself as a potential target to develop immune checkpoint inhibitors against the production of Gal-9 protein in PDAC TME as it exhibits a 16.5-fold increase in tumor tissues (<span class="html-italic">p</span> &lt; 0.0001).</p>
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<p>Simulation of OS curves calculated from the multivariate Cox proportional hazards models demonstrating the prognostic impact of TGFB2 mRNA levels at low levels of mRNA, TAM markers, and IRF9. The predicted survival proportion was calculated from the Cox proportional hazards regression model parameters that included the statistical interaction term for combinations of TGFB2<sup>high</sup> (black line) versus TGFB2<sup>low</sup> (blue line) groups of PDAC patients in the context of the macrophage marker groups’ high and low mRNA expression (mean diagnosis age for this cohort of patients was set at 64.5 years to run the models for N = 177 and 92 death events for each model (<b>A</b>–<b>H</b>)). The four most significantly impacted increases in HR for the effect of high levels of TGFB2 mRNA are presented for the paired analysis (see <a href="#ijms-25-11221-f005" class="html-fig">Figure 5</a>) with HLA-F (<b>A</b>,<b>B</b>), CD74 (<b>C</b>,<b>D</b>), LGALS9 (<b>E</b>,<b>F</b>), and IRF9 (<b>G</b>,<b>H</b>). These four macrophage markers exhibited significant interaction effects in the multivariate model in which the negative prognostic effect of high TGFB2 levels occurred at low levels of the macrophage marker. The impact of the significant interaction term in the models is presented as improvements in OS at low levels of TGFB2 mRNA when there are low levels of the paired marker genes (<b>A</b>,<b>C</b>,<b>E</b>,<b>G</b>). At high TAM markers and IRF9 levels, the TGFB2<sup>low</sup> group of PDAC patients did not exhibit improvements in median OS (<b>B</b>,<b>D</b>,<b>F</b>,<b>H</b>).</p>
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<p>TGFB2 and components of the Interferon type I response mRNA levels prognostically impact OS outcomes in PDAC patients. This Figure illustrates a simplified model for the Interferon type-I (IFN-I) stimulated gene (ISG) transcription mediated by STAT1/STAT2/IRF9 complexes. IFN-I is recognized by a dimeric receptor composed of IFNAR1 and IFNAR2 subunits (blue, light blue subunits) [<a href="#B48-ijms-25-11221" class="html-bibr">48</a>,<a href="#B49-ijms-25-11221" class="html-bibr">49</a>,<a href="#B50-ijms-25-11221" class="html-bibr">50</a>]. After IFN binding and receptor dimerization, the juxtaposition of JAK1 (pink filled box) and TYK2 (orange filled box) increases kinase activity via transphosphorylation and subsequent STAT1 (light brown ellipse) and STAT2 (brown filled ellipse) and IRF9 (yellow filled ellipse) protein recruitment. STAT1/STAT2/IRF9 complex proteins are successively phosphorylated (blue circles), dimerized, and translocated to the nucleus, where ISG transcription is initiated after binding interferon-sensitive response element (ISRE) to produce mRNA for Interferon Alpha Inducible Protein 27 (IFI27; orange filled ellipse) [<a href="#B47-ijms-25-11221" class="html-bibr">47</a>]. Activation of the Transforming growth factor receptor is depicted by TGFB2 dimer binding to a tetrameric receptor structure composed of TGFBR1 (2 dark red subunits) and TGFBR2 (2 red subunits). Significant prognostic indicators that exhibited an increase in HR for OS outcomes are indicated by red outlines (TGFB2, IFNAR1, STAT1, IRF9, and IFI27 mRNAs). This figure was adapted from [<a href="#B51-ijms-25-11221" class="html-bibr">51</a>,<a href="#B52-ijms-25-11221" class="html-bibr">52</a>].</p>
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9 pages, 1294 KiB  
Brief Report
Blood Eosinophils Matter in Post-COVID-19 Pneumonia
by Nicol Bernardinello, Gioele Castelli, Dylan Pasin, Giulia Grisostomi, Marco Cola, Chiara Giraudo, Elisabetta Cocconcelli, Annamaria Cattelan, Paolo Spagnolo and Elisabetta Balestro
Diagnostics 2024, 14(20), 2320; https://doi.org/10.3390/diagnostics14202320 - 18 Oct 2024
Abstract
Background: Even after the development of vaccines, SARS-CoV-2 continues to cause severe pneumonia all over the world. Consequently, in order to improve the management of patients and optimize the use of resources, predictors of disease severity and lung complications after COVID-19 pneumonia are [...] Read more.
Background: Even after the development of vaccines, SARS-CoV-2 continues to cause severe pneumonia all over the world. Consequently, in order to improve the management of patients and optimize the use of resources, predictors of disease severity and lung complications after COVID-19 pneumonia are urgently needed. Blood cell count is an easily available and reproducible biomarker. With this study, we aimed to explore the role of eosinophils in predicting disease behavior and pulmonary sequelae at first follow-up with computed tomography (CT). Methods: we evaluated blood cell count and other inflammatory markers, both at baseline and during hospitalization, in a large population of hospitalized COVID-19 patients. Results: 327 patients were finally enrolled, 214 were classified as low-intensity medical care (LIMC) and 113 as high-intensity medical care. Eosinophils were higher at discharge in the HIMC group [0.1 (0–0.72) vs. 0.05 (0–0.34) × 109/L; p < 0.0001]. Moreover, in the multivariable analysis, age ≥ 62 years (OR 1.76 (1.05–2.8) p = 0.03) and Δ eosinophils ≥ 0.05 (OR 1.75 (1.05–2.9) p = 0.03) were two independent predictors of residual lung abnormalities in the whole patient population at first follow-up. Conclusions: an eosinophil increase during hospitalization could be a potential predictor of pulmonary sequelae in surviving patients after COVID-19 pneumonia. Full article
(This article belongs to the Special Issue Diagnosis and Management of Thoracic Disease)
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<p>Eosinophil trends from admission to hospital discharge in HIMC and LIMC groups. Wilcoxon signed-rank test was used to compare eosinophil values between admission and discharge in HIMC patients (<span class="html-italic">p</span> &lt; 0.0001) and LIMC patients (<span class="html-italic">p</span> &lt; 0.0001). HIMC: high-intensity medical care; LIMC: low-intensity medical care.</p>
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<p>Example of chest CT scan 3 months after hospital discharge. Panel (<b>A</b>): patient with HIMC and a high rise in eosinophil count with GGO and reticular lung abnormalities (Not-Rec); panel (<b>B</b>): patient with HIMC and a low rise in eosinophil count without residual lung abnormalities (Rec).</p>
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8 pages, 191 KiB  
Article
Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM)
by Ayrton Bangolo, Behzad Amoozgar, Lili Zhang, Vignesh K. Nagesh, Imranjot Sekhon, Simcha Weissman, David Vesole, Pooja Phull, Michele Donato, Noa Biran, David Siegel and Harsh Parmar
J. Clin. Med. 2024, 13(20), 6207; https://doi.org/10.3390/jcm13206207 - 18 Oct 2024
Abstract
Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and [...] Read more.
Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18–70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution’s records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan–Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy. Full article
(This article belongs to the Special Issue Clinical Applications of Tumor Immunotherapy)
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12 pages, 999 KiB  
Article
The Impact of FDA-Approved Novel Agents for Steroid-Refractory Chronic Graft vs. Host Disease on Treatment Patterns and Outcomes—A Single-Center Longitudinal Cohort Analysis
by Gil Fridberg, Odelia Amit, Chen Karni, Dina Tshernichovsky, David Shasha, Vanessa Rouach, David Varssano, Amir Bar-Shai, Ilan Goldberg, Gilad Wasserman, Irit Avivi and Ron Ram
Cancers 2024, 16(20), 3521; https://doi.org/10.3390/cancers16203521 - 17 Oct 2024
Viewed by 189
Abstract
Objectives—chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods—we [...] Read more.
Objectives—chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods—we retrospectively analyzed all patients > 18 years with cGVHD after their first hematopoietic cell transplantation (HCT) between 2012 and 2020 (n = 91), divided into three treatment periods: 2012–2014, 2015–2017, and 2018–2020 (groups 1, 2, and 3, respectively). Results—mean cumulative steroid dose and dose/total cGVHD-treatment days was lower in groups 2–3 compared to 1 (p = 0.008 and p = 0.042, respectively). The median IST-free survival was 79 (95%CI54–94) months, with more patients in group 3 (47% (95%CI 25–54%) discontinuing IST at 3 years, p = 0.1). Groups 2–3 compared to 1 had better glycemic control (p < 0.01), higher bone density (p = 0.06), and fewer cardiovascular events. The number of admissions/patient dropped from 0.7/year in group 1 to 0.24/year and 0.36/year in groups 2–3, respectively (p = 0.36). Employment reintegration was higher in groups 2–3 compared with 1 (p = 0.05) and so was earlier return to work (p = 0.01). There were no differences in survival outcomes. Conclusions—the incorporation of novel agents appears to be associated with reduced overall steroid burden, improved cGVHD control, and fewer long-term side effects. Full article
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<p>Patient flow chart.</p>
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<p>Accumulated steroid burden across time periods.</p>
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<p>Mortality or relapse rates and IST discontinuation.</p>
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12 pages, 421 KiB  
Article
Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia: Results of a Single-Center Study
by Davide Stella, Jessica Gill, Roberto Passera, Sofia Zompi, Chiara Maria Dellacasa, Ernesta Audisio, Marco Cerrano, Irene Dogliotti, Michele Dicataldo, Carolina Secreto, Benedetto Bruno, Roberto Freilone, Alessandro Busca and Luisa Giaccone
Hematol. Rep. 2024, 16(4), 636-647; https://doi.org/10.3390/hematolrep16040062 - 17 Oct 2024
Viewed by 165
Abstract
Background: Despite the adoption of pediatric-like chemotherapy protocols, the introduction of new immunotherapies and a better understanding of the oncogenic landscape, the outcome for adult patients with acute lymphoblastic leukemia (ALL) remain substantially dismal. The aim of the present study was to evaluate [...] Read more.
Background: Despite the adoption of pediatric-like chemotherapy protocols, the introduction of new immunotherapies and a better understanding of the oncogenic landscape, the outcome for adult patients with acute lymphoblastic leukemia (ALL) remain substantially dismal. The aim of the present study was to evaluate the outcome in terms of survival in a cohort of adult patients with ALL who received allogeneic hematopoietic stem cell transplantation (alloSCT) between 2013 and 2023. Methods: This was a single-center observational retrospective study including all consecutive adult patients with ALL who received an alloSCT between April 2013 and April 2023 at the Stem Cell Transplant Center AOU Città della Salute e della Scienza of Torino. The primary endpoints were overall survival (OS), graft-versus-host disease (GVHD) Relapse-Free Survival (GRFS), Leukemia-Free Survival (LFS) and cumulative incidence (CI) of Non-Relapse Mortality (NRM). Results: The 4-year OS and LFS were 63.4% and 48.1%, respectively, and the 1-year GRFS was 42.9%. The 1-year CI of bloodstream infections (BSI), invasive fungal infections and NRM were 38%, 7% and 18.4%, respectively. Multivariate analysis showed that the use of total body irradiation (TBI), a time interval from diagnosis to alloSCT 7 months and female gender were factors significantly associated with better OS. Relapse of the underlying malignancy and BSI were the main causes of death. Conclusion: Our study suggests that alloSCT from a matched sibling donor (MSD) and alternative donors may be considered an effective tool for patients with ALL achieving a CR. Full article
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<p>GRFS (<b>A</b>), OS (<b>B</b>), LFS (<b>C</b>) and cumulative incidence of Non-Relapse Mortality (<b>D</b>) of 69 patients with ALL who received alloSCT.</p>
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Article
Evolving Practice and Outcomes in Grade 2 Glioma: Real-World Data from a Multi-Institutional Registry
by Lucy Gately, Katharine Drummond, Anthony Dowling, Iwan Bennett, Ronnie Freilich, Claire Phillips, Elizabeth Ahern, David Campbell, Megan Dumas, Robert Campbell, Rosemary Harrup, Grace Y. Kim, Simone Reeves, Ian M. Collins and Peter Gibbs
Cancers 2024, 16(20), 3514; https://doi.org/10.3390/cancers16203514 - 17 Oct 2024
Viewed by 154
Abstract
Background: Grade-2 gliomas (G2-glioma) are uncommon. In 2016, RTOG9802 established the addition of chemotherapy after radiation (CRT) as a new standard of care for patients with high-risk G2-glioma, defined as subtotal resection or age ≥40 yrs. Here, we report current practices using [...] Read more.
Background: Grade-2 gliomas (G2-glioma) are uncommon. In 2016, RTOG9802 established the addition of chemotherapy after radiation (CRT) as a new standard of care for patients with high-risk G2-glioma, defined as subtotal resection or age ≥40 yrs. Here, we report current practices using real-world data. Methods: Patients diagnosed with G2-glioma from 1 January 2016 to 31 December 2022 were identified in BRAIN, a prospective clinical registry collecting data on patients with brain tumours. High- and low-risk were defined as per RTOG9802. Two time periods, January 2016–December 2019 (TP1) and January 2020–December 2022 (TP2), were defined. Survival was estimated using the Kaplan–Meier method. Results: 224 patients were identified. Overall, 38 (17%) were low-risk, with 35 (91%) observed without further treatment. A total of 186 (83%) were high-risk, with 96 (52%) observed, 63 (34%) receiving CRT, and 19 (10%) receiving radiation. Over time, CRT use increased (TP1 vs. TP2: 22% vs. 36%, p = 0.004), and the rate of biopsy (TP1 vs. TP2: 35% vs. 20%, p = 0.02) and radiotherapy alone (TP1 vs. TP2: 14% vs. 4%, p = 0.01) decreased. Median progression-free survival (PFS) was significantly longer in high-risk patients who received CRT (NR) over observation (39 months) (HR 0.49, p = 0.007). In high-risk patients who were observed, 59 (61%) were progression-free at 12 months and 10 (10%) at 5 years. OS data remains immature. Conclusions: Congruent with RTOG9802, real-world BRAIN data shows CRT is associated with improved PFS compared to observation in high-risk G2-glioma. Whilst CRT use has increased over time, observation after surgery remains the most common strategy, with some high-risk patients achieving clinically meaningful PFS. Validated biomarkers are urgently required to better inform patient management. Full article
(This article belongs to the Collection Treatment of Glioma)
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<p>Sankey diagram of patient treatment flows in the first-line setting for all patients.</p>
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<p>Sankey diagram of patient treatment flows in the first-line setting for all patients with low-risk grade 2 glioma (<b>a</b>) and high-risk grade 2 glioma (<b>b</b>).</p>
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<p>PFS for patients with grade 2 glioma based on treatment received following surgical resection.</p>
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13 pages, 1260 KiB  
Article
Analysis of the Polyculture Model of the Bivalves Anadara broughtonii and Chlamys farreri in Suspension Cages in Shallow Seas
by Chunnuan Zhao, Liqun Ren, Shuai Xu, Yuping Wu, Haiying Han, Bo Li, Yanxin Zheng, Yang Chen, Xiwen Wang, Nini Fan, Junjie Li, Chaoyi Xie, Shuai Cai and Tao Yu
Fishes 2024, 9(10), 413; https://doi.org/10.3390/fishes9100413 - 17 Oct 2024
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Abstract
This study examined the survival rates of Anadara broughtonii and Chlamys farreri with varying heights throughout winter and summer aquaculture periods under varying ratios of mixed-culture conditions in marine environments. The aim was to assess the viability and economic advantages of mixed-culture practices [...] Read more.
This study examined the survival rates of Anadara broughtonii and Chlamys farreri with varying heights throughout winter and summer aquaculture periods under varying ratios of mixed-culture conditions in marine environments. The aim was to assess the viability and economic advantages of mixed-culture practices among different bivalve species. Results indicate that the winter (from December to February of the following year) mortality rate for A. broughtonii in mixed culture ranges from 12.04% to 16.85%, markedly lower than in single-species cultures. Mixed-culture A. broughtonii measuring 2.5–4.0 cm exhibit a significantly reduced summer (from July to September) mortality rate compared to those in single-species cultures (p < 0.05). No significant mortality difference was observed between the monoculture and polyculture of C. farreri. Growth rates of C. farreri and A. broughtonii showed no significant differences between monoculture and polyculture conditions. The optimal size for combining two different species of bivalves is 2.5 cm, with a 1:1 ratio being the most effective. An equal number of seedlings were cultivated across various seawater aquaculture systems for a period of one year. The survival rates of monoculture seedlings of Anadara broughtonii and Chlamys farreri were 60.34% and 86.55%, respectively. In contrast, polyculture seedlings exhibited higher survival rates after one year of mariculture, with Anadara broughtonii at 73.36% and Chlamys farreri at 89.74%. The polyculture of A. broughtonii and C. farreri in suspension cages demonstrates a favorable input–output ratio of 1:2.02. This approach effectively reduces winter and summer mortality rates of A. broughtonii, representing an efficient new method for marine bivalve aquaculture. Full article
(This article belongs to the Special Issue Advances in Bivalve Aquaculture)
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<p>Culture cage structure (<b>A</b>) and raft frame culture sea area (<b>B</b>).</p>
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<p>Mortality (<b>A</b>,<b>B</b>), height (<b>C</b>), and wet weight (<b>D</b>) growth rate of <span class="html-italic">Anadara broughtonii</span> during winter and summer periods.</p>
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<p>Mortality and growth rate of <span class="html-italic">Anadara broughtonii</span> in different polyculture proportions. (<b>A</b>) Survival rates across different proportions. (<b>B</b>) Height size and wet weight across different proportions.</p>
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<p>Mortality and growth rate of <span class="html-italic">Anadara broughtonii</span> in different polyculture proportions. (<b>A</b>) Survival rates across different proportions. (<b>B</b>) Height size and wet weight across different proportions.</p>
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<p>Mortality (<b>A</b>) and growth rate of <span class="html-italic">Chlamys farreri</span> with different heights after winter (<b>B</b>) and summer (<b>C</b>).</p>
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8 pages, 619 KiB  
Article
Perioperative and Long-Term Outcomes After Combined Liver and Kidney Transplantation: A Single-Center Experience
by Kosta Cerović, Benjamin Hadžialjević, Simon Hawlina and Blaž Trotovšek
Life 2024, 14(10), 1319; https://doi.org/10.3390/life14101319 - 17 Oct 2024
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Abstract
Combined liver–kidney transplantation (CLKT) has evolved as a therapeutic option for patients with concurrent end-stage liver and renal diseases. This study evaluates the perioperative and long-term outcomes of CLKT at a single center in Slovenia, highlighting the challenges and successes of simultaneous organ [...] Read more.
Combined liver–kidney transplantation (CLKT) has evolved as a therapeutic option for patients with concurrent end-stage liver and renal diseases. This study evaluates the perioperative and long-term outcomes of CLKT at a single center in Slovenia, highlighting the challenges and successes of simultaneous organ transplantation. We retrospectively analyzed all patients undergoing simultaneous CLKT at the University Medical Centre Ljubljana from April 2014 to June 2023. Data on demographics, cause of liver and kidney disease, operative details, postoperative complications, patient and graft survival, and follow-up were collected and analyzed. Five patients aged 27 to 60 years underwent CLKT within the study period. All transplants involved deceased donors with whole-liver grafts. Indications for CLKT were polycystic liver disease (n = 3), Caroli’s disease (n = 1), and alcoholic cirrhosis (n = 1). The mean follow-up duration was 45.2 months, with a 100% survival rate. The incidence of surgical and postoperative complications was low. This pioneering series of simultaneous CLKTs in Slovenia demonstrates the feasibility and effectiveness of the procedure in smaller transplant centers. Despite challenges, including T cell-mediated kidney rejection and surgical complications, the study emphasizes the importance of comprehensive postoperative care and management in optimizing outcomes for CLKT recipients. Full article
(This article belongs to the Section Medical Research)
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<p>A contrast-enhanced abdominal computed tomography (CT) scan shows a hypodense area in the lower parts of segments 5 and 6 of the transplanted liver, resulting from an obstruction of flow to a branch of the right hepatic artery (white arrow). In addition, the transplanted kidney can be seen in the right iliac fossa (white arrowhead).</p>
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16 pages, 2015 KiB  
Review
The Roles of Mitochondria in Human Being’s Life and Aging
by Hiroko P. Indo, Moragot Chatatikun, Ikuo Nakanishi, Ken-ichiro Matsumoto, Motoki Imai, Fumitaka Kawakami, Makoto Kubo, Hiroshi Abe, Hiroshi Ichikawa, Yoshikazu Yonei, Hisashi J. Beppu, Yukiko Minamiyama, Takuro Kanekura, Takafumi Ichikawa, Atthaphong Phongphithakchai, Lunla Udomwech, Suriyan Sukati, Nurdina Charong, Voravuth Somsak, Jitbanjong Tangpong, Sachiyo Nomura and Hideyuki J. Majimaadd Show full author list remove Hide full author list
Biomolecules 2024, 14(10), 1317; https://doi.org/10.3390/biom14101317 - 17 Oct 2024
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Abstract
The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth [...] Read more.
The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth was to become individual rather than cellular life. The birth of mitochondria made this possible to be the individual life. Since then, individuals have had a limited time of life. It was 1.4 billion years ago that a bacterial cell began living inside an archaeal host cell, a form of endosymbiosis that is the development of eukaryotic cells, which contain a nucleus and other membrane-bound compartments. The bacterium started to provide its host cell with additional energy, and the interaction eventually resulted in a eukaryotic cell, with both archaeal (the host cell) and bacterial (mitochondrial) origins still having genomes. The cells survived high concentrations of oxygen producing more energy inside the cell. Further, the roles of mitochondria in human being’s life and aging will be discussed. Full article
(This article belongs to the Special Issue Mitochondrial Quality Control in Aging and Neurodegeneration)
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<p>Schema of the electron transport chain. ATP production by oxidative phosphorylation with an electron transport chain (ETC).</p>
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<p>A scheme of mitochondrial generation of ROS. O<sub>2</sub><b><sup>•</sup></b><sup>−</sup> generated from mitochondria binds with NO and further produces peroxynitrous acid (ONOOH), and further ONOOH produces NO<sub>2</sub><b><sup>•</sup></b> and <b><sup>•</sup></b>OH. In the figure red arrow of up means up-regulations, and stable means no expression change. (Figure transferred from Reference [<a href="#B1-biomolecules-14-01317" class="html-bibr">1</a>]).</p>
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<p>Illustration of the 4.6-billion-year-old Earth, acknowledging “Andrée Valley, University of Wisconsin—Madison”. (Reference [<a href="#B6-biomolecules-14-01317" class="html-bibr">6</a>]). The author, H.J.M. added mitochondria to the figure.</p>
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<p>Increase of atmospheric oxygen in the history of Earth through 4.6 billion years. The figure was transferred from Reference [<a href="#B11-biomolecules-14-01317" class="html-bibr">11</a>] with a license.</p>
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<p>Conclusion: relationship between aging and mitochondria. Upon aging, arrow stable means no change, arrow down means down regulation, and arrow up means up regulation.</p>
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13 pages, 679 KiB  
Article
Adverse Events of Radioligand Therapy in Patients with Progressive Neuroendocrine Neoplasms: The Biggest Eastern European Prospective Study
by Adam Daniel Durma, Marek Saracyn, Maciej Kołodziej, Katarzyna Jóźwik-Plebanek, Dorota Brodowska-Kania, Beata Dmochowska, Adrianna Mróz, Beata Kos-Kudła and Grzegorz Kamiński
Cancers 2024, 16(20), 3509; https://doi.org/10.3390/cancers16203509 - 17 Oct 2024
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Abstract
Background: Neuroendocrine neoplasms (NENs) are neoplastic tumors developing in every part of the body, mainly in the gastrointestinal tract and pancreas. Their treatment involves the surgical removal of the tumor and its metastasis, long-acting somatostatin analogs, chemotherapy, targeted therapy, and radioligand therapy (RLT). [...] Read more.
Background: Neuroendocrine neoplasms (NENs) are neoplastic tumors developing in every part of the body, mainly in the gastrointestinal tract and pancreas. Their treatment involves the surgical removal of the tumor and its metastasis, long-acting somatostatin analogs, chemotherapy, targeted therapy, and radioligand therapy (RLT). Materials and Methods: A total of 127 patients with progressive neuroendocrine neoplasms underwent RLT—4 courses, administered every 10 weeks—with the use of 7.4 GBq [177Lu]Lu-DOTA-TATE or tandem therapy with 1.85 GBq [177Lu]Lu-DOTA-TATE and 1.85 GBq [90Y]Y-DOTA-TATE. Assessment of short- and long-term complications, as well as the calculation of progression-free survival (PFS) and overall survival (OS) were performed. Results: RLT caused a statistically but not clinically significant decrease in blood morphology parameters during both short- and long-term observations. Glomerular filtration rate (GFR) significantly decreased only in a long-term observation after RLT; however, it was clinically acceptable. Computed predictions of progression-free survival (PFS) and overall survival (OS) indicated that five years post-RLT, there is a 74% chance of patients surviving, with only a 58.5% likelihood of disease progression. Conclusions: Computed predictions of PFS and OS confirmed treatment efficiency and good patient survival. RLT should be considered a safe and reliable line of treatment for patients with progressive NENs as it causes only a low number of low-grade adverse events. Full article
(This article belongs to the Special Issue Radioligand Therapy (RLT) in Neuroendocrine Neoplasms)
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<p>Overall survival probability calculations.</p>
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<p>Progression-free survival probability calculations.</p>
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