Influence of Sires on Population Substructure in Dülmen Wild Horses.

The objectives of the present study were to analyze the influence of the stallions employed in the Dülmen wild horses on the genetic diversity and population substructure using Bayesian cluster analysis. The Dülmen wild horse is maintained as a unique horse population exposed to the natural conditions all year round in the Merfelder Bruch near Dülmen in Westphalia, Germany. Stallions selected for breeding have to prove their abilities to survive under this harsh environment. We used multilocus genotypic information from a set of 29 autosomal microsatellites to determine the paternity of 185 male foals sired by nine stallions. As females could not be sampled, we could not make inferences on all yearlings and test whether there are differences in the genetic population parameters between both sexes. The mean number of progeny was 19.92 with a range of 2-32, caused by the length of the service period per stallion. The average observed and unbiased expected heterozygosity was 0.688 and 0.631, the mean number of alleles was 4.448, and Wright's FIS was -0.173. Pairwise genetic distances (FST and Nei's unbiased genetic distances) were significant and varied between 0.038 to 0.091 and 0.085 to 0.290, respectively. Neighbor-joining dendrogram plots clustered a large proportion of the paternal progeny groups in different branches. Posterior Bayesian analyses using seven paternal half-sib groups with 10-74 members supported a maximum of six clusters, with two paternal progeny groups not differing, and a median of five clusters, with two groups of two sires each falling into the same clusters. When sires were employed in non-consecutive years, progeny from these different years of the same sires were grouped in the same cluster, whereas the progeny of one sire from two consecutive years were in different clusters. We were able to distinguish male progeny from Dülmen wild horse stallions and to show the effects of stallion use on the genetic substructure in the Dülmen wild horse herd. In conclusion, the analyses showed the genetic potential of the Dülmen wild horse stallions to maintain a high genetic diversity and also the effects in which breeding seasons and for how long stallions are used to sire foals. The selection of stallions may be sensitive for the further development of genetic diversity and preserve this closed population as a valuable resource for further studies on the evolution of the horse.

CVD-Synthesized Titanium Carbide Nanoflowers as High-Performance Anodes for Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have emerged as promising candidates for energy storage applications due to the abundance and low cost of sodium. However, the larger radius of sodium ions limits their diffusion kinetics within electrode materials and contributes to electrode volume expansion. Here, we successfully synthesized porous titanium carbide (TiC) nanoflowers through chemical vapor deposition (CVD). The TiC nanoflowers exhibit exceptional electrochemical performance as SIB anodes, with their porous structure enhancing the conductivity, mechanical stability, and Na-ion diffusion. The TiC nanoflowers demonstrate a high reversible specific capacity of 73.5 mAh g-1 at 1 A g-1 after 2500 cycles, corresponding to an impressive capacity retention of 80.81%. Additionally, we developed a full sodium-ion cell utilizing TiC nanoflowers as the anode and Na3V2(PO4)3 as the cathode, which demonstrates a substantial reversible capacity and outstanding cycling stability. Our work presents a promising strategy for synthesizing nanostructured TiC materials as anode electrodes for SIBs.

Efficacy and safety of MR-guided adaptive simultaneous integrated boost radiotherapy to primary lesions and positive lymph nodes in the neoadjuvant treatment of locally advanced rectal cancer: a randomized controlled phase III trial.

BACKGROUND: In locally advanced rectal cancer (LARC), optimizing neoadjuvant strategies, including the addition of concurrent chemotherapy and dose escalation of radiotherapy, is essential to improve tumor regression and subsequent implementation of anal preservation strategies. Currently, dose escalation studies in rectal cancer have focused on the primary lesions. However, a common source of recurrence in LARC is the metastasis of cancer cells to the proximal lymph nodes. In our trial, we implement simultaneous integrated boost (SIB) to both primary lesions and positive lymph nodes in the experimental group based on magnetic resonance-guided adaptive radiotherapy (MRgART), which allows for more precise (and consequently intense) targeting while sparing neighboring healthy tissue. The objective of this study is to evaluate the efficacy and safety of MRgART dose escalation to both primary lesions and positive lymph nodes, in comparison with the conventional radiotherapy of long-course concurrent chemoradiotherapy (LCCRT) group, in the neoadjuvant treatment of LARC. METHODS: This is a multi-center, randomized, controlled phase III trial (NCT06246344). 128 patients with LARC (cT3-4/N+) will be enrolled. During LCCRT, patients will be randomized to receive either MRgART with SIB (60-65 Gy in 25-28 fractions to primary lesions and positive lymph nodes; 50-50.4 Gy in 25-28 fractions to the pelvis) or intensity-modulated radiotherapy (50-50.4 Gy in 25-28 fractions). Both groups will receive concurrent chemotherapy with capecitabine and consolidation chemotherapy of either two cycles of CAPEOX or three cycles of FOLFOX between radiotherapy and surgery. The primary endpoints are pathological complete response (pCR) rate and surgical difficulty, while the secondary endpoints are clinical complete response (cCR) rate, 3-year and 5-year disease-free survival (DFS) and overall survival (OS) rates, acute and late toxicity and quality of life. DISCUSSION: Since dose escalation of both primary lesions and positive nodes in LARC is rare, we propose conducting a phase III trial to evaluate the efficacy and safety of SIB for both primary lesions and positive nodes in LARC based on MRgART. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov with the Identifier: NCT06246344 (Registered 7th Feb 2024).

[Moderately hypofractionated dose escalation radiotherapy for localized prostate cancer, ESHYPRO: Results of a retrospective single-centre series evaluating safety and efficacy]. / Escalade de dose en radiothérapie modérément hypofractionnée pour les cancers de la prostate localisés, ESHYPRO : résultats d'une série monocentrique rétrospective évaluant la toxicité et l'efficacité.

PURPOSE: Prostate cancer is the most frequent cancer among men and radiotherapy hypofractionation regimens have become standard treatments for the localized stages, but the absence of increased risk of acute and late genitourinary or gastrointestinal toxicity of the dose escalation still must be demonstrated. MATERIAL AND METHODS: The study population included all patients with localized prostatic adenocarcinoma treated at the institut Curie from February 2016 to March 2018 by external radiation delivered by a linear accelerator using an image-guided conformal intensity modulation technique at a total dose of 75Gy in 30 fractions of 2.5Gy in the planning target volume that included the prostate and the proximal seminal vesicles, and could be paired with a prophylactic lymph node radiotherapy at 46Gy in 23 fractions with simultaneous integrated boost. RESULTS: A total of 166 patients were included. Among them, 68.6% were unfavourable intermediate or (very) high risk. The median age and follow-up were 71.4years and 3.96years. One hundred and forty-nine patients received prophylactic lymph node radiotherapy (89.8%). One hundred and thirty-one patients received hormonotherapy (78.9%). Genito-urinary toxicity events of grades 2 or above during radiotherapy, at 6months, 1year and 5years were respectively 36.7%, 8.8%, 3.1% and 4.7%. Two patients had late grade 4 toxicity at 5years (1.6%). Grade 2 gastrointestinal toxicity events during radiotherapy, 6months, 1year and 5years were respectively 15.1%, 1.9%, 14.6% and 9.3%. Of these, eight patients had grade 3 toxicity (6.2%). There was no grade 4 toxicity. Analyses did not reveal any predictive factor for toxicity. The 5-year overall, progression-free, and specific survival rates were respectively 82.4%, 85.7%, and 93.3%. Serum prostate specific antigen concentration and cardiovascular risk factors were found to be predictive factors of deterioration in overall survival (P=0.0028 for both). CONCLUSION: External radiotherapy for localized prostatic cancer with our moderately hypofractionated dose escalation regimen is well tolerated. In the absence of increased late toxicity, the analysis of the modes of long-term relapses will be interesting to determine the benefit of this dose escalation on local and distant relapses.

Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

[Short- and medium-term tolerance of hypofractionated prostate radiotherapy with simultaneous integrated boost]. / Tolérance à court et moyen terme d'une radiothérapie prostatique hypofractionnée selon la technique du boost intégré.

PURPOSE: This retrospective study was conducted to ensure that irradiation of the pelvic lymph node areas associated with simultaneous hypofractionated boost to the prostate according to the protocol implemented at the university hospital of Tours (France) does not result in excess urinary and digestive toxicity in the short and medium term. MATERIALS AND METHODS: The study population included patients with localized unfavourable intermediate or high-risk prostate cancer. The dose delivered was 65Gy in 25 fractions of 2.6Gy to the prostate and seminal vesicles, and 50Gy in 25 fractions of 2Gy to the pelvic lymph nodes. Acute toxicity events (between the start of radiotherapy and the first follow-up consultation) and medium-term toxicity events (after the first follow-up consultation) were assessed using the CTCAE version 5.0 classification. RESULTS: Sixty-three patients were treated according to the protocol between January 1st, 2020, and October 31st, 2022. The majority of them had high-risk prostate cancer (79%). The median follow-up was 15 months. Very few patients reported grade 3-4 toxicity acutely (6% urinary and 0% digestive toxicity) or in the medium term (7% urinary and 0% and digestive toxicity). CONCLUSION: Radiotherapy of pelvic lymph node areas with simultaneous hypofractionated boost to the prostate is feasible, with low rates of severe acute and medium-term toxicity.

The neuropathology of Self-Injurious Behavior: Studies using animal models.

Self-injurious behavior is a debilitating characteristic that is highly prevalent in autism and other neurodevelopmental disorders. In these populations, self-injury has typically been interpreted in relation to behavioral reinforcement and/or sensory stimulation. However, self-injury is also commonly exhibited by people with a variety of neuropsychiatric disorders, where it is typically described in relation to emotional regulation and the presence or absence of suicidal ideation. Interestingly, self-injury has also been documented in many non-human animal species, especially when exposed to early environmental deprivation, isolation, and distress. Despite the propensity of animals to self-injure under adverse conditions, animal models of self-injury have not been the focus of much research, and translation of the data from these models has largely been limited to autism and neurodevelopmental disorders. This review summarizes evidence that common biological and environmental mechanisms may contribute to vulnerability for self-injury in neurodevelopmental disorders, psychiatric disorders, and distressed animals, and that investigations using animal models may be highly beneficial when considering self-injury as a behavioral phenotype that exists across diagnostic categories. Investigations using animal models have revealed that individual differences in stress responses and anxiety-related behavior contribute to vulnerability for self-injury. Animal models have implicated dysregulation of monoaminergic, glutamatergic, and other neurotransmitter systems in expression of self-injury, and these models have suggested neural targets for pharmacotherapy that have potential relevance for diverse clinical populations.

Survival outcomes and failure patterns for oropharyngeal cancers treated with simultaneous integrated boost in intensity modulated radiotherapy (SIB-IMRT) and concurrent chemotherapy.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes. MATERIAL AND METHODS: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method. RESULTS: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9). CONCLUSION: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

Hereditary nature of death-feigning frequency in a parasitoid wasp Heterospilus prosopidis using sib analysis.

Death feigning, a state of immobility observed in many animals in response to external stimuli, is an anti-predator behaviour. Although previous studies showed that death-feigning behaviours are quantitative genetic traits, the knowledge of the heritable basis of death-feigning behaviour is lacking. To investigate the heritable basis of death-feigning behaviour, we used 3 laboratory strains of a braconid parasitoid wasp, Heterospilus prosopidis. The heritable basis using half-sib analysis, and the effects of different geographical backgrounds, rearing conditions in the laboratory, and host age were evaluated. The results of the half-sib analysis showed that the frequency of death feigning varied among sires, suggesting a certain extent of additive genetic variance. Also, the frequency of death feigning varied between geographical backgrounds and among strains. Death-feigning frequency was not affected by the age of the host. Our findings highlight the importance of genetic factors underlying the basis of the death-feigning behaviour and provide support for the genetic alterations of traits from the perspective of evolution in various animal species.

Simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II clinical trial.

OBJECTIVE: To evaluate the feasibility, safety and efficacy of concurrent simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with nimotuzumab in the treatment of locally advanced esophageal squamous cell cancer (ESCC). METHODS: Eligible patients were histologically proven to have locally advanced ESCC, and were unable to tolerate or refuse concurrent chemoradiotherapy (CCRT). Enrolled patients underwent concurrent SIB-IMRT in combination with nimotuzumab. SIB-IMRT: For the planning target volume of clinical target volume (PTV-C), the prescription dose was 50.4 Gy/28fractions, 1.8 Gy/fraction, 5fractions/week, concurrently, the planning target volume of gross tumor (PTV-G) undergone an integrated boost therapy, with a prescription dose of 63 Gy/28fractions, 2.25 Gy/fraction, 5 fractions/week. Nimotuzumab was administered concurrently with radiotherapy, 200 mg/time, on D1, 8, 15, 22, 29, and 36, with a total accumulation of 1200 mg through intravenous infusion. The primary endpoint of the study was the safety and efficacy of the combined treatment regimen, and the secondary endpoints were 1-year, 2-year, and 3-year local control and survival outcomes. RESULTS: (1) From December 2018 to August 2021, 35 patients with stage II-IVA ESCC were enrolled and 34 patients completed the full course of radiotherapy and the intravenous infusion of full-dose nimotuzumab. The overall completion rate of the protocol was 97.1%. (2) No grade 4-5 adverse events occurred in the entire group. The most common treatment-related toxicity was acute radiation esophagitis, with a total incidence of 68.6% (24/35). The incidence of grade 2 and 3 acute esophagitis was 25.7% (9/35) and 17.1% (6/35), respectively. The incidence of acute radiation pneumonitis was 8.6% (3/35), including one case each of Grades 1, 2, and 3 pneumonitis. Adverse events in other systems included decreased blood cells, hypoalbuminemia, electrolyte disturbances, and skin rash. Among these patients, five experienced grade 3 electrolyte disturbances during the treatment period (three with grade 3 hyponatremia and two with grade 3 hypokalemia). (3) Efficacy: The overall CR rate was 22.8%, PR rate was 71.4%, ORR rate was 94.2%, and DCR rate was 97.1%.(4) Local control and survival: The 1-, 2-, and 3-year local control (LC) rate, progression-free survival(PFS) rate, and overall survival(OS) rate for the entire group were 85.5%, 75.4%, and 64.9%; 65.7%, 54.1%, and 49.6%; and 77.1%, 62.9%, and 54.5%, respectively. CONCLUSIONS: The combination of SIB-IMRT and nimotuzumab for locally advanced esophageal cancer demonstrated good feasibility, safety and efficacy. It offered potential benefits in local control and survival. Acute radiation esophagitis was the primary treatment-related toxicity, which is clinically manageable. This comprehensive treatment approach is worthy of further clinical exploration (ChiCTR1900027936).

Stereotactic radiosurgery for prostate cancer spine metastases: local control and fracture risk using a simultaneous integrated boost approach.

OBJECTIVE: Variation exists in approaches to delivery of spine stereotactic radiosurgery (SSRS). Here, the authors describe outcomes following single-fraction SSRS performed using a simultaneous integrated boost for the treatment of prostate cancer spine metastases. METHODS: Health records of patients with prostate cancer spine metastases treated with single-fraction SSRS at the authors' institution were reviewed. Treatment was uniform, with 16 Gy to the clinical tumor volume and 18 Gy to the gross tumor volume. The primary endpoint was local recurrence, with secondary endpoints including vertebral fracture and overall survival. Univariate and multivariate competing risk regression models made using the Fine and Gray method were used to identify factors predictive of local recurrence, considering death to be a competing event for local recurrence. RESULTS: A total of 87 targets involving 108 vertebrae in 68 patients were included, with a median follow-up of 22.5 months per treated target. The 1-, 2-, and 4-year cumulative incidence rates of local failure for all targets were 4.6%, 8.4%, and 19%, respectively. The presence of epidural disease (subdistribution hazard ratio [sHR] 5.43, p = 0.04) and SSRS as reirradiation (sHR 16.5, p = 0.02) emerged as significant predictors of local failure in a multivariate model. Hormone sensitivity did not predict local control. Vertebral fracture incidence rates leading to symptoms or requiring intervention at 1, 2, and 4 years were 1.1%, 3.7%, and 8.4%, respectively. In an exploratory analysis of patterns of failure, 3 (25%) failures occurred in the epidural space and only 1 (8%) occurred clearly in the clinical tumor volume. There were several lesions for which the precise location of failure with regard to target volumes was unclear. CONCLUSIONS: High rates of local control were observed, particularly for radiotherapy-naïve lesions without epidural disease. Hormone sensitivity was not predictive of local control in this cohort and fracture risk was low. Further research is needed to better predict which patients are at high risk of recurrence and who might benefit from treatment escalation.

Toward Maximizing Assessment Efficiency: A Synthesized Trial-Based Functional Analysis and Competing Stimulus Assessment.

Despite the success of the standard functional analysis (FA), some limitations to conducting an FA in practice include time, resources, ecological relevance, and safety, which have led to the development of procedural adaptations such as trial-based and synthesized FA formats. The purpose of this case study was to identify the function(s) of self-injurious behavior (SIB) for a 3-year-old female with developmental disabilities using a brief trial-based FA with ecologically relevant synthesized contingencies, based on caregiver input, to minimize opportunities for SIB. We identified that positive physical attention likely functioned, at least in part, as a reinforcer for SIB, in less than 42 min. Overall harm to the child as a result of the synthesized trial-based FA was minimal, and the caregiver viewed the modified conditions favorably. We then assessed the role of competing stimuli on SIB rates with the child's mother and identified two potential items that may compete with attention as a reinforcer for SIB. Our findings highlight the utility and importance of individualized assessment as the first step in the safe treatment of severely challenging behavior.

Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients by whole exome sequencing.

Eating disorders (EDs) are a type of psychiatric disorder characterized by pathological eating and related behavior and considered to be highly heritable. The purpose of this study was to explore rare variants expected to display biological functions associated with the etiology of EDs. We performed whole exome sequencing (WES) of affected sib-pairs corresponding to disease subtype through their lifetime and their parents. From those results, rare single nucleotide variants (SNVs) concordant with sib-pairs were extracted and estimated to be most deleterious in the examined families. Two non-synonymous SNVs located on corticotropin-releasing hormone receptor 2 (CRHR2) and glutamate metabotropic receptor 8 (GRM8) were identified as candidate disease susceptibility factors. The SNV of CRHR2 was included within the cholesterol binding motif of the transmembrane helix region, while the SNV of GRM8 was found to contribute to hydrogen bonds for an α-helix structure. CRHR2 plays important roles in the serotoninergic system of dorsal raphe nuclei, which is involved with feeding and stress-coping behavior, whereas GRM8 modulates glutamatergic neurotransmission. Moreover, GRM8 modulates glutamatergic neurotransmission, and is also considered to have effects on dopaminergic and adrenergic neurotransmission. Thus, identification of rare and deleterious variants in this study is expected to increase understanding and treatment of affected individuals. Further investigation regarding the biological function of these variants may provide an opportunity to elucidate the pathogenesis of EDs.

Establishment of a zebrafish inbred strain, M-AB, capable of regular breeding and genetic manipulation.

Inbred strains of organisms are genetically highly uniform and thus useful for life science research. We have previously reported the ongoing generation of the zebrafish IM strain from the India (IND) strain through full sib-pair mating for 16 generations. However, the IM fish laid a small number of offspring and had a short lifespan, implying the need for discreet care in breeding. Here, we report the subsequent establishment of IM strain as well as the generation of a new inbred zebrafish strain, Mishima-AB (M-AB). M-AB was derived from the *AB strain by full sib-pair mating for over 20 generations, which fulfills the general criterion for the establishment of an inbred strain. In contrast to the IM case, maintenance of the M-AB strain by sib-pair mating required almost no special handling. Genome sequencing of IM individuals from the 47th generation and M-AB individuals from the 27th generation revealed that SNP-based genomic heterogeneity across whole-genome nucleotides was 0.008% and 0.011%, respectively. These percentages were much lower than those of the parental IND (0.197%) and *AB (0.086%) strains. These results indicate that the genomes of these inbred strains were highly homogenous. We also demonstrated the successful microinjection of antisense morpholinos, CRISPR/Cas9, and foreign genes into M-AB embryos at the 1-cell stage. Overall, we report the establishment of a zebrafish inbred strain, M-AB, which is capable of regular breeding and genetic manipulation. This strain will be useful for the analysis of genetically susceptible phenotypes such as behaviors, microbiome features and drug susceptibility.

Dose-escalated SBRT for borderline and locally advanced pancreatic cancer. Feasibility, safety and preliminary clinical results of a multicenter study.

Background: Pancreatic Stereotactic Body Radiotherapy (SBRT) allows for the administration of a higher biologically effective doses (BED), that would be essential to achieve durable tumor control. Escalating treatment doses need a very accurate tumor positioning and motion control during radiotherapy.The aim of this study to assess the feasibility and safety of a Simultaneous Integrated Boost (SIB) dose-escalated protocol at 45 Gy, 50 Gy and 55 Gy in 5 consecutive daily fractions, in Border Line Resectable Pancreatic Cancer (BRCP) /Locally Advanced Pancreatic Cancer (LAPC) by means of a standard LINAC platform. Methods: Patients diagnosed of BRPC/LAPC, candidates for neoadjuvant chemotherapy and SBRT, in four university hospitals of the province of Las Palmas (Canary Islands, Spain) were included in this prospective study. Radiotherapy was administered using standard technology (LINACS) with advanced positioning (Lipiodol® and metallic stent used as fiducial markers) and tumor motion control (4D, DBH, Calypso®). There were 3 planned dose-escalated SIB groups, 45 Gy/5f (9 patients) 50 Gy/5f (9 + 9 patients) and 55 Gy/5f (9 patients). The defined primary end points of the study were the safety and feasibility of the proposed treatment protocol. Secondary endpoints included radiological tumor response after SBRT, local control and survival. Results: From June 2017 to December 2022, sixty-two patients were initially assessed for eligibility in the study in the four participating centers, and 49 were candidates for chemotherapy (CHT). Forty-one were referred to radiotherapy after CHT and 33 finally were treated by escalated-dose SIB, 45 Gy (9 patients) 50 Gy (16 patients), 55 Gy(8 patients). All patients completed the scheduled treatment and no acute or late severe (≥grade3) gastrointestinal toxicity was observed.Local response was analyzed by CT/MRI two months after the end of SBRT. Ten patients (31,25 %) achieved objective response (2/9:45 Gy, 5/15:50 Gy, 3/8:55 Gy). Follow-up was closed as July 2023. Freedom from local progression at 1-2y were 89,3% (95 %CI:83,4-95,2%) and 66 % (95 %CI:54,6-77,4%) respectively. The 1-2y survival rates were 95,7% (95 %CI:91,4-100 % and 48,6% (95 %CI:37,7-59,5%) respectively. Conclusion: These promising results should be confirmed by further studies with larger sample size and extended follow-up period.

An Evaluation of Treatment Outcomes and Associated Factors in Nasopharyngeal Cancer Patients at a Tertiary Cancer Center in the United Arab Emirates.

Background and objective Nasopharyngeal carcinoma (NPC) presents a complex epidemiological pattern influenced by demographic characteristics, risk factors such as Epstein-Barr virus (EBV) infection, and smoking. Understanding the clinical profile and optimizing treatment strategies for NPC requires comprehensive analyses of these factors. In light of this, this study aimed to analyze the epidemiological patterns, histological characteristics, and treatment outcomes of NPC patients diagnosed and treated at a single center from 2016 to 2023. Materials and methods This retrospective study was conducted at Tawam Hospital in the United Arab Emirates (UAE), focusing on patients diagnosed with NPC. It involved the analysis of patient age distribution to identify epidemiological patterns, histological examination to classify NPC types according to WHO guidelines, and evaluation of treatment outcomes based on induction chemotherapy regimens and concurrent chemoradiotherapy protocols. The effectiveness of various chemotherapy combinations, particularly cisplatin and 5-fluorouracil (Cis+5FU), was assessed alongside the integration of advanced radiotherapy techniques like intensity-modulated radiotherapy (IMRT). Results In this study of 41 NPC patients, the age distribution varied widely, ranging from 10 to 74 years, with a mean age of >40 years. There was a significant male predominance (82.93%). Most patients were non-smokers (68.29%) and did not consume alcohol (92.68%), and there was a high prevalence of EBV positivity (100%). At diagnosis, 80.49% had no metastases. The primary treatment was chemotherapy induction, with a 73.17% uptake and a 92.68% completion rate, leading to a 65.85% complete response (CR) rate. No significant association was found between smoking status and treatment response (p=0.7657). Pathologically, non-keratinizing undifferentiated squamous carcinoma was the most common variant (75.61%). The Cis+5FU regimen was the most frequently employed method (56.67%), associated with a 76.47% CR rate. Concurrent chemotherapy was administered to 87.80% of patients, with the weekly Cis regimen being the most used one (56.09%), resulting in a significant CR rate. Combining radiation therapy with concurrent and induction chemotherapy yielded high CR rates (RT+cCT: 66.66%, RT+cCT+iCT: 80%). Survival analysis revealed the highest 36-month survival rate (46.43%) in the RT+cCT+iCT group, suggesting a potential benefit from incorporating induction chemotherapy into the treatment regimen. Conclusions This study illustrates the impact of demographic variables, EBV infection, and smoking on the development and treatment outcomes of NPC. It points to the success of customized chemotherapy and advanced radiotherapy strategies. Yet, it is limited by its retrospective nature and single-center focus, and hence we recommend multicentric studies to broaden the applicability of the results and improve NPC treatment approaches for varied patient groups.

Stereotactic body radiotherapy (SIB-VMAT technique) to dominant intraprostatic lesion (DIL) for localized prostate cancer: a dose-escalation trial (DESTROY-4).

PURPOSE: DESTROY-4 (DOSE-ESCALATION STUDY OF STEREOTACTIC BODY RADIATION THERAPY) was a Phase I trial aimed to evaluate the safety and the feasibility of escalating doses of stereotactic body radiation therapy (SBRT) on MRI-defined Dominant Intraprostatic Lesion (DIL) in low- and intermediate-risk pCa patients using a simultaneous integrated boost-volumetric arc therapy (SIB-VMAT) technique. METHODS: Eligible patients included those with low- and intermediate-risk prostate carcinoma (NCCN risk classes) and an International Prostatic Symptoms Score (IPSS) ≤ 15. No restriction about DIL and prostate volumes was set. Pretreatment preparation required an enema and the placement of intraprostatic gold fiducials. SBRT was delivered in five consecutive daily fractions. For the first three patients, the DIL radiation dose was set at 8 Gy per fraction up to a total dose of 40 Gy (PTV1) and was gradually increased in succeeding cohorts to total doses of 42.5 Gy, 45.0 Gy, 47.5 Gy, and finally, 50.0 Gy, while keeping the prescription of 35 Gy/7 Gy per fraction for the entire prostate gland. Dose-limiting toxicity (DLT) was defined as grade 3 or worse gastrointestinal (GI) or genitourinary (GU) toxicity occurring within 90 days of follow-up (Common Terminology Criteria of Adverse Events scale 4.0). Patients completed quality-of-life questionnaires at defined intervals. RESULTS: Twenty-four patients with a median age of 75 (range, 58-89) years were enrolled. The median follow-up was 26.3 months (8.9-84 months). 66.7% of patients were classified as intermediate-risk groups, while the others were low-risk groups, according to the NCCN guidelines. Enrolled patients were treated as follows: 8 patients (40 Gy), 5 patients (42.5 Gy), 4 patients (45 Gy), 4 patients (47.5 Gy), and 3 patients (50 Gy). No severe acute toxicities were observed. G1 and G2 acute GU toxicities occurred in 4 (16%) and 3 patients (12.5%), respectively. Two patients (8.3%) and 3 patients (12.5%) experienced G1 and G2 GI toxicities, respectively. Since no DLTs were observed, 50 Gy in five fractions was considered the MTD. The median nadir PSA was 0.20 ng/mL. A slight improvement in QoL values was registered after the treatment. CONCLUSION: This trial confirms the feasibility and safety of a total SIB-VMAT dose of 35 Gy on the whole gland and 50 Gy on DIL in 5 fractions daily administered in a well-selected low- and intermediate-risk prostate carcinoma population. A phase II study is ongoing to confirm the tolerability of the schedule and assess the efficacy.

Dosimetric and radiobiological comparison of IMRT, VMAT, and helical tomotherapy planning techniques in hippocampal sparing whole brain radiotherapy with simultaneous integrated boost for multiple brain metastases.

To compare treatment planning and dosimetric outcomes for hippocampal sparing whole brain radiotherapy (WBRT) with the simultaneous integrated boost (SIB) in brain metastasis (BM) patients using tumour control probability (TCP) and normal tissue complication probability (NTCP) formalism between IMRT, VMAT, and HT techniques. In this retrospective study, the treatment data of 20 BM patients who typically received whole brain radiation with SIB treatment were used. Prescription doses of 30 Gy and 36 Gy was delivered in 10 fractions for WBRT and SIB, respectively. Niemierko and LKB models were applied for calculating TCP and NTCP. All the plans were evaluated for the RTOG 0933 protocol criteria and found acceptable. Additionally, the homogeneity of the PTV boost is 0.07 ± 0.01, 0.1 ± 0.04, and 0.08 ± 0.02 for IMRT, VMAT, and HT, respectively (P < 0.05). The percentage of TCP for the PTV boost was 99.99 ± 0.003, 99.98 ± 0.004, and 99.99 ± 0.002 of IMRT, VMAT, and HT, respectively, (P < 0.005). The NTCP value of the lenses was higher with the VMAT plan as compared to IMRT and HT Plans. The hippocampal NTCP values are equal in all three planning proficiencies. The techniques like IMRT, VMAT, and HT can reduce the dose received by hippocampus to the dosimetric threshold during the delivery of WBRT with hippocampal sparing and can simultaneously boost multiple metastases. Overall, the high-quality dose distribution, TCP, and NTCP comparison between all three planning techniques show that the HT technique has better results when compared to the VMAT and IMRT techniques.

Simultaneous Integrated Boost (SIB) Versus Sequential Boost in Anal Cancer Patients: A Single-Center Experience.

PURPOSE: Concurrent chemoradiation is the standard of care for the treatment of anal cancer. Radiation can be delivered by sequential or simultaneous integrated boost (SIB) approach. The present study was conducted to compare the treatment outcomes and toxicity profile of patients with anal cancer treated with sequential boost and SIB approach. METHODS: A single-institution retrospective analysis of patients with squamous cell carcinoma of the anal canal treated between 2019 and 2022 with radical chemoradiation was performed. The sequential boost schedule consisted of 45 Gy in 25 fractions (1.8 Gy daily) to the gross tumor, nodes, and elective nodal volume, followed by a 9 Gy in five fractions boost to the gross disease. Patients receiving SIB were treated as per RTOG 0529 protocol. In both the groups, patients were treated with volumetric modulated arc therapy (VMAT). The two groups were compared in terms of overall survival (OS), colostomy-free survival (CFS), relapse-free survival (RFS), and acute toxicity profile. p-values < 0.05 were considered statistically significant. RESULTS: The patient and disease characteristics in both treatment arms were comparable. The only difference was a significantly longer overall treatment time of ≥ 50 days in the sequential arm (77.8% vs 43.8%, p = 0.04). The median follow-up was 18 months. The 2-year CFS was 80% in sequential vs 87.5% at 2 years for the SIB arm, 2-year OS 83.3% vs 58.6%, and 2-year RFS was 38.9% vs 41.7%, respectively. A total of 14 (77.8%) in sequential and 8 (50%) in the SIB arm had disease relapse. On univariate analysis, the involved pelvic lymph node significantly affected OS (HR 10.45, p = 0.03) while inguinal lymph node involvement adversely affected RFS (HR 6.16, p = 0.02). The most common acute toxicity was radiation-induced dermatitis, 15 (83.4%; 5 grade II, 10 grade III) in sequential vs 7 (43.8%; 3 each grade II and III) in the SIB group followed by hematological (61.1% vs 68.75%). However, the incidence of overall acute toxicities was significantly less in the SIB arm (p = 0.006). CONCLUSION: Our study showed that concurrent chemoradiation with the SIB-VMAT approach is well tolerated in patients of anal carcinoma and resulted in lesser treatment interruptions and comparable outcomes as compared to the sequential approach. Our results warrant further evaluation in a prospective study.

Placental Abruption and Cardiovascular Event Risk (PACER): Design, data linkage, and preliminary findings.

BACKGROUND: Obstetrical complications impact the health of mothers and offspring along the life course, resulting in an increased burden of chronic diseases. One specific complication is abruption, a life-threatening condition with consequences for cardiovascular health that remains poorly studied. OBJECTIVES: To describe the design and data linkage algorithms for the Placental Abruption and Cardiovascular Event Risk (PACER) cohort. POPULATION: All subjects who delivered in New Jersey, USA, between 1993 and 2020. DESIGN: Retrospective, population-based, birth cohort study. METHODS: We linked the vital records data of foetal deaths and live births to delivery and all subsequent hospitalisations along the life course for birthing persons and newborns. The linkage was based on a probabilistic record-matching algorithm. PRELIMINARY RESULTS: Over the 28 years of follow-up, we identified 1,877,824 birthing persons with 3,093,241 deliveries (1.1%, n = 33,058 abruption prevalence). The linkage rates for live births-hospitalisations and foetal deaths-hospitalisations were 92.4% (n = 2,842,012) and 70.7% (n = 13,796), respectively, for the maternal cohort. The corresponding linkage rate for the live births-hospitalisations for the offspring cohort was 70.3% (n = 2,160,736). The median (interquartile range) follow-up for the maternal and offspring cohorts was 15.4 (8.1, 22.4) and 14.4 (7.4, 21.0) years, respectively. We will undertake multiple imputations for missing data and develop inverse probability weights to account for selection bias owing to unlinked records. CONCLUSIONS: Pregnancy offers a unique window to study chronic diseases along the life course and efforts to identify the aetiology of abruption may provide important insights into the causes of future CVD. This project presents an unprecedented opportunity to understand how abruption may predispose women and their offspring to develop CVD complications and chronic conditions later in life.