BACKGROUND: Understanding stakeholders\' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC.
METHODS: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified.
RESULTS: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public).
CONCLUSIONS: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value.

Salmonella enterica serovar Typhimurium (S. Typhimurium) controls lipopolysaccharide (LPS) biosynthesis by regulating proteolysis of LpxC, the rate-limiting enzyme and target of preclinical antibiotics. PbgA/YejM/LapC regulates LpxC levels and controls outer membrane (OM) LPS composition at the log-to-stationary phase transition. Suppressor substitutions in LPS assembly protein B (LapB/YciM) rescue the LPS and OM integrity defects of pbgA-mutant S. Typhimurium. We hypothesized that PbgA regulates LpxC proteolysis by controlling LapB\'s ability to bind LpxC as a function of the growth phase. According to existing models, when nutrients are abundant, PbgA binds and restricts LapB from interacting with LpxC and FtsH, which limits LpxC proteolysis. However, when nutrients are limited, there is debate whether LapB dissociates from PbgA to bind LpxC and FtsH to enhance degradation. We sought to examine these models and investigate how the structure of LapB enables salmonellae to control LpxC proteolysis and LPS biosynthesis. Salmonellae increase LapB levels during the stationary phase to promote LpxC degradation, which limits lipid A-core production and increases their survival. The deletion of lapB, resulting in unregulated lipid A-core production and LpxC overabundance, leads to bacterial growth retardation. Tetratricopeptide repeats near the cytosol-inner membrane interface are sufficient for LapB to bind LpxC, and remarkably, LapB and PbgA interact in both growth phases, yet LpxC only associates with LapB in the stationary phase. Our findings support that PbgA-LapB exists as a constitutive complex in S. Typhimurium, which differentially binds LpxC to control LpxC proteolysis and limit lipid A-core biosynthesis in response to changes in the environment.IMPORTANCEAntimicrobial resistance has been a costly setback for human health and agriculture. Continued pursuit of new antibiotics and targets is imperative, and an improved understanding of existing ones is necessary. LpxC is an essential target of preclinical trial antibiotics that can eliminate multidrug-resistant Gram-negative bacterial infections. LapB is a natural LpxC inhibitor that targets LpxC for degradation and limits lipopolysaccharide production in Enterobacteriaceae. Contrary to some studies, findings herein support that LapB remains in complex instead of dissociating from its presumed negative regulator, PbgA/YejM/LapC, under conditions where LpxC proteolysis is enhanced. Advanced comprehension of this critical protein-lipid signaling network will lead to future development and refinement of small molecules that can specifically interfere.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: These promising results should be confirmed by further studies with larger sample size and extended follow-up period.

UNASSIGNED: This systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT).
UNASSIGNED: Following PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies.
UNASSIGNED: 31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib\'s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

BACKGROUND: Locally advanced unresectable pancreatic cancer (LAPC) has a dismal prognosis, with intratumoral therapies showing limited benefits. We assume that the dense stroma within these tumors hampers drug dispersion.
OBJECTIVE: This study explores the efficacy of multisite intratumoral injections in improving a drug\'s distribution while minimizing its side effects.
RESULTS: In mice with orthotopic LAPC tumors, weekly intratumoral injections of oxaliplatin at four separate sites reduced the tumor growth by 46% compared with saline (p < 0.003). Oxaliplatin exhibited the greatest impact on the tumor microenvironment relative to gemcitabine, Abraxane, or their combination, with increased necrosis, apoptosis, fibroblasts, inflammation, and infiltrating lymphocytes (p < 0.008). When combined with intravenous FOLFIRINOX (FFX), multisite intratumoral oxaliplatin reduced the tumor weight by 35% compared with single-site injection (p = 0.007). No additional visible toxicity was observed even at a 10-fold occurrence of intratumoral treatment. This co-modality treatment significantly improved survival compared with other groups (p = 0.007).
CONCLUSIONS: Multisite intratumoral therapy in tandem with systemic treatment holds promise for reducing the tumor size and enhancing the overall survival in LAPC.

UNASSIGNED: The role of stereotactic ablative radiation therapy (SABR) as local treatment option after chemotherapy for locally advanced pancreatic cancer (LAPC) is evolving. However adequate patient selection criteria for SABR in patients with LAPC are lacking.
UNASSIGNED: A prospective institutional database collected data of patients with LAPC treated with chemotherapy, mainly FOLFIRINOX, followed by SABR, which was delivered using magnetic resonance guided radiotherapy, 40 Gy in 5 fractions within two weeks. Primary endpoint was overall survival (OS). Cox regression analyses were performed to identify predictors for OS.
UNASSIGNED: Overall, 74 patients were included, median age 66 years, 45.9% had a KPS score of ≥90. Median OS was 19.6 months from diagnosis and 12.1 months from start of SABR. Local control was 90% at one year. Multivariable Cox regression analyses identified KPS ≥90, age <70, and absence of pain prior to SABR as independent favorable predictors for OS. The rate of grade ≥3 fatigue and late gastro-intestinal toxicity was 2.7%.
UNASSIGNED: SABR is a well-tolerated treatment in patients with unresectable LAPC following chemotherapy, with better outcomes when applied in patients with higher performance score, age <70 years and absence of pain. Future randomized trials will have to confirm these findings.

Survival outcomes for localized pancreatic adenocarcinoma remains poor. Multimodality therapeutic regimens are critical to maximizing survival outcomes for these patients, which includes the use of systemic therapy, surgery, and radiation. In this review, the evolution of radiation techniques are discussed with a focus on modern techniques such as intensity modulated radiation and stereotactic body radiation therapy. However, the current role of radiation within the most common clinical scenarios for pancreatic cancer in the neoadjuvant, definitive, and adjuvant settings continues to be highly debated. The role of radiation in these settings is reviewed in the context of historical and modern clinical studies. In addition, emerging concepts including dose-escalated radiation, magnetic resonance-guided radiation therapy, and particle therapy are discussed to promote an understanding of how such concepts may change the role of radiation in the future.

BACKGROUND: We studied the added value of digital FDG-PET/CT in disease staging and restaging compared to the standard work-up with contrast enhanced CT (ceCT) and CA19-9 in patients with resectable or borderline resectable pancreatic cancer who received neo-adjuvant therapy. Primary endpoints were tumor response compared to ceCT and CA19.9 as well as the ability to detect distant metastatic disease.
METHODS: 35 patients were included in this dual-center prospective study. FDG-PET using digital photon counting technology combined with CT scans were acquired before (T1) and after neo-adjuvant therapy (T2). Patients were staged and restaged based on standard protocol with ceCT and CA 19.9, while all PET/CT scans were stored securely and not included in clinical decision making. After the pancreatic resection, an expert team retrospectively assessed the CT tumor diameter, CA19-9, tumor FDG-uptake, and appearance of metastatic disease of all patients for both time points.
RESULTS: CA19-9 levels, CT tumor diameter, and tumor FDG-uptake on PET significantly decreased from T1 to T2 (p = 0.017, p = 0.001, and p < 0.0001). The change in FDG-uptake values showed a strong positive correlation with the change in CT tumor diameter and change in CA19-9 (R = 0.75 and R = 0.73, respectively). In addition, small-volume liver lesions were detected on digital PET/CT in 5/35 patients (14%), 4 of which were pathology confirmed at laparotomy. Only one of these five cases was detected on baseline staging ceCT (3%).
CONCLUSIONS: We found that adding digital PET/CT strengthens restaging after neo-adjuvant therapy based on the observed strong correlation with ceCT tumor diameter and Ca19.9. Also, digital PET/CT was found to detect occult metastatic disease not visualized on ceCT, that would have resulted in altered disease staging and therapeutic strategy in a substantial proportion of patients.

BACKGROUND: Treatment of locally advanced pancreatic cancer (LAPC) has long been calling for advances in technology of radiotherapy. Patients who received radiotherapy still had high risks of local recurrence, while suffering from gastrointestinal side effects. Based on the inherent characteristics of the x-ray and γ-Ray radiation techniques, here we proposed and investigated an unexplored radiation therapy.
OBJECTIVE: To investigate the potential clinical benefit of a novel x-ray and γ-Ray combination radiation technique in patients with LAPC.
METHODS: Retrospective intensity-modulated radiotherapy (IMRT) treatment plans of 10 LAPC patients were randomly selected to compare with dual-modality plans. The prescribed dose to PGTV was 60.2 Gy. The PGTV dose was further escalated in dual-modality plan while maintaining clinically tolerable dose to organs at risk (OARs). Dosimetric comparisons were made and analyzed for three treatment plans (tomotherapy, standard dual-modality plan, escalated dual-modality plan) to assess the ability to increase dose to target volume while minimizing dose in adjacent OARs. Finally, radiobiological models were utilized for comparison.
RESULTS: All strategies resulted in dosimetrically acceptable plans. Dual-modality plans were present with similar conformity index (CI) and significantly lower gradient index (GI) compared with tomotherapy (3.64 ± 0.37 vs. 4.14 ± 0.61, p = 0.002; 3.64 ± 0.42 vs. 4.14 ± 0.61, p = 0.003). Dmean of PGTV (65.46 ± 3.13 vs. 61.56 ± 1.00, p = 0.009; 77.98 ± 5.86 vs. 61.56 ± 1.00, p < 0.001) and PCTV (55.04 ± 2.14 vs. 53.93 ± 1.67, p = 0.016; 58.24 ± 3.24 vs. 53.93 ± 1.67, p = 0.001) were significantly higher, while Dmean of the stomach was reduced in both dual-modality plans (17.98 ± 10.23 vs. 19.34 ± 9.75, p = 0.024; 17.62 ± 9.92 vs. 19.34 ± 9.75, p = 0.040). The lower V30Gy in the liver (4.83 ± 5.87 vs. 6.23 ± 6.68, p = 0.015; 4.90 ± 5.93 vs. 6.23 ± 6.68, p = 0.016) and lower V45Gy of the small intestine (3.35 ± 3.30 vs. 4.06 ± 3.87, p = 0.052) were found in dual-modality plans. Meanwhile, radiobiological models demonstrated higher probability of tumor control (29.27% ± 9.61% vs. 18.34% ± 4.70%, p < 0.001; 44.67% ± 18.16% vs. 18.34% ± 4.70%, p = 0.001) and lower probability of small intestine complication (2.16% ± 2.30% vs. 1.25% ± 2.72%, p = 0.048) in favor of dual-modality strategy.
CONCLUSIONS: A novel dual-modality strategy of x-ray and γ-Ray combination radiation appears reliable for target dose escalation and normal tissue dose reduction. This strategy might be beneficial for local tumor control and the protection of normal organs in patients with LAPC.