bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor , Cho Nicholas , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Fain Shmueli Shifra , Nathanson David , Wen Patrick Y. , Cloughesy Timothy Francis 
Published: June 2023

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<0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P<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<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 .
Immune checkpoint inhibitor (ICI) therapy in glioblastoma: Institutional experience at the Massachusetts General Hospital (MGH).
Authors: Rhee John Yohan , Song Kun Wei , Arrillaga-Romany Isabel , Forst Deborah Anne , Jordan Justin T. , Ly Ina , Plotkin Scott Randall , Wang Nancy , Parsons Michael , Gerstner Elizabeth R , Dietrich Jorg 
Published: June 2023

2065 Background: Immune checkpoint inhibitors (ICI) have resulted in promising outcomes in systemic cancer but response in glioblastoma (GBM) has not met early expectations based on early clinical trial results. Conflicting data exists regarding the incidence of pseudoprogression after ICI in brain tumors. Here, we present our institutional experience of the radiographic response following ICI therapy in GBM both at initial diagnosis and recurrence. Methods: We retrospectively identified IDH-wildtype GBM (per 2021 WHO criteria) patients treated either at time of initial diagnosis or at recurrence with nivolumab, pembrolizumab, or durvalumab between 2015 and 2022 at MGH. Overall radiographic and clinical responses after initiation of ICI were assessed in both groups. Results: 56 pts (18 female, 38 male) were identified (average age 58.6). Eight (14.3%) patients had ICI-related non-hematological toxicities, including granulomatosis folliculitis, arthritis and myositis, headache, acneiform rash, transaminitis, and gastritis). Four (7.1%) of the eight patients had to discontinue treatment due to ICI-related severe toxicity (hepatitis and/or gastritis) and were not included in the final response assessment. Of the remaining 52 patients, none had evidence of pseudoprogression related to ICI. We did not identify any complete response (CR) or partial response (PR) secondary to ICI monotherapy. In the 13 patients treated at initial diagnosis, the following radiographic responses were seen: CR=0, PR=0, stable disease (SD)=5 (38.5%), and progressive disease (PD)=8 (61.5%). In the 39 patients treated at disease recurrence, the responses were: CR=0, PR=4 (10.3%), SD=10 (33.3%), PD= 22 (56.4%). Noteworthy, all patients with PR were concurrently treated with bevacizumab. Conclusions: 0/52 patients showed radiographic response after ICI monotherapy. While treatment was overall tolerated, ICI therapy was discontinued due to toxicity in 7% of patients. Pseudoprogression attributable to ICI was not seen in any of the patients treated.
Intraoperative glioma characterization using time-resolved fluorescence spectroscopy.
Authors: Menaker Simon , Patil Chirag , Krawczyk Kamil , Chu Ray M. , Mamelak Adam N. , Bannykh Serguei I. , Hu Jethro Lisien , Black Keith L. , Butte Pramod V. 
Published: June 2023

2072 Background: Extent of surgical resection significantly improves progression-free and overall survival in glioma patients. Due to the infiltrative nature of gliomas, tumor margin detection is often difficult, and current intraoperative visualization methods are limited. Time-resolved fluorescence spectroscopy (TRFS) has the potential of differentiating glioma from normal brain tissue, thereby maximizing extent and safety of resection. Methods: Twenty-seven preoperative patients diagnosed with glioma met inclusion criteria for an IRB-approved study aimed to assess the accuracy of TRFS relative to tissue histopathology for differentiating glioma from normal cortex (NC), normal white matter (NWM), and white matter with edema (WME). A multi-channel TRFS system was developed for in vivo brain tissue and tumor characterization during glioma surgery. A custom-designed fiber optic probe was used to deliver ultrafast laser pulses to tissue regions of interest and collect fluorescence signals, with simultaneous registration to intraoperative neuronavigation. The fluorescence light was collected using a photomultiplier tube and digitized across six wavelength bands. Biopsies were taken at each measurement site for evaluation by a blinded neuropathologist to determine the accuracy of TRFS, which was calculated using parameters derived from the recorded fluorescence pulse and used to characterize tissue signatures. Results: During surgical resection of 27 patients, 162TRFS measurements were collected in vivo followed by biopsy of the same tissue. Samples from brain tumors (39 low grade gliomas (LGG, WHO grade I to III), 35 high grade gliomas (HGG, WHO grade IV)) were compared with 47 samples of normal brain tissue (NC and NWM). The time-resolved system was able to differentiate LGG from normal tissue with 97% sensitivity and 93% specificity (93% PPV and 98% NPV). When all tumor grades were tested, the sensitivity dropped to 91% (96% PPV and 86% NPV), which we believe reflects the heterogeneity of HGG. HGG alone showed a sensitivity of 83% and specificity of 93% (91% PPV and 88% NPV). Normal cortex had the fastest decays across all wavelength bands among different tissue types, WME had longer decays compared to other tissue types at all wavelengths, and HGG had a variable but predictably different fluorescence decay pattern. Conclusions: TRFS is an intraoperative tool that can distinguish glioma from normal brain tissue and has the potential to maximize safe surgical resection.
The ketogenic diet plus standard of care for adults with recently diagnosed glioblastoma: Results from a phase 1 trial.
Authors: Amaral Lj , Gresham Gillian , Kim Sungjin , Tighiouart Mourad , Nelson Thomas , Welborn Amelia , Lockshon Laura , Noorvash Brandon , Rudnick Jeremy David , Irwin Scott A , Freedland Stephen J. , Hu Jethro Lisien 
Published: June 2023

2076 Background: Facing limited treatment options, brain tumor patients are often highly motivated to use complementary therapies, including diet, to help themselves. There is now an abundance of preclinical evidence suggesting possible benefit with a ketogenic diet (KD) for brain tumor patients, but clinical evidence is still limited. Thus, we conducted a single-arm, phase 1 safety and feasibility trial of a KD among patients with recently diagnosed glioblastoma (GBM) during standard- of-care (SOC) treatment. Methods: Adults with GBM within 3 months of diagnosis followed a supervised 16-week diet intervention of a standard 3:1 KD (Fat(g):Carbohydrate+Protein(g)) plus SOC chemoradiation. Primary outcome was safety, evaluated by weekly assessments of weight and body mass index (BMI). Secondary outcomes included feasibility (pre-specified as > 50% of patients maintaining blood ketone levels > 0.3 mM over 50% of study days), progression-free survival (PFS), overall survival (OS), health-related quality-of-life (QOL), and cognitive function. Twice daily blood glucose and ketone levels, weight/BMI, physical activity, and sleep were assessed by remote monitoring. Results: Seventeen patients were evaluable: 53% women, median age 55, median Karnofsky Performance Status 85. All participants met the primary safety objective with no instances of excessive weight loss or related serious adverse events. Adherence to KD was high: all 17 patients maintained nutritional ketosis (≥0.3 mM/dL) >50% of study days, where 14 patients maintained nutritional ketosis >85% of study days. Median time to ketosis from diet initiation was 3 days. Diet-related AEs were mild and manageable; no patients came off study due to inability to tolerate KD. Median progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28.6 months from KD initiation respectively. QOL, symptom control, and cognitive function remained stable or improved, although these did not reach statistical significance. Conclusions: This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for future randomized trials to assess efficacy. Clinical trial information: NCT03451799 .
Osmotic blood-brain barrier disruption with mannitol followed by methotrexate, rituximab, and carboplatin in treating patients with newly diagnosed primary central nervous system lymphoma.
Authors: Ambady Prakash , Doolittle Nancy Diane , Neuwelt Edward A. , Fu Rongwei (Rochelle) , Teglassy Gerda , Vo Anh Huan 
Published: June 2023

2077 Background: Osmotic blood-brain barrier disruption (BBBD) uses intra-arterial (IA) mannitol to open the neuro-vascular unit to enhance delivery of therapeutic agents to the brain. We report the results of a multi-institutional, single arm, phase 2 study evaluating the efficacy and safety of BBBD-enhanced chemotherapy in combination with immunotherapy in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). PCNSL is a rare non-Hodgkin’s lymphoma that is limited to the brain, cerebrospinal fluid, spinal cord and/or the vitreoretinal compartment. Methods: Non-immunocompromised subjects with newly diagnosed PCNSL received rituximab IV over 5 hours on day 1. On days 2 and 3, under general anesthesia in the angiography suite, subjects received IA mannitol immediately followed by IA methotrexate over 10 minutes, and then IA carboplatin over 10 minutes. Subjects received sodium thiosulfate IV for hearing protection at 4 and 8 hours after each carboplatin dose. Treatment was repeated every month for up to 12 courses in the absence of disease progression or unacceptable toxicity. Per institutional recommendations, further accrual was terminated during the COVID-19 pandemic. Contrast MRI was used for response assessment based on IPCG criteria. Results: Twenty subjects (10 F, 10 M, Median KPS = 80; range 40-100) received a median of 8 cycles at 3 US institutions. Sixteen radiographic complete responses (80%) and 1 partial response were documented, 3 subjects were not evaluable (2 withdrew consent and 1 unrelated death). Median PFS was 55.2 months (95% CI :10.3 – not reached) and Median Overall survival was 82.8 months (95% CI :19.8-145.8). Fourteen patients (82% of evaluable patients) had grade 3 or 4 adverse events (AE). Grade 4 AEs (n = 14 in n = 7 patients) included neurologic toxicities (ischemia, cervical cord inflammation, neuropathy) and blood/bone marrow toxicities (lymphopenia, neutropenia, granulocytopenia). There were no treatment-related deaths. Conclusions: We demonstrate the feasibility of performing BBBD in a multi-institutional setting with excellent PFS and OS in patients without whole brain radiation or autologous transplant. Our CR rates, PFS and OS are comparable to other IV high-dose MTX regimens, with acceptable toxicity profile and no documented treatment-related deaths. Clinical trial information: NCT00293475 .
Belzutifan treatment of Von Hippel-Lindau (VHL) related central nervous system (CNS) hemangioblastomas (HBs): A single institution experience.
Authors: Iliopoulos Othon , Rapalino Otto , Barker Frederick G. , Coumans Jean-Valery , Jones Pamela , Bear Lauren , Konstantakou Eumorphia , Orr Christina , Mahar Maura , Nahed Brian 
Published: June 2023

2078 Background: Patients with inactivating germline mutations in the VHL gene develop CNS (brain and/or spine) HBs and/or renal cancers, pheochromocytomas and pancreatic neuroendocrine tumors. The oral HIF2a inhibitor belzutifan has been approved by FDA for the treatment of VHL-related HBs. We present here data on a cohort of VHL patients with CNS HBs treated with belzutifan in a single institution. Methods: Adult VHL patients, with radiologically documented CNS (brain and/or spine) HBs that displayed documented growth within the last 6 months prior to therapy, were treated with an initial dose of 120 mg belzutifan orally per day. Target lesions included HBs > 0.4cm long in one maximal cross-sectional diameter. Lesions were imaged by MRI at 1.5, 3, 6 months after initiation of treatment and at 6-month intervals thereafter. Solid enhancing lesions, associated cysts and peritumoral edema were recorded and quantified. Tumor sizes were evaluated by RECIST 1.1 criteria and volumetric analysis. All patients were evaluated and treated in the Hemangioblastoma Center and the VHL Clinic of the Massachusetts General Hospital Cancer Center. Results: At the time of analysis, 9 females and ten 10 male VHL patients (n=19) have been treated. Median age at treatment initiation was 36 yo (range 19-59). Median follow up is 12 months (range 1-19.5 months). Two patients were not yet evaluable for response. Of 17 evaluable patients, 8 had a PR (ORR 47%; 95% CI, 34-60), 8 had SD and 1 patient had progression (PD, 5.8%). Two patients had dose reduction to 80 mg/d because of anemia. No patient had grade 3 or greater toxicity and no patient experienced a CNS related toxicity during treatment. Volumetric analysis of solid and cystic components of the lesions, VHL germline mutations and other correlates of response to belzutifan will be presented. Conclusions: Real world data collected at a single institution confirm the high response rate of both solid and cystic components of CNS HBs to the FDA approved HIF2a inhibitor, belzutifan. Belzutifan was well tolerated. Further prospective controlled studies addressing the optimal dose, schedule and duration of treatment of HBs with belzutifan are required.
Phase I study of the bifunctional anti-PD-L1/TGF-βRII agent SHR-1701 combined with SHR2554, an EZH2 inhibitor, in patients with previously treated advanced lymphoma and solid tumors.
Authors: Feng Kaichao , Liu Yang , Wang Chunmeng , Nie Jing , Xia Yan , Jiang Jingting , Han Weidong 
Published: June 2023

2507 Background: Despite the remarkable successes of cancer immunotherapies, the majority of patients (pts) experience only partial response and most pts will progress. Enhancer of zeste homolog 2 (EZH2) as an epigenetic target for cancer therapy has been shown to enhanced antigen presentation and synergize with immunotherapy in preclinical studies. This study investigates the safety and efficacy of SHR-1701 (anti-PD-L1/TGF-βRII) plus SHR2554 (EZH2i) in pts with pretreated advanced lymphoma and solid tumors. Methods: This open-label, single-arm, phase 1 study enrolled pts with pretreated advanced lymphoma and solid tumors. Escalating doses of SHR2554 (300–350mg bid) plus fixed-dose SHR-1701 (30mg/kg q3w) were evaluated in the dose-escalation phase. SHR2554 at the recommended phase 2 dose (RP2D) plus SHR-1701 were administered in the dose-expansion phase. The primary end point was determination of the RP2D of SHR2554 plus SHR-1701. Secondary end points included safety and preliminary activity. Results: By January 6, 2023, 33 patients were enrolled (dose-escalation: n=7; dose-expansion, n=26). No dose-limiting toxicities were observed, and RP2D was established as SHR2554 350mg bid plus SHR-1701 30mg/kg q3w. Treatment-related adverse events (TRAEs) occurred in 13 of 32 patients (40.6%), mainly including platelet count decreased (21.9%), anemia (15.6%) and vomiting (15.6%). The most common Grade ≥3 TRAEs were anemia (3.1%) and fever (3.1%). In the efficacy-evaluable population (n = 26), objective response rate (ORR) was 57.7%, including 2 complete response (CR) achieved by patients with Metastatic Renal Cell Carcinoma and classical Hodgkin lymphoma (cHL). 16 patients with relapsed/refractory classical Hodgkin lymphoma (cHL) after a median of 10 prior lines of therapy have been enrolled. 16 (100%) cHL pts had received prior anti-PD1/PD-L1 antibody therapy, and 15 ( 93.8%) prior epigenetic therapies, such as decitabine or chidamide. Out of 14 cHL-evaluable patients, ORR was 100% and the CR rate was 7.1%. Conclusions: SHR-1701 combined with SHR2554 showed acceptable safety profile and encouraging antitumor activity in immunotherapy-pretreated cHL, establishing the foundation for further exploration. Clinical trial information: NCT04407741 .
A phase 1a dose-escalation study of PY159, a monoclonal antibody targeting TREM1 (triggering receptor expressed on myeloid cells 1).
Authors: Winer Ira Seth , Patnaik Amita , Barve Minal A. , Kummar Shivaani , Schenk Erin Lynn , LoRusso Patricia , Yeku Oladapo O. , Fu Siqing , Jahchan Nadine , Myers Matthew , Liang Linda , Deegan Denise , Jackson Lynnae , Li Yunfeng , Reyno Len , Chamberlain Marc Charles 
Published: June 2023

2523 Background: This study aimed to characterize the safety of PY159 (an agonist antibody to TREM1 that reprograms immunosuppressive intratumoral myeloid cells) as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors, including subjects refractory to immune checkpoint inhibitors. Methods: Two strata were evaluated, PY159 as a single agent and in combination with pembrolizumab, using an accelerated 3+3 dose escalation study design. Dosing was intravenous once every 3 weeks. Disease assessment by RECIST 1.1 was performed every 6 weeks. The single-agent stratum included 7 dose levels of PY159 (range, 0.01–10 mg/kg). The combination stratum included 4 dose levels of PY159 (range, 0.3–10 mg/kg). Pharmacokinetics were evaluated at specified time points. Archival tumor tissue was analyzed for TREM1 expression by immunohistochemistry. Based on preclinical immunohistochemistry data, HR+ HER2– and triple-negative breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, and gynecologic cancers were studied. Results: Thirty-seven subjects (median age 65 years; range 29–86 years; 22 female and 15 male) with an ECOG PS <2 were enrolled and all but 5 were RECIST-evaluable (3 withdrew consent, 1 sustained a TEAE, and 1 had a DLT, an asymptomatic grade-3 transaminitis). Twenty subjects received single-agent PY159 and 17 received PY159 in combination with pembrolizumab. Four subjects experienced a grade-3 TRAE, 14 a low-grade immune-related reaction, 18 an SAE (related in 2), and 14 an immune-related adverse event (arthralgias). There were no SUSARs. Five subjects sustained high-grade TRAE resulting in discontinuation. TREM1 levels in the tumors ranged from 0 to 15%. Pharmacokinetic parameters were linear beyond the 0.3 mg/kg dose, dose proportional with a half-life of 8–9 days, and unaffected by pembrolizumab. Radiographic response included 2 partial responses (1 each in an ovarian and pancreatic cancer subject) and stable disease in 9 subjects, ranging from 12 to 96+ weeks. Two subjects continue receiving PY159. Conclusions: PY159 was well tolerated, with an acceptable safety profile, as a single agent and in combination with pembrolizumab. A dose for expansion was derived and enrollment of subjects with 7 prespecified cancers is ongoing. Clinical trial information: NCT04682431 .