Changes In Tumor Volume Research Articles

CTNI-74. SONODYNAMIC THERAPY (SDT) USING INTRAVENOUS 5-AMINOLEVULINIC ACID WITH NON-ABLATIVE FOCUSED ULTRASOUND FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS IN PEDIATRICS: INITIAL SAFETY AND OUTCOMES THE MULTICENTER SDT-201 TRIAL

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality amongst pediatric neuro-oncologic diseases. Sonodynamic therapy with non-ablative MR-guided focused ultrasound (MRgFUS) is being investigated in multiple clinical trials. We describe safety outcomes and initial efficacy of SDT with 5-ALA for the treatment of pediatric patients with DIPG. Twelve patients with DIPG were treated from August 2022-April 2024 as part of a dose-escalation protocol with SDT in a multicenter Phase 1/2 clinical trial (NCT05123534). MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells. Treatment is delivered every 4 weeks for up to 12 treatments. Patient ages ranged from 3-23 years and 60% were male. Twelve patients underwent a total of 45 SDT treatments (range 2-9). When enrolled, median tumor volume was 1,337 cm3 (range, 310-2078 cm3) and duration since diagnosis was 5 months. SONALA-001 doses tested were 5 mg/kg and 10 mg/kg. Delivered ultrasonic acoustic energy ranged from 190-444 joules/cm3. After 6 months of median follow-up (range 2-18), 2 partial responses occurred, and 9 of 12 patients had stable or improved baseline symptoms (Lansky Status), including improved mobility and diplopia. One adverse clinical event included a small non-operative epidural hematoma secondary to a stereotactic frame pin. There have been no grade 3 or worse treatment-related adverse events or dose-limiting toxicities. Ten patients are alive a median of 11 months after diagnosis; 2 have deceased; 4 have discontinued treatment. Maximum percent tumor volume changes throughout treatment ranged from a -68% reduction to over 100% enlargement. Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy.

SURG-41. OPTIMIZING PATIENT OUTCOMES IN PETROCLIVAL MENINGIOMA TREATMENT: EVALUATING SURGICAL, RADIOSURGICAL, RADIOTHERAPY AND COMBINED TREATMENT APPROACHES

Abstract Petroclival meningiomas pose a formidable challenge due to their proximity to critical neurovascular structures, necessitating complex surgical interventions with a high risk of complications. Stereotactic radiosurgery (SRS) offers an alternative or complementary treatment option, yet the optimal treatment strategy remains undefined. We aimed to evaluate the local control rates following surgical resection, radiotherapy, and SRS for petroclival meningiomas and to assess the incidence of cranial nerve palsies associated with each treatment modality. This retrospective study reviewed medical records of patients treated for petroclival meningiomas at Stanford University between 1980-April 2024. Pre- and post-treatment radiological data were analyzed to assess local control. Cranial nerve function was evaluated pre- and post-treatment, and at last follow-up. A total of 171 patients (129 females; median age 54.65 years) diagnosed with petroclival meningioma were identified. Treatment modalities included: 31 patients underwent surgical resection alone, 27 received SRS alone, 11 received radiotherapy alone, 36 underwent combined surgical resection and SRS, 28 received combined surgical resection and radiotherapy, 9 were treated with a triad of surgical resection, SRS, and radiotherapy, and 29 were managed with serial imaging alone. The percentage change of tumor volume from diagnosis to follow-up for these groups was -55.6%, 28.9%, 73.0%, -64.9%, -12.0%, 35.3%, and -8.8%, respectively. The incidence of new cranial nerve palsies was highest (68%) in patients who underwent surgical resection. The percentage of worsening pre-existing palsies was greater in patients receiving single-modality non-surgical treatment. Surgery, radiotherapy, and SRS demonstrated promising local control rates for specific patient cohorts with petroclival meningiomas. Patients receiving combination therapies generally fared better than those receiving single-modality treatments, with surgery followed by SRS yielding the best outcome. The incidence of cranial nerve palsies was lower following SRS and radiotherapy compared to surgery. Future research should focus on refining multi-modal treatment strategies to minimize complications and improve patient quality of life.

Utilizing Patient-derived Xenografts to Model Precision Oncology for Biliary Tract Cancer.

Biliary tract cancers (BTCs), which are rare and aggressive malignancies, are rich in clinically actionable molecular alterations. A major challenge in the field is the paucity of clinically relevant BTC models which recapitulate the diverse molecular profiles of these tumors. The purpose of this study was to curate a collection of patient-derived xenograft (PDX) models that reflect the spectrum of genomic alterations present in BTCs to create a resource for modeling precision oncology. PDXs were derived from BTC collected from surgical resections or metastatic biopsies. Alterations present in the PDXs were identified by whole exome sequencing and RNASeq. PDXs were treated with approved and investigational agents. Efficacy was assessed by change in tumor volume from baseline. Event-free survival was defined as time to tumor doubling from baseline. Responses were categorized at day 21: >30% decrease=partial response; >20% increase in tumor volume=progressive disease, and any non-PR/PD was considered stable disease. Genomic sequencing demonstrated key actionable alterations across this cohort, including alterations in FGFR2, IDH1, ERRB2, PIK3CA, PTEN and KRAS. RNAseq demonstrated fusions and expression of antibody drug conjugate targets including TROP2, HER2 and Nectin4. Therapeutic matching revealed objective responses to approved and investigational agents that have been shown to have antitumor activity clinically. Here, we developed a catalog of BTC PDXs which underwent comprehensive molecular profiling and therapeutic modeling. To date, this is one of the largest collections of BTC PDX models and will facilitate the development of personalized treatments for patients with these aggressive malignancies.

Ultrasound-guided ablation for T1N0M0 papillary thyroid carcinoma adjacent and non-adjacent danger triangle area: a retrospective comparative study

Objectives To compare the safety and efficacy of ultrasound-guided radiofrequency ablation (RFA) in the treatment of T1N0M0 papillary thyroid carcinoma (PTC) with adjacent and non-adjacent danger triangle area (DTA). Materials and methods This retrospective study involved collecting clinical data of all T1N0M0 PTC patients who underwent RFA between January 2018 and December 2020 at the hospital. A total of 211 patients were enrolled in the study (mean age 43.25 ± 12.30 years, male-to-female ratio = 1:3). Among them, 91 had adjacent DTA involvement, while 120 had non-adjacent DTA involvement. Comparisons were made between the two groups patients regarding tumor volume changes, technical success rates, tumor disappearance, disease progression, complications. Results In both groups, the technical success rate was 100%, with a median follow-up period of 30 months. The rates of complete tumor disappearance were 78% (71/91) and 74.2% (89/120) for the adjacent and non-adjacent DTA(p = .517). Disease progression rates were 2.2% (2/91) and 1.7% (2/120) (p > .99), Complication rates were 3.3%(3/91) in the adjacent DTA group and 1.7% (2/120) in the non-adjacent DTA group (p = .654). At 6th month after ablation, the volume reduction rate (VRR) in the non-adjacent DTA group (42.3%) was higher than in the adjacent DTA group (37.3%) (p = .002). However, no significant differences were observed in VRR between the two groups at 1, 3, 12, 18, 24, 30, and 36 months (p > .05). Conclusion In the treatment of T1N0M0 PTC, the complication rates and short-term efficacy of RFA in adjacent to the DTA did not differ from those of non-adjacent DTA.

STRAP Knockdown Inhibits Migration and Growth of Non-Small Cell Lung Cancer.

Serine-threonine kinase receptor-associated protein (STRAP) regulates cell proliferation and apoptosis by binding to many target proteins and plays an important regulatory role in tumor development. We studied the effects of STRAP on non-small cell lung cancer (NSCLC) in vivo and in vitro in order to elucidate possible mechanisms underlying the regulatory effects of this protein. The levels of STRAP in NSCLC tissues and cells were determined by quantitative reverse transcription PCR, immunohistochemical staining, and Western blotting. In in vitro experiments, A549 and HCC827 cells were transfected with small interfering RNA (siRNA) to knockdown STRAP (si-STRAP) or with negative control sequence; cell migration and invasion were detected by scratch and Transwell assays, respectively. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), caspase-3, and caspase-9 were determined by Western blotting. In addition, we analyzed changes of tumor volume in a nude mouse NSCLC model. STRAP was highly expressed in NSCLC tissues and cells, but its expression was significantly suppressed in A549 and HCC827 cells transfected with si-STRAP. STRAP knockdown resulted in a significant inhibition of migration and invasion of A549 and HCC827 cells. It also significantly reduced the expression of XIAP and elevated expression of caspase-3 and caspase-9. In nude mice with tumor originated from transplanted A549 cells, inhibition of STRAP expression retarded the tumor growth. Overall, these findings indicate that STRAP is overexpressed in NSCLC, while knockdown of STRAP gene inhibits the growth of NSCLC.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

Euphorbia helioscopia inhibits proliferation, invasion, and migration and promotes apoptosis of non-small cell lung cancer cells

To investigate the effect of Euphorbia helioscopia on biological behaviors of non-small cell lung cancer (NSCLC) cells. NSCLC cell lines PC-9 and A549 treated with different concentrations of Euphorbia helioscopia preparations were examined for changes in proliferation, apoptosis, invasion and migration using CCK-8 assay, colony formation assay, flow cytometry, wound healing assay and Transwell assay. Western blotting was performed to detect the changes in protein expressions of Bax, Bcl-2, E-cadherin, vimentin, MMP2, and MMP9 in the treated cells. PC-9 cells were injected subcutaneously into BALB/C nude mice to establish a nude mouse subcutaneous tumor model. According to the growth of subcutaneous tumors, mice were randomly divided into control group: gavaged daily with saline; Euphorbia helioscopia-treated group: gavaged daily with Euphorbia helioscopia 65 mg/mL, and Euphorbia helioscopia granules were dissolved in saline; cisplatin-treated group: injected intraperitoneally with cisplatin 4 mg/kg every 5 days, 6 mice per group. The subcutaneous tumor volume and mass changes of mice were measured, and the toxic effects of Euphorbia helioscopia on heart, liver, spleen, lung and kidney as well as the therapeutic effects of Euphorbia helioscopia were observed in the mice bearing tumor. Euphorbia helioscopia granules concentration-dependently inhibited the proliferation and survival of PC-9 and A549 cells, significantly promoted cell apoptosis, suppressed invasion and migration abilities of the cells, up-regulated the expression levels of E-cadherin and Bax, and down-regulated the expressions of Bcl-2, vimentin, MMP2, and MMP9. In the tumor-bearing mice, treatment with Euphorbia helioscopia significantly inhibited tumor growth without producing obvious toxicity in the vital organs. Euphorbia helioscopia can inhibit proliferation, invasion, and migration and induces apoptosis of NSCLC cells in vitro.

Treatment of isolated pediatric optic nerve glioma: A nationwide retrospective cohort study and systematic literature review on visual and radiological outcome.

Progressive isolated optic nerve glioma (ONG) in children is a rare disease, treated with various modalities. A global treatment consensus is not available. We conducted a national retrospective multicenter cohort study (1995-2020) to investigate how different treatment strategies impact outcome for ONG in children, by assessing treatment responses to systemic anticancer therapy (SAT), surgery, and radiotherapy for ONG. The primary endpoints included changes in best-corrected visual acuity (BCVA) and tumor volume (TV) on MRI, both evaluated at the start and end of therapy and at long-term follow up. A total of 21 ONGs (20 patients) received SAT (n=14 (66.7%)), surgery (n=4 (19.0%)), and radiotherapy (n=3 (14.3%)). After SAT BCVA stabilized or improved in 66.6% (n=4) and the TV decreased by a median of 45.1% (range: -88.6% to +31.5%) (n=13). Before resection two eyes were already blind. After resection BCVA decreased to blindness in one eye. In total all four eyes were blind after resection. After first-line RT BCVA decreased in 66.7% of ONG to counting fingers or less, TV increased<3 months after RT by a median of 47.3% (range: -42.8% to +245.1%) (n=3), followed by a long-term decrease of 94.4 and 13.8% (n=2), respectively. SAT appears to be the preferred modality for progressive ONG in case of potential rescue of visual functions. Complete resection of ONG appears effective to reduce proptosis in case of preexisting blindness. The use of radiotherapy requires careful consideration due to the risk of severe visual impairment and secondary disease.

8404 Use of the Acromegaly Symptom Diary (ASD) in a Phase 3, Placebo-Controlled Study of Once-Daily, Oral Paltusotine in Patients With Acromegaly Switched From Injected Octreotide or Lanreotide

Abstract Disclosure: M.R. Gadelha: Consulting Fee; Self; Crinetics, Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics and Recordati. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. C.J. Strasburger: Consulting Fee; Self; Amolyt Pharma, Consilient Health, Novo Nordisk, Recordati, and Sandoz-Hexal. Research Investigator; Self; Crinetics. M. Bidlingmaier: Consulting Fee; Self; Crinetics, Ionis, Novo Nordisk, Pfizer, Roche, and Sandoz. Research Investigator; Self; Amolyt, Camurus, Chiasma, Crinetics, IDS, Ionis, Lumos, and OPKO. Speaker; Self; Euroimmun, Novo Nordisk, and Pfizer. P.J. Snyder: Research Investigator; Self; Crinetics. M.A. Guitelman: Consulting Fee; Self; Recordati, Sanofi Aventis, and Varifarma. Research Investigator; Self; Crinetics. Speaker; Self; Recordati, Sanofi Aventis, and Varifarma. C.L. Boguszewski: Consulting Fee; Self; Ipsen, Novo Nordisk, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Novo Nordisk, and Recordati. M. Buchfelder: Research Investigator; Self; Crinetics. I. Shimon: Consulting Fee; Self; Medison and Pfizer. Research Investigator; Self; Crinetics and Debiopharm. Speaker; Self; Medison and Pfizer. G. Raverot: Consulting Fee; Self; Amolyt, Crinetics, Ipsen, Novo Nordisk, Pfizer, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Pfizer, and Recordati. M. Toth: Consulting Fee; Self; Ipsen, Lilly, Novartis, and Recordati. Research Investigator; Self; Crinetics. Speaker; Self; Ipsen, Lilly, Novartis, and Recordati. E. Mezosi: Research Investigator; Self; Crinetics. M. Doknic: Advisory Board Member; Self; Pfizer in CEE. Research Investigator; Self; Crinetics. X. Fan: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. D. Clemmons: Consulting Fee; Self; Crinetics. M. Keeley: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. R. Struthers: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A. Krasner: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. B.M. Biller: Consulting Fee; Self; Amryt, Camurus, Crinetics, and Recordati. Research Investigator; Self; Crinetics and Ionis. Paltusotine is a once-daily, selective, non-peptide, SST2 receptor agonist in development as an oral treatment for patients with acromegaly or carcinoid syndrome. The Acromegaly Symptom Diary (ASD) is a novel patient-reported outcome tool developed in accordance with US FDA guidance to assess disease-related symptom burden. The ASD consists of 7 core items (headache, joint pain, sweating, fatigue, leg weakness, swelling, numbness/tingling, score range: 0-70; higher scores indicate greater symptom burden) plus 2 additional items (sleep difficulty, memory difficulty) and is completed daily. We previously reported the topline results of PATHFNDR-1 (NCT04837040), a phase 3 trial evaluating the efficacy and safety of paltusotine in adults with acromegaly who were previously controlled (IGF-I ≤1.0 ×ULN) on stable (≥12 weeks) injected octreotide or lanreotide. Patients were randomly allocated to once-daily paltusotine 40 mg or placebo for 36 weeks, with uptitration to 60 mg/day permitted through week 24. IGF-I and GH levels (IDS-iSYS) and pituitary tumor volume (MRI) were measured centrally. Fifty-eight patients (paltusotine, n=30; placebo, n=28) were enrolled: mean (±SD) age 54.9±13.7 years; 55.2% female; prior treatment octreotide LAR (n=34) or lanreotide depot (n=24). The primary endpoint (proportion of patients maintaining IGF-I ≤1.0 ×ULN [mean of weeks 34 and 36]) was met by significantly more patients on paltusotine (83.3%) versus placebo (3.6%; odds ratio: 126.53; 95% CI: 13.73, &amp;gt;999.99; P&amp;lt;0.0001). All secondary endpoints were met: mean (±SE) change in IGF-I of 0.04±0.09 ×ULN versus 0.83±0.1 ×ULN (P&amp;lt;0.0001); and GH maintained at &amp;lt;1.0 ng/mL in 87.0% versus 27.8% of patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P&amp;lt;0.001). The most common adverse events (AEs) were typical of the somatostatin receptor ligand (SRL) class or acromegaly symptoms. There were no severe or serious AEs in the paltusotine group. One patient in the placebo group discontinued study participation (patient decision). There were no clinically significant changes in pituitary tumor volume. The mean completion rate of the daily ASD questionnaire was 79.1%. At the end of randomized treatment, the ASD total score was significantly increased from baseline (indicating worsening) in the placebo group compared with the paltusotine group, meeting the secondary endpoint (-0.6±1.5 versus 4.6±1.6; P=0.02). For individual ASD symptoms, mean scores were consistently indicative of improvement with paltusotine compared to placebo; the between-group difference was statistically significant for joint pain (P&amp;lt;0.05), numbness/tingling (P&amp;lt;0.01), and the “most bothersome” symptom (P&amp;lt;0.05). In conclusion, once-daily oral paltusotine maintained symptom control in concert with biochemical values in well-controlled patients switched from injected SRLs and was well tolerated. Support: Crinetics Pharmaceuticals Presentation: 6/3/2024

Construction of Lactobacillus casei-loaded Water-in-oil High Internal Phase Emulsion and its Study on Anti-breast Cancer Properties

Objective: To prepare an oil-in-water high internal phase emulsion containing Lactobacillus casei, and to optimize and characterize the preparation process. To explore the therapeutic effect of the probiotic-carrying emulsion on in situ breast cancer in mice. Methods: Using corn oil, sodium alginate, polyglycerin ricinoleate and L. casei as raw materials, the high internal phase emulsion containing probiotic oil-in-water was prepared by high-speed homogenization method. The optimal preparation process was obtained through single factor investigation, microstructure characterization, stability investigation and in vitro simulation digestion experiment. Ten female BALB/c mice (SPF grade, 18–20 g) were selected. After the in situ breast cancer model was successfully established, the mice were randomly divided into experimental group and control group, with 5 mice in each group. The mice were administrated with probiotic-loaded emulsion and normal saline respectively, and were administrated with the stomach every other day for 10 days. The change of tumor volume during treatment and tumor mass at the end of treatment were recorded. Results: The optimum process of emulsion was: With the concentration of 5% Polyglycerin ricinolate, 75% aqueous volume, 3000r/min homogenizing speed, 30 s homogenizing time and 2% aqueous sodium alginate concentration, a high internal phase emulsion with a particle size of 9.33 ± 1.74 μm and an appearance of milky paste was prepared. The inclusion rate of probiotics reached 90.97 ± 27.09%. Breast cancer anti-tumor experiment showed that the tumor inhibition rate of the experimental group reached 33.78% compared with the control group. Conclusion: Water-in-oil high internal phase emulsion can effectively protect L. casei and reduce the loss of live probiotic when probiotics pass through the digestive fluid environment. Oral intragastric high internal phase emulsion containing L. casei oil-in-water has a certain therapeutic effect on breast cancer.

Pharmacodynamic Activity of [18F]-Fluorthanatrace Poly(ADP-ribose) Polymerase Positron Emission Tomography in Patients With BRCA1/2-Mutated Breast Cancer Receiving Talazoparib.

We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib. Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points. Blocking of [18F]FTT was observed on the second scan. Potentially strong but nonsignificant correlations were found between changes in tumor volume (on ultrasound at 1 month v baseline) and percentage changes in tumor-to-muscle uptake ratio at 14 days from baseline (Spearman rank correlation coefficient r = 1; P = .083); and between the highest-grade hematologic toxicity and baseline bone marrow-to-muscle (B/M) uptake ratio (r = 0.72; P = .068) and percentage change in B/M ratio at 14 days from baseline (r = 0.87; P = .058). We conclude that [18F]FTT can image target engagement by PARPi, but larger studies are needed to determine whether [18F]FTT uptake can predict response to PARPi and whether uptake of [18F]FTT in bone marrow may be an early predictor of hematologic toxicity.

CD206 accelerates hepatocellular carcinoma progression by regulating the tumour immune microenvironment and increasing M2-type polarisation of tumour-associated macrophages and inflammation factor expression

ObjectiveThis study aims to investigate the effect of CD206 on the progression of hepatocellular carcinoma (HCC) and the regulation of the tumour immune microenvironment.MethodsA subcutaneous mouse model of HCC was established and treated with CD206-overexpressing adenovirus by tail vein injection or CD206 antibody C068C2 by intratumoral injection. The hepatocarcinoma-bearing mice were divided into four groups (IgG+ tail vein adenovirus group, IgG group, C068C2+ tail vein adenovirus group and C068C2 group) to observe the changes in tumour weight and volume with different expression levels of CD206. The proportion of M2-type tumour-associated macrophages (TAMs) was detected by flow cytometry and immunofluorescence. The apoptosis of tumour cells was detected using terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining, and inflammatory factors in serum and tissues were detected using the ENZYME-LINKED IMMUNOSORBENT ASSAY.ResultsCompared with the mice with low CD206 expression, the hepatocarcinoma-bearing mice with high CD206 expression in HCC exhibited faster tumour growth and more aggressive progression. Flow cytometry and immunofluorescence staining revealed that the expression level of CD206-positive M2-type TAMs was highest in the IgG + adenovirus group and lowest in the C068C2 group (p < 0.001). Compared with the IgG + adenovirus group, the proportion of TUNEL-positive cells in tumour cells was significantly reduced in the C068C2 group. The IgG + adenovirus group had the highest concentrations of transforming growth factor-β (TGF-β) and interleukin 6 (IL-6) in both serum and tumour tissues.ConclusionThe overexpression of CD206 accelerates the progression of HCC and changes the tumour immune microenvironment. The high expression of CD206 in HCC increases the M2-type polarisation of TAMs and induces the expression of both TGF-β and IL-6 in tumour tissues and serum, thereby promoting HCC progression.

Expression of cancer susceptibility candidate 11 in ovarian cancer tissues and its role in doxorubicin resistance.

We aimed to investigate the expression of cancer susceptibility candidate 11 (CASC11) in ovarian cancer (OC) tissues and its role in doxorubicin (Dox) resistance. A total of 98 patients were included as subjects. Reverse transcription-polymerase chain reaction was employed to determine the expressions of CASC11 in OC and para-OC tissues, and in OC cells (A2780, SKOV3, OVCAR3 and A547) and human normal ovarian epithelial cells (IOSE-80) from these patients. OC SKOV3/R cell line with Dox resistance was established and transfected with small interfering (si)-CASC11 to down-regulate CASC11 expression. Based on the constructed nude mouse model of orthotopic transplanted tumor, the growth curves were plotted, and the changes in tumor volume and apoptosis were observed by hematoxylin-eosin staining. OC tissues had a significantly higher mRNA expression of CASC11 than that of para-OC tissues (P < 0.05). A547, OVCAR3, A2780 and SKOV3 cells had significantly higher mRNA expressions of CASC11 than that of IOSE-80 cells (P < 0.05). The transplanted tumor was significantly smaller in volume in the si-CASC11 group than that in the si-normal control (NC) group from the 8th days after transplanted tumor inoculation (P < 0.05). The tumor growth inhibition rate significantly rose in the si-CASC11 group in comparison with that in the si-NC group (P < 0.05). CASC11 has high expression in OC tissues. Knockout of CASC11 weakens the proliferative, invasive and migratory potentials and enhances the apoptotic potential of Dox-resistant OC cells, thereby reversing their Dox resistance.

Tumor volume changes after stereotactic, hypofractionated and conventional radiotherapy in paragangliomas of head and neck.

The aim of this study is comparison the effectiveness of stereotactic, hypofractionated and conventional radiotherapy assessed by the tumor volume changes of paraganglioma located in the head and neck region concerning fractional and total doses. We analyzed 76 patients after radiotherapy due to paraganglioma who were assigned to 3 groups considering fractional (≤2 Gy, 3-5.5 Gy, ≥6 Gy) and total (≤20 Gy, 21-40 Gy, >40 Gy) doses. The volumes of irradiated tumors were measured and compared based on diagnostic images performed before and after the treatment. The mean tumor volume after the treatment with the lowest fractional dose (≤2 Gy) was decreased by 14.4 cm3. In patients treated with higher fractional doses (>2 Gy), the mean tumor volumes decreased by less than 1 cm3 for hypofractionated and stereotactic radiotherapy. 15.9 cm3 reduction of the mean tumor volume after the treatment with the highest RT total dose (>40 Gy) was stated. In patients treated with total doses ≤20 Gy and 21-40 Gy, the mean tumor volume was stable and reduced by 1.15 cm3, respectively. The analysis demonstrates a statistically significant (p < 0.05) treatment advantage in patients after the lowest fractional and highest total doses. The reduction of the tumor's volume was reported after conventional and unconventional radiotherapy. The most significant depletion of the paraganglioma volume was noted after a factional dose ≤2 Gy and a total dose >40 Gy.

Morphological MRI features as prognostic indicators in brain metastases

BackgroundStereotactic radiotherapy is the preferred treatment for managing patients with fewer than five brain metastases (BMs). However, some lesions recur after irradiation. The purpose of this study was to identify patients who are at a higher risk of failure, which can help in adjusting treatments and preventing recurrence.MethodsIn this retrospective multicenter study, we analyzed the predictive significance of a set of interpretable morphological features derived from contrast-enhanced (CE) T1-weighted MR images as imaging biomarkers using Kaplan–Meier analysis. The feature sets studied included the total and necrotic volumes, the surface regularity and the CE rim width. Additionally, we evaluated other nonmorphological variables and performed multivariate Cox analysis.ResultsA total of 183 lesions in 128 patients were included (median age 61 [31–95], 64 men and 64 women) treated with stereotactic radiotherapy (57% single fraction, 43% fractionated radiotherapy). None of the studied variables measured at diagnosis were found to have prognostic value. However, the total and necrotic volumes and the CE rim width measured at the first follow-up after treatment and the change in volume due to irradiation can be used as imaging biomarkers for recurrence. The optimal classification was achieved by combining the changes in tumor volume before and after treatment with the presence or absence of necrosis (p < < 0.001).ConclusionThis study demonstrated the prognostic significance of interpretable morphological features extracted from routine clinical MR images following irradiation in brain metastases, offering valuable insights for personalized treatment strategies.

Fast model calibration for predicting the response of breast cancer to chemotherapy using proper orthogonal decomposition

Constructing digital twins for predictive tumor treatment response models can have a high computational demand that presents a practical barrier for their clinical adoption. In this work, we demonstrate that proper orthogonal decomposition, by which a low-dimensional representation of the full model is constructed, can be used to dramatically reduce the computational time required to calibrate a partial differential equation model to magnetic resonance imaging (MRI) data for rapid predictions of tumor growth and response to chemotherapy. In the proposed formulation, the reduction basis is based on each patient’s own MRI data and controls the overall size of the “reduced order model”. Using the full model as the reference, we validate that the reduced order mathematical model can accurately predict response in 50 triple negative breast cancer patients receiving standard of care neoadjuvant chemotherapy. The concordance correlation coefficient between the full and reduced order models was 0.986 ± 0.012 (mean ± standard deviation) for predicting changes in both tumor volume and cellularity across the entire model family, with a corresponding median local error (inter-quartile range) of 4.36 % (1.22 %, 15.04 %). The total time to estimate parameters and to predict response dramatically improves with the reduced framework. Specifically, the reduced order model accelerates our calibration by a factor of (mean ± standard deviation) 378.4 ± 279.8 when compared to the full order model for a non-mechanically coupled model. This enormous reduction in computational time can directly help realize the practical construction of digital twins when the access to computational resources is limited.

AB052. A multicenter prospective exploratory phase II study of neoadjuvant bevacizumab for newly diagnosed malignant glioma.

We conducted a multicenter study for neoadjuvant bevacizumab (neoBev) for newly diagnosed glioblastoma (nGB). In this study, median overall survival (mOS) related to radiological response, of which reliability as a prediction of overall survival (OS) was explored. A total of 15 patients with nGB were enrolled, and given ring enhancement and perifocal edema on magnetic resonance imaging (MRI). Two weeks after neoBev, the tumor volumes on T1 weighted image with contrast medium (T1CE) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev, surgery was performed. Clinical outcomes including mOS as well as the safety of neoBev were evaluated. Severe adverse events were observed in two of 15 patients as one postoperative hematoma and one wound infection. The average volume decrease rates on T1CE and FLAIR were -37% and -54%, respectively. The decrease rate on T1CE was not correlated with that on FLAIR. Based on MRI, good (GR) and poor responders (PR) on T1CE were defined as more or less of the average volume reduction rate, respectively. In addition, there was a case with discordance in tumor volume changes between T1CE and FLAIR. And OS in a discordant case was 20.4 months, which was not unfavorable. mOS of GR and PR on T1CE were 19.8 and 12.9 months, respectively. In contrast, mOS of GR and PR on FLAIR were 16.0 and 17.0 months, respectively. Preoperative neoBev was confirmed a safe procedure. mOS in the present cohort was not significantly prolonged. Early tumor volume regression on T1CE but not FLAIR after neoBev therapy has a significant prognostic indicator for mOS in nGB.

Synergistic antitumor activity of baicalein combined with almonertinib in almonertinib-resistant non-small cell lung cancer cells through the reactive oxygen species-mediated PI3K/Akt pathway.

Almonertinib is an important third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) exhibiting high selectivity to EGFR-sensitizing and T790M-resistant mutations. Almonertinib resistance is a major obstacle in clinical use. Baicalein possesses antitumor properties, but its mechanism of antitumor action against almonertinib-resistant non-small cell lung cancer (NSCLC) remains unelucidated. CCK-8 assay was used to examine the survival rate of H1975/AR and HCC827/AR cells following treatment for 24h with different concentrations of baicalein, almonertinib or their combination. The changes in colony formation ability, apoptosis, and intracellular reactive oxygen species (ROS) levels of the treated cells were analyzed using colony formation assay and flow cytometry. Western blotting was performed to detect the changes in protein expressions in the cells. The effects of pre-treatment with NAC on proliferation, apoptosis, and PI3K/Akt signaling pathway were observed in baicalein- and/or almonertinib-treated cells. A nude mouse model bearing subcutaneous HCC827/AR cell xenograft were treated with baicalein (20mg/kg) or almonertinib (15mg/kg), and the tumor volume and body mass changes was measured. Both baicalein and almonertinib represses the viability of HCC827/AR and H1975/AR cells in a concentration-dependent manner. Compared with baicalein or almonertinib alone, the combined application of the two drugs dramatically attenuates cell proliferation; triggers apoptosis; causes cleavage of Caspase-3, PARP, and Caspase-9; downregulates the protein expressions of p-PI3K and p-Akt; and significantly inhibits tumor growth in nude mice. Furthermore, baicalein combined with almonertinib results in massive accumulation of reactive oxygen species (ROS) and preincubation with N-acetyl-L-cysteine (ROS remover) prevents proliferation as well as inhibits apoptosis induction, with partial recovery of the decline of p-PI3K and p-Akt. The combination of baicalein and almonertinib can improve the antitumor activity in almonertinib-resistant NSCLC through the ROS-mediated PI3K/Akt pathway.

Role of adaptive radiotherapy during concomitant chemoradiotherapy for limited-stage small-cell lung cancer.

Tumor shrinkage is frequently observed during conventionally fractionated chemoradiotherapy for limited-stage small-cell lung cancer (SCLC). The specific goals of this study are to evaluate the gross tumor volume (GTV) changes due to treatment-induced tumor reduction during the course of radiotherapy (RT) and to examine its potential use in adaptive radiotherapy (ART) for tumor dose escalation or normal tissue sparing in patients with SCLC. A total of 10 patients with SCLC eligible for chemoradiotherapy underwent computed tomography (CT) scan after Fractions 13 and 23 (at nominal doses of 23.4 Gy and 41.4 Gy, respectively). The GTV was delineated on the repeat CT scans, and two treatment plans were generated with or without adaptation to tumor shrinkage during RT for each patient. Dosimetric and volumetric analyses were performed. The average GTV reduction observed over 13 fractions was 58.5% (range: 13.2%-92.3%; P < 0.001) and over 23 fractions was 70% (range: 36.9%-84.5%; P < 0.001). Compared with the plan without adaptation, ART resulted in mean lung dose relative decreases of 8.7%, mean lung volume receiving ≥20 Gy relative decreases of 5%, mean lung volume receiving ≥5Gy relative decreases of 10%, mean medulla spinalis dose relative decreases of 21 cGy, mean esophagus volume receiving ≥50 Gy relative decreases of 19%, and mean heart volume receiving ≥42 Gy relative decreases of 13%. The benefits of ART were the greatest for tumor volumes ≥30 cm3 and are directly dependent on GTV reduction during treatment. ART for SCLC achieved a significant benefit in terms of organ at risk (OAR) and dose escalation.

Establishment of an animal model of immune-related adverse events induced by immune checkpoint inhibitors.

Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment. However, it can also cause immune-related adverse events (irAEs). This study aimed to develop a clinically practical animal model of irAEs using BALB/c mice. Subcutaneous tumors of mouse breast cancer 4T1 cells were generated in inbred BALB/c mice. The mice were treated with programmed death-1 (PD-1) and cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors once every 3 days for five consecutive administration cycles. Changes in tumor volume and body weight were recorded. Lung computed tomography (CT) scans were conducted. The liver, lungs, heart, and colon tissues of the mice were stained with hematoxylin-eosin (H&E) staining to observe inflammatory infiltration and were scored. Serum samples were collected, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of ferritin, glutamic-pyruvic transaminase (ALT), tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-6 (IL-6). Mouse liver and lung cell suspensions were prepared, and changes in macrophages, T cells, myeloid-derived suppressor cells (MDSCs), and regulatory (Treg) cells were detected by flow cytometry. Mice treated with PD-1 and CTLA-4 inhibitors showed significant reductions in tumor volume and body weight. The tissue inflammatory scores in the experimental group were significantly higher than those in the control group. Lung CT scans of mice in the experimental group showed obvious inflammatory spots. Serum levels of ferritin, IL-6, TNF-α, IFN-γ, and ALT were significantly elevated in the experimental group. Flow cytometry analysis revealed a substantial increase in CD3+T cells, Treg cells, and macrophages in the liver and lung tissues of mice in the experimental group compared with the control group, and the change trend of MDSCs was opposite. The irAE-related animal model was successfully established in BALB/c mice using a combination of PD-1 and CTLA-4 inhibitors through multiple administrations with clinical translational value and practical. This model offers valuable insights into irAE mechanisms for further investigation.