Larger Tumor Volume Research Articles

Combination Immunotherapy with Partial Versus Whole Tumor Radiotherapy in a Preclinical Melanoma Tumor Model

Partial tumor radiotherapy (PTRT) with immune checkpoint inhibition (ICI) is currently the subject of clinical trials and may be used clinically for large volume tumors when the full gross tumor volume (GTV) cannot be safely treated with full dose. PTRT delivers RT to a portion of the GTV, underdosing or not treating the remainder of the GTV, hypothesizing that ICI-mediated tumor infiltrating lymphocyte (TIL) infiltration will produce adequate disease control in un- or under-irradiated GTV. Standard treatment is whole tumor radiotherapy (WTRT), and potential differences in disease control between PTRT and WTRT with ICI have not been robustly assessed. We hypothesized that PTRT with ICI and WTRT with ICI will demonstrate similar tumor regression, and both RT regimens will demonstrate superior tumor regression as compared to ICI alone. B78 melanoma flank tumors were generated in C57B/L6 mice, with randomization at tumor size of 1 cm to experimental cohorts of PTRT + ICI and WTRT + ICI and control groups of no RT ± ICI. Custom lead shields were fabricated to deliver 16 Gy single fraction PTRT (50% tumor treatment) and WTRT, with dosimetry confirmation via radiochromic film. ICI was delivered through I.P. injection of murine anti-CTLA4 and anti-PD-L1 at days 0, 3, and 6 post-RT. Tumor regression was assessed via differences in tumor volume at ten days post completion of ICI, and mean cohort tumor volumes were compared with ANOVA (α <0.05). Variances between individual cohorts were assessed via t-test (α <0.05). Treatment cohorts demonstrated significant variance in tumor volume at ten days following treatment completion (p = 0.007, Table 1). WTRT + ICI demonstrated superior tumor regression when compared to PTRT + ICI (p = 0.006), ICI alone (p = 0.002), and control cohorts (p = 0.013). There was no difference in tumor regression between PTRT + ICI and ICI alone (p = 0.709), and PTRT + ICI did not achieve significant regression when compared to control (p = 0.083). Tumor regression did not differ between cohorts receiving no RT ± ICI (p = 0.103). Our results in this ICI resistant melanoma model demonstrated superior tumor regression with WTRT + ICI as compared to PTRT + ICI and ICI alone, suggesting that even with concurrent ICI, PTRT may not be sufficient treatment for melanoma. PTRT + ICI tumor regression was similar to ICI alone, suggesting that PTRT may not overcome immune resistance in the unirradiated tumor volume. Further investigation of optimal RT regimens to potentiate ICI response is warranted and correlative studies examining spatial immunomodulation in unirradiated and irradiated portions of the same tumor are underway.

Investigation on the physical dose filtered by linear energy transfer for treatment plan evaluation in carbon ion therapy.

Large tumor size has been reported as a predicting factor for inferior clinical outcome in carbon ion radiotherapy (CIRT). Besides the clinical factors accompanied with such tumors, larger tumors receive typically more low linear energy transfer (LET) contributions than small ones which may be the underlying physical cause. Although dose averaged LET is often used as a single parameter descriptor to quantify the beam quality, there is no evidence that this parameter is the optimal clinical predictor for the complex mixed radiation fields in CIRT. Purpose of this study was to investigate on a novel dosimetric quantity, namely high-LET-dose ( , the physical dose filtered based on an LET threshold) as a single parameter estimator to differentiate between carbon ion treatment plans (cTP) with a small and large tumorvolume. Ten cTPs with a planning target volume, (large) and nine with a (small) were selected for this study. To find a reasonable LET threshold ( ) that results in a significant difference in terms of , the voxel based normalized high-LET-dose ( ) distribution in the clinical target volume (CTV) was studied on a subset (12 out of 19 cTPs) for 18 LET thresholds, using standard distribution descriptors (mean, variance and skewness). The classical dose volume histogram concept was used to evaluate the and distributions within the target of all 19 cTPs at the before determined . Statistical significance of the difference between the two groups in terms of mean and volume histogram parameters was evaluated by means of (two-sided) t-test or Mann-Whitney-U-test. In addition, the minimum target coverage at the above determined was compared and validated against three other thresholds to verify its potential in differentiation between small and large volumetumors. An of approximately was found to be a reasonable threshold to classify the two groups. At this threshold, the and were significantly larger ( ) in small CTVs. For the small tumor group, the near-minimum and median (and ) in the CTV were in average (0.31 ± 0.08) and (0.46 ± 0.06), respectively. For the large tumors, these parameters were (0.20 ± 0.01) and (0.28 ± 0.02). The difference between the two groups in terms of mean near-minimum and median ( ) was 2.7 Gy (11%) and 5.0 Gy (18%),respectively. The feasibility of high-LET-dose based evaluation was shown in this study where a lower was found in cTPs with a large tumor size. Further investigation is needed to draw clinical conclusions. The proposed methodology in this work can be utilized for future high-LET-dose basedstudies.

Abstract PO-005: Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head &amp; neck squamous cell carcinoma (HNSCC)

Abstract The project pursues clinical testing of a gene-based treatment for refractory malignancy of the head and neck. Background We are evaluating intratumoral nucleoside cleavage by E. coli purine nucleoside phosphorylase (PNP) as an experimental therapy for refractory solid tumors. The approach requires delivery of PNP transgene to tumor parenchyma followed by prodrug administration, and provides “bystander” killing by a very potent purine antimetabolite (F-Ade) generated intratumorally. F-Ade is 1,000-times more potent than fluorouracil, the chemotherapeutic produced by cytosine deaminase (CD; a first-generation construct used for tumor sensitization). PNP/F-Ade has been found to be superior to CD/fluorouracil by several laboratories. In a Phase 1 study (Rosenthal et al., Ann. Oncol.), antitumor activity was observed after IT injections of a recombinant adenovirus encoding PNP (Ad/PNP), followed by IV fludarabine phosphate (F-araAMP, a prodrug converted by PNP to F-Ade). Methods Patients in the present trial have RECIST 1.1 measurable HNSCC amenable to local injection and no other palliative treatment options. A single-arm protocol is being used to evaluate safety of repeat cycles of Ad/PNP and F-araAMP. Ad/PNP is injected intratumorally twice on Day 1 and once on Day 2, followed by infusion of F-araAMP on Days 3, 4, and 5 every 4 weeks for up to 5 cycles. Results Eight patients have been enrolled to date. There have been no dose limiting toxicities, no serious adverse events (SAEs) definitively attributable to treatment, and no AEs above grade 3 severity. Up to five cycles of Ad/PNP treatment have been administered without limiting sequelae. Intratumoral expression of PNP transgene by RT-PCR has been established in treated tumors. Other correlative endpoints are in process and will be discussed. One patient exhibited tumor volume reduction by approximately 21% (as judged by CT imaging) and did not increase during five months of treatment, consistent with clinically stable disease. Two other patients completed three months of Ad/PNP with stable disease by RECIST criteria during the treatment period. Another patient’s tumor (largest dimension 3.1 cm) demonstrated 25% decrease after one treatment cycle. Challenges have included: 1) complexity of distribution of agent into large volume tumors (e.g., &amp;gt;100 ml) with small volume of Ad/PNP, and 2) acute swelling of tumor tissue following intratumoral virus injection in two patients, consistent with inflammatory response and/or disease progression. Conclusions Administration of Ad/PNP is safe and feasible. Injections of large volume tumors remains a challenge. The strategy is also being considered for earlier-stage HNSCC with less tumor burden, including a role similar to neoadjuvant or cytoreductive radiotherapy in combination with checkpoint blockade inhibition. A muti-center trial is planned to define MTD and feasibility in smaller tumors. Citation Format: A. Dimitrios Colevas, Eric J. Sorscher, William B. Parker, Roan Courtney Raymundo, Jeong S. Hong, Regina Rab, Camilo Henao, Nikki Schmitt, Madison Stallings, Kelly T. McKee, Eben Rosenthal, Joseph Curry. Phase 1/2 study of Ad/PNP with fludarabine for the treatment of head &amp; neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-005.

Association of clinical characteristics and recurrence of conventional colorectal adenomas with patient age: a single-center study.

We performed a clinical study comparing early-onset and late-onset conventional colorectal adenomas (CCRAs) since little is known about the differences in their characteristics. Pearson's chi-square test and the Kruskal‒Wallis test were used to compare basic information. MCAR tests and multiple imputation were performed to complete missing values. Multivariate logistic analysis and propensity score matching were used to identify the risk factors for recurrence. We included 2793 patients (688 with early-onset CCRAs and 2105 with late-onset CCRAs) from January 2017 to December 2021. Patients with early-onset CCRAs had higher levels of Hb, ALB, and triglycerides but lower HDL levels and N/L ratios. Moreover, we found that more early-onset CCRAs were in the left colon than late-onset CCRAs, and the size of early-onset CCRAs was larger. Early-onset CCRAs tended to lack pedicles compared to late-onset CCRAs. Additionally, the ratio of EMR and APC in early-onset CCRAs was higher than that in late-onset CCRAs, and the ratio of ESD and surgery for late-onset CCRAs was higher. We found that age ≥ 50years, abnormal vessels, drinking alcohol, and DB and ALB levels may be risk factors for recurrence, while the LDL level may be a protective factor. Finally, analysis of cumulative recurrence rates after PSM showed that patients with late-onset CCRAs exhibited higher recurrence rates (P < 0.05). Compared with late-onset CCRAs, early-onset CCRAs were associated with higher triglyceride levels, lower HDL levels, and larger tumor volumes. Age ≥ 50years, abnormal vessels, alcohol consumption, and DB and ALB levels were independent risk factors for recurrence of CCRAs.

P11.74.A EXPERIENCE OF PREOPERATIVE GAMMA KNIFE RADIOSURGERY FOR RECURRENT BRAIN METASTASES

Abstract BACKGROUND Resection of brain metastases (BM) without additional radiation therapy yields a high local failure rate. Surgical resection of newly diagnosed BM combined with post-operative stereotactic radiosurgery (SRS) to reduce the risk of a local recurrence is an accepted and effective treatment option. Drawbacks of postoperative SRS include uncertainty in target delineation, potential delay in the administration of SRS and intraoperative risk of tumor spillage. Preoperative SRS might address these potential drawbacks. We present our experience with preoperative Gamma Knife radiosurgery (GKRS) for recurrent BM. MATERIAL AND METHODS Data of patients with recurrent BM treated with GKRS followed by surgical resection between June 2019 and June 2021 at the Elisabeth-TweeSteden Hospital Tilburg were retrospectively collected. Surgery was necessary according to the multidisciplinary team because of mass effect, a symptomatic lesion or a large tumor volume not eligible for salvage stereotactic radiosurgery. Pre-operative SRS was performed with GKRS followed by surgery within 24 hours. All patients had follow-up appointments with MRI scan as long as clinical meaningful. In case of new intracranial disease new treatment was offered if appropriate. Descriptive analyses were used to give an overview of the patient characteristics. Kaplan-Meier curves were used to analyze overall survival. RESULTS 25 patients (male 8, female 17; median age 64 years (range 20-79 years)) underwent preoperative GKRS for recurrent brain metastases. Most patients were previously treated with GKRS (76%) or SRS (24%). Most patients had non-small cell lung cancer (44%), followed by breast (12%), small cell lung cancer (12%), and melanoma (12%). The median overall survival was 18.5 months (95% CI, 4.9 to 32.1 months). Eight patients (32%) had (multiple) surgical complications, three of these patients died due to the postoperative complications. Twelve patients (48%) developed a local recurrence. The median time to local recurrence was 6.9 months (95% CI, 4.7 to 9.1months). Of the 16 patients with a subtotal resection, 10 patients developed a local recurrence, with 6 recurrences at the site of the macroscopic residual tumor. Two patients (8%) developed leptomeningeal disease at 2.8 months and 3.9 months. Two patients (8%) developed new brain metastases (distant failure) at 5.4 months and 23.8 months. CONCLUSION Pre-operative radiosurgery was well tolerated in a group of patients with recurrent BM who were eligible for surgery. Larger series are needed to perform multivariate analyses on predictors of local recurrence in order to evaluate for which patients this treatment option is best suited.

P01.08.B MENTAL FATIGUE IN PATIENTS WITH LOW-GRADE GLIOMA: ASSOCIATIONS WITH NEUROCOGNITIVE FUNCTIONING AND TUMOR CHARACTERISTICS

Abstract BACKGROUND Fatigue is a frequent consequence of low-grade glioma (LGG), but the causes are still barely understood. Specifically mental fatigue might be related to cognitive impairment such as mental slowness and decreased attention. Also, patients with greater tumor volumes or tumors in certain locations (such as the frontal cortex) might have more cognitive impairments and experience more fatigue. The aim of the present study was twofold: (1) to examine the relationship between mental fatigue and information processing speed and complex attention and (2) to investigate the associations between mental fatigue and tumor volume and location in patients with LGG. MATERIAL AND METHODS 124 patients with LGG (IDH mutated astrocytoma and oligodendroglioma grade 2 and 3) were included before the start of proton therapy. Different facets of fatigue, including mental fatigue, were measured after surgery, with a multidimensional fatigue scale, the Dutch Multifactor Fatigue Scale (DMFS). The Vienna Test System was used to examine simple information processing speed, response inhibition, and divided attention. Tumor location and tumor volume (radiation target volume) were scored on the pre-radiotherapy MRI scan. Descriptive statistics, Spearman’s correlations, and between group comparisons were performed. RESULTS 41% of patients with LGG reported severe mental fatigue. No significant differences were found in mean performance on simple information processing speed, response inhibition and divided attention between severely mental fatigued patients and non-severely mental fatigued patients. However, the percentage of patients with impaired divided attention was significantly higher in the severely mental fatigued group (39%) compared to the non-severely mental fatigued group (16.2%), χ2 = 7.6, p &amp;lt; 0.05. No significant relationships were found between mental fatigue and tumor volume and location. Also, tumor location was not related to neurocognitive functioning, but larger tumor volume was significantly associated with poorer performance on divided attention (r = -0.19, p &amp;lt; 0.05). CONCLUSION A high rate of mental fatigue was found in patients with LGG. Furthermore, a relationship between impaired divided attention and severe mental fatigue was found. This implies that patients may develop mental fatigue due to increased cognitive efforts to compensate for attentional deficits. This might be especially important in patients with larger tumors, considering the relationship between tumor volume and divided attention. The results stress the importance of neuropsychological assessment in this patient group before the start of adjuvant treatment, to timely offer individual rehabilitation.

Larger Tumor Volume is Associated with Visual Acuity Loss and Axonal Degeneration in Children with Optic Pathway Gliomas Secondary to Neurofibromatosis Type 1

Abstract BACKGROUND We investigated whether volumetric magnetic resonance imaging (MRI) measures of the anterior visual pathway (AVP) in optic pathway gliomas secondary to Neurofibromatosis type 1 (NF1-OPG) are associated with visual acuity (VA) loss and axonal loss, as measured using optical coherence tomography (OCT). METHODS Children with NF1-OPGs enrolled in a prospective study of VA and OCT measures of the circumpapillary retinal nerve fiber layer (cpRNFL) thickness were eligible if they had undergone 3-Tesla MRI that included a T1-weighted volumetric sequence. The linear dimension and volume of the optic nerves, chiasm and optic tracts were measured using our semi-automated algorithm. The combined volume of these components comprising the proximal AVP was used as a surrogate of total tumor burden. Regression models for VA and cpRNFL thickness were reported on a per-eye basis. RESULTS Fifty-two study eyes (26 children, mean 7.1 years) met inclusion criteria, of which 40% (N=21 eyes) had abnormal VA. In regression analysis, only total AVP volume demonstrated a significant relationship to axonal loss, such that for every 1 ml increase in AVP volume, cpRNFL declined by 5.4 microns (p = 0.01). Total AVP volume &amp;gt; 1.75 ml predicted both axonal loss and abnormal VA (positive predictive value of 83.3% and 70.8%, respectively; negative predictive value of 80.0% and 88.0%, respectively). CONCLUSIONS Volumetric measures of NF1-OPGs identified children with VA loss and axonal degeneration. Total tumor burden, as measured by AVP volume, had the strongest relationship with axonal injury. NF1-OPG volumetric measures may be helpful in making treatment decisions.

Leptomeningeal metastasis in patients with non-small cell lung cancer after stereotactic radiosurgery for brain metastasis.

Stereotactic radiosurgery (SRS) is an effective treatment for brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). However, factors associated with the development of post-SRS leptomeningeal metastasis (LM) remain unclear. The authors analyzed the incidence and risk factors of LM development in patients with NSCLC and BMs after SRS and examined the survival outcomes and prognostic factors after LM development. This retrospective study included patients with NSCLC treated with SRS for MRI-diagnosed BM from 2002 to 2021. The authors recorded various clinical and demographic data, including age, sex, tumor histology, molecular profile of tumors, extracranial disease status, previous craniotomy, Karnofsky Performance Status, systemic treatments, tumor volume, and number of BMs. The management and survival outcomes after LM diagnosis were also recorded. LM developed in 13.7% of patients with NSCLC and BMs after SRS treatment. Large initial tumor volume and more than 5 BM lesions, but not EGFR mutation status and post-SRS treatment, were associated with LM development after SRS. Multivariate analysis revealed that chemotherapy and targeted therapy after LM were associated with better survival in patients with LM after SRS. This study is the first to evaluate the risk factors for LM in a relatively large cohort of patients with NSCLC after SRS. In patients with BMs harboring risk factors for subsequent LM, such as initial tumor volume and number of metastatic lesions, aggressive therapies with high CNS penetrating ability should be considered.

Surgical approach for convexity meningiomas: An analysis of the preoperative clinical signs, radiological features and surgical outcomes of these tumors

BackgroundConvexity meningiomas (CM) can be successfully treated with neurosurgery. However, clinical complications due to CM have been reported. Moreover, systematic investigations of CM with respect to all relevant clinical factors are currently lacking. MethodsWe performed a systematic investigation in 210 patients with supratentorial CM considering all relevant clinical and radiological factors, with a follow-up time of 19.5 years. ResultsAmong 812 patients with intracranial meningiomas treated in our department (2003–2020), 28.2 % of intracranial meningiomas were located over the supratentorial convexity, and the patients had a median age of 62 years (95 % CI:59–64). The median follow-up was 30.4 months (95 % CI:21.6–37.1). Tumor-related symptoms were observed in 88.1 % of patients. The most common preoperative symptom was headache (28.1 %), followed by seizure (19.5 %). Symptomatic patients had significantly higher tumor volumes than asymptomatic patients (p = 0.0003; 24.5 cm3 and 6.98 cm3, respectively).Complete tumor resection was achieved in 92.9 % of patients. The most common postoperative complication was bleeding (7.1 %) in the approach area. Of all bleedings, only three were intracerebral hemorrhages and did not require surgical intervention. The second most common complication was postoperative seizure (4.7 %). The multiple logistic regression analyses showed that tumor volume (OR:1.007; 95 % CI:1.001–1.013; p = 0.02) and brain infiltration by the tumor (OR:1.961; 95 % CI:1.028–3.741; p = 0.04) had a significant impact on postoperative complications. The postoperative and final KPS scores significantly improved (p < 0.001). The tumor recurrence rate was 6.2 %, with a median time of 38 months. No surgery-related deaths occurred. ConclusionA large tumor volume and brain infiltration by the tumor were significant factors for postoperative complications. The clinical conditions significantly improved postoperatively and further during the follow-up period.

18F]FDG PET-MRI provides survival biomarkers in primary central nervous system lymphoma in the elderly: an ancillary study from the BLOCAGE trial of the LOC network.

Primary central nervous system lymphoma (PCNSL) incidence is rising among elderly patients, presenting challenges due to poor prognosis and treatment-related toxicity risks. This study explores the potential of combining [18F]fluorodeoxyglucose ([18F]FDG) PET scans and multimodal MRI for improving management in elderly patients with de novo PCNSL. Immunocompetent patients over 60years with de novo PCNSL were prospectively enrolled in a multicentric study between January 2016 and April 2021. Patients underwent brain [18F]FDG PET-MRI before receiving high-dose methotrexate-based chemotherapy. Relationships between extracted PET (metabolic tumor volume (MTV), sum of MTV for up to five lesions (sumMTV), metabolic imaging lymphoma aggressiveness score (MILAS)) and MRI parameters (tumor contrast-enhancement size, cerebral blood volume (CBV), cerebral blood flow (CBF), apparent diffusion coefficient (ADC)) and treatment response and outcomes were analyzed. Of 54 newly diagnosed diffuse large B-cell PCNSL patients, 52 had positive PET and MRI with highly [18F]FDG-avid and contrast-enhanced disease (SUVmax: 27.7 [22.8-36]). High [18F]FDG uptake and metabolic volume were significantly associated with low ADCmean values and high CBF at baseline. Among patients, 69% achieved an objective response at the end of induction therapy, while 17 were progressive. Higher cerebellar SUVmean and lower sumMTV at diagnosis were significant predictors of complete response: 6.4 [5.7-7.7] vs 5.4 [4.5-6.6] (p = 0.04) and 5.5 [2.1-13.3] vs 15.9 [4.2-19.5] (p = 0.01), respectively. Two-year overall survival (OS) was 71%, with a median progression-free survival (PFS) of 29.6months and a median follow-up of 37months. Larger tumor volumes on PET or enhanced T1-weighted MRI were significant predictors of poorer OS, while a high MILAS score at diagnosis was associated with early death (< 1year). Baseline cerebellar metabolism and sumMTV may predict response to end of chemotherapy in PCNSL. Tumor volume and MILAS at baseline are strong prognostic factors.

Low-Dose Radiosurgery for Brain Metastases in the Era of Modern Systemic Therapy.

Dose selection for brain metastases stereotactic radiosurgery (SRS) classically has been based on tumor diameter with a reduction of dose in the settings of prior brain irradiation, larger tumor volumes, and critical brain location. However, retrospective series have shown local control rates to be suboptimal with reduced doses. We hypothesized that lower doses could be effective for specific tumor biologies with concomitant systemic therapies. This study aims to report the local control (LC) and toxicity when using low-dose SRS in the era of modern systemic therapy. We reviewed 102 patients with 688 tumors managed between 2014 and 2021 who had low-margin dose radiosurgery, defined as ≤14 Gy. Tumor control was correlated with demographic, clinical, and dosimetric data. The main primary cancer types were lung in 48 (47.1%), breast in 31 (30.4%), melanoma in 8 (7.8%), and others in 15 patients (11.7%). The median tumor volume was 0.037cc (0.002-26.31 cm 3 ), and the median margin dose was 14 Gy (range 10-14). The local failure (LF) cumulative incidence at 1 and 2 years was 6% and 12%, respectively. On competing risk regression analysis, larger volume, melanoma histology, and margin dose were predictors of LF. The 1-year and 2-year cumulative incidence of adverse radiation effects (ARE: an adverse imaging-defined response includes increased enhancement and peritumoral edema) was 0.8% and 2%. It is feasible to achieve acceptable LC in BMs with low-dose SRS. Volume, melanoma histology, and margin dose seem to be predictors for LF. The value of a low-dose approach may be in the management of patients with higher numbers of small or adjacent tumors with a history of whole brain radio therapy or multiple SRS sessions and in tumors in critical locations with the aim of LC and preservation of neurological function.

Effect of Radiotherapy Dose on Outcome in Nonmetastatic Ewing Sarcoma

Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS. The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response. S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P=.42) and in the RT group 52.9%, 62.5%, and 70.3% (P=.63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P=.96; histologic response, P=.07; tumor volume, P=.50; dose, P=.10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P=.15; age, P=.08; sex, P=.40). In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.

SIRT4 is an independent prognostic factor in bladder cancer and inhibits bladder cancer growth by suppressing autophagy

BackgroundNucleosome-localized sirtuin 4 (SIRT4) was found to function as an oncogene and tumor suppressor gene in different tumors. However, the clinical significance of SIRT4 in bladder urothelial carcinoma (BLCA) has not been assessed, nor has the function of SIRT4 in BLCA been analyzed.MethodsIn this study, we assessed the levels of SIRT4 protein in BLCA tissues and its association with clinicopathological parameters and overall survival time of BLCA patients by immunohistochemical staining of tissue microarrays containing 59 BLCA patients. Then, we constructed BLCA cell lines (T24) with overexpression or interference of SIRT4 by lentiviral infection. The effects of SIRT4 on the proliferation, migration and invasive ability of T24 cells were investigated using cell counting kit-8 (CCK-8) assays, wound healing assays, and migration and invasion assays. Moreover, we also investigated the effect of SIRT4 on the cell cycle and apoptosis of T24 cells. Mechanistically, we explored the relationship between SIRT4 and autophagy and its role in the inhibition of BLCA.ResultsWe found by immunohistochemistry that SIRT4 protein levels were reduced in BLCA and that lower SIRT4 levels were associated with larger tumor volumes, later T-staging and later AJCC staging in BLCA patients and were an independent prognostic factor in BLCA patients. Overexpression of SIRT4 significantly inhibited the proliferative viability, scratch healing capacity, migratory capacity, and invasive capacity of T24 cells, while interference with SIRT4 had the opposite effect. Moreover, overexpression of SIRT4 significantly inhibited the cell cycle and increased the apoptosis rate of T24 cells. Mechanistically, SIRT4 inhibits BLCA growth by suppressing autophagic flow.ConclusionsOur study suggests that SIRT4 is an independent prognostic factor for BLCA and that SIRT4 plays a tumor suppressor role in BLCA. This suggests a potential target for SIRT4 in the diagnosis and treatment of BLCA.

Evaluation of local control strategies on patterns of treatment failure in patients with localized ewing sarcoma treated on AEWS1031: A report from the children’s oncology group.

11529 Background: To evaluate clinical characteristics and patterns of treatment failure in patients with localized Ewing sarcoma (ES) treated on AEWS1031 according to local control (LC) strategies, tumor size, and tumor site. Methods: AEWS1031 was a phase 3 randomized trial comparing two interval compressed chemotherapy regimens. Patients who completed LC on AEWS1031 were analyzed. LC was with surgery alone (S), definitive radiation therapy (RT), or surgery plus radiation (S+RT), and determined by the treating investigator. Local failure (LF) and distant failure (DF) were defined as recurrence at primary tumor site or distant site, respectively. Fine and Gray method was used to estimate cumulative incidence of LF and DF from time LC was completed. P-values were calculated using logrank or Gray’s test, as appropriate. A two-sided p-value of ≤0.05 was considered significant. Results: 588 patients completed LC. Median age at enrollment was 13.0 years (range: 0.6- 33.9 years). Tumor sites were categorized as extremity (230; 39%), axial (142; 24%), extraosseous (110; 19%), and pelvis (106; 18%). At diagnosis, tumor volume (TV) was ≥200 mL in 170 patients (31%) and maximum tumor dimension (MTD) was ≥8 cm in 289 patients (52%). LC was with S in 320 patients (54%), RT in 160 (27%), and S+RT in 108 (18%). Eight patients received preoperative RT. Fifty-three patients (13.1%) who received S±RT had an R1 resection. LC with S was more likely for extremity (58%), RT for pelvis (38%) and S+ RT for axial (36%) and extraosseous (34%) primary tumors (p &lt;0.01). With median follow up of 67.6 months from LC, the 5-year cumulative incidences of LF and DF for the entire cohort were 6.0% (95% CI, 4.3-8.3%) and 11.0% (95% CI, 8.6-13.9%), respectively. Eleven patients experienced simultaneous LF and DF. LF incidence was 5.0% for S, 8.4% for RT, and 5.6% for S+RT (p=0.47). DF incidence was 11.8% for S, 6.4% for RT, and 15.1% for S+RT (p=0.16). LF incidence by tumor site was 3.6% for extremity, 8.7% for pelvis, 7.3% for axial, and 6.8% for extraosseous (p=0.08). LF incidence was higher for primary tumors ≥200 mL (11.3%) compared to tumors &lt; 200 mL (3.9%; p&lt;0.01) and for tumors ≥8 cm (7.8%) compared to tumors &lt; 8 cm (4.4%; p=0.02). Tumor size was associated with a higher LF incidence for S and RT, but not for S+RT (Table). LF incidence was 4.0% for R0, 7.5% for R1 with RT, and 16.7% for R1 without RT (p=0.02). Conclusions: We report the lowest LF incidence to date for prospective ES trials conducted. Both larger TV and MTD were associated with higher LF. Future investigations will aim to evaluate the impact of chemotherapy dose-intensity on LC and identify risk-stratification variables for improved LC. Five-year LF incidence by LC and tumor size. Clinical trial information: NCT01231906 . [Table: see text]

Radiation-induced nasopharyngeal necrosis in locally-recurrent nasopharyngeal carcinoma patients after re-radiotherapy.

e18063 Background: Re-radiotherapy (re-RT) is the main treatment for locally recurrent nasopharyngeal carcinoma (lrNPC) patients, and commonly led to radiation-induced nasopharyngeal (NP) necrosis, which was lethal but rare study has focused on it. The aim of this study was to evaluate the cause and impact of radiation-induced NP necrosis in lrNPC patients who received re-RT. Methods: Totally 252 lrNPC patients who received re-RT between January 2013 and December 2020 were retrospectively collected. The inclusion criteria were as follows: (1) no NP necrosis before re-RT; (2) complete medical records, including treatment, clinical and dosimetric information; (3) conventional fractionated radiotherapy. All patients received intensity-modulated radiotherapy ± chemotherapy. Radiation-induced NP necrosis was diagnosed by magnetic resonance imaging and/or electronic nasopharyngoscopy. Dosimetric factors of the planning target volume of primary tumor (PTVp) were extracted from the dose-volume histogram (DVH), which was rescaled to an equivalent dose of 2 Gy per fraction (EQD 2 Gy) using a linear quadratic model. Logistic regression was used to identify the independent prognostic factors for generating the nomogram. Results: With a median follow-up of 44.63 months (inter-quartile range [IQR], 27.70 – 69.20 months), 47.6% of patients (120/252) occurred radiation-induced NP necrosis, which mostly happened within 1 year post re-RT (median [IQR], 5.83 [3.37 – 11.57] months). The 3-year overall survival was 83.0% vs 39.7% ( P＜0.001) in lrNPC patients with or without radiation-induced NP necrosis. Except for the fractionated dose, other dosimetric factors of PTVp were not significantly different between two groups, including D98 (dose to 98% of PTVp), D50, D2 and homogeneity index (Table). Furthermore, multivariate analysis showed that continuous variable age (HR [95%CI]: 1.04 [1.02 – 1.07], P = 0.003) and tumor volume (HR [95%CI]: 1.02 [1.01 – 1.03], P＜0.001), and fractionated dose &gt; 2.22 Gy (HR [95%CI]: 2.36 [1.32 – 4.21], P = 0.004) were independent factors in predicting radiation-induced NP necrosis, which yielded a C-index of 0.742 (95% CI, 0.682 - 0.803) for OS in the nomogram. Conclusions: The incidence of radiation-induced NP necrosis was high in lrNPC patients who received re-RT. Patients with older age, larger tumor volume or receiving fractionated dose over 2.22 Gy were more easily to suffer NP necrosis, which need to explore novel treatment strategies to improve patients’ survivals. [Table: see text]

Comparison of methodologies for creating spread-out Bragg peaks in proton therapy using TOPAS and MCNP codes

In proton beam treatments, the superposition of several weighted Bragg curves with different incident energies is required to homogeneously irradiate a large tumor volume, creating a spread-out Bragg peak (SOBP). This paper confirms on the suitability of two different methods to create SOBPs – Bortfeld/Jette's and MCMC (Monte Carlo calculations and Matrix Computations), using Monte Carlo simulations performed with TOPAS and MCNP6.1. To generate the SOBPs, algorithms were developed for implementation of the two methods, which enabled to find the weights for thirty variations of SOBPs, categorized according to their width and maximum depths. The MCMC method used weight optimization in designing SOBPs to avoid negative values. In contrast, the Bortfeld/Jette's method yielded the SOBPs according to the variation of a power-law parameter (p) introduced by the range-energy relationship. Optimal values of p, from MCNP and TOPAS, were selected in order to retrieve SOBPs with the best smoothness and then related to those obtained from the literature. In comparing both methods and codes, dose homogeneity parameters (HOM) were used to examine the SOBP flatness and gamma analyses were employed to assess the dose deposition along its full extension. The results showed that the SOBPs designed using the MCMC method had better HOM values and computational performance for both codes when compared to the Bortfeld/Jette's method. The gamma analyses highlighted significant differences between the entrance doses comparing the two different methods, for SOBPs with intermediate and high depths and small width. This evaluation was not possible with the HOM values alone, which stresses the relevance of a broad analysis to avoid unintended doses in healthy tissues.

Establishment of a novel co-cultured liver cancer model based on tumor microenvironment

Objective: To construct a new co-cultured liver cancer research model composed of activated hepatic stellate cells (aHSC) and liver cancer cells, explore the efficacy difference between it and traditional model, so as to establish a liver cancer research model in vitro and in vivo that can reflect the real clinical efficacy. Methods: A new co-culture model of liver cancer consisting of aHSC and liver cancer cells was constructed. The differences in efficacy between the new co-culture model and the traditional single cell model were compared by cytotoxicity test, cell migration test, drug retention test and in vivo tumor inhibition test. Western blot was used to detect the drug-resistant protein P-gp and epithelial-mesenchymal transition-related proteins. Masson staining was used to observe the deposition of collagen fibers in tumor tissues of tumor-bearing mice. CD31 immunohistochemical staining was used to observe the microvessel density in tumor tissues of tumor-bearing mice. Results: The cytotoxicity of single cell model and co-culture model was dose-dependent. With the increase of curcumin (CUR) concentration, the cell viability decreased, but the cell viability of single cell model decreased faster than that of co-culture model. When the concentration of CUR was 10 μg/ml, the cell viability of the co-culture model was 62.3% and the migration rate was (28.05±3.68)%, which were higher than those of the single cell model [38.5% and (14.91±5.92)%, both P<0.05]. Western blot analysis showed that the expressions of P-gp and vimentin were up-regulated in the co-culture model, which were 1.55 and 2.04 fold changes of the single cell model, respectively. The expression of E-cadherin was down-regulated, and the expression level of E-cadherin in the single cell model was 1.17 fold changes of the co-culture model. Drug retention experiment showed that the co-culture model could promote drug efflux and reduce drug retention. In vivo tumor inhibition experiment showed that the m-HSC+ H22 co-transplantation model had faster tumor growth and larger tumor volume than those of the H22 single cell transplantation model. After CUR treatment, the tumor growths of m-HSC+ H22 co-transplantation model and H22 single cell transplantation model were inhibited. Masson staining showed that the deposition of collagen fibers in tumor tissues of m-HSC+ H22 co-transplantation model mice was more than that of H22 single cell transplantation model. CD31 immunohistochemical staining showed that the microvessel density in tumor tissue of m-HSC+ H22 co-transplantation model was higher than that of H22 single cell transplantation model. Conclusions: The aHSC+ liver cancer cell co-culture model has strong proliferation and metastasis ability and is easy to be resistant to drugs. It is a new type of liver cancer treatment research model superior to the traditional single cell model.

Preoperative prediction of Ki-67 and p53 status in meningioma using a multiparametric MRI-based clinical-radiomic model.

To investigate the utility of preoperative multiparametric magnetic resonance imaging (mpMRI)-based clinical-radiomic analysis combined with machine learning (ML) algorithms in predicting the expression of the Ki-67 proliferative index and p53 tumor suppressor protein in patients with meningioma. This multicenter retrospective study included 483 and 93 patients from two centers. The Ki-67 index was classified into high (Ki-67≥5%) and low (Ki-67<5%)-expressed groups, and the p53 index was classified into positive (p53≥5%) and negative (p53<5%)-expressed groups. Clinical and radiological features were analyzed using univariate and multivariate statistical analyses. Six ML models were performed with different types of classifiers to predict Ki-67 and p53 status. In the multivariate analysis, larger tumor volumes (p<0.001), irregular tumor margin (p<0.001), and unclear tumor-brain interface (p<0.001) were independently associated with a high Ki-67 status, whereas the presence of both necrosis (p=0.003) and the dural tail sign (p=0.026) were independently associated with a positive p53 status. A relatively better performance was yielded from the model constructed by combined clinical and radiological features. The area under the curve (AUC) and accuracy of high Ki-67 were 0.820 and 0.867 in the internal test, and 0.666 and 0.773 in the external test, respectively. Regarding p53 positivity, the AUC and accuracy were 0.858 and 0.857 in the internal test, and 0.684 and 0.718 in the external test. The present study developed clinical-radiomic ML models to non-invasively predict Ki-67 and p53 expression in meningioma using mpMRI features, and provides a novel non-invasive strategy for assessing cell proliferation.

Elevated LILRB1 expression predicts poor prognosis and is associated with tumor immune infiltration in patients with glioma

BackgroundLeukocyte immunoglobulin-like receptor subfamily B1 (LILRB1) is regarded as an inhibitory molecule. However, the importance of LILRB1 expression in glioma has not yet been determined. This investigation examined the immunological signature, clinicopathological importance and prognostic value of LILRB1 expression in glioma.MethodsWe used data from the UCSC XENA database, the Cancer Genome Atlas (TCGA) database, the Chinese Glioma Genome Atlas (CGGA) database, the STRING database, the MEXPRESS database and our clinical glioma samples to perform bioinformatic analysis and used vitro experiments to examine the predictive value and potential biological roles of LILRB1 in glioma.ResultsHigher LILRB1 expression was considerably present in the higher WHO grade glioma group and was linked to a poorer prognosis in patients with glioma. Gene set enrichment analysis (GSEA) revealed that LILRB1 was positively correlated with the JAK/STAT signaling pathway. LILRB1 combined with tumor mutational burden (TMB) and microsatellite instability (MSI) may be a promising indicator for the effectiveness of immunotherapy in patients with glioma. Increased LILRB1 expression was positively linked with the hypomethylation, M2 macrophage infiltration, immune checkpoints (ICPs) and M2 macrophage makers. Univariate and multivariate Cox regression analyses determined that increased LILRB1 expression was a standalone causal factor for glioma. Vitro experiments determined that LILRB1 positively enhanced the proliferation, migration and invasion in glioma cells. MRI images demonstrated that higher LILRB1 expression was related with larger tumor volume in patients with glioma.ConclusionDysregulation of LILRB1 in glioma is correlated with immune infiltration and is a standalone causal factor for glioma.

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.