Increase In Tumor Volume Research Articles

MR Electrical Properties Tomography (MREPT) at 9.4T to Assess Treatment Response of Choline Kinase Inhibition on GL261 Glioblastoma

Abstract AIMS To monitor changes in tissue-conductivity based MR parameter in response to JAS239 treatment in preclinical glioblastoma model. METHOD C57BL/6 mice were injected intracranially with 5x105 GL261 glioblastoma cells and tumours were observed on T2 weighted MRI. Mice were imaged on day 0 (baseline), day 3 , 6 of treatment and post-treatment day 10. For MREPT, multi-slice-multi-echo sequence was used. Laplacian algorithm was employed to obtain the phase-based MREPT image reconstruction. RESULTS Saline treated mice showed a greater increase in tumour volume compared to JAS239 treated animals with respect to baseline. Percentage changes in conductivity values with respect to baseline from saline treated mice were compared to JAS239 treated animals. JAS239 group showed a slight increase in mean conductivity on day 3 and 6 compared to saline group. There were no statistically (p> 0.05) significant differences between the two groups. 4 days after treatment completion (Day10), the mean of conductivity values of JAS239 treated animals compared to saline treated animals showed no statistically (p> 0.05) significant differences. These results may indicate that GL261 tumour model is treatment resistant. Our findings agree with a study conducted by Bhaduri et al, where tumours were treated with JAS239. CONCLUSION EPT technique provides unique data on tissue conductivity which can be used to improve the assessment of treatment response in glioblastoma. MREPT parameter might be insensitive to evaluate choline kinase inhibitor. For future work, this technique can be incorporated into multiparametric MRI to complement diffusion and perfusion-weighted imaging of assessing treatment response in glioblastoma.

Active Surveillance of Papillary Thyroid Cancer: Frequency and Time Course of the Six Most Common Tumor Volume Kinetic Patterns.

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

NEIL3 promotes hepatoma epithelial-mesenchymal transition by activating the BRAF/MEK/ERK/TWIST signaling pathway.

Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland.

Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis.

Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells.

P18.10.B Natural history of meningiomas - a serial volumetric analysis of 240 tumors

Abstract Background The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, we aimed to create the basis for practicable clinical pathways for the management of these tumors. Material and Methods We volumetrically analyzed meningiomas radiologically diagnosed at our institution between 2003 and 2015. For this purpose, we used exclusively thin-layered MR images (i.e. ≤ 2mm slice thickness). The primary endpoint was tumor growth defined as a 14.35% increase in tumor volume. We identified predictive clinical and radiological characteristics and used the significant variables from a multivariable regression model to construct a decision tree based on the exhaustive Chi-squared Automatic Interaction Detection (exhaustive CHAID) algorithm. Results Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR=0.979 (0.958-1.000), p=0.048) and presence of calcification (OR=0.442 (0.224-0.872), p=0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR=4.415 (2.056-9.479), p&amp;lt;0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2-signal intensity and presence of calcifications with a proportion of growing tumors of 34.1% in the low risk group, 60.0% in the intermediate risk group and 80.2% in the high risk group. Median tumor volume doubling time (Td) was 185.7 months in the low risk, 100.1 months in the intermediate risk and 51.7 months in the high risk group (p&amp;lt;0.001). While 0% of meningiomas in the low and intermediate risk group had a Td of ≤12 months, 8.9% in the high risk group did so (p=0.021). Conclusion Most meningiomas demonstrated growth during follow-up. The presence or absence of calcifications and the signal intensity on T2-weighted imaging allow a practical and simple stratification of meningiomas into low, intermediate and high risk tumors. Small tumors in the low or intermediate risk categories can be monitored with longer follow-up intervals, whereas in the high risk category proactive management decisions can be justified.

Growth risk classification and typical growth speed of convexity, parasagittal, and falx meningiomas: a retrospective cohort study.

Meningiomas are the most common primary intracranial tumors, and their clinical and biological characteristics vary by location. Convexity, parasagittal, and falx meningiomas account for approximately 50%-65% of intracranial meningiomas. Focusing only on these locations, the aim of this study was to determine the typical speed of tumor growth, to assess the growth risk, and to show the possible tumor volume that many lesions can reach after 5 years. Patients with radiologically suspected convexity, parasagittal, or falx meningiomas at the authors' institution were studied retrospectively. The relative growth rate (RGR) and annual volume change (AVC) were calculated from MRI at more than 3-month intervals. Based on sex, age, and signal intensity on T2-weighted MRI, the cases were classified into three groups: extremely high-growth, high-growth, and low-growth groups. The data of 313 cases were analyzed. The median RGR and AVC for this entire cohort were 6.1% (interquartile range [IQR] 2.4%-16.0%) and 0.20 (IQR 0.04-1.18) cm3/year, respectively. There were significant differences in sex (p = 0.018) and T2-weighted MRI signal intensity (p < 0.001) for RGR, and T2-weighted MRI signal intensity (p < 0.001), tumor location (p = 0.025), and initial tumor volume (p < 0.001) for AVC. The median RGR and AVC were 17.5% (IQR 8.3%-44.1%) and 1.05 (IQR 0.18-3.53) cm3/year, 8.2% (IQR 2.9%-18.6%) and 0.33 (IQR 0.06-1.66) cm3/year, and 3.4% (IQR 1.2%-5.8%) and 0.04 (IQR 0.02-0.21) cm3/year for the extremely high-growth, high-growth, and low-growth groups, respectively, with a significant difference among the groups (p < 0.001). A 2.24-times, or 5.24 cm3, increase in tumor volume over 5 years was typical in the extremely high-growth group, whereas the low-growth group showed little change in tumor volume even over a 5-year follow-up period. For the first time, the typical speed of tumor growth was calculated, focusing only on patients with convexity, parasagittal, and falx meningiomas. In addition, the possible tumor volume that many lesions in these locations can reach after 5 years was shown based on objective indicators. These results may allow clinicians to easily detect lesions that require frequent follow-up or early treatment by determining whether they deviate from the typical range of the growth rate, similar to a growth chart for children.

1224P Final analysis of clinical outcomes in the DELIVER trial: Observational study of nivolumab treatment in advanced gastric cancer (JACCRO GC-08)

We conducted a prospective observational study to evaluate the real-world effectiveness of nivolumab (Nivo) monotherapy in previously treated advanced gastric cancer (GC) (Gastric Cancer 2021). Pre-planned 2-year final analysis was performed to confirm survival and tumor behavior of Nivo treatment. The DELIVER trial enrolled 501 patients (pts) with advanced gastric or GEJ adenocarcinoma treated with Nivo alone from Mar 2018 to Aug 2019 (UMIN000030850). Primary endpoint was overall survival (OS), secondary endpoints were response rate (RR), disease control rate, progression-free survival (PFS), tumor regression rate (TRR) / tumor progression rate (TPR) at 1st evaluation, tumor growth rate (TGR) which was calculated as a percentage increase in tumor volume during 1 month, and safety. 487 pts were evaluable (median age 70y [26-90], 71% male, ECOG PS0/1/2 42/44/14%, No. of prior regimen 1/2/≥3 2/39/59%, 42% pts with ascites). Median OS was 5.8 months (m) (95%CI 5.3-6.9) with 1y-survival rate of 30% and 2y-survival rate of 14%, and median PFS was 1.8 m (95%CI 1.7-2.0). The RR was 14.5% in 282 pts with measurable lesions. The sub-group analysis of OS by clinical factors was the following: male/female; 6.5/5.1m (p=0.001), PS0/1/2; 8.7/5.6/2.5m(p<0.001), tub/por or sig; 8.1/5.2m (p<0.001), albumin<3.5/≥3.5; 4.2/8.8m (p<0.001), and with/without peritoneal metastases; 4.9/8.4m (p<0.001). Median OS and PFS by tumor response (CR or PR/SD/PD) were 32.8/11.4/4.2m and 13.9/11.7/3.8/1.5m, respectively. In 147 elderly pts aged ≥75-y, RR, PFS, and OS were 14.3%, 2.0m, and 6.5m, respectively, and the safety profile was comparable to pts aged <75-y. Median TRR and TPR were 20.0% and 26.7%, in 75 pts with tumor regression and 185 pts with tumor progression, respectively. The TGR decreased from 3.8 to 2.8 after Nivo introduction. There were no associations between PFS/OS and tumor burden or TGR at baseline before Nivo. The final analysis confirmed the efficacy of Nivo for advanced GC pts in clinical practice, with comparable outcomes in the elderly pts. Nivo was effective regardless of tumor burden or TGR at pre-treatment in advanced GC.

The longitudinal volumetric response of vestibular schwannomas after Gamma Knife radiosurgery.

Gamma Knife radiosurgery (GKRS) is an effective treatment for vestibular schwannomas (VSs) and has been used in > 100,000 cases worldwide. In the present study the authors sought to define the serial volumetric tumor response of Koos grade I-IV VS after radiosurgery. A total of 201 consecutive VS patients underwent GKRS at a single institution between 2015 and 2019. All patients had a minimum follow-up of 18 months and at least 2 interval postprocedure MRI scans. The contrast-enhanced tumor volumes were contoured manually and compared between pre- and post-GKRS imaging. The percentages of tumor volume change at 18 months (short-term follow-up) and up to 5 years after GKRS (long-term follow-up) were compared with the baseline tumor volume. An increase of 20% was considered a significant increase of tumor volume. Trends of tumor volume over time were assessed with linear models using time as a continuous variable. A test for linear trend was evaluated according to the initial Koos tumor classification. Koos grade II VS was the most frequently occurring tumor (n = 74, 36.8%), followed by grade III (n = 57, 28.4%), grade I (n = 41, 20.4%), and grade IV (n = 29, 14.4%). The mean tumor volume at the time of GKRS was 2.12 ± 2.82 cm3 (range 0.12-18.77 cm3) and the median margin dose was 12 Gy. Short-term follow-up revealed that tumor volumes transiently increased in 34.2% and 28.4% of patients at 6 and 18 months, respectively, regardless of Koos grade. Linear regression analysis of Koos grade II, III, and IV tumors showed a significant longitudinal volume decrease on long-term follow-up. At last follow-up (median 30 months, range 18-54 months), 19 patients (9.4%) showed a persistent increase of tumor volume. Five patients received additional management after GKRS. Although selected VS patients demonstrate an early and measurable transient volumetric increase after GKRS, > 90% have stable or reduced tumor volumes over an observed period of up to 5 years. Volumetric regression is most pronounced in Koos grade II, III, and IV tumors and may not be fully detectable until 3 years after GKRS.

Clinical performance evaluation of O-Ring Halcyon Linac: A real-world study.

BACKGROUNDRadiation therapy, especially the development of linear accelerators, plays a key role in cancer management. The fast-rotating coplanar O-ring Halcyon Linac has demonstrated many advantages. The previous literature has mainly focused on the machine parameters and plan quality of Halcyon, with a lack of relevant research on its clinical application.AIMTo evaluate the clinical performance of the O-ring Halcyon treatment system in a real-world application setting.METHODSData from sixty-one patients who were treated with the Halcyon system throughout the entire radiotherapy process in Peking Union Medical College Hospital between August 2019 and September 2020 were retrospectively reviewed. We evaluated the target tumour response to radiotherapy and irradiation toxicity from 1 to 3 mo after treatment. Dosimetric verification of Halcyon plans was performed using a quality assurance procedure, including portal dosimetry, ArcCHECK and point dose measurements for verification of the system delivery accuracy.RESULTSOf the 61 patients in the five groups, 16, 12, 7 and 26 patients had complete response, partial response, progressive disease and stable disease, respectively. No increase in the irradiated target tumour volume was observed when separately evaluating the local response. Regarding irradiation toxicity, no radiation-induced deaths were observed. Thirty-eight percent (23/61 patients) had no radiation toxicity after radiotherapy, 56% (34/61 patients) experienced radiation toxicity that resolved after treatment, and 6% (4/61 patients) had irreversible adverse reactions. The average gamma passing rates with a 2% dose difference and 2-mm distance to agreement for IMRT/VMAT/SRT plans were ArcCHECK at 96.4% and portal dosimetry at 96.7%, respectively. All of the validated clinical plans were within 3% for point dose measurements, and Halcyon’s ArcCHECK demonstrated a high pass rate of 99.1% ± 1.1% for clinical gamma passing criteria of 3%/3 mm.CONCLUSIONThe O-ring Halcyon Linac could achieve a better therapeutic effect on the target volume by providing accurate treatment delivery plans with tolerable irradiation toxicity.

Ketogenic Diet Promotes Epithelial Ovarian Cancer Progression and Alters Tumor Gene Expression in-vivo (104)

<b>Objectives:</b> The ketogenic diet (KD) is hypothesized to impact tumor progression indirectly through altering the immune system as well as directly at the cellular level. Our studies were designed to assess changes in tumor resident immune cells and tumor gene expression in relation to epithelial ovarian cancer (EOC) progression in KD-fed mice. <b>Methods:</b> ID8 EOC cells, syngeneic with C57Bl/6J mouse strain, transfected with luciferase (ID8-Luc), were injected and monitored for tumor development via imaging with an <i>in vivo</i> Imaging System (IVIS) intraperitoneal D-luciferin. Tumor-bearing mice were fed a KD (10% protein, 0% carbohydrates, 90% fat), high fat diet (HFD) (10% protein, 15% carbohydrates, 75% fat), or control diet (CD) (10% protein, 77% carbohydrates, and 13% fat) (<i>n</i>=10 mice per group). EOC tumor growth was monitored weekly, and tumor burden was determined based on total flux recorded in photons/second measured. At the endpoint, tumors were collected and processed for flow cytometry and RNAseq analysis. Single-cell dissociated tumors (Papain System) were stained with an immune targeted antibody panel and analyzed on the BD Cytek Aurora. RNA was isolated (Qiagen), and sequencing was performed. Statistical tests included analysis of variance (ANOVA), permutational multivariate analysis (PERMANOVA), linear regression, and Wilcoxon test; a p-value of <0.05 was considered statistically significant. <b>Results:</b> Throughout the study, KD-fed mice exhibited a statistically significant increase in tumor progression. We observed a 9.1-fold increase in tumor volume from baseline in the KD-fed group compared to HFD and CD-fed groups (9.1 vs 2.0 vs 3.1-fold, respectively, p<0.001). At the endpoint, tumor-associated macrophages (TAM) were significantly enriched and activated lymphoid cells (NK cells) were significantly diminished in the KD group (p<0.001). There was a trend toward increased M2:M1 polarization in KD-fed mice. However, there was no significant difference in Treg cells or activated CD8+ cells among diet groups. EOC tumors in KD-fed mice exhibited a significant decrease in differential gene expression on RNA seq compared to CD- and HFD-fed tumors, with no significant difference between CD- and HFD-fed groups at the gene expression level. Gene set enrichment analysis (GSEA) demonstrated that EOC tumors from KD-fed mice had enhanced angiogenesis, inflammatory response, and epithelial to mesenchymal transition (EMT) phenotype, as well as altered lipid metabolism. Specifically, an increase in lipid catalytic activity and catabolism and decrease in lipid synthesis were noted among KD-fed mice versus HFD-fed mice. <b>Conclusions:</b> KD induced tumor progression in our murine EOC model compared to HFD and CD. KD was associated with an increase in TAM and a decrease in activated NK cells consistent with a protumorigenic immune environment. KD-fed mice exhibited markedly increased alterations in angiogenesis, inflammation, and EMT pathways with enhanced lipid catabolic activity. Further testing of KD in human EOC cells is needed to clarify the <i>in-vivo</i> effect of KD on EOC growth.Fig. 1

Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non-small cell lung cancer patients with brain metastases.

Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations. Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses. The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97). Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.

Gene expression of Nectin-4 and its clinical significance in dogs with primary lung adenocarcinoma.

BackgroundCanine primary lung adenocarcinoma (CPLA) is suspected by radiography or computed tomography; however, since there are no tumour markers, early diagnosis is difficult, and the prognosis is poor due to increased tumour volume. Nectin‐4 has been reported to be expressed in human lung, ovarian, and pancreatic cancers and promotes tumour growth. It has been reported to be a tumour marker and prognostic factor, and oncolytic virotherapy is being investigated using nectin‐4 as a therapeutic target.ObjectivesThe purpose of this study was to investigate the expression of Nectin‐4 in CPLA and its clinical significance in dogs with pulmonary adenocarcinomas.MethodsThe relationships between Nectin‐4 expression and signalling, tumour volume, tumour weight, and prognosis were analyzed in 34 CPLA patients.ResultsThe expression of canine Nectin‐4 (high Nectin‐4) was found in 25 of 34 cases (73%), and Nectin‐4 expression levels did not show any significant associations with gender, body weight, and tumour stage. However, there was a significant positive correlation between Nectin‐4 expression and tumour volume (r = 0.623, p < 0.05) and tumour weight (r = 0.735, p < 0.05). Regarding prognosis, the median survival time was 427 days in high Nectin‐4 cases and 420 days in cases with no Nectin‐4 expression.ConclusionOur study demonstrated that Nectin‐4 is highly expressed in CPLA. In addition, nectin‐4 might be a tumour growth factor in CPLA and thus is a promising biomarker for CPLA. Further investigations on nectin‐4 in CPLA are warranted for its diagnosis and novel targets for oncolytic virotherapy.

VIPR1 promoter methylation promotes transcription factor AP-2α binding to inhibit VIPR1 expression and promote hepatocellular carcinoma cell growth in vitro

To explore the transcriptional regulation mechanism and biological function of low expression of vasoactive intestinal peptide receptor 1 (VIPR1) in hepatocellular carcinoma (HCC). We constructed plasmids carrying wild-type VIPR1 promoter or two mutant VIPR1 promoter sequences for transfection of the HCC cell lines Hep3B and Huh7, and examined the effect of AP-2α expression on VIPR1 promoter activity using dual-luciferase reporter assay. Pyrosequencing was performed to detect the changes in VIPR1 promoter methylation level in HCC cells treated with a DNA methyltransferase inhibitor (DAC). Chromatin immunoprecipitation was used to evaluate the binding ability of AP-2α to VIPR1 promoter. Western blotting was used to assess the effect of AP-2α knockdown on VIPR1 expression and examine the differential expression of VIPR1 in the two cell lines. The effects of VIPR1 overexpression and knockdown on the proliferation, cell cycle and apoptosis of HCC cells were analyzed using CCK8 assay and flow cytometry. We also observed the growth of HCC xenograft with lentivirus-mediated over-expression of VIPR1 in nude mice. Compared with the wild-type VIPR1 promoter group, co-transfection with the vector carrying two promoter mutations and the AP-2α-over-expressing plasmid obviously restored the luciferase activity in HCC cells (P < 0.05). DAC treatment of the cells significantly decreased the methylation level of VIPR1 promoter and inhibited the binding of AP-2α to VIPR1 promoter (P < 0.01). The HCC cells with AP-2α knockdown showed increased VIPR1 expression, which was lower in Huh7 cells than in Hep3B cells. VIPR1 overexpression in HCC cells caused significant cell cycle arrest in G2/M phase (P < 0.01), promoted cell apoptosis (P < 0.001), and inhibited cell proliferation (P < 0.001), while VIPR1 knockdown produced the opposite effects. In the tumor-bearing nude mice, VIPR1 overexpression in the HCC cells significantly suppressed the increase of tumor volume (P < 0.001) and weight (P < 0.05). VIPR1 promoter methylation in HCC promotes the binding of AP-2α and inhibits VIPR1 expression, while VIPR1 overexpression causes cell cycle arrest, promotes cell apoptosis, and inhibits cell proliferation and tumor growth.

The role of stereotactic radiosurgery in the management of petroclival meningioma: a systematic review.

Petroclival meningioma (PM) is a challenging neuro oncology case and stereotactic radiosurgery (SRS) is proposed as one treatment option. This systematic review aimed to examine the role of SRS in treating PM cases. We constructed a systematic review using the PRISMA guidelines using peer-reviewed English literature until 16 February 2022 from EuroPMC and PubMed. We used the terms petroclival meningioma, clival meningioma, apex petrous meningioma, spheno petroclival meningioma, stereotactic radiosurgery, radiosurgery, CyberKnife, Gamma Knife, linear accelerator, LINAC, and radiotherapy. 10 out of 266 studies were chosen for this systematic review, two of which are case reports. The study comprised 719 patients, 73.7% of whom were female (n = 530) and had a median age of 56.99years (18-90years). At the time of diagnosis, the median tumor volume was 6.07 cm3 (0.13-64.9 cm3). The tumors were frequently located near the petroclival junction (83.6%, n = 598). Following SRS, the median follow-up was 64.52months (3-252months). 46.5% of 719 PMs exhibited a decrease in tumor size. 46% and 7.5% showed no change and increase in tumor volume, respectively. At the last radiographic follow-up (7-21.2years), tumor control with a median of 98.8% (85-100%). Complications occurred in 6% of patients, with hydrocephalus (2.2%) as the prevalent complication.The use of SRS as a primary treatment for petroclival cases was not associated with increased complication rate RR 0.62 (95% CI [0.11, 3.59], p = 0.59) but statistically correlated with clinical failure clinical failure RR 0.56 (95% CI [0.32, 0.98], p = 0.04). We found a low number of complications following SRS intervention and has been effectively controlling tumor progression.

Abstract CT185: A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors

Abstract Introduction: The hallmark of sporadic desmoid tumors is increased nuclear β-catenin levels. Tegavivint (BC2059) selectively disrupts the interaction of β-catenin and TBL1/TBLR1 resulting in the specific degradation of nuclear β-catenin. The primary objective of this dose escalation study was to determine the maximum tolerated dose (MTD) and safety of tegavivint. Methods: This phase I study (NCT03459469) utilized an accelerated dose escalation phase for the initial two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D). The study included adult patients with desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery or desmoid symptoms), unresectable, and measurable via WHO criteria. Patients were excluded if they had familial adenomatous polyposis, metabolic bone disease, or history of significant pulmonary disease. Tegavivint was administered IV and dosed weekly (three weeks on, one week off) for up to two years. Results: A total of 17 patients with a median age of 41 years (range 18-66 years) were enrolled in six dose levels from 0.5 mg/kg to 5 mg/kg. The median time from initial desmoid diagnosis to study treatment was 2.1 years with a median of one prior systemic treatment (range 0-6). Prior radiation and/or surgical resection occurred in 42% (n=7). No dose-limiting toxicities were observed and the MTD was not determined. The RP2D was declared at 5 mg/kg based on achieving pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Tegavivint exposure (AUC and Cmax) correlated with total dose administered. Treatment-related adverse events (TRAEs) occurring in ≥20% of patients included fatigue (71%), nausea (35%), headache (35%), decreased appetite (24%) and dysgeusia (24%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, ALT increased, and headache occurred in 4 separate patients. No grade 4-5 adverse events were observed. One serious adverse event of Grade 2 infusion site extravasation occurred. Median time on study was 11.8 months, with a median relative dose intensity of 97%; one patient remains on study. Three (18%) partial responses (WHO criteria) were observed at 1, 4 and 5 mg/kg with a median duration of response of 329 days and all responses were ongoing. The clinical benefit rate was 82% (n = 14). Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 adverse events and no Grade 3 TRAEs occurring in more than one patient. The preliminary objective response rate of 18% in progressive desmoid tumors warrants continued research in the ongoing dose expansion portion of the study at the 5 mg/kg RP2D. Citation Format: Lee Cranmer, Albiruni A. RAZAK, Ravin Ratan, Edwin Choy, Suzanne George, David Liebner, David Stenehjem, Mrinal Gounder. A phase I dose escalation study of a tegavivint (BC2059) a first-in-class TBL1 inhibitor for patients with progressive, unresectable desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT185.

Abstract 3047: Investigating the interaction between the microbiome and mutant p53 in Li-Fraumeni Syndrome

Abstract Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome in which affected individuals are prone to developing a wide spectrum of malignancies. LFS is caused by germline mutations in the TP53 tumour suppressor gene. LFS patients develop cancer significantly earlier than the general population and may experience multiple malignancies in their lifetime. Studies have indicated that environmental influences like radiation exposure and tobacco smoke may further increase cancer risk in LFS patients. Currently, there is no cure for LFS, and screening for early tumour detection is the standard of care for LFS patients. Recently, microbes have been found to be involved in cancer development, progression, and treatment responsiveness. Moreover, microbes have anti-tumourigenic properties that can be harnessed for therapeutic intervention. The interaction between microbes and cancer can be through contact-dependent, contact-independent, and/or immunological interactions. Profiling the microbiome in the context of cancer may provide prognostic and/or diagnostic options for patients. However, interactions between the microbiome and mutant p53 in LFS has not been studied to date. We induced dysbiosis using a combination of antibiotics in LFS mice harbouring the heterozygous Trp53 R172H mutation. Following 7 days of treatment, we challenged mice with subcutaneous injections of the MC38 colon adenocarcinoma cell line. We observed an increase in tumour volume in LFS mice treated with antibiotics; this change was not observed in p53 wildtype mice. These findings highlight potentially unique interactions between mutant p53 and the microbiome which influence tumour growth in the context of LFS. We also found that LFS mice treated with metformin have smaller tumours compared to untreated mice. A particular genus of bacteria, Faecalibaculum sp., was found to be upregulated in a cohort of metformin treated mice, and the abundance of this bacterium is inversely proportional to tumour volume. Zagato et al. have shown that Faecalibaculum rodentium has anti-tumourigenic properties through the production of short-chain fatty acid (SCFA). Altogether, these observations suggest that microbes may influence tumour growth in LFS mice. The study of interactions between the microbiome and mutant p53 and the influence of these interactions on cancer development in LFS may, with further study, provide avenues of prognostic and/or diagnostic interest. Differences in the microbiome in cancer-affected and cancer-free LFS patients may also introduce the possibility to exploit the microbiome for treatment and/or preventative purposes in these patients. Citation Format: Noel Wei Ong, Camilla Maria Giovino, Nicholas William Fischer, Pamela Psarianos, David Malkin. Investigating the interaction between the microbiome and mutant p53 in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3047.

Abstract 6184: Kras Co-mutations lead to resistance to mutant TP53 targeted therapy in mouse models of spontaneous non-small cell lung cancer

Abstract Background: Lung cancer results in more than 131,000 deaths per year with estimated 236,000 new cases in 2021 in the United States. About 85% of lung cancers are non-small cell lung cancer (NSCLC). TP53 is an important tumor-suppressor and about 50% of human lung NSCLCs contain a mutant TP53. Targeting of mutant p53 is very limited due to the lack of drugs. PRIMA-1 is a first in class anti-mutant TP53 molecule with the ability to induce apoptosis by restoring the wild-type function of TP53 through covalently binding and modifying thiol groups in the central domain of the mutated protein. Recently, the FDA granted breakthrough therapy designation to the PRIMA-1 methylated analog, APR-246 in combination with azacytidine for the treatment of patients with myelodysplastic syndromes and a TP53 mutation. The major setback of targeted therapy today continues to be resistance. Herein, we report our findings related to resistance to PRIMA-1 targeted therapy in spontaneous P53 mutant driven NSCLC. Methods: We have previously reported the generation of a line of transgenic mice with a human mutant p53(273H) expressed in a lung-specific manner. Human mutant TP53 expression was regulated under the transcriptional control of the human surfactant protein C (SP-C) promoter. After the age of 12 months, the mice developed spontaneous lung adenocarcinomas. We treated SPC-p53-273H lung tumor mice via intraperitoneal injection (i.p) with PRIMA-1 at a dose of 100 mg/kg in 0.2 mL PBS every other day for two weeks. The tumors were identified using micro-computed tomography (micro-CT) system and pre-and post-treatment diameters were estimated based on the CT image. K-ras status was analyzed by PCR-based Sanger sequencing. Results: Of the 10 lung tumor-bearing mice treated with PRIMA-1, micro-CT derived sum of the largest diameters indicated that six mice (60%) experienced tumor volume reductions whereas four mice experienced tumor volume increase. Sequencing analysis showed five tumors contained K-ras mutations (two p.G12D, one p.G12F, one p.G12V and one p.Q61L). On average, lung tumor diameter had a 31% reduction post-treatment of PRIMA-1 for the lung tumors containing wild-type K-ras gene. Whereas it increased 18% on the average post-treatment of PRIMA-1 for the lung tumors containing a mutant K-ras gene. There is a significant difference statistically (p = 0.016) in the response to the treatment of PRIMA-1 between the mutant K-ras cohort and the wild-type K-ras cohort. Conclusion: PRIMA 1 therapy results in antitumor activity against P53 mutant lung tumors. However, the presence of K-ras co-mutation is a significant resistance factor. Combination of APR-246 and K-ras inhibitor therapy would be needed to overcome this resistance. Citation Format: David T. Costa, Shaylyn Grier, Melanie Perez, Li Gao, Miguel A. Villalona-Calero, Wenrui Duan. Kras Co-mutations lead to resistance to mutant TP53 targeted therapy in mouse models of spontaneous non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6184.

Primary tumor volume and prognosis for patients with p16-positive and p16-negative oropharyngeal squamous cell carcinoma treated with radiation therapy

BackgroundThe prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT).MethodsFive hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume.ResultsThe volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm3 increase in tumor volume was 2.3% (95% CI 0–4.9) for p16-positive and 1.3% (95% 0.3–2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume.ConclusionsOutcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.

The Significant Role of Tumor Volume on the Surgical Approach Choice, Surgical Complexity, and Postoperative Complications in Renal Cell Carcinoma With Venous Tumor Thrombus From a Large Chinese Center Experience.

ObjectiveTo explore the role of tumor volume (TV) on surgical approach choice, surgical complexity, and postoperative complications in patients with renal cell carcinoma (RCC) and inferior vena cava tumor thrombus.MethodFrom January 2014 to January 2020, we retrospectively analyzed the clinical data of 132 patients who underwent radical nephrectomy with inferior vena cava thrombectomy (RN-IVCT). Primary renal tumor volume (PRTV), renal vein tumor thrombus volume (RVTTV), inferior vena cava tumor thrombus volume (IVCTTV), and total tumor thrombus volume (TTTV) were measured with the help of an internationally recognized 3D volume measurement software. The patients were divided into three groups according to the tumor volume within the inferior vena cava (IVC). Group 1 included 48 patients with IVCTTV between 0 and 15 cm3 (36.6%), group 2 included 38 patients with IVCTTV between 16 and 30 cm3 (28%), and group 3 included 46 patients with IVCTTV above 30 cm3 (35%). The three IVCTTV groups, as well as four different volume groups, were compared in terms of surgical approach choice, surgical complexity, and postoperative complications. One-way ANOVA and a non-parametric test were used to compare the clinicopathological characteristics and distribution differences between the three groups.ResultThis study found significant differences among the three groups in the proportion of open surgery (P < 0.001), operation time (P < 0.044), intraoperative bleeding (P < 0.001), and postoperative complications (P < 0.001). When the four different volumes were compared, we found that for higher volumes IVCTTV and TTTV, open surgery is used more often compared with laparoscopic surgery (P < 0.001). In addition, with the increase in renal vein tumor thrombus volume, inferior vena cava tumor thrombus volume, and total tumor thrombus volume, the operation time also increased. Finally, with the increase in tumor thrombus volume and total tumor thrombus volume, the amount of intraoperative bleeding increased.ConclusionWith the increase in tumor volume, the proportion of open surgery and the incidence of postoperative complications increased. In addition, larger tumor volume prolongs operation time, increases intraoperative blood loss, and makes the surgery more complicated.

Experimental photodynamic therapy in the treatment of lung tumor.

e20515 Background: Study of the effect of photodynamic therapy (PDT) with Photoditazine using a high-energy laser at various periods after tumor transplantation on the dynamics of growth of experimental Lewis lung carcinoma in mice. Methods: The study included 176 male C57Bl6 mice weighing 18-20 g with Lewis lung carcinoma (LLC) transplanted subcutaneously. The animals received experimental PDT sequential overlapping of fields of influence (662 nm, 3 W, Photoditazine 25 mg/kg, 300 J/cm2). Animals received PDT on day 11 after the transplantation (experimental series I) and on day 21 (experimental series II). Experimental groups were divided in dependence on the exposure area (to the primary tumor -1gr, thorax (area of metastases)-2 gr and to both zones-3 gr). Animals with tumors without PDT were used as controls. Results: PDT with Photoditazine using the 3W laser stimulated the growth of primary tumor node. The degree of stimulation depended on the time of PDT. Increase in tumor sizes differed already on day 7 after PDT at various periods of the LCC growth. During PDT on the 11th day from the moment of tumor inoculation, the percentage of growth on the 7th day after the end of treatment was 60.7; 69.6 and 86.7% in groups 1, 2 and 3, respectively. In the groups of animals that underwent PDT on the 21st day of the growth of the grafted tumor on the 7th day after the end of treatment, the percentage of tumor growth was 20; 35.6 and 24.4% in groups 1, 2 and 3, respectively. Increase in the median survival was registered in experimental animals with PDT on 22.6% compared to control. A smaller increase in tumor volume was observed in animals receiving PDT to the primary tumor, and the group receiving therapy to both areas was in between. Conclusions: The study was shown that with an earlier initiation of PDT, a greater stimulation of tumor growth was revealed than with therapy at a later date. The revealed characteristics of the development of experimental LLC at PDT exposure allows further selection of parameters for photodynamic therapy regimens.