Mean Tumor Volume Research Articles

Anticancer Effects of Urtica Dioica in Breast Cancer.

Objective:The goal of this study is to look into the antiproliferative capabilities of Urtica Dioica (UD) on breast cancer. Methods:The cytotoxicity of UD extracts against breast cancer cell lines was investigated. Flow cytometry analyses were used to investigate in vitro apoptosis of breast cancer cells using Annexin V labeling. In vivo tests also performed.Results:UD showed cytotoxicity to three cancer cell lines. The number of Annexin-positive cells was higher in UD-treated cell lines than in untreated control cells. When compared to the untreated control group, the rats treated with UD had greater expressions of caspase 3, p53 protein, and TUNEL positive cells. When compared to the control group, Ki-67 expression was reduced in the treatment groups. In vivo tests revealed that, when compared to untreated rats, the mean tumor volume inhibition ratio in the UD group was 38 percent. Conclusion:These findings suggest that Urtica Dioica may have antitumoral properties in the treatment of breast cancer.

The immune impact of PI3K-AKT pathway inhibition in colorectal cancer.

154 Background: Our prior work has shown that PI3K-altered colorectal cancer (CRC), with PIK3CA mutation or PTEN loss, has increased expression of key immune checkpoints (including PD-L1) resulting in immune evasion, despite increased immune engagement. Here, we investigated the impact of PI3K-AKT inhibition on the immune repertoire of CRC. Methods: Multiplex immunofluorescence was performed using two Vectra panels [1: AE1/AE3, CD3, CD8, PD-1, PD-L1, CD68; and 2: AE1/AE3, CD3, CD8, Granzyme B (GzB), CD45RO, FoxP3] on paired biopsies (baseline and cycle 1 day 15) from 6 patients with PI3K-altered metastatic CRC (mCRC) treated with AKT inhibitor, MK2206 (200 mg oral weekly), on a phase 2 clinical trial. Separately, one million CT26 CRC cells were implanted in BALB/C-e mice. After 48 hours, 10 mice/group were randomized for treatment with pan-PI3K inhibitor copanlisib (C, 10 mg/Kg IV 2x/week), anti-PD-1 (P, 200 µg IP 2x/week), copanlisib + anti-PD-1 (C+P), or control (Ct), for 21 days. Mouse tumors were stained with 6-plex immunohistochemistry (CD3, CD8, PD-L1, Ki67, GzB, AE1/AE3). Data were analyzed using related-samples Wilcoxon Signed-Rank test, Mann-Whitney U test, Kruskal-Wallis test, and Student’s t-test, as appropriate. Results: In PI3K-altered mCRC patients, AKT inhibition resulted in a trend towards increased median densities of intratumoral CD8+ T cells (0.8 vs 4.8 density/mm2, P = 0.14) and memory T cells (0 vs 10.3, P = 0.07), and decreased density of macrophages (12.4 vs 0, P = 0.07). No antigen experienced T cells were seen and activated CD8+ T cells were present in 1 patient only. In CT26 mice, PI3K and PD-1 co-inhibition resulted in the smallest mean tumor volumes (C+P 12% of Ct vs C 40% and P 42% of Ct, P < 0.05 for both), and the highest median % of intratumoral CD8+Ki67+ T cells as compared to all other treatment arms (C+P 1.6% vs C 0.5%, P 0.4%, Ct 0.6%, P < 0.05 for each pairwise comparison). C+P also increased the % of total CD3+ and CD8+ cells as compared to Ct and C (P < 0.05 for all). C alone did not increase immune infiltration in this non-PI3K activated model. Conclusions: PI3K-AKT pathway inhibition has the potential to improve effector T cell infiltration in PI3K-altered CRC. PI3K inhibitor synergizes with anti-PD-1 to improve treatment efficacy and CD8+ T cell proliferation. The mechanisms behind this immune repertoire shift are yet to be elucidated, such as via cytokine modulation. Therapeutic approaches to activate the proliferating CD8+ cells would be useful, and may require PI3Kα/β specific inhibitors to allow early T cell activation through PI3Kδ/γ isoforms.

Long-term outcome of adjunctive Gamma Knife radiosurgery in skull-base chordomas and chondrosarcomas: An Indian experience

Skull-base chordomas (CD) and chondrosarcomas (CS) are locally-invasive tumors, have similar clinical presentations, while differing in their nature of growth and outcomes. In this study, we compare the long-term outcomes of Gamma Knife Radiosurgery (GKRS) as an adjunctive treatment modality for residual skull-base CD and CS. A retrospective analysis of clinico-radiological, pathological, radiotherapeutic and outcome data was carried out in patients who underwent adjunctive GKRS for residual skull-base CD and CS at P D Hinduja Hospital, Mumbai, between 1997 and 2020. All 27 patients included had either histopathologically proven CD (20 patients) or CS (7 patients). Brachyury immunohistochemistry in CD specimens gave 70.6% positivity. Total sessions of GKRS in CD and CS groups were 22 and 7, respectively. Mean tumor volume and mean margin dose in CD group were 6.53 ± 4.18 cm3 and 15.95 ± 1.49 Gy respectively, while for CS group, they were 4.16 ± 2.79 cm3 and 18.29 ± 3.15 Gy. With mean follow-up periods of 5.25 ± 4.73 years and 6 ± 2.07 years respectively, the CD and CS groups showed 5-year progression free survival (PFS) of 56.8% and 57.1%, and a 5-year overall survival (OS) of 82.1% and 100%. Sub-group analysis in both CD and CS groups revealed a better 5-year PFS with the following factors – CS histopathology, patient age < 45 years, margin dose > 16 Gy, tumor volume < 7 cm3 (p-value < 0.05), gross total resection, and brachyury positivity. Adjunctive radiotherapy for skull-base CD and CS holds promise.

Prospective clinical trial on the learning curve of high-intensity-focused ultrasound for the treatment of breast fibroadenoma.

High-intensity-focused ultrasound (HIFU) is a safe and feasible treatment option for breast fibroadenoma. However, its learning curve has not been described in the medical literature. All patients with biopsy-proven fibroadenoma considered indicated for HIFU were screened for eligibility for HIFU treatment. A total of 60 patients were recruited according to the pre-defined sample size calculation. Sixty consecutive patients were divided into three cohorts in chronological order. The mean tumor volume shrinkage rates in cohorts 1, 2, and 3 at 6months post-HIFU ablation were 38%, 34%, and 59%, respectively. Significant tumor shrinkage was observed from case 41 onward (p < 0.0001). Similarly, the mean tumor volume shrinkage rates in cohorts 1, 2, and 3 at 12months post-HIFU ablation were 45%, 51%, and 71%, respectively. Significant tumor shrinkage was observed from case 41 onwards (p < 0.0473). The mean procedure time for the first 20 patients was 48.5 (range 45-75) minutes, while that in the second 20 patients was 39.7 (range 20-60) minutes, and that in the last 20 patients was 28.9 (range 15-45) minutes. The treatment time was significantly shorter from case 41 onwards (p = 0.0481). Treatment outcomes and treatment time improved significantly after performing approximately 40 HIFU procedures.

Hyperfractionated Treatment with 177Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model.

Simple SummaryNeuroendocrine tumors are slow growing and initially associated with vague symptoms and, therefore, often spread in the patient’s body at diagnosis, leading to a poor prognosis without means of curation through surgery. Although tumor-targeting treatments exist and are used in clinics, they are not fully optimized. The aim of this study was to test different dosages and time intervals of the radioactive pharmaceutical 177Lu-octreotate. We found that dividing a dosage into several portions and administering it at short time intervals resulted in a stronger tumor reduction and/or prolonged time for regrowth in mice than if given as a single dose. The biggest differences were seen in the lower dosage levels of the study. The findings indicate that there is clear room for improvements in the treatment of neuroendocrine tumors with 177Lu-octreotate.Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of 177Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.

Двухэтапная стажированная стереотаксическая радиохирургия на Гамма-ноже в лечении метастазов в головной мозг

The aim of this study was to assess the efficacy and safety of two-stage stereotactic radiosurgery using Gamma Knife for treatment of brain metastases. Staging was applied to patients with large metastases, as well as to metastases located near critical structures. In a group of 31 patients, treatment was carried out in 2 stages with 2-4 weeks interval. The mean tumor volume at the time of the first radiosurgery was 10.4 cm3 (0.52 to 19.07; 95% CI: 8.2-12 cm3). The marginal dose at the first and second stages of radiosurgery ranged from 12 to 14.4 Gy, respectively. Median fol-low-up time was 169 days. Overall survival rate, local control, the incidence of complications, as well as changes in functional status were evaluated. Decrease in volume of tumors between irra-diation sessions averaged 36.2%. Overall survival at 3, 6, 12 months was 70, 57.7 and 52%, re-spectively. Local control after 3, 6, 12 months was 92, 87 and 66%, respectively. Radionecrosis was found out in 2 patients. Increase of Carnovsky index in study group after treatment was by an average of 10 points (p=0.007). Thus, two-stage trained stereotactic radiosurgery can be a safe and effective alternative to surgical treatment of brain metastases without worsening the neuro-logical status of patients.

Laparoscopic nephron-sparing surgery and laparoscopic nephrectomy for Wilms' tumor.

The place of laparoscopy in the resection of Wilms' tumors has remained debatable, but evidence that neoadjuvant chemotherapy causes tumor shrinkage has made laparoscopic nephrectomy (LN) a feasible option. Laparoscopic nephron-sparing surgery (NSS) is technically very demanding and seems to be feasible and effective only when performed by a very experienced surgeon. We report 7 cases of laparoscopic nephrectomy and 1 case of laparoscopic heminephrectomy for Wilms' tumor. Forty-two consecutive children with primary renal tumor underwent nephrectomy between 2013 and 2020; 11 had an LN. Among them there were 8 children with Wilms' tumor, with age between 13 months and 7 years. All patients received neoadjuvant chemotherapy according to the current SIOP protocol. The mean tumor volume before and after chemotherapy was 174.4 ml (range: 14.7-501) and 32.8 ml (range: 4.3-68) respectively. Seven laparoscopic nephrectomies and one heminephrectomy were performed. No patient had an intraoperative tumor rupture. All children had an attempt of lymph node sampling (their number per pathology assessment was in the range 0-5). There were no intraoperative events. One complication after heminephrectomy occurred, which was urine leak. Five patients had stage I tumor and 3 had stage II. Seven patients had an intermediate-risk and one had a high-risk tumor. There were no local or distant relapses. All patients remained disease-free at a median follow-up of 71 months (range: 16-94). This report demonstrates the feasibility of LN in children with Wilms' tumors. The patients should be carefully selected and specific training in laparoscopy is necessary, particularly with regard to laparoscopic heminephrectomy.

Meningiomas of the Cerebellopontine Angle: Tips and Pearls for Safe Surgical Resection.

To present our series of cerebellopontine angle (CPA) meningiomas, and to provide some innovative surgical steps for safe removal of these tumors. The clinical, radiological, and surgical characteristics of 32 patients with meningioma in the CPA were retrospectively analyzed. A statistical analysis was performed to determine the factors that affect the incidence of complication. The mean age was 49.5 yr, and 87.5% of patients were men had World Health Organization (WHO) grade I meningioma, while the remaining patients had WHO grade II tumors. The mean tumor volume was 33.98 mL, and gross total resection was performed on 65.6% of the patients. Preoperative tumor size/extension and extent of resection were related with the development of complications. CPA meningiomas are challenging tumors to remove safely. Important risk factors for the development of postoperative complications include tumor size and extent of resection.

Diagnostic Accuracy of Calculated Tumor Volumes and Apparent Diffusion Coefficient Values in Predicting Endometrial Cancer Grade.

Background:Magnetic resonance imaging (MRI) has been shown to be an accurate imaging technique for the preoperative assessment of local staging of endometrial cancer and for evaluating the depth of myometrial invasion.Materials and Methods:This was a single-center retrospective study performed on patients with histopathologically proven endometrial carcinoma who underwent an MRI examination of the pelvis between October 2017 and May 2020.Results:In the present analysis, mean apparent diffusion coefficient (ADC) values for each histologic grade were 0.72 ± 0.13 × 10−3 mm2/s (G1), 0.76 ± 0.17 × 10−3 mm2/s (G2), and 0.74 ± 0.12 × 10−3 mm2/s (G3), respectively, showing no significant correlation between ADC values and tumor grade (P = 0.73). Overall, ADC minimum was significant in differentiating grades of endometrial carcinoma (P = 0.02) with the ability to differentiate Grade I and II lesions (P = 0.01). A mean tumor volume of 25.2 cc could differentiate low-grade tumors (Grade I and Grade II) from high-grade tumors (Grade III) with a sensitivity and specificity of 88% and specificity of 89%. The tumor volume/uterine volume ratio (TV/UV) differentiates high-grade tumors from low-grade tumors (P < 0.001), however, no significant difference in the ratio was observed among Grade I and II lesions (P = 0.48). The area under the curve of tumor volume was 0.875 (95% confidence interval 0.0–1.00) (P = 0.001), indicating that tumor volume was an effective tool for distinguishing high-grade and low-grade endometrioid adenocarcinomas. The corresponding sensitivity and specificity were 88.0% and 89.0%, respectively.Conclusion:Preoperative noninvasive radiological assessment for tumor volume, TV/ UV or tumor volume/uterine volume is important surrogate markers for preoperative prognostication of endometrial carcinoma.

Recurrence rate of sphenoid wing meningiomas and role of peritumoural brain edema: a single center retrospective study

Objective: To evaluate the recurrence rate of the operatively treated sphenoid wing meningiomas (SWMs) in relation to other factors and role of PTBE in recurrence as a prognostic factors in a series of 67 patients. Materials and methods: The magnetic resonance imaging (MRI), and pathology data for 67 patients with SWM, who underwent surgery at Uzhhorod Regional Neurosurgical Center between 2007 and 2021 were examined. The recurrence rate and role of PTBE in recurrence in relation to: gender, age, extend of resection, histopathology, tumor volume, location and time of recurrence were evaluated. Follow-up period ranged from 6 to 168 months (median, 87 months) after surgical resection. Results: In our study, the mean age of patients is 47 years, ranged (20-74), at the average (53.5). Male 16 (23.9%), female 51 (76.1%). Mean tumor volume was (32.8cm3), ranged 4.2cm3-143.7cm3. Edema Index (EI) 1; 27 (40.3%) absent edema, and (EI) &gt;1; in 40 (59.7%) present edema. Recurrence rate was 11 (16.4%) patients, 8 (20.0%) patients with PTBE, as compared to 3 (11.1%) patients without PTBE, (p=0,50). Female (8 patients, 15.7%), male (3 patients, 18.7%). The mean age of recurrence was 50.9 years, ranged (21-75), at the average 52.0 years. The mean age in female was 50.8 years, in male 51.0. Bivariate analysis of simultaneous effect of gender and age on SWM recurrence with logistic regression yield both main effect and interaction effect (β gender=M=7.56±6.44, P=0.24; β age=-0.034±0.031, p=0.28; β interaction term=-0.13±0.12, p=0.26). Out of 11 recurrence cases, (2 cases, 9.5%) with small tumour volume, (5 cases, 15.6%) with medium, (3 cases, 33.3%) with large, and (one case, 20.0%) with giant tumour volume. The effect of tumour volume on recurrence rate is insignificant, χ2=2.42, p=0.49.Location of SWM; the recurrence was in (6 cases, 25.0%) of CM location, (2 cases, 25.0%) of SOM and (3 cases, 11.5%) in lateral SWM, (p=0.19). Pathological grade, in the low grade (Gr.I) 7 recurrence cases (13.0%), as compared to 4cases (44.4%) in atypical Gr II, (p=0.01). Simpson grade, the recurrence rate was; 0% in Gr. I; 13.9% in Gr. II; 20.0% in Gr.III; and 33.3% in Gr. IV and 3 cases had died in the early post op (p&lt;0.05). Conclusion: The factors which had a strong impact on the recurrence rate in our study,; i) pathological grade (Gr. II, atypical type) p=0.01 and ii) Simpson grade (extend of tumor resection, p&lt;0.05), while, PTBE (P=0.50), tumor volume (χ2=2.42, p=0.49) and location (χ2=3.37, p=0.19), are weak and non strong factors for recurrence. However, time of recurrence is shorter in patients with PTBE (W=20.5, p=0.092). WHO Gr. II (Spearman’s p=-0.86, p=0.00063) and negligible for Simpson grade (Spearman’s=-0.15, p=0.66).

Extra-abdominal desmoid fibromatosis: An evaluation of clinical factors affecting local recurrence rates.

The aim of this study was to determine the prognostic factors for recurrence in patients with extra-abdominal desmoid tumors (EDTs) treated surgically. This single-institution, retrospective study included patients with a histologically-proven extra-abdominal desmoid tumor between 2007 and 2018. The demographic characteristics (age, sex) of the patients, tumor characteristics (region, size, proximity to neurovascular structures, margins), treatment management (surgery and/or adjuvant radiotherapy), and clinical results were analyzed. The effects of these possible prognostic factors on overall and disease-free survival rates and the risk of local recurrence were evaluated. Evaluation was made of 22 patients (16 females, 6 males) with a mean age at diagnosis of 34.7 years (range = 22-76 years). The mean follow-up was 104 months (range = 4.8-168). Tumor localization was in the upper extremity in 4 patients (18.1%), the lower extremity in 11 (50.0%), and the trunk in 7 (31.8%). The mean tumor size (maximum diameter) was 5.2 cm (range = 0.6-13 cm; median = 5.8 cm), and the mean tumor volume was 181.3 ± 531.4 ml. All the 22 patients were treated surgically along with adjuvant radiotherapy (RT) administered to 8 in addition to surgery for the primary treatment of the tumor. Following primary surgery, resection margins were R0 in 11 patients, R1 in 9 and R2 in 2. Local recurrence (LR) developed in 6 patients (27.2%) during the follow-up period. Recurrence-free survival rate (RFS) was 90.9% at one year, 74.1% at 5 years, and 61.7% at 10 years. During the follow-up, no patient died, and distant metastasis was not detected. Tumor length, resection margins, and adjuvant RT were observed to influence the risk of local recurrence (P < 0.05). The results of this study have demonstrated that tumor size ≥ 5 cm and the presence of microscopic or macroscopic positive surgical margins can increase the risk of LR, and adjuvant RT can reduce the development of LR in the management of EDT.

Impact of the COVID-19 pandemic on the stage and the type of surgical treatment of laryngeal cancer

PurposeChanges in the entire health care system during COVID-19 epidemic have affected the management of patients with head and neck cancer and posed several clinical challenges for ENT surgeons. Therefore, the present study aimed to investigate the effect of COVID-19 on the stage and the type of surgical treatments used in laryngeal cancer (including total laryngectomy, supracricoid partial laryngectomy (SCPL) and transoral laser microsurgery (TLM)) and also to compare the results of April 2020 to April 2021 with the previous year. Materials and MethodsThis cross-sectional study was performed on all patients with a diagnosis of laryngeal cancer who underwent surgery in the tertiary care center from April 2020 to April 2021 and the year before the pandemic in the same time. Demographic, cancer stage, and treatment data of all patients were recorded and analysis in two groups. ResultsPatients referred at the time of the virus outbreak; 111 were male and 5 were female, and in the group of patients referred before COVID-19, 90 were male and 12 were female. The type of surgical treatment of laryngeal cancer, mean time elapsed from sampling to surgery, stage of disease and mean tumor volume was statistically significant differences in patients before and during the outbreak. ConclusionPatients who referred for diagnosis and treatment at the time of COVID-19 outbreak had more advanced stages of the disease and also the tumor volume was higher in them than patients who had referred before the outbreak. It is necessary to provide new solutions, education and treatment management for patients with laryngeal cancer in such pandemics.

Anticancer Potential of Ethyl Acetate Extract Fractions of Ipomoea horsfalliae Hook on DMBA- Induced Breast Cancer Model

The genus Ipomoea is distributed globally and honored as the largest genus of the family Convolvulaceae. Several varieties of this family have been shown to be effective in treating various diseases, including cancer. This research aimed to explore the anticancer activity of ethyl acetate fractions of Ipomoea horsfalliae Hook (EAIH) in female Sprague-Dawley rats. 7, 12-dimethylbenz (a) anthracene (DMBA) was used to produce breast cancer. The Fractions were selected based on the cytotoxicity analysis in vitro, which was reported in our earlier studies. The study employed two dosages of EAIH (25 and 50 mg/kg). Biochemical, hematological, and antioxidant characteristics were investigated. A decrease in mean tumor volume and tumor weight was detected in EAIH treated groups. The blood parameters were seen as normal. In both DMBA and doxorubicin groups, malondialdehyde was increased, and the level was significantly reduced in EAIH-treated groups. The effect of catalase was shown to be diminished in the groups given DMBA and doxorubicin but normal in the EAIH groups. Nitrate and nitrite levels increased in the DMBA control groups but were normal in the others. There was less necrosis and infiltration in breast tissues treated with doxorubicin as well as in EAIH. In animals treated with EAIH, the therapeutic effect was found to be dose-dependent. The therapies helped to repair some of the altered breast patterns. The study concludes that I. horsfolliae may be a potential anticancer candidate and need to explore further.

Visual Outcomes in Spheno-Orbital Meningioma: A 10-Year Experience

Spheno-orbital meningiomas (SOMs) present distinct surgical challenges because they involve important neurovascular structures, such as the orbit, cavernous sinus, superior orbital fissure, and opticcanal. Resection thus focuses on maximum safe resection while preserving these neurovascular structures. Our objective was to describe our method of surgical management of SOMs and summarize visual outcomes. A retrospective chart review was performed to identify patients who underwent surgery for SOM in 2011-2021. Demographics, preoperative visual summary, operative details, visual outcomes, and recurrence data were collected. The 33 patients (10 male, 23 female) had a mean age of 56 years (range 27-74 years). The mean tumor volume was 39 mL (range 4.7-220 mL). The mean follow-up period was 18 months (range 1-120 months). Thirty-two patients had preoperative radiographic evidence of proptosis (based on exophthalmos index), 23 (70%) presented with diminished visual acuity, and 10 (30%) had a concomitant visual field deficit. At last postoperative follow-up, vision was stable for 25 patients (83.3%), improved for 1 (3.3%), and worsened for 3 (10%; 2 occurring after tumor recurrence beyond 2 years). Proptosis was stable or improved in all patients. One patient had an enucleated eye. A total of 7 patients (21%) had recurrence of the tumor at 19-72 months from the operation. In this study, maximum safe resection, including periorbital resection, provided adequate visual and cosmetic outcomes, as well as reasonable tumor control in the long term. Rigid orbital reconstruction was not required to prevent pulsatile enophthalmos.

CTNI-29. SAFETY AND FEASIBILITY OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA: THE RESPECT™ PHASE 1 TRIAL

Abstract BACKGROUND Liposomal rhenium-186 (186RNL) is a potent source of beta particles with short path length, variable dose rate, high radiation density and gamma emission. Preclinically, 186RNL delivered via convection enhanced delivery (CED) achieves very high doses of targeted radiation with a wide therapeutic index. We report the results of ReSPECT, the first in man, dose escalation phase 1 trial of 186RNL in recurrent glioma. METHODS Following computer assisted treatment planning and placement of intracranial catheter(s), we performed a single administration of 186RNL by CED. We obtained whole body planar and SPECT/CT imaging on days 1-8 following treatment for dosimetry and distribution and followed patients for safety, progression and survival. RESULTS Twenty-one patients across 7 cohorts received 1.0-22.3mCi in a volume of 0.6-8.80mL. Mean tumor volume was 8.3mL (0.9-22.8mL). Patients had a mean of 1.7 recurrences, 5 received prior bevacizumab. Overall, 19/21 patients and all after cohort 4 had grade 4 glioma (glioblastoma). We used a CED rate of 5-20µl/min per catheter, with 1-4 catheters used per patient. Mean absorbed radiation dose to the tumor was 255Gy (8.9-740Gy) while exposure outside the brain was negligible. The mean percentage tumor in the treated volume (Tu/Tv) was 60.3% (19.8%-100%). Thus far, we have observed no dose limiting toxicities, one grade 3 treatment related adverse event (AEs), and the majority of AEs were mild in intensity. The incidence and severity of AEs did not correlate with increasing dose. Mean Tu/Tv in patients not receiving prior bevacizumab was 75% vs. 48% in those that had. Thus far, overall survival (OS) in 16 bevacizumab naïve patients is 49 weeks with 7 (44%) patients still alive and a positive correlation of OS to Tu/Tv. CONCLUSIONS 186RNL achieves high absorbed doses without significant toxicity with favorable overall survival.

EXTH-14. PRECLINICAL EVALUATION OF NOVEL CDK4/6 INHIBITOR GLR2007 IN GLIOBLASTOMA MODELS

Abstract Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. None of the approved CDK4/6 inhibitors are indicated for GBM. Poor blood–brain barrier (BBB) penetration is a potential factor limiting treatment efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved penetration across the BBB. These preclinical studies investigated the anti-tumor efficacy in GBM xenograft models and central nervous system distribution of GLR2007. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in two BALB/c nude mouse GBM xenograft models. Efficacy was expressed as tumor growth inhibition (TGI, change in mean tumor volume from baseline as a percentage of change in vehicle group) or increased survival time. Following 21 days of treatment, TGI in BN2289 subcutaneous xenografts was 39.4% and 56.4% for 25 mg/kg and 50 mg/kg GLR2007 groups, respectively, 34.0% for 25 mg/kg palbociclib, and 24.9% for 25 mg/kg abemaciclib (p &amp;lt; 0.001 in all groups vs vehicle control). In U87-luc orthotopic xenografts, compared with vehicle controls, median survival time was 50.0% (p = 0.0009) longer in the 12.5 mg/kg GLR2007 group, similar to the 150 mg/kg abemaciclib group (54.4%, p = 0.0002), and was 182.6% (p &amp;lt; 0.0001) longer in mice treated with 50 mg/kg GLR2007. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in Sprague Dawley rats following a single oral dose. Total radioactivity levels in the brain exceeded those in plasma by 2.3–4.5-fold from 2–6 h after dosing. These preclinical studies suggest the potential of GLR2007 for the treatment of GBM, supported by evidence that GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors palbociclib and abemaciclib in GBM xenograft models, and evidence of substantial central nervous system distribution.

EXTH-01. SECOND GENERATION OF INDUCED NEURAL STEM CELLS TO MIGRATE AND KILL AS AN ADJUVANT TO RADIOTHERAPY IN NON-SMALL CELL LUNG CANCER METASTASIS

Abstract Non-small cell lung cancer (NSCLC) spread to the leptomeninges is devastating with a median survival of only a few months. Radiation is frequently offered for symptomatic relief but alone does not eliminate leptomeningeal metastases (LMM). With no standard-of-care for patients with LMM, new adjuvant therapies are desperately needed in order to combat this disease. Neural stem cells (NSCs) have shown remarkable promise as drug delivery vehicles in the treatment of brain tumors due to their inherent tumoritropic properties. Using a cell sphere culture-based system, we have transdifferentiated fibroblasts into a second-generation induced neural stem cell (hiNeuroS) secreting the cytotoxic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to allow for the possibility of readily available, autologous cell carriers. Herein, we provide evidence that hiNeuroS-TRAIL cells can migrate to and suppress growth of NSCLC metastases in combination with radiation. In vitro time-lapse motional analysis and in vivo post-mortem tissue analysis showed that hiNeuroS-TRAIL cells migrate to NSCLC tumors. In vitro co-cultures with isobologram analysis suggests that TRAIL and radiation together have a synergistic cytotoxic effect on NSCLC tumors. In an intratumoral injection model of hiNeuroS-TRAIL, mice treated with the combination therapy of hiNeuroS-TRAIL and 2 Gy together had a small fraction of the mean tumor volume (6.4%) of controls (100%) compared to monotherapies (107.3% radiation-only, 46.6% hiNeuroS-TRAIL only). Only combination-treated mice demonstrated a significant extension in survival, which amounted to a 42% extension compared to controls. In the LMM model with ICV-infused therapy, the combination-treated mice showed significantly smaller tumor volumes (2.0%) compared to control (100%) or 2 Gy (54.9%) treated mice. Mice treated with hiNeuroS-TRAIL-only also showed only 4.6% of the tumor volume of control mice. Combination-treated mice and hiNeuroS-TRAIL-treated mice both showed significant improvements in survival (36.6% and 46.3% median extension in survival, respectively compared to controls).

CTNI-56. EVALUATING DRUG DISTRIBUTION IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH CONVECTION ENHANCED DRUG DELIVERY

Abstract BACKGROUND There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in Diffuse Intrinsic Pontine Glioma (DIPG). AIMS To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS ADC and T2W demonstrated a significant (&amp;lt; 0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&amp;lt; 0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&amp;lt; 0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS ADC and T2W MR sequences could potentially be used to evaluate the volume of distribution of infusate delivered by CED, paramount to ensure tumour coverage and leading to more effective therapy evaluation. This will facilitate the use of CED in future clinical trials.

Pre-Infusion Neurofilament Light Chain (NfL) Levels Predict the Development of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) - a Multicenter Retrospective Study

Chimeric antigen receptor (CAR) T-cell therapy is often associated with neurological complications termed immune effector cell-associated neurotoxicity syndrome (ICANS). There remains a critical need to identify patients most at risk for ICANS. Yet a biomarker for the development of ICANS is lacking. This retrospective multicenter study evaluates pre-infusion levels of plasma neurofilament light chain (NfL), a marker of neurodegeneration, as a predictive biomarker the development of ICANS.Study inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (e.g. dementia, recent stroke). Plasma NfL was assayed using a Simoa HD-X kit (Quanterix TM). Demographic (age, sex), oncologic (primary, stage, mean tumor volume (MTV), and history of central nervous system (CNS) involvement), and medical history (history of non-oncologic CNS disease or neuropathy) were obtained from the medical record. MTV was derived from total lesion burden on pre-infusion positron emission tomography (PET) scans using a 41% maximum standard uptake value (SUV) threshold. Pre-infusion (i.e. during lymphodepletion) and Post-infusion Day 1 (D1) platelet count, C-reactive protein (CRP), fibrinogen, lactate dehydrogenase (LDH), and ferritin levels were also obtained from the medical record. Group comparisons used log-rank testing, followed by receiver operating characteristic (ROC) curve classification and hierarchical clustering. Validation testing used a 10,000 fold cross-validation on 80% of the data. Finally, demographic and clinical characteristics correlated with pre-infusion biomarkers using point-biserial and Spearman (rank) correlation.Our results demonstrated that individuals who would go on to develop ICANS had elevations in pre-infusion NfL ([87.6 v 29.4 pg/ml; Fig 1A], p = 0.00004) with excellent classification accuracy for the development of ICANS (AUC 0.96; Fig 1B), sensitivity (0.91) and specificity (0.95). NfL further correlated with ICANS development (r = 0.74, p < 0.0001; Fig 1C). Among known post-infusion risk factors, D1 ferritin had the highest classification accuracy, but was inferior to baseline NfL (p < 0.05; Fig 1B). Both baseline NfL and D1 ferritin elevations clustered with ICANS grade (Fig 1D).Our findings show that pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. This suggests the risk of developing ICANS reflects pre-existing latent neuroaxonal injury. Predictive identification of patients at risk of developing ICANS prior to cellular infusion would permit early, preemptive or prophylactic ICANS-directed therapies, thereby improving patient outcomes.Figure 1: Baseline (pre-infusion) NfL Levels in ICANS (A) Baseline (pre-infusion) levels of NfL in patients who develop Grade 0 ICANS, Grade 1-2 ICANS, and Grade 3+ ICANS. (B) Receiver operating characteristic curve classification of patients who developed any grade ICANS (1+) vs grade 0 for baseline NfL and post-infusion day 1 (D1) markers. (C) Correlation between pre-treatment factors and pre-infusion biomarkers. All significant relationships after correction for multiple comparisons using false discovery rate (FDR) are outlined (*). (D) Hierarchical clustering of age, baseline NfL, and D1 markers. Clusters associating with ICANS are labeled in red, while those associating with cytokine release syndrome (CRS) are in blue. [Display omitted] DisclosuresCaimi: Verastem: Consultancy; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife); Kite Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Amgen Therapeutics.: Consultancy; TG Therapeutics: Honoraria. de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding. Campian: AbbVie, Inc.: Speakers Bureau; NeoImmuneTech: Research Funding. Ghobadi: Amgen: Consultancy, Research Funding; Atara: Consultancy; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding.

Effect of Steroid Treatment on the Diagnostic Yield of Baseline PET CT in Aggressive B Cell Lymphoma

Aggressive B cell lymphomas often require prompt steroid treatment prior to baseline 18f-fluorodeoxyglucose positron-emission tomography (PET CT) scan and definitive treatment in order to alleviate symptoms and/or prevent organ damage. Since lymphomas are a steroid sensitive malignancy, there is a concern that steroid prophase might affect PET CT results and diagnostic yield.We conducted a retrospective cohort study to evaluate the effect of steroid treatment prior to baseline PET CT scan on the standardized uptake value (SUV) max and additional PET CT parameters by examining two groups of patients: steroid-naïve and steroid-treated patients. The effect of steroid administration on SUV max was examined across different daily and weekly steroid doses and durations of treatment.Between January of 2017 and May 2020, 187 newly diagnosed patients with aggressive B cell lymphoma who had a pre-treatment PET CT scan were evaluated. 160 patients (85.5%) had Diffuse large B-cell lymphoma (DLBCL)/ High-grade B-cell lymphoma, 13 patients (7%) had primary mediastinal (thymic) large B-cell lymphoma, 9 patients (4.8%) had primary DLBCL of the central nervous system and 5 patients (2.7%) had Burkitt lymphoma.132 patients (70.6%) were included in the steroid-naïve group and 55 patients (29.4%) in the steroid-treated group. In the steroid-treated group, the mean duration of steroid treatment was 10.49 (±9.28) days. Average daily dose of steroid treatment was equivalent to 72.27 (±36) mg of prednisone and the mean cumulative prednisone dose during the week prior to PET CT scan was equivalent to 367.95 (±239.9) mg of prednisone.There was no statistical significant difference between the groups in age, gender or KI67. However, patients in the steroid treated group had a significantly higher stage of disease compared to the steroid-naïve group (mean 3.44 compared to 2.99, respectively, p=0.01). The steroid-treated group also had a trend towards a higher IPI score (mean 2.45 versus 2.08, p=0.08) and a trend towards a higher LDH level (mean 2309.89 U/L, range 250-81374 versus mean 877.65 U/L, range 272-22036, p= 0.07), as depicted in table 1.There was no statistical difference in SUV max between the steroid-naïve and steroid-treated groups (p=0.97). This was consistent across various steroid treatment durations and dosage regimes. Patients in the steroid-treated group had a trend towards a higher tumor burden and a larger tumor volume compared to the steroid-naïve group, however it did not reach statistical significance. Mean tumor volume was 179.04 cm 3 in the steroid naïve group and 337.06 cm 3 in the steroid treated group (p=0.17). Mean tumor burden was 1944.84 in the steroid-naïve group and 3016.94 in the steroid-treated group (p=0.09).There was no difference in additional PET CT parameters including SUV mean, SUV max and SUV mean of liver and mediastinum between the groups as depicted in table 2.In conclusion, in aggressive B cell lymphoma, pre-treatment with steroids prior to initial PET CT scan does not affect SUV max or other PET CT parameters and does not reduce PET CT diagnostic yield. [Display omitted] DisclosuresGurion: Medison: Consultancy; Gilead Sciences: Consultancy; Takeda Pharmaceuticals: Consultancy; JC Health Care: Honoraria; Roche: Honoraria.