Tumor Regrowth Research Articles

Unusual location of a central neurocytoma: Particularities of a rare brain tumor

Introduction: Central neurocytoma is a typically rare intraventricular glioneuronal tumor in young adults. Clinically, it is revealed by symptomatology of intracranial hypertension. Intra-parenchymal, extraventricular, and intramedullary localizations are exceptional. Central neurocytoma is considered a benign tumor that can recur locally, but craniospinal dissemination remains as an exception. Case Report: We report a case in a 35-year-old male subject who consulted for quadriparesis and genito-sphincter dysfunctions. The clinical examination noted a syndrome of intracranial hypertension, a kinetic and static cerebellar syndrome, spastic tetraplegia with crural predominance, and anesthesia going up to the sixth thoracic vertebra (T6). A magnetic resonance imaging (MRI) showed a heterogeneous left cerebellar lesion. This lesion was excised, and the sample was freshly sent to the pathological anatomy laboratory. Extemporaneous cytology using the Smear technique was performed and was consistent with a hemangioblastoma. The standard histological examination also revealed the diagnosis of hemangioblastoma, and an additional immunohistochemical (IHC) study was performed for better diagnostic accuracy. The study was conducted in a North African laboratory and was conclusive of a neurocytoma. The evolution was marked by cerebellar tumor regrowth at five months, then the death of the patient at eight (08) months after surgery. Conclusion: Central neurocytoma is a rare tumor that can be confused with several other tumors of the central nervous system. Immunohistochemistry is essential for diagnostic confirmation.

Pyk2/FAK Signaling Is Upregulated in Recurrent Glioblastoma Tumors in a C57BL/6/GL261 Glioma Implantation Model.

The majority of glioblastomas (GBMs) recur shortly after tumor resection and recurrent tumors differ significantly from newly diagnosed GBMs, phenotypically and genetically. In this study, using a Gl261-C57Bl/6 mouse glioma implantation model, we identified significant upregulation of proline-rich tyrosine kinase Pyk2 and focal adhesion kinase (FAK) phosphorylation levels-pPyk2 (579/580) and pFAK (925)-without significant modifications in total Pyk2 and FAK protein expression in tumors regrown after surgical resection, compared with primary implanted tumors. Previously, we demonstrated that Pyk2 and FAK are involved in the regulation of tumor cell invasion and proliferation and are associated with reduced overall survival. We hypothesized that the use of inhibitors of Pyk2/FAK in the postsurgical period may reduce the growth of recurrent tumors. Using Western blot analysis and confocal immunofluorescence approaches, we demonstrated upregulation of Cyclin D1 and the Ki67 proliferation index in tumors regrown after resection, compared with primary implanted tumors. Treatment with Pyk2/FAK inhibitor PF-562271, administered through oral gavage at 50 mg/kg daily for two weeks beginning 2 days before tumor resection, reversed Pyk2/FAK signaling upregulation in recurrent tumors, reduced tumor volume, and increased animal survival. In conclusion, the use of Pyk2/FAK inhibitors can contribute to a delay in GBM tumor regrowth after surgical resection.

Downfield Proton MRSI at 3 Tesla: A Pilot Study in Human Brain Tumors.

To investigate the use of 3D downfield proton magnetic resonance spectroscopic imaging (DF-MRSI) for evaluation of tumor recurrence in patients with glioblastoma (GBM). Seven patients (4F, age range 44-65 and mean ± standard deviation 59.3 ± 7.5 years) with previously treated GBM were scanned using a recently developed 3D DF-MRSI sequence at 3T. Short TE 3D DF-MRSI and water reference 3D-MRSI scans were collected with a nominal spatial resolution of 0.7 cm3. DF volume data in eight slices covered 12 cm of brain in the cranio-caudal axis. Data were analyzed using the 'LCModel' program and a basis set containing nine peaks ranging in frequency between 6.83 to 8.49 ppm. The DF8.18 (assigned to amides) and DF7.90 peaks were selected for the creation of metabolic images and statistical analysis. Longitudinal MR images and clinical history were used to classify brain lesions as either recurrent tumor or treatment effect, which may include necrosis. DF-MRSI data were compared between lesion groups (recurrent tumor, treatment effect) and normal-appearing brain. Of the seven brain tumor patients, two were classified as having recurrent tumor and the rest were classified as treatment effect. Amide metabolite levels from recurrent tumor regions were significantly (p < 0.05) higher compared to both normal-appearing brain and treatment effect regions. Amide levels in lesion voxels classified as treatment effect were significantly lower than normal brain. 3D DF-MRSI in human brain tumors at 3T is feasible and was well tolerated by all patients enrolled in this preliminary study. Amide levels measured by 3D DF-MRSI were significantly different between treatment effect and tumor regrowth.

The ultimate local failure rate after the watch-and-wait strategy for rectal cancer: a systematic review of literature and meta-analysis

Background We hypothesise that a high rate of tumour regrowth after the watch-and-wait (w&w) strategy may lead, despite salvage surgery, to a significant impairment of ultimate local control compared with immediate surgery. Materials and methods To test this hypothesis, we conducted meta-analyses of studies on the w&w strategy (both opportunistic and planned) with an ultimate local failure rate as an endpoint in three patient groups: (1) in all starting radio(chemo)therapy as potential w&w candidates, (2) in a subgroup starting w&w, and (3) in a subgroup with regrowth. Results We identified eight studies for evaluation of local failure in group 1 (N = 837) and 36 studies in group 2 (N = 1914) and in group 3 (N = 439). The meta-analysis revealed an ultimate local failure rate of 8.0% (95% CI 4.8%–12.1%) in group 1 and 5.4% (95% CI 3.9%–7.1) in group 2. These rates are similar to those reported in the literature following preoperative chemoradiation and surgery. However, in the most unfavourable group 3 (with regrowth), the rate of ultimate local failure was 24.1% (95% CI 17.9%–30.9%), with the most common causes being patients’ refusal of salvage total mesorectal excision (TME) (9.1%), recurrence after salvage TME (7.8%), distant metastases (4.1%), frailty (2.4%), and pelvic tumour unresectability (1.7%). Conclusion Nearly 25% of patients with regrowth (unfavourable subgroup) experienced ultimate local failure, primarily due to refusing salvage TME. The risk of ultimate local failure in patients initiating radio(chemo)therapy as potential w&w candidates, or in patients starting w&w, appears comparable to that reported after preoperative chemoradiation and surgery. However, this comparison may be biased, because w&w studies included more early tumours compared with surgical studies.

Oclacitinib and Myxoma Virus Therapy in Dogs with High-Grade Soft Tissue Sarcoma.

Human rhabdomyosarcomas are rarely cured by surgical resection alone. This is also true for high-grade soft tissue sarcomas in dogs. Dogs with spontaneous sarcoma are good models for clinical responses to new cancer therapies. Strategic combinations of immunotherapy and oncolytic virotherapy (OV) could improve treatment responses in canine and human cancer patients. To develop an appropriate combination of immunotherapy and OV for dogs with soft tissue sarcoma (STS), canine cancer cells were inoculated with myxoma viruses (MYXVs) and gene transcripts were quantified. Next, the cytokine concentrations in the canine cancer cells were altered to evaluate their effect on MYXV replication. These studies indicated that, as in murine and human cells, type I interferons (IFN) play an important role in limiting MYXV replication in canine cancer cells. To reduce type I IFN production during OV, oclacitinib (a JAK1 inhibitor) was administered twice daily to dogs for 14 days starting ~7 days prior to surgery. STS tumors were excised, and MYXV deleted for serp2 (MYXV∆SERP2) was administered at the surgical site at two time points post-operatively to treat any remaining microscopic tumor cells. Tumor regrowth in dogs treated with OV was decreased relative to historical controls. However, regrowth was not further inhibited in patients given combination therapy.

A Novel Magnetic Resonance Imaging-Based Radiomics and Clinical Predictive Model for the Regrowth of Postoperative Residual Tumor in Non-Functioning Pituitary Neuroendocrine Tumor.

Background and Objectives: To develop a novel magnetic resonance imaging (MRI)-based radiomics-clinical risk stratification model to predict the regrowth of postoperative residual tumors in patients with non-functioning pituitary neuroendocrine tumors (NF-PitNETs). Materials and Methods: We retrospectively enrolled 114 patients diagnosed as NF-PitNET with postoperative residual tumors after the first operation, and the diameter of the tumors was greater than 10 mm. Univariate and multivariate analyses were conducted to identify independent clinical risk factors. We identified the optimal sequence to generate an appropriate radiomic score (Rscore) that combined pre- and postoperative radiomic features. Three models were established by logistic regression analysis that combined clinical risk factors and radiomic features (Model 1), single clinical risk factors (Model 2) and single radiomic features (Model 3). The models' predictive performances were evaluated using receiver operator characteristic (ROC) curve analysis and area under curve (AUC) values. A nomogram was developed and evaluated using decision curve analysis. Results: Knosp classification and preoperative tumor volume doubling time (TVDT) were high-risk factors (p < 0.05) with odds ratios (ORs) of 2.255 and 0.173. T1WI&T1CE had a higher AUC value (0.954) and generated an Rscore. Ultimately, the AUC of Model 1 {0.929 [95% Confidence interval (CI), 0.865-0.993]} was superior to Model 2 [0.811 (95% CI, 0.704-0.918)] and Model 3 [0.844 (95% CI, 0.748-0.941)] in the training set, which were 0.882 (95% CI, 0.735-1.000), 0.834 (95% CI, 0.676-0.992) and 0.763 (95% CI, 0.569-0.958) in the test set, respectively. Conclusions: We trained a novel radiomics-clinical predictive model for identifying patients with NF-PitNETs at increased risk of postoperative residual tumor regrowth. This model may help optimize individualized and stratified clinical treatment decisions.

Antitumor effect of anti-vascular therapy with STING agonist depends on the tumor microenvironment context.

Targeting tumor vasculature is an efficient weapon to fight against cancer; however, activation of alternative pathways to rebuild the disrupted vasculature leads to rapid tumor regrowth. Immunotherapy that exploits host immune cells to elicit and sustain potent antitumor response has emerged as one of the most promising tools for cancer treatment, yet many treatments fail due to developed resistance mechanisms. Therefore, our aim was to examine whether combination of immunotherapy and anti-vascular treatment will succeed in poorly immunogenic, difficult-to-treat melanoma and triple-negative breast tumor models. Our study was performed on B16-F10 melanoma and 4T1 breast tumor murine models. Mice were treated with the stimulator of interferon genes (STING) pathway agonist (cGAMP) and vascular disrupting agent combretastatin A4 phosphate (CA4P). Tumor growth was monitored. The tumor microenvironment (TME) was comprehensively investigated using multiplex immunofluorescence and flow cytometry. We also examined if such designed therapy sensitizes investigated tumor models to an immune checkpoint inhibitor (anti-PD-1). The use of STING agonist cGAMP as monotherapy was insufficient to effectively inhibit tumor growth due to low levels of STING protein in 4T1 tumors. However, when additionally combined with an anti-vascular agent, a significant therapeutic effect was obtained. In this model, the obtained effect was related to the TME polarization and the stimulation of the innate immune response, especially activation of NK cells. Combination therapy was unable to activate CD8+ T cells. Due to the lack of PD-1 upregulation, no improved therapeutic effect was observed when additionally combined with the anti-PD-1 inhibitor. In B16-F10 tumors, highly abundant in STING protein, cGAMP as monotherapy was sufficient to induce potent antitumor response. In this model, the therapeutic effect was due to the infiltration of the TME with activated NK cells. cGAMP also caused the infiltration of CD8+PD-1+ T cells into the TME; hence, additional benefits of using the PD-1 inhibitor were observed. The study provides preclinical evidence for a great influence of the TME on the outcome of applied therapy, including immune cell contribution and ICI responsiveness. We pointed the need of careful TME screening prior to antitumor treatments to achieve satisfactory results.

Tyrosine kinase inhibitor therapy in pediatric sarcoma: Prognostic implications of pulmonary metastatic cavitation.

This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess whether cavitation can predict clinical response and survival outcomes. In a single-center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16years; age range: 4-25years) with histopathologically confirmed bone (n=10) or soft tissue (n=7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression-free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan-Meier survival analysis and log-rank test. Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79days (range: 46-261days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7months) was significantly longer compared to patients without cavitated nodules (3.8months; log-rank p-value=.03). Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non-progressive disease, and significantly correlates with PFS.

Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma.

Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. Optimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.

Growth potential of small residual tumors after vestibular schwannoma surgery: comparison between remnants and the natural history of small tumors.

Due to the heterogeneous definitions of tumor regrowth and various tumor volume distributions, the nature of small remnants after vestibular schwannoma (VS) surgery and the appropriate timing of adjuvant stereotactic radiosurgery for these remnants remain unclear. In this study, the growth potential of small remnants (< 1 cm3) after VS surgery was compared with that of treatment-naïve (TN) small VSs. This retrospective single-center study included 44 patients with VS remnants following subtotal resection (STR) of a large VS (remnant group) and 75 patients with TN VS (< 1 cm3; TN group). A 20% change in tumor volume over the imaging interval indicated radiographic progression or regression. Tumor progression-free survival (TPFS) rates were estimated using the Kaplan-Meier method. In the remnant group, the mean preoperative tumor volume was 13.8 ± 9.0 cm3 and the mean tumor resection rate was 95% ± 5%. The mean tumor volume at the start of the observation period did not differ significantly between the two groups (remnant vs TN: 0.41 ± 0.29 vs 0.34 ± 0.28 cm3, p = 0.171). The median periods until tumor progression was detected were 15.1 (range 4.9-76.2) months and 44.7 (range 12.6-93.2) months in the TN and remnant groups, respectively. In the remnant group, the TPFS rates were 74% and 70% at 3 and 5 years after the surgery, respectively, compared with 59% and 47% in the TN group. The log-rank test demonstrated a significant difference (p = 0.008) in the TPFS rates between the two groups. Furthermore, 42 patients each from the remnant and TN groups were matched based on tumor volume. TPFS was significantly longer in the remnant group than in the TN group (3-year rates, 77% vs 62%; 5-year rates, 73% vs 51%; p = 0.02). In the remnant group, 18% of the tumor remnants demonstrated regression during follow-up, compared with 9% in the TN group, but this intergroup difference was not significant (p = 0.25). This study demonstrated that the growth potential of small VS remnants was lower than that of TN tumors. Observing for small remnants may be appropriate after STR of a large VS. Given the risk of tumor regrowth, careful observation using MRI should be mandatory during follow-up.

Outcome assessment of intraoperative radiotherapy for brain metastases: results of a prospective observational study with comparative matched-pair analysis

PurposeIntraoperative radiation therapy (IORT) is an emerging alternative to adjuvant stereotactic external beam radiation therapy (EBRT) following resection of brain metastases (BM). Advantages of IORT include an instant prevention of tumor regrowth, optimized dose-sparing of adjacent healthy brain tissue and immediate completion of BM treatment, allowing an earlier admission to subsequent systemic treatments. However, prospective outcome data are limited. We sought to assess long-term outcome of IORT in comparison to EBRT.MethodsA total of 35 consecutive patients, prospectively recruited within a study registry, who received IORT following BM resection at a single neuro-oncological center were evaluated for radiation necrosis (RN) incidence rates, local control rates (LCR), distant brain progression (DBP) and overall survival (OS) as long-term outcome parameters. The 1 year-estimated OS and survival rates were compared in a balanced comparative matched-pair analysis to those of our institutional database, encompassing 388 consecutive patients who underwent adjuvant EBRT after BM resection.ResultsThe median IORT dose was 30 Gy prescribed to the applicator surface. A 2.9% RN rate was observed. The estimated 1 year-LCR was 97.1% and the 1 year-DBP-free survival 73.5%. Median time to DBP was 6.4 (range 1.7–24) months in the subgroup of patients experiencing intracerebral progression. The median OS was 17.5 (0.5-not reached) months with a 1 year-survival rate of 61.3%, which did not not significantly differ from the comparative cohort (p = 0.55 and p = 0.82, respectively).ConclusionIORT is a safe and effective fast-track approach following BM resection, with comparable long-term outcomes as adjuvant EBRT.

Non-functioning pituitary macroadenoma following surgery: long-term outcomes and development of an optimal follow-up strategy.

Recurrence and regrowth of non-functioning pituitary macroadenomas (NFPMs) after surgery are common but remain unpredictable. Therefore, the optimal timing and frequency of follow-up imaging remain to be determined. We sought to determine the long-term surgical outcomes of NFPMs following surgery and develop an optimal follow-up strategy. Patients underwent surgery for NFPMs between 1987 and 2018, with a follow-up of 6 months or more, were identified. Demographics, presentation, management, histology, imaging, and surgical outcomes were retrospectively collected. In total, 383 patients were included; 256 were men (256/383; 67%) with median follow-up of 8 years. Following primary surgery, 229 patients (229/383; 60%) achieved complete resection. Of those, 28 (28/229; 11%) developed recurrence, including six needed secondary surgery (6/229; 3%). The rate of complete resection improved over time; in the last quartile of cases, 77 achieved complete resection (77/95; 81%). Reoperation-free survival at 5, 10 and 15 years was 99%, 94% and 94%, respectively. NFPMs were incompletely resected in 154 patients (154/383; 40%); of those, 106 (106/154; 69%) had regrowth, and 84 (84/154; 55%) required reoperation. Surgical reintervention-free survival at 5, 10 and 15 years was 74%,49% and 35%, respectively. Young age and cavernous sinus invasion were risk factors for undergoing reoperation (P < 0.001 and P < 0.0001, respectively) and radiotherapy (P = 0.003 and P < 0.001, respectively). Patients with residual tumour required reoperation earlier than those underwent complete resection (P = 0.02). Radiotherapy to control tumour regrowth was delivered to 65 patients (65/383; 17%) after median time of 1 year following surgery. Radiotherapy was administered more in patients with regrowth of residual disease (61/106; 58%) than those who had NFPMs recurrence (4/28; 14%) (P ≤ 0.001) Following postoperative radiotherapy, one patient (1/65; 2%) had evidence of regrowth, seven (7/65; 11%) had tumour regression on imaging, and no patients underwent further surgery. NFPMs recurrence and regrowth are common, particularly in patients with residual disease post-operatively. We propose a follow-up strategy based on stratifying patients as "low risk" if there is no residual tumour, with increasing scan intervals, or "high risk" if there is a residual tumour, with annual scans for at least five years and extended lifelong surveillance after that.

Estrogen receptor blockade and radiation therapy cooperate to enhance the response of immunologically cold ER+ breast cancer to immunotherapy

BackgroundMost patients with estrogen receptor positive (ER+) breast cancer do not respond to immune checkpoint inhibition (ICI); the tumor microenvironment (TME) of these cancers is generally immunosuppressive and contains few tumor-infiltrating lymphocytes. Radiation therapy (RT) can increase tumor inflammation and infiltration by lymphocytes but does not improve responses to ICIs in these patients. This may result, in part, from additional effects of RT that suppress anti-tumor immunity, including increased tumor infiltration by myeloid-derived suppressor cells and regulatory T cells. We hypothesized that anti-estrogens, which are a standard of care for ER+ breast cancer, may ameliorate these detrimental effects of RT by reducing the recruitment/ activation of suppressive immune populations in the radiated TME, increasing anti-tumor immunity and responsiveness to ICIs.MethodsTo interrogate the effect of the selective estrogen receptor downregulator, fulvestrant, on the irradiated TME in the absence of confounding growth inhibition by fulvestrant on tumor cells, we used the TC11 murine model of anti-estrogen resistant ER+ breast cancer. Tumors were orthotopically transplanted into immunocompetent syngeneic mice. Once tumors were established, we initiated treatment with fulvestrant or vehicle, followed by external beam RT one week later. We examined the number and activity of tumor infiltrating immune cells using flow cytometry, microscopy, transcript levels, and cytokine profiles. We tested whether fulvestrant improved tumor response and animal survival when added to the combination of RT and ICI.ResultsDespite resistance of TC11 tumors to anti-estrogen therapy alone, fulvestrant slowed tumor regrowth following RT, and significantly altered multiple immune populations in the irradiated TME. Fulvestrant reduced the influx of Ly6C+Ly6G+ cells, increased markers of pro-inflammatory myeloid cells and activated T cells, and augmented the ratio of CD8+: FOXP3+ T cells. In contrast to the minimal effects of ICIs when co-treated with either fulvestrant or RT alone, combinatorial treatment with fulvestrant, RT and ICIs significantly reduced tumor growth and prolonged survival.ConclusionsA combination of RT and fulvestrant can overcome the immunosuppressive TME in a preclinical model of ER+ breast cancer, enhancing the anti-tumor response and increasing the response to ICIs, even when growth of tumor cells is no longer estrogen sensitive.

MDB-20. IMPROVING THE PERSISTENCE OF CAR T CELLS AGAINST GROUP 3 MEDULLOBLASTOMAS VIA EPIGENETIC REGULATION OF EXHAUSTION

Abstract Medulloblastomas (MB) are the most common malignant pediatric brain tumor with molecular subclass Group 3 (G3) requiring the most intense treatment regimen including surgery, intensive radiation followed by chemotherapy. Despite an overall 40% survival rate, survivors’ quality of life is often impaired due to whole-brain radiation leading to neurocognitive defects. Chimeric antigen receptor (CAR) T cell therapy has emerged clinically as a safe, tumor-targeted immunotherapy with the most success observed against hematological malignancies. Translating CAR T cell therapy to brain tumors has proven challenging due to lack of targetable antigens on the surface of tumor cells and lack of persistence of CAR T cells. We have previously identified that patient samples and PDOX-derived cell lines of G3 MBs consistently over-express B7-H3 (CD267) compared to normal tissue. Herein, we investigated B7-H3 targeted CAR T cell products against G3 MB in vitro and in vivo. Initial results show that B7-H3 CAR T cells are highly effective in clearing human MB tumors in NSG mice, however, 4 out 5 mice experienced late relapses that showed reduced, but still present, B7-H3 antigen expression. We hypothesize that the lack of CAR T cell persistence is ultimately responsible for tumor regrowth. To overcome this limitation, we have identified epigenetic regulators DNMT3A and TET2 that control T cell exhaustion. Using CRISPR/Cas9, we genetically knocked out DNMT3A and TET2 in CAR T cells and investigated the impact on persistence and anti-tumor activity. Our data supports the hypothesis that knock out of DNMT3A and TET2 improves antigen-dependent proliferation and persistence of B7-H3 CAR T cells against G3 MB tumor lines in vitro. DNMT3A KO shows a more sustained effect over TET2. Currently, we are optimizing in vivo experiments to investigate prolonged tumor clearance in both immunocompromised and fully immunocompetent murine models.

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

Abstract A074: In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat

Abstract Prostate cancer is the second most common cause of cancer-related deaths in American men. When locally targeted approaches fail, androgen deprivation therapy is administered to block androgen stimulated prostate cancer growth signals. Most tumors initially exhibit rapid and dramatic regression following androgen deprivation therapy. However, many patients treated with androgen deprivation therapy will have disease recurrence and develop castration-resistant prostate cancer (CRPC), which is highly metastatic with poor survival rates. To improve clinical options for CRPC, pre-clinical animal models that closely recapitulate the human disease course are an essential component of drug development. SRG OncoRats are highly immunocompromised Rag2/Il2rg double knockouts that lack mature B cells, T cells, and circulating NK cells. To establish an in vivo model of CRPC, we inoculated VCaP cells subcutaneously into the hind-flank of SRG OncoRats and monitored tumor growth. On Day 24 rats underwent orchiectomy and tumor growth was further monitored through Day 46. As seen with androgen deprivation therapy in humans, VCaP tumors initially regressed in the SRG OncoRats. However, VCaP tumors resumed growth 14 days after castration, faithfully modeling the progression of CRPC. After tumor regrowth, animals were enrolled into a therapeutic efficacy study that mimics the current clinical challenges in prostate cancer treatment. Citation Format: R. Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Abigail Ross, Razoanul Haque, Fallon K. Noto. In vivo modeling of castration-resistant prostate cancer in the immunodeficient SRG OncoRat [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A074.

Sustained organ preservation in patients with rectal cancer treated with total neoadjuvant therapy: Long-term results of the OPRA trial.

3520 Background: The preliminary results of the OPRA trial demonstrated that a substantial number of patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) could achieve organ preservation. Although most tumor regrowths seem to occur within the first 3 years, longer follow-up is needed to assess the ongoing risk of regrowth. Here, we report the long-term organ preservation rate and oncologic outcomes of the OPRA trial. Methods: A prospective, multi-institutional phase II trial, in which patients with stage II or III rectal cancer were randomized to receive either induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients underwent reassessment for treatment response 8-12 weeks after TNT. Patients who achieved a complete or near-complete response after finishing TNT were offered a watch and wait approach (WW). Those with incomplete response were recommended total mesorectal excision (TME). We report 5-year disease-free survival (DFS), organ preservation (defined as TME-free survival), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) for each treatment group. We also compared DFS between patients who underwent upfront TME after restaging and patients who underwent TME after tumor regrowth. All analyses followed the intention-to-treat principle and groups were compared using the log-rank test. Results: Of the 324 patients randomized, 158 were assigned to the INCT-CRT group and 166 to the CRT-CNCT group. Median follow-up was 56 months; 85 DFS events were observed. The rates of 3- and 5-year DFS, TME-free survival, LRFS, DMFS and OS are listed in the Table. In total, 80 of the 225 (36%) patients who started WW developed a regrowth; 94% occurred within 2 years and 99% occurred within 3 years. The rate of TME-free survival at 5 years was significantly higher for CRT-CNCT (54%) than in INCT-CRT (39%). 5-year DFS was similar for patients who underwent TME after restaging (61%) compared to patients who underwent TME after regrowth (62%, p = 0.86). Conclusions: In patients with rectal cancer treated with TNT and WW, the majority of tumor regrowths occur in the first 2 years, and regrowth after 3 years is vanishingly rare. Salvage TME for tumor regrowth during WW appears to offer similar outcome to immediate TME after incomplete response to TNT. Distant metastases remain the most frequent cause of treatment failure, with similar rates in the two treatment groups. Clinical trial information: NCT02008656 . [Table: see text]

Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.

2063 Background: Anti-angiogenic therapies, anti-VEGF agents, cause high radiographic response rates due to reduction in vascular permeability. However, we theorized the degree of tumor shrinkage combined with the duration of response might be a more meaningful measure of tumor control and may better reflect real patient benefit. In the current study, we investigate the association between model-derived parameters describing enhancing tumor volumetric dynamics and overall survival (OS) in recurrent glioblastoma treated with anti-VEGF therapy from multiple clinical trials. Methods: N=134 patients treated with bevacizumab +/- irinotecan (BRAIN Trial; NCT00345163) and N=121 patients treated with cabozantinib (XL184-201; NCT00704288) were used to identify potential imaging biomarkers, and N=63 patients in the bevacizumab control arm in a phase III trial (GLOBE Trial; NCT02511405) were used as a validation dataset. Enhancing tumor volumes were estimated using T1 subtraction maps, and a biexponential model was used to model tumor response ( d) and regrowth ( g) rates, as well as time to tumor regrowth ( TTG), the inflection point where the tumor stops shrinking and starts to regrow, and the depth of response ( DpR) after initiation of anti-VEGF therapy for each patient. Log-rank, univariate, and multivariable Cox regression were used to quantify the relationship of these parameters and OS. Results: Optimized thresholds based on maximum hazard ratio occurred at d =0.11 months-1 ( P=5x10-9 training; P=0.0082 validation); g=0.07 months-1 ( P=5x10-20 training; P&lt;0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P&lt;0.0001 validation); and DpR of 11.3% ( P=0.0026 training; P=0.0177 validation). Univariate and multivariable Cox regression using these thresholds and controlling for age and baseline tumor volume confirmed that d, g, TTG, and DpR were all significant and independent predictors of OS in both phase II training and phase III validation datasets ( P&lt;0.01). Additionally, patients exhibiting combinations of a high DpR and/or long TTG showed differential median OS, while patients with favorable diffusion MR phenotypes exhibited a longer OS and significantly longer TTG. Conclusions: Volumetric response and regrowth rates, TTG, and DpR using a biexponential model are significant and independent predictors of OS in recurrent glioblastoma treated with anti-VEGF therapy. Clinical trial information: NCT00345163 ; NCT00704288 ; NCT02511405 .

Low-dose total body irradiation enhances systemic anti-tumor immunity induced by local cryotherapy.

Strategies that restore the immune system's ability to recognize malignant cells have yielded clinical benefits but only in some patients. Tumor cells survive cryotherapy and produce a vast amount of antigens to trigger innate and adaptive responses. However, because tumor cells have developed immune escape mechanisms, cryotherapy alone may not be enough to induce a significant immune response. The mice were randomly divided into four groups: Group A: low-dose total body irradiation combined with cryotherapy (L-TBI+cryo); Group B: cryotherapy (cryo); Group C: low-dose total body irradiation(L-TBI); Group D: control group (Control). The tumor growth, recurrence, and survival time of mice in each group were compared and the effects of different treatments on systemic anti-tumor immunity were explored. L-TBI in conjunction with cryotherapy can effectively control tumor regrowth, inhibit tumor lung metastasis, extend the survival time of mice, and stimulate a long-term protective anti-tumor immune response to resist the re-challenge of tumor cells. The anti-tumor mechanism of this combination therapy may be related to the stimulation of inflammatory factors IFN-γ and IL-2, as well as an increase in immune effector cells (CD8+ T cells) and a decrease in immunosuppressive cells (MDSC, Treg cells) in the spleen or tumor tissue. We present unique treatment options for enhancing the immune response caused by cryotherapy, pointing to the way forward for cancer treatment.

Surgically targeted radiation therapy (STaRT) for recurrent glioblastoma: Initial outcomes from a prospective multicenter registry.

2038 Background: Surgically targeted radiation therapy (STaRT), using a novel bioresorbable collagen brachytherapy device containing 4 Cesium-131 sources, is FDA-cleared for use as adjuvant radiation therapy (RT) post-resection in both newly diagnosed and recurrent intracranial neoplasms. Intraoperative initiation of brachytherapy potentially minimizes post-resection tumor regrowth with a favorable dosimetric profile compared to external beam radiation. This work sought to determine early patterns of care and the safety of this approach in recurrent GBM. Methods: This prospective multi-institutional observational study (NCT04427384) included recurrent GBM patients who underwent maximum safe resection (MSR) and permanent implantation of the device(s) (GammaTile, GT Medical Technologies, Tempe, AZ, US). Descriptive and comparative analyses regarding patient characteristics and early clinical outcomes were performed. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. Results: During 10/2020–01/2023, 14 participating sites enrolled 45 patients with recurrent GBM for STaRT; 2 patients had two sites treated for a total of 47 implants. 67% of patients were treated at the first recurrence, 24% at the second, and 13% at the third, respectively. The median age was 61 (range 28-75), 36% were female, and 23% were &gt; 65 years. 85% of patients received prior same-site RT with the median time from last RT to implantation of 14.6 months (range 3.5-57). The median maximum preoperative size was 4.2 cm (range 1.6-7.0) and the median volume was 20.8 cm3 (range 0.8-130). 68% of resections were gross-total, 17% near-total, and 15% sub-total; the median time needed for device implantation was 5 minutes (range 1.0-13). Median follow-up was 5.2 months (range 0.6-23.2). Median Karnofsky performance status (KPS) at screening, at initial postoperative assessment, and 3 months were all 80 (range 40-100). 7 attributed AEs occurred in 13% (6/45) of patients, all grade 3 AEs: 2 CSF leaks, 2 seizures, 1 cerebral edema, 1 pseudomeningocele, and 1 left hemiparesis. All except one were coded as related to both radiation and surgery; the patient with pseudomeningocele experienced a seizure at 47 days that was considered related to radiation alone. Conclusions: Early data from this prospective registry demonstrate the feasibility and safety of STaRT in recurrent GBM. Data on 6-month progression-free survival will be presented at the conference. A prospective randomized trial of adjuvant systemic therapy (AST) +MSR+STaRT versus MSR+AST is planned for initiation in 2023.