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Background. Magnetic resonance imaging (MRI) has been found to be better than computed tomography for defining the extent of primary gross tumor volume (GTV) in advanced nasopharyngeal cancer. It is routinely applied for target delineation in planning radiotherapy. However, the specific MRI sequences/planes that should be used are unknown.

Abstract Introduction Prostate Specific Membrane Antigen (PSMA) imaging with Positron Emission Tomography (PET) plays a crucial role in prostate cancer management. However, there is a lack of comprehensive data on how PSMA PET/CT (Computed Tomography) influences radiotherapeutic decisions, particularly in node-positive prostate cancer cases. This study aims to address this gap by evaluating two primary objectives: (1) Mapping the regional and non-regional lymph nodes (LNs) up to the aortic bifurcation and their distribution using conventional methods with CT compared to PSMA PET/CT, and (2) assessing the impact of PSMA PET/CT findings on radiotherapeutic decisions. Methods A retrospective analysis of 95 node-positive prostate cancer patients who underwent both CT and PSMA PET/CT imaging prior to primary radiotherapy and androgen deprivation therapy (ADT) was conducted. The analysis focused on identifying LNs in various regions including the common iliac, external iliac, internal iliac, obturator, presacral, mesorectal, inguinal, and other stations. Treatment plans were reviewed for modifications based on PSMA PET/CT findings, and statistical analysis was performed to identify predictors for exclusive nodal positivity on PSMA PET/CT scans. Results PSMA PET/CT identified additional positive nodes in 48% of cases, resulting in a staging shift from N0 to N1 in 29% of patients. The most frequent metastatic LNs were located in the external iliac (76 LNs; 34%), internal iliac (43 LNs; 19%), and common iliac (35 LNs; 15%) stations. In patients with nodes only detected on PSMA PET the most common nodes were in the external iliac (27, 40%), internal iliac (13, 19%), obturator (11, 15%) stations. Within the subgroup of 28 patients exclusively demonstrating PSMA PET-detected nodes, changes in radiotherapy treatment fields were implemented in 5 cases (18%), and a dose boost was applied for 23 patients (83%). However, no discernible predictors for exclusive nodal positivity on PSMA PET/CT scans emerged from the analysis. Discussion The study underscores the pivotal role of PSMA PET/CT compared to CT alone in accurately staging node-positive prostate cancer and guiding personalized radiotherapy strategies. The routine integration of PSMA PET/CT into diagnostic protocols is advocated to optimize treatment precision and improve patient outcomes.

Tobi Reuveni1, Menachem Motiei1, Zimam Romman2, Aron Popovtzer3, Rachela Popovtzer11Faculty of Engineering and the Institute of Nanotechnology and Advanced Materials, Bar-ilan University, Ramat Gan, 2GE HealthCare, Tirat Hacarmel, 3Department of Otorhinolaryngology, Head and Neck Surgery and Onology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, IsraelAbstract: In recent years, advances in molecular biology and cancer research have led to the identification of sensitive and specific biomarkers that associate with various types of cancer. However, in vivo cancer detection methods with computed tomography, based on tracing and detection of these molecular cancer markers, are unavailable today. This paper demonstrates in vivo the feasibility of cancer diagnosis based on molecular markers rather than on anatomical structures, using clinical computed tomography. Anti-epidermal growth factor receptor conjugated gold nanoparticles (30 nm) were intravenously injected into nude mice implanted with human squamous cell carcinoma head and neck cancer. The results clearly demonstrate that a small tumor, which is currently undetectable through anatomical computed tomography, is enhanced and becomes clearly visible by the molecularly-targeted gold nanoparticles. It is further shown that active tumor targeting is more efficient and specific than passive targeting. This noninvasive and nonionizing molecular cancer imaging tool can facilitate early cancer detection and can provide researchers with a new technique to investigate in vivo the expression and activity of cancer-related biomarkers and molecular processes.Keywords: functional computed tomography, molecular imaging, gold nanoparticles, biologically targeted in vivo imaging, contrast agents

PurposeThe focus of this article is to describe the configuration, testing, and commissioning of a novel gantry-less synchrotron-based proton therapy (PT) facility.Materials and methodsThe described PT system delivers protons with a water equivalent range between 4 and 38 cm in 1800 energy layers. The fixed beam delivery permits a maximum field size of 28 × 30 cm2. The patient positioning and imaging system includes a six-degree-of-freedom robotic arm, a convertible patient chair, a vertical 4DCT, and an orthogonal 2D X-ray imaging system.ResultsThe spot positioning reproducibility was consistent within ±1 mm. The width (σ) of the beam profile at the isocenter was energy dependent and ranged from 2.8 mm to 7.7 mm. Absolute dose reproducibility was measured and deviations were found to be

Background: The liver and lungs are the most common sites of colorectal cancer (CRC) metastases. Their involvement can take five different clinical scenarios: lung metastases only, liver metastases only, lung metastases before liver metastases, liver metastases before lung metastases and simultaneous lung and liver metastases. Using clinical and morphological data we studied the clonal trajectory of these scenarios. Materials and methods: A total of 465 (CRC) patients with 7952 liver and 6406 lung metastases were evaluated. Metastases clinical route was deciphered from metastases number, timing, and linear/parallel ratio (LPR)- a computerized parameter used for deducing clonal trajectories. LPR of +1 suggest pure linear dissemination and −1 pure parallel. Results: Lung-only metastases: high percentage of metachronous disease with a long lead time and a low LPR suggest parallel dissemination. Liver-only metastases: Rare metachronous disease with a short lead time, and a high LPR suggest linear spread. Lung-before-liver metastases: rare solitary metastasis, a median gap of 21 months between the organs, high lung and low liver LPRs suggest linear progression to the lungs and parallel dissemination to the liver. Liver-before-lung metastases: low liver and high lung LPRs and a median gap of 16.5 months between the organs suggest parallel dissemination to the liver and linear spread from the liver to the lungs. Simultaneous liver and lung metastases: rare solitary metastasis and similar and high LPRs suggest simultaneous linear progression to both organs. Conclusions: CRC metastases have different dissemination trajectories in different clinical scenarios. This information can potentially impact on clinical management.

Substance use disorder, and particularly cocaine use disorder, is a complex disease that affects societal, economic, and psychological factors. Endogenous β-endorphin released after prolonged cocaine withdrawal has been reported to activate the accumbal delta-opioid receptor (DOR), leading to attenuated cocaine seeking. However, using DOR β-endorphin activation to treat cocaine use disorder is impractical since β-endorphin does not cross the blood-brain barrier. Also, only activation of the sub-group DOR1 efficiently attenuates craving, as activation of DOR2 yields an opposite effect. Here, we isolated a specific peptide, PEP1, from a phage display peptide library with similar biological properties to β–endorphin, demonstrating specificity for DOR1 and functioning as full receptor agonists. Our pharmacodynamic results showed fast trafficking incorporation of DOR into the cell membrane, interpreted as superior rehabilitation of the receptor and its bioavailability compared to commercial agonists. We administered PEP1, either intrabrain or intranasal, to rats trained to self-administer cocaine. PEP1 induced a significant decrease in cocaine-craving behavior and reinstatement in three different animal models of addiction. Also, PEP1 did not exhibit rewarding properties and did not interfere with the natural reward system. ICP-OES analysis revealed that at least one hour post-administration, PEP1 was retained in the brain rather than in peripheral organs. These findings render PEP1 a potential novel regulator of cocaine craving, especially for being non-addictive. Hence, PEP1 should be further examined as a possible new therapy for substance use disorder.

Abstract Background Adaptive radiation therapy (ART) offers a dynamic approach to address structural and spatial changes that occur during radiotherapy (RT) for locally advanced head and neck cancers. The integration of daily ART with Cone-Beam CT (CBCT) imaging presents a solution to enhance the therapeutic ratio by addressing inter-fractional changes. Methods We evaluated the initial clinical experience of daily ART for patients with head and neck cancer using an online adaptive platform with intelligence-assisted workflows on daily CBCT. Treatment included auto-contour and structure deformation of Organs at Risk (OARs) and target structures, with adjustments by the treating physician. Two plans were generated: one based on the initial CT simulation with the edited structures (scheduled) and a re-optimized plan (adaptive). Both plans were evaluated and the superior one approved and delivered. Clinical and dosimetric outcomes were reviewed. Results Twenty two patients with head and neck cancers (7 Nasopharynx, 6 Oropharynx, 1 oral cavity, 8 larynx) stages I-IVA were treated with daily ART. 770 adaptive and scheduled radiotherapy plans were generated. 703 (91.3%) adaptive plans were chosen. Median time to deliver ART was 20 minutes (range: 18-23). Adaptive compared to scheduled plans demonstrated improved mean V95 values for the PTV70, PTV59.5, and PTV56 by 1.2%, 7.2%, and 6.0% respectively and a mean 1.4% lower maximum dose in PTV70. Fourteen of 17 OARs demonstrated improved dosimetry with adaptation, with select OARs reaching statistical significance. At a median follow up of 14.1 months, local control was 95.5%, two patients developed metastatic disease and four patients died. 9.1% of patients had acute grade 3 dysphagia and 13.6% had grade 2 chronic xerostomia. Discussion These findings provide real world evidence of the feasibility and dosimetric benefit of incorporating daily ART on CBCT in the treatment of head and neck cancer. Prospective study is needed to determine if these dosimetric improvements translate into improved outcomes.

IntroductionThe main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)-based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability.MethodsA 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib—an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence.ResultsAt 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded.SummaryThe results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach.

Introduction: The main obstacle in treating cancer patients is drug resistance. Lenvatinib treatment poses challenges due to loss of response and the common dose-limiting adverse events (AEs). The Constrained-disorder-principle (CDP)- based second-generation artificial intelligence (AI) systems introduce variability into treatment regimens and offer a potential strategy for enhancing treatment efficacy. This proof-of-concept clinical trial aimed to assess the impact of a personalized algorithm-controlled therapeutic regimen on lenvatinib effectiveness and tolerability. Methods: A 14-week open-label, non-randomized trial was conducted with five cancer patients receiving lenvatinib--an AI-assisted application tailored to a personalized therapeutic regimen for each patient, which the treating physician approved. The study assessed changes in tumor response through FDG-PET-CT and tumor markers and quality of life via the EORTC QLQ-THY34 questionnaire, AEs, and laboratory evaluations. The app monitored treatment adherence. Results: At 14 weeks of follow-up, the disease control rate (including the following outcomes: complete response, partial response, stable disease) was 80%. The FDG-PET-CT scan-based RECIST v1.1 and PERCIST criteria showed partial response in 40% of patients and stable disease in an additional 40% of patients. One patient experienced a progressing disease. Of the participants with thyroid cancer, 75% showed a reduction in thyroglobulin levels, and 60% of all the participants showed a decrease in neutrophil-to-lymphocyte ratio during treatment. Improvement in the median social support score among patients utilizing the system supports an ancillary benefit of the intervention. No grade 4 AEs or functional deteriorations were recorded. Summary: The results of this proof-of-concept open-labeled clinical trial suggest that the CDP-based second-generation AI system-generated personalized therapeutic recommendations may improve the response to lenvatinib with manageable AEs. Prospective controlled studies are needed to determine the efficacy of this approach. [ABSTRACT FROM AUTHOR]

Simple Summary: While the initial favorable efficacy and safety profile for a novel diffusing alpha-emitter radiation therapy (Alpha DaRT) have been previously demonstrated, the longer-term safety and durability of the treatment are unknown. In this pooled analysis of 81 treated head and neck or skin tumors from four clinical trials with a median follow-up of 14 months, a complete response was observed in 89% of treated lesions, two-year local recurrence-free survival was 77%, and there were no grade 2 or higher late toxicities observed. These results suggest that Alpha DaRT is a safe and effective treatment for skin and head and neck tumors. The initial favorable efficacy and safety profile for Alpha DaRT have been demonstrated (NCT04377360); however, the longer-term safety and durability of the treatment are unknown. This pooled analysis of four prospective trials evaluated the long-term safety and efficacy of Alpha DaRT for the treatment of head and neck or skin tumors. A total of 81 lesions in 71 patients were treated across six international institutions, with a median follow-up of 14.1 months (range: 2–51 months). Alpha DaRT sources were delivered via a percutaneous interstitial technique and placed to irradiate the tumor volume with the margin. The sources were removed two to three weeks following implantation. A complete response was observed in 89% of treated lesions (n = 72) and a partial response in 10% (n = 8). The two-year actuarial local recurrence-free survival was 77% [95% CI 63–87]. Variables, including recurrent versus non-recurrent lesions, baseline tumor size, or histology, did not impact long-term outcomes. Twenty-seven percent of patients developed related acute grade 2 or higher toxicities, which resolved with conservative measures. No grade 2 or higher late toxicities were observed. These data support the favorable safety profile of Alpha DaRT, which is currently being explored in a pivotal US trial. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate whether patient, tumour and radiation therapy factors are associated with development of middle ear effusion (MEE) in nasopharyngeal carcinoma (NPC) patients. Deign, Settings, and Participants: A retrospective review of NPC patients treated between January 2000 and June 2018 at Rabin Medical Center. Patient factors, tumour factors, radiation doses, and radiation fields were collected and outlined if needed (middle ear, eustachian tube [ET], tensor veli palatini [TVP], and levator palatini [LVP] muscles), then analysed and compared between patients with MEE and those without and between sides in patients with unilateral MEE. Main Outcome Measures and Results: Seventy‐three patients were enrolled. Most were males (71.2%) with advanced‐stage diseases (78%). At the time of diagnosis 14 patients (19.2%) presented with MEE. Following radiation, 18 patients, with no evidence of MEE at presentation, developed MEE. Tumour stage, histology, and laterality were not associated with development of MEE. Comparison of mean radiation field dosages including—gross target volume, clinical target volume, and patient target volume showed no association with post‐radiation MEE. In addition, no difference was found in the radiation doses to the middle ear, ET or the LVP nor the TVP between ears with and without MEE. Conclusions: Post‐irradiation MEE remains a common adverse effect in NPC patients. Surprisingly, tumour stage, tumour laterality, and histology were not associated with MEE. Similar findings were observed for total radiation doses and specific doses to the middle ear, ET, and ET muscles. [ABSTRACT FROM AUTHOR]

Abstract Background One of the main side effects of head and neck (H&N) radiation therapy (RT) is alteration in taste sensation. It causes significant morbidity and has a major effect on quality of life (QoL). The aim of this study was to prospectively define the effect of RT on taste sensation (general, and four basic tastes) and correlate these findings with changes in saliva secretion and QoL questionnaires. Methods Patients with H&N cancer treated with RT, in which the oral cavity was expected to receive a mean dose of 30 Gray (Gy). Patients were evaluated by Whole-Saliva Sialometry, validated Taste Strips and European Organization for Research and Treatment of Cancer H&N QoL questionnaires prior to RT (T0), mid-point of radiotherapy dose (T1), at the end of radiotherapy (T2) and 1 (T3), 3 (T4) and 12 months (T5) after completion of treatment course. Results Twenty-eight patients were recruited, and 21 patients completed study procedures and were analyzed. Median age was 66 years (range 18–90). The most common tumor site was the oral cavity. The median prescribed radiation dose to the high dose volume was 66 (range 60–70). The median mean and max dose to the oral cavity were 25.1 (range 14–69) and 64.9 (range 30–70), respectively. There was a significant decrease in overall taste sensation between T0 and T1 and T2. With specific tastes, there were significant decreases in sensation of sweet and salty, a trend with bitter and no change with sour. All returned to baseline at T3 and onwards. There was no significant correlation between the max or mean dose to the oral cavity and overall taste sensation or between doses to different areas of the tongue and overall or specific tastes. At T0 there was a significant positive correlation between overall taste sensation and whole-saliva sialometry, and at T1 and T2 there were strong trends. There were significant declines in QoL scores during RT. Conclusions We found a significant immediate reduction in taste sensation due to RT in H&N cancer patients with taste recovery 1 month after treatment completion. There were strong trends to a correlation with saliva production that requires further exploration.

BackgroundLinear and parallel are the two leading models of metastatic progression. In this study we propose a simple way to differentiate between them. While the linear model predicts accumulation of genetic and epigenetic alterations within the primary tumor by founder cells before spreading as waves of metastases, the parallel model suggests preclinical distribution of less advanced disseminated tumor cells with independent selection and expansion at the ectopic sites. Due to identical clonal origin and time of dispatching, linear metastases are expected to have comparable diameters in any specific organ while parallel metastases are expected to appear in variable sizes.Methods and findingsRetrospective revision of chest CT of oncological patients with lung metastases was performed. Metastasis number and largest diameters were recorded. The sum number of metastases with a similar diameter (c) and those without (i) was counted and the linear/parallel ratio (LPR) was calculated for each patient using the formula (∑c-∑i)/(∑c+∑i). A LPR ratio of 1 implies pure linear progression pattern and -1 pure parallel. 12,887 metastases were measured in 503 patients with nine malignancy types. The median LPR of the entire group was 0.71 (IQR 0.14-0.93). In carcinomas of the pancreas, prostate, and thyroid the median LPR was 1. Median LPRs were 0.91, 0.65, 0.60, 0.58, 0.50 and 0.43 in renal cell carcinomas, melanomas, colorectal, breast, bladder, and sarcomas, respectively.ConclusionsMetastatic spread of thyroid, pancreas, and prostate tumors is almost exclusively by a linear route. The spread of kidney, melanoma, colorectal, breast, bladder and sarcoma is both linear and parallel with increasing dominance of the parallel route in this order. These findings can explain and predict the clinical and genomic features of these tumors and can potentially be used for evaluation of metastatic origin in the individual patient.

Background: Treatment selection for squamous cell carcinoma patients aged over 84 years is controversial. This retrospective chart review examined and compared characteristics of laryngeal squamous cell carcinoma in very elderly (over 84 years) and younger patients (approximately 65 years). The secondary objective was to further evaluate the outcome of radiotherapy as a treatment modality in this patient population. Methods: Of all 23 very elderly patients with laryngeal squamous cell carcinoma treated with radiotherapy, with or without surgery, in the Davidoff Cancer Center, from 1992 to 2012, 19 had sufficient data for analysis, and comprised the study group. Results: Median age at diagnosis was 86 years. Disease stage at diagnosis was I, II, III and IVA in 53 per cent, 21 per cent, 21 per cent and 5 per cent, respectively. Median radiotherapy dose was 60 Gy given in 25 fractions. Three patients had recurrence. No patient discontinued treatment because of toxicity. Median overall survival was 3.6 years (range, 0–10 years). Conclusion: Very elderly laryngeal squamous cell carcinoma patients may derive a similar survival advantage as younger counterparts. Modern radiotherapy is effective and safe for treating laryngeal squamous cell carcinoma in this study population. Further, large-scale studies are needed. [ABSTRACT FROM AUTHOR]