First experience with intraperitoneal 224Ra-labeled microparticles after cytoreductive surgery in patients with peritoneal recurrence of platinum-sensitive epithelial ovarian cancer.

Carbon ion therapy for pancreatic cancer with risk-adapted dose escalation: initial clinical experience.

Subcutaneous adalimumab is the preferred treatment for most children with juvenile idiopathic arthritis (JIA) and non-infectious uveitis, usually administered every other week. Some patients do not respond or lose responsiveness over time, leading to dose escalation to weekly administration. This study evaluated the efficacy and pharmacokinetics of weekly subcutaneous adalimumab in children with JIA and idiopathic uveitis. This is a retrospective study on clinical and pharmacokinetic characteristics of patients treated with subcutaneous adalimumab for psoriatic arthritis or non-infectious uveitis (idiopathic or JIA-associated) who did not respond or ceased to respond to biweekly administration. Four patients were enrolled: three females and one male, with a median age of 15 years (range 7-18; IQR 6). One had juvenile psoriatic arthritis, two had idiopathic uveitis, and one had JIA-related uveitis. They all presented a poor control of the disease on biweekly administrations, while it was successfully controlled on weekly administrations. None of them presented adverse events. Pharmacokinetic analyses identified two groups of patients: those with high clearance and those with low clearance. In both groups, weekly dosing increased the predicted drug concentrations, and in patients with high clearance only weekly administration provided the predicted concentration exceeding the therapeutic cut-off of 9.6mg/L. Weekly adalimumab administrations were safe and effective in controlling both articular and ocular inflammation. In cases where the disease is poorly controlled with regular biweekly administrations, we encourage escalating adalimumab treatment to weekly administration before adding other therapies or switching to different biologics.

IntroductionCrohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract distinguished by progressive bowel damage with a risk of structuring and penetrating complications. It is characterised by focal or segmental transmural inflammation that disrupts intestinal mucosal integrity and favours the development of abscesses and fistulas. Perianal fistula develops in 13%–39% of patients with CD. Their care is difficult but improves with medical and surgical treatment to preserve anal continence and avoid a maximum proctectomy. Combined treatment with seton placement and concomitant anti-TNF (infliximab, adalimumab) allows wound healing in 40%–70% of cases. The currently available treatments are not curative and fail to provide a long-term resolution. The injection of adipose stromal cells is currently being evaluated in clinical studies for repair-damaged tissues in various diseases (limb ischaemia, osteoarthritis, systemic sclerosis, etc). Immunoregulatory and anti-inflammatory properties of AdMSC (adipose-derived stroma/stem cells) are responsible for accelerating healing and represent an innovative approach for treating perianal fistulas associated with CD.Methods and analysisThis phase I/IIa study is designed to assess the treatment of complex perianal fistulas linked with CD after failure of conventional treatment by injection of AdMSC (CellReady) into the fistula. Two doses of associated AdMSC will be tested for a dose escalation (5×107 and 10×107 cells) and injected into the wall of the fistula. Those eligible for inclusion include patients with controlled luminal CD characterised by a Harvey-Bradshaw score below or equal to eight and diagnosed on clinical, endoscopic, histological and/or radiological criteria, a colonoscopy dating back less than 1 year without ulcer in the rectum and presence of complex chronic perianal fistula with a maximum of two internal ports and three external ports. All patients must have social security insurance or equivalent social protection. The aim of this study is to determine the optimal dose corresponding to maximum efficacy 6 months after injection of cells with a treatment-related adverse event rate of 20%.Ethics and disseminationThe EU CT number 2024-511821-75-00 was approved by the following Ethics Committee: CPP (committee for the protection of persons in French: comité de protection des personnes) Ouest 1 – Tours #2024UEMED-18 and ANSM (French Agency for the Safety of Health and Medicinal Products in French : Agence nationale de sécurité du médicament et des produits de santé) #2024-511821-75-00 (Sponsor number RC31/13/7030, protocol V2.1). The results will be disseminated through conventional scientific channels.Trial registration numberNCT06636032.The results will be disseminated through conventional scientific channels.

BackgroundThe ASPIRE‐FTD study aims to evaluate the safety, tolerability and preliminary efficacy of AVB‐101 in patients with frontotemporal dementia due to progranulin mutations (FTD‐GRN). AVB‐101 uses an adeno‐associated virus 9 vector to deliver a functional copy of the GRN gene to thalamic neurons, which secrete and distribute progranulin (PGRN) throughout the brain. Direct intrathalamic delivery of AAV gene therapy has potential to achieve broad cortical biodistribution of PGRN, overcoming the challenges associated with the blood‐brain‐barrier and pial membrane, while using relatively low AAV doses versus intrathecal delivery. Here, we report preliminary safety from the first completed cohort.MethodThis ongoing Phase 1/2 open‐label, ascending dose study (NCT06064890) will evaluate up to three dose levels of AVB‐101 in the dose escalation part, and further subjects may be dosed in the expansion part to provide additional safety and efficacy data. All subjects will receive a one‐time, bilateral intrathalamic infusion of AVB‐101 under real‐time magnetic resonance imaging (MRI) guidance. The primary objective is to evaluate safety and tolerability of AVB‐101: safety measures include adverse events (AEs) (related or not to AVB‐101 and the administration procedure), change from baseline in MRI results and clinical/laboratory assessments. Neurofilament light (NfL) protein in plasma and cerebrospinal fluid (CSF) is also measured.ResultsAVB‐101 was well‐tolerated in all three patients at the dose level tested in this initial cohort. No clinically significant safety findings have been observed through the follow‐up period of up to 39, 26 and 12 weeks respectively for the three dosed subjects to date. Serial safety MRI demonstrated no significant hemorrhage, edema or inflammation.There have been no serious AEs reported to date and no AEs related to AVB‐101 or the neurosurgical procedure. Additionally, neither prophylactic nor reactive immunosuppression has been required for any subject.As expected, an early transient peak in serum and CSF NfL protein expression was observed after AVB‐101 administration, with trend to baseline thereafter.ConclusionPreliminary data from the ongoing ASPIRE‐FTD trial suggests a favorable safety profile for AVB‐101 and the administration procedure. Recruitment is ongoing for the subsequent escalated dose cohort.

Utilization and opioid outcomes of a transitional pain service in high-risk surgical veterans: a cohort study.

PurposeThe DNA methyltransferase (DNMT) inhibitor 5-fluoro-2’-deoxycytidine (FdCyd) combined with tetrahydrouridine (THU) yielded promising activity in patients with advanced solid tumors, but the intravenous administration schedule of FdCyd limited the clinical feasibility of this treatment program. Therefore, we developed an orally bioavailable formulation of FdCyd and determined the safety, recommended phase 2 dose (RP2D), pharmacokinetics, molecular pharmacodynamic (PD) effects, and antitumor activity of this agent combined with THU.MethodsAdult patients with advanced solid tumors received FdCyd and THU orally on an intermittent schedule in 21-day cycles; dose levels included once- or twice-daily dosing administered on the first 3–7 days (depending on the dose level) of weeks 1 and 2 of each cycle, with no administration on week 3. Dose escalation followed a standard 3 + 3 design; doses were increased until the target FdCyd maximum plasma concentration corresponding to DNMT inhibition in preclinical studies (1 µM) was reached, after which, the total dose was escalated by increasing the number of days and/or frequency of FdCyd-THU administration. Blood specimens were collected for pharmacokinetic analysis and circulating tumor cell (CTC) PD analyses. Paired pre- and on-treatment (cycle 1 week 3) tumor biopsies were collected during the expansion phase to assess changes in expression of DNMT1 and the epigenetically regulated tumor suppressor protein p16 by immunohistochemistry (IHC), as well as changes in genome-wide DNA promoter methylation.ResultsFifty-nine patients with solid tumors were enrolled. The RP2D was 160 mg FdCyd once daily combined with 3000 mg THU once daily on days 1–6 and 8–13 of each 21-day cycle. Dose-limiting toxicities (DLT) were grade 3 diarrhea and grade 3 refractory nausea, vomiting, and diarrhea; the most common grade 3–4 adverse events were hematological toxicities. The best response was prolonged stable disease (17 cycles). Active FdCyd plasma concentrations were achieved at doses of 60 mg and higher, and THU exposure was associated with DLT. One of the 7 patients (14%) with analyzable paired tumor biopsy specimens exhibited an appreciable increase in tumor p16 expression, and none had appreciable decreases in qualitative tumor DNMT1 levels. An increase in the proportion of p16-expressing cytokeratin-positive (CK+) CTCs was detected in 77% of patients (23 of 30) evaluable for CK+ CTC response, while that for vimentin-positive (V+) CTCs was 9% of patients (2 of 22) evaluable for V+ CTC response. Patients with paired biopsies and a best response of stable disease showed treatment-induced promoter hypomethylation for several epigenetically regulated genes, including tumor suppressor genes.ConclusionWe determined the RP2D for the combination of orally administered FdCyd and THU and measured prolonged stable disease and tumor suppressor gene hypomethylation in some patients, suggesting potential clinical benefit and molecular activity for this regimen in some patients. The paucity of tumor DNMT1 decreases and p16 re-expression are consistent with the lack of clinical response. However, it may also reflect the timing of on-treatment biopsies (following the 1-week break in FdCyd administration), since increases in p16-expressing CTCs were measured for the majority of CTC-assessable patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00280-025-04844-y.

BackgroundNeoadjuvant chemoradiotherapy for locally advanced rectal cancer yields pathological complete response rates of only 10%–20%. Dose‐escalation strategies may improve outcomes, but optimal GTV‐to‐PGTV margins for CT‐guided radiotherapy with daily IGRT remain undefined.MethodsTwelve LARC patients undergoing CT‐guided daily IGRT with a simultaneous integrated boost were included. Daily diagnostic‐quality fan‐beam CT (FBCT) scans were acquired for IGRT. GTV and CTV were delineated on planning CT and all FBCTs. Target coverage margins were assessed by isotropically expanding the planning GTV until more than 95% of the voxels of the sequential GTVs were covered. A margin with a coverage probability threshold of 90% was defined as adequate. An independent validation cohort of 30 patients who underwent weekly FBCT‐guided image guidance was further analyzed. Overlap volumes between PGTVs and organs‐at‐risk (OARs; bladder and small bowel) were calculated to assess OAR sparing.ResultsAnalysis of 286 FBCT scans showed that a 6 mm isotropic GTV‐to‐PGTV margin achieved>95% coverage in>90% of fractions. Compared with 10 mm expansion, a 6 mm PGTV reduced the overlap volumes with the bladder and small bowel by 68.5% and 68.4%, respectively. A 6 mm isotropic expansion achieved>95% coverage in 91.3% of fractions in the validation cohort.ConclusionA 6 mm isotropic GTV to PGTV margin provides adequate target coverage for most middle‐ and lower‐rectal tumors while reducing OAR overlap. This finding could facilitate safer dose escalation while maintaining target coverage. However, larger margins may be necessary for smaller tumors or those located in the high rectum.

ABSTRACTIntroductionBI 891065, a second mitochondria‐derived activator of caspases mimetic targets the inhibitor of apoptosis (IAP) family member cIAP1. We describe two first‐in‐human phase 1 trials assessing BI 891065 ± the anti‐programmed cell death protein‐1 (PD1) antibody, ezabenlimab, in advanced solid tumors.MethodsTrials were conducted in the USA (NCT03166631) and Japan (NCT04138823). Dose escalation of BI 891065 monotherapy (part A) and combined with ezabenlimab (part B) was guided by a Bayesian Logistic Regression Model with overdose control. Primary endpoints were maximum tolerated dose (MTD) and number of patients with dose‐limiting toxicities (DLTs) in Cycle 1. Other endpoints included objective response (RECIST v 1.1), pharmacokinetics, and changes in peripheral blood mononuclear cell (PBMC) and tumor cIAP1 levels.ResultsTwenty‐five patients (USA study) received 5–400 mg daily BI 891065 monotherapy; 12 patients (Japan study) received 100 mg daily, 200 mg daily, or 200 mg twice‐daily BI 891065 monotherapy. No DLTs occurred in the USA study; three occurred in the Japan study: grade 3 increased bilirubin (n = 2) and maculopapular rash (n = 1). Neither study reached MTD for monotherapy. Treatment‐related adverse events (TRAEs) occurred in 52% and 75% of patients, respectively. BI 891065 plus ezabenlimab combination (USA study part B only) was received by 37 patients (50–400 mg daily, 200 mg twice‐daily) plus ezabenlimab (240 mg fixed‐dose, Day 1 of 21‐day cycles). One DLT occurred (grade 2 pneumonitis). MTD was not reached. TRAEs occurred in 81% of patients. Neither study reported objective responses; 25%–40% and 35% of patients achieved stable disease with BI 891065 monotherapy and the combination, respectively. cIAP1 levels were reduced in PBMCs and biopsies.ConclusionsBI 891065 was tolerable in patients with advanced solid tumors, demonstrating target engagement as monotherapy and combined with ezabenlimab. Both studies ended early due to efficacy data that were insufficiently promising to justify continuation.Trial RegistrationNCT03166631, NCT04138823

The therapeutic landscape for obesity and type 2 diabetes mellitus (T2DM) is being reshaped by glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Orforglipron (LY3502970) represents a significant evolution in this class. Given the limitations of injectable GLP-1 RAs and the administration constraints of oral semaglutide, orforglipron offers a major convenience advantage: it is a small molecule with ~79% oral bioavailability that requires no food or water restrictions. Mechanistically, it acts by stimulating cyclic adenosine monophosphate without inducing β-arrestin recruitment, thus potentially limiting receptor desensitization and tachyphylaxis. Phase 3 trials demonstrated potent, dose-dependent efficacy. In the ACHIEVE-3 head-to-head trial (T2DM), orforglipron 36 mg proved superior to oral semaglutide 14 mg, delivering significantly greater reductions in hemoglobin A1c (-2.2% vs -1.4%) and body weight (-9.2% vs -5.3%). In the ATTAIN-2 trial (obesity and T2DM), the same dose achieved 10.5% mean weight loss. The safety profile is consistent with the GLP-1 RA class, dominated by manageable gastrointestinal events mitigated by slow dose escalation. A nondose-dependent heart rate increase and a small signal for mild pancreatitis were observed. A class-specific concern exists regarding increased ventricular arrhythmia risk in patients with heart failure with reduced ejection fraction treated with conventional GLP-1 RAs.

Rectal spacers in high-dose-rate-brachytherapy: Optimizing peripheral zone radiation delivery.

Abstract Background and Aims This study explores the effectiveness of vedolizumab dose escalation among patients with ulcerative colitis or Crohn’s disease who experienced a suboptimal or loss of clinical response in a Canadian real-world cohort. Methods Patients with moderately to severely active ulcerative colitis or Crohn’s disease treated with vedolizumab were prospectively followed in a patient support program in Canada from 2015 to 2023. In patients who dose escalated to every 4 weeks from every 8 weeks intravenous maintenance dosing, Harvey-Bradshaw Index and Partial Mayo Scores were assessed 12 and 52 weeks after dose escalation. Clinical remission was defined as Harvey-Bradshaw Index < 5 or Partial Mayo Score < 3. Results This study included 924 patients with Crohn’s disease (45% bio-naïve) and 1816 patients with ulcerative colitis (71% bio-naïve). Of patients with Crohn’s disease, 39% bio-naïve and 54% bio-experienced dose-escalated within the first 2 years. Of patients with ulcerative colitis, 39% bio-naïve and 50% bio-experienced dose escalated within the first 2 years. For Crohn’s disease patients receiving every 8 weekly intravenous maintenance dosing who were not in clinical remission, 50% bio-naïve and 23% bio-experienced patients were in clinical remission 12 weeks after dose escalation, while for ulcerative colitis, 43% bio-naïve and 35% bio-experienced patients were in clinical remission 12 weeks after dose escalation, which was sustained through 52 weeks. Conclusions For patients who experienced a suboptimal or loss of clinical response to vedolizumab, this study supports the real-world effectiveness of intravenous vedolizumab dose escalation in improving clinical response and clinical remission rates among patients with ulcerative colitis or Crohn’s disease.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs)-along with the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA tirzepatide-are widely acknowledged for their efficacy in managing both type 2 diabetes mellitus and obesity, with expanding indications in cardiometabolic risk reduction. While their glycemic, weight-lowering, and cardiovascular benefits are well established through randomized trials and meta-analyses, concerns remain regarding their safety and tolerability across diverse populations and clinical settings. Gastrointestinal (GI) adverse events-particularly nausea, vomiting, diarrhea, and constipation-are the most common side effects, generally emerging during dose escalation and resolving over time. However, accumulating evidence has identified additional GI complications, including cholelithiasis, cholecystitis, gastroparesis, and bowel obstruction, which may warrant caution in susceptible individuals. Injection-site reactions and worsening of pre-existing diabetic retinopathy are also relevant clinical concerns. Although rare, associations with nonarteritic anterior ischemic optic neuropathy, pancreatitis, medullary thyroid carcinoma, and acute kidney injury (AKI) have been reported, primarily through pharmacovigilance and case-based evidence. Importantly, large-scale randomized trials, meta-analyses, and observational studies suggest that GLP-1RAs do not significantly increase AKI risk and may even confer renal benefits in high-risk populations. There is no confirmed elevated risk of suicidality, but surveillance remains warranted. Safety data in special populations-such as pregnant or lactating women, pediatric patients, and those with advanced renal or hepatic impairment-remain limited and require further study. This state-of-the-art narrative review synthesizes current evidence from clinical trials, pharmacovigilance databases, and real-world cohorts to provide a comprehensive evaluation of the safety and tolerability of GLP-1RAs and tirzepatide. We present clinical strategies for adverse event mitigation, monitoring recommendations, contraindications, and practical considerations for treatment discontinuation or switching. Although these agents offer transformative therapeutic potential, their optimal use requires individualized care, careful patient selection, and ongoing safety surveillance. Future research should prioritize long-term safety in underrepresented populations and strategies to mitigate lean mass loss during therapy.

Background/Objectives: Asthma action plans (AAPs) are recommended for patients’ self-management of asthma and should be adapted to a country’s situation. This study aimed to develop expert consensus on the optimal structure, content, and action of asthma action plans for Vietnamese settings to ensure feasibility, acceptance, and implementation. Methods: A Delphi consensus was conducted over two rounds. The proposed items were evaluated by a Vietnamese panel of pulmonologists, allergists, tuberculosis/lung disease specialists, and general practitioners. Structured online questionnaires with five-point Likert scales were used. Consensus was defined as >80% agreement and <10% strong disagreement. Results: A total of 26 and 21 participants completed round 1 and round 2, respectively. The 4-zone format of AAP was preferred (42.3%) over the 3-zone (38.5%) or 2-zone (19.2%) formats. The AAP should include some key statements for asthma, symptoms for self-monitoring, an objective asthma control questionnaire, actions for changes in maintenance medication, and instructions in emergency situations. AAP zones should be classified by symptom frequency and severity. Patient actions should be tailored to their treatment regimen (MART or ICS/LABA + SABA). The APP might not include peak expiratory flow monitoring and oral corticosteroid self-administration for both the MART and ICS/LABA + SABA regimens and might not add SABA together with ICS dose escalation for the ICS/LABA + SABA regimen. Conclusions: This study established an expert consensus on fundamental AAP structural elements and actions for the Vietnamese. The failure to achieve consensus on PEF monitoring tools and OCS for the self-management of asthma exacerbation reflects concerns about medication abuse, especially in Vietnamese healthcare settings.

BackgroundIn 2019, EUCAST redefined its categories of sensitive (S), intermediate (I) and resistant (R). ‘Intermediate’ now indicates likely therapeutic success if higher doses or optimized routes are used. This change particularly affects Pseudomonas aeruginosa, where WT isolates are now reported as ‘I’ for most agents. To support clinicians, Berkshire and Surrey Pathology Services (BSPS) introduced the designation S* in laboratory reports while the electronic patient record, EPIC, introduced the term ‘sensitive-increased exposure.’ Although designed to aid clinical decision-making, the change introduces additional terminology that risks confusion at the point of care.Objectives(i) To investigate knowledge and understanding of the S*/sensitive-increased exposure category among physicians and pharmacists at Frimley Health NHS Foundation Trust. (ii) To assess whether patients with Pseudomonas bacteraemia are receiving appropriately escalated antibiotic dosing in line with EUCAST recommendations.MethodsWe conducted a cross-sectional survey, disseminated by email, to physicians and pharmacists across Wexham Park and Frimley Park hospitals. The questionnaire assessed awareness of the S* category, its interpretation and reported prescribing behaviours. In parallel, we performed a retrospective audit of all adult patients with blood culture–confirmed Pseudomonas bacteraemia across both hospitals between January and December 2024. Case notes and prescribing records were reviewed to determine whether ciprofloxacin and/or piperacillin/tazobactam, specifically, were used, and if dosing was standard or appropriately escalated.ResultsA total of 131 responses were received: 100 from physicians and 31 from pharmacists. Among physicians, 69% reported no prior awareness of S*, and 83% were unaware it indicated safe treatment with higher antibiotic doses. Only 29% reported altering their prescribing practice in response to S*. Notably, 33% were more likely to prescribe an antibiotic marked S*, possibly reflecting misinterpretation of S* as a recommendation rather than a caution. Among pharmacists, 48% were unaware of the category, 68% were unsure about dose escalation and 71% did not advise prescribers to modify dosing. The audit identified 70 patients with Pseudomonas bacteraemia across both sites in 2024. Of these, 46 (65.7%) were treated with either ciprofloxacin, piperacillin/tazobactam, or both. 30/46 patients (61%) consistently received low doses, 17% were partially escalated and only 24% consistently received correct high doses. Patients at Frimley Park Hospital were significantly more likely to receive appropriate dosing compared to Wexham Park Hospital (P<0.001).ConclusionsKnowledge of the S* category is limited among both doctors and pharmacists, leading to frequent undertreatment of Pseudomonas bacteraemia. This gap poses risks for patient outcomes and antimicrobial stewardship. Our findings highlight the need for structured education, clearer microbiology reporting and standardized dosing guidance. In response, we have launched an educational programme across the Trust and plan repeat surveys and audits to evaluate its impact. Improving understanding and practice around the S* category is essential to ensure that EUCAST’s redefinitions translate into improved patient outcomes rather than confusion and underdosing.

Abstract SMARCB1 is a tumor suppressor gene and encodes a core subunit of the SWI-SNF chromatin remodeling complex. Loss of SMARCB1 leads to the development of highly aggressive pediatric malignancies, termed “SMARCB1-deficient cancers.” This includes malignant rhabdoid tumor, atypical teratoid rhabdoid tumor (ATRT), and renal medullary carcinoma (RMC). Survival rates in these patients remain low, and resistance to chemotherapeutic agents, including doxorubicin, are common. Therefore, this project aims to characterize the evolution of doxorubicin resistance in SMARCB1-deficient cancers. To address this question, we generated doxorubicin resistant (DR) cells from the ATRT cell line, BT16, and RMC cell line, PEDS005T, utilizing a dose escalation approach. This resulted in DR cell lines that are 10-to-30-fold resistant compared to the parental cell line. Furthermore, we generated two independent DR cell lines from each parental cell line, enabling the capture of distinct evolutionary trajectories leading to resistance. We profiled the transcriptomes by bulk RNA-sequencing and found an upregulation of the multidrug transporter ABCB1, also known as MDR1, in 3 of 4 models. To assess whether ABCB1 upregulation alone was sufficient for DR, we treated them with an ABCB1 pharmacological inhibitor and found that ABCB1-upregulated DR cells were re-sensitized to doxorubicin, whereas an ABCB1-negative BT16 DR cell line remained resistant. To determine a shared mechanism of resistance between these models, we profiled the methylomes by Oxford Nanopore Technologies long-read sequencing. We observed global hypermethylation when compared to the parental counterparts. Treatment with a hypomethylating agent reduced cell viability up to 75%. Future studies will focus on identifying and therapeutically targeting these commonalities to overcome resistance regardless of evolutionary trajectory. These preliminary findings suggest that despite a common genetic driver (loss of SMARCB1), there are different pathways to developing resistance to the DNA-damaging agent, doxorubicin. Furthermore, reduced cell viability resulting from treatment with a hypomethylating agent suggests there are common vulnerabilities despite differing evolutionary trajectories. Citation Format: Katie T. Skinner, Benjamin P. Lee, Jessica S. Yoon, Andrew L. Hong. The evolution of doxorubicin resistance in SMARCB1-deficient cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B017.

Previous findings reported increased toxicity of FLASH radiotherapy (FLASH) delivered under supplemental oxygen but failed to quantify the change in magnitude of the FLASH sparing effect. This study investigated the impact of oxygen breathing on normal tissue complication probability (NTCP) following FLASH and conventional radiotherapy (CONV) using murine models of acute gastrointestinal and skin toxicity. Tumor-free C57BL/6 and BALB/c mice received whole-abdominal or skin irradiation, respectively, using either CONV or FLASH. Dose escalation was performed under air- and oxygen-breathing in both models to determine NTCP curves. The FLASH dose modifying factor (DMF) was derived as the dose ratio at 50% NTCP. Changes in tissue oxygenation, going from air- to oxygen-breathing, were measured in vivo using oxygen sensing by phosphorescence quenching. Abdominal irradiation under air breathing showed a significant FLASH sparing effect, with a mean DMF of 1.14. This effect was abolished under oxygen breathing, with a mean DMF reduced to 1.00. In contrast, skin irradiation under air breathing demonstrated a strong FLASH sparing effect, with a mean DMF of 1.42, which was largely preserved under oxygen breathing (mean DMF = 1.40). Oxygen breathing markedly increased tissue oxygenation in both the intestine and skin. Maintaining of the FLASH sparing effect under increased oxygenation is tissue dependent. Our findings indicate potential difference in CONV and FLASH oxygen enhancement ratio (OER) curves. By conducting dose escalation experiments in animal models we provided first quantification of change in magnitude of FLASH sparing effect under increased tissue oxygenation.

The adenosinergic pathway represents a critical immunometabolic checkpoint within the tumor microenvironment of non-small cell lung cancer (NSCLC), contributing to immune suppression and therapeutic resistance. PBF-1129, an oral, selective A2B adenosine receptor (A2BAR) antagonist, was evaluated in a phase 1, open-label, dose-escalation trial (NCT03274479) in patients with advanced/metastatic NSCLC who had progressed on standard therapies. All patients had previously received chemotherapy and immune checkpoint blockade. Twenty-one patients received escalating doses (40-320mg once daily), with no dose-limiting toxicities observed. The most frequently reported treatment related adverse events of any grade were lymphocytopenia (n = 8, 38.1%), vomiting (n = 8, 38.1%), anorexia (n = 6, 28.5%), and fatigue (n = 6, 28.5%). PBF-1129 showed dose-proportional pharmacokinetics and maintained plasma concentrations above the 90% maximal inhibitory concentration (IC90) of A2BAR at 320mg for 24h, which was determined to be the recommended phase 2 dose (RP2D). Best response was stable disease in 3 out of 21 patients including 2 of 6 treated at RP2D. Immunophenotyping revealed post-treatment reductions in programmed cell death protein 1 (PD-1) expression on CD8⁺ T cells, which correlated with improved survival. The reduction of PD-1 expression on CD4⁺ T cells and decreased myeloid-derived suppressor cells were also associated with better outcomes. These findings suggest PBF-1129 is safe and modulates the systemic immune parameters, warranting further evaluation in combination with immune checkpoint blockade.

Nodal response to neoadjuvant therapy predicts prognosis of breast cancer patients with clinically positive internal mammary nodes

Model-informed precision dosing of vancomycin in Chinese adult patients receiving renal replacement therapy: Systematic evaluation of published pharmacokinetic models and dosing regimen simulations.