tbuckley/cabot-search huggingface dataset:
Phase I Study of a CD45-Targeted Antibody–Radionuclide Conjugate for High-Risk Lymphoma
Authors: Ryan D. Cassaday, Oliver W. Press, John M. Pagel, Joseph G. Rajendran, Ted A. Gooley, Darrell R. Fisher, Leona A. Holmberg, Robert S. Miyaoka, Brenda M. Sandmaier, Damian J. Green, Ajay K. Gopal
Journal: Clinical Cancer Research (2019)

External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression.We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), or Hodgkin lymphoma. The primary objective was to estimate the maximum tolerated radiation absorbed dose.Sixteen patients were enrolled: 7 patients had B-NHL, 6 had Hodgkin lymphoma, and 3 had T-NHL. Median number of prior therapies was three (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Nonhematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later.CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.
Adoptive T-cell therapy (ACT) with TILs for metastatic melanoma: Clinical responses and durable persistence of anticancer responses in peripheral blood.
Authors: Marco Donia, Rikke Andersen, Eva Ellebaek, Trine Zeeberg Iversen, Mads Hald Andersen, Per thor Straten, Inge Marie Svane
Journal: Journal of Clinical Oncology (2013)

3028 Background: TIL treatment holds the promise to introduce a new treatment paradigm into oncology practice. To demonstrate the logistical feasibility of this complex approach in Europe, at Herlev Hospital, Denmark, we have initiated a trial for patients with metastatic melanoma and evaluated the melanoma-specific immunity in the peripheral blood. Methods: We present the updated results of trial NCT00937625. The study takes place in a medium-size academic center (30 in-patient oncology beds) equipped with a 36 square meters cGMP cell production lab integrated in a hematopoietic stem cell transplantation unit. Patients were treated with autologous TILs preceded by standard lymphodepleting chemotherapy but followed by attenuated regimens of IL-2 (n=6 low-dose s.c. for 14 days; n=9 i.v. intermediate decrescendo dose). Melanoma-specific responses were assessed with intracellular cytokine staining. Results: We have generated TILs from 28/31 patients, with 15 patients treated so far and many TILs cryopreserved for future use. Patients were treated with an average of &gt;50x10 9 CD4 + , CD8 + and a small but consistent fraction of γδ TILs. The lower doses of IL-2 have significantly decreased the classical toxicity of the treatment associated with more harsh IL-2 regimens, and response evaluation showed the achievement of three CR lasting &gt; 1 year and four PR. Clinical responses were associated with high numbers of tumour reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence (up to 1 year) of anti-melanoma T-cell responses in the peripheral blood. Conclusions: A high response rate including durable complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which significantly reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. By showing that TIL-based ACT is logistically feasible and accessible to medium-size academic centers, we open the possibility for testing this treatment in a large randomized setting in Europe. Clinical trial information: NCT00937625.
Mitohormesis, UPRmt, and the Complexity of Mitochondrial DNA Landscapes in Cancer
Authors: Timothy C. Kenny, Maria L. Gomez, Doris Germain
Journal: Cancer Research (2019)

Abstract The discovery of the Warburg effect, the preference of cancer cells to generate ATP via glycolysis rather than oxidative phosphorylation, has fostered the misconception that cancer cells become independent of the electron transport chain (ETC) for survival. This is inconsistent with the need of ETC function for the generation of pyrimidines. Along with this misconception, a large body of literature has reported numerous mutations in mitochondrial DNA (mtDNA), further fueling the notion of nonfunctional ETC in cancer cells. More recent findings, however, suggest that cancers maintain oxidative phosphorylation capacity and that the role of mtDNA mutations in cancer is likely far more nuanced in light of the remarkable complexity of mitochondrial genetics. This review aims at describing the various model systems that were developed to dissect the role of mtDNA in cancer, including cybrids, and more recently mitochondrial–nuclear exchange and conplastic mice. Furthermore, we put forward the notion of mtDNA landscapes, where the surrounding nonsynonymous mutations and variants can enhance or repress the biological effect of specific mtDNA mutations. Notably, we review recent studies describing the ability of some mtDNA landscapes to activate the mitochondrial unfolded protein response (UPRmt) but not others. Furthermore, the role of the UPRmt in maintaining cancer cells in the mitohormetic zone to provide selective adaptation to stress is discussed. Among the genes activated by the UPRmt, we suggest that the dismutases SOD2 and SOD1 may play key roles in the establishment of the mitohormetic zone. Finally, we propose that using a UPRmt nuclear gene expression signature may be a more reliable readout than mtDNA landscapes, given their diversity and complexity.
P09.01 case series: meningioma in young adult male
Authors: Y Diansari, N Karindang, D Anggraeni
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Intracranial meningiomas are most common among patients in their fifth to seventh decade of life, typically found in older women. Meningiomas are rare in children and young adults; they represent 1–3% of all intracranial tumors in individuals up to age 20 years and 13.5% of intracranial tumors in the 20–34 age group. Meningioma in young adult male is a rare finding. Management of meningioma is similar between young or older patient. The prognosis is depent on the histology finding and type of resection. This case series was made to report an uncommon case including clinical characteristic and management of meningioma in young adult male. MATERIAL AND METHODS We reported 2 cases of meningioma in young adult male. The first patient was hospitalized on 2016 and diagnosed with atypical meningioma (WHO grade II). The second patient was hospitalized on 2018 and diagnosed with trantitional meningioma (WHO grade I). RESULTS First case: 23 y.o male was hospitalized because of severe headache. His physical exam showed weakness of his left side of the body. There was diplopia that significant for bilateral six nerves palsy. Funduscopy examination revealed papil edema in both eyes correlated with his complained of blurry visions. There was no cranial irradiation from his past medical history. Second case, a male 22 y.o was because of decreased of visual acquity progressively since two month before. There was history of throbbing headache in his left head with mild to moderate intensity. On his neurological examination, there was mild weakness in his right body side. Visual acquity on his right and left eyes were 1/300 and 1/60. Bilateral papil edema was found in funduscopy examination. In his past medical history, there was no history of cranial iradiation. Both cases showed similar initial symptoms consist of headache and others neurological deficit. Radiological examination was performed with result leading to meningioma in convexity area in both cases. Craniotomy tumor removal with gross total resection as simpson grade 2 was achieved in both patients. In the second case pre-operative embolization was performed in order to achieve optimal resection. Histopathology examination confirmed as atypical (WHO grade II) in the first case and trantitional Meningioma (WHO grade I) in second case. Follow up imaging post operation showed no residual mass lesion in both patients. There were no further management in these patients. Both of patients showed improvement in their neurologic function and able to activity without restriction in daily living. Serial imaging examination is planned to observe reccurence of the tumor. CONCLUSION Clinical presentation and management of meningioma in these patients are similar as meningioma commonly. Both of patients showed clinical improvement after craniotomy tumor removal succesfully.
P09.02 Surgical treatment for intracranial meningiomas in elderly patients growing during follow-up study
Authors: M Okuma
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND In Japan in which life expectancy exceeds 85 years old, there are many elderly people who have sufficient healthy life even over 75 years of age and maintain social activities. With the increase in life expectancy and widespread use of magnetic resonance imaging (MRI), it is estimated that the number of asymptomatic meningioma diagnosed in elderly patients will increase. They are often followed up for the elderly, but they often become symptomatic as the tumor grows. Considering the inherent complications of the elderly and the patient’s life expectancy, it is often difficult to decide whether to operate. Here, we report the results of surgical treatment for intracranial meningiomas in elderly patients growing during follow-up study. MATERIAL AND METHODS Between January 2010 and December 2018, we treated 322 meningioma patients, including 18 patients older than 75 years old who had grown during follow-up. We performed a retrospective analysis of the 18 patients and measured Tumor doubling time (TDT) using CT scan or MRI image. We mainly examined the relationship between TDT and WHO classification, MIB-1 index, edema and calcification, intensity on MRI T2 weighted-imaging. RESULTS 5 were male and 13 were female. There were 6 cases of skull base meningioma and 13 cases in which the tumor showed high intensity on the MRI T2 weighted-imaging. 4 cases showed intratumoral hemorrhage. 8 cases had edema. 11 cases were symptomatic meningiomas and 7 cases were asymptomatic meningiomas. There were 7 cases of WHO grade I meningioma and 11 cases of WHO grade II or III meningiomas. TDT was an average of 1.82 year (0.37–3.74). 9 patients have taken anticoagulant or antiplatelet medication. CONCLUSION In following up elderly meningioma patients, MRI should be performed at periodic intervals if the tumor showed high intensity on the MRI T2 weighted-imaging or had edema. In case of surgical treatment, we should pay attention to taking anticoagulant or antiplatelet medication, and treatment strategy is needed to avoid complications with sufficiently preoperative examination.
Trainees and locums will get “NHS passports” to cut admin when they work between sites
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Trainees and locums who often work at different NHS sites will soon be able to get an “NHS passport” that will enable them to move easily between sites, without the need of two day inductions and other admin including pre-employment checks.

The scheme, which has been piloted at five hospitals in London, will now be available for all hospitals in England to join. It comes as part of a package announced at the NHS Health and Care Innovation Expo held in Manchester this week, which also included …
P11.11 Circulating Pro-Angiogenic Cells and Proteins in Patients with Glioma and Acute Myocardial Infarction: Differences in Neovascularization between Neoplasia and Tissue Regeneration
Authors: K Huizer, A Sacchetti, W Dik, J M Kros, D Mustafa
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Although extensive angiogenesis takes place in glial tumors, anti-angiogenic therapies have remained without the expected success. In the peripheral circulation of glioma patients increased numbers of endothelial precursor cells (EPCs) are present, potentially offering targets for anti-angiogenic therapy (Zheng et al., Ann Neurol, 2007). However, for an anti-angiogenic therapy to be successful, the therapy should specifically target glioma-related EPC subsets and secreted factors. Here we compared the EPC subsets and plasma factors in the peripheral circulation of patients with gliomas to acute myocardial infarctions (representing fysiologic regeneration). MATERIAL AND METHODS We investigated the five most important EPC subsets and 21 angiogenesis-related plasma factors in peripheral blood samples of 29 patients with glioma, 14 patients with myocardial infarction and 20 healthy people as controls, by an advanced FACS protocol (Huizer et al., PlosOne 2018) and Luminex assay. RESULTS In GBM patients all EPC subsets were elevated as compared to healthy subjects. In addition, HPC and KDR+ cell fractions were higher than in MI, while CD133+ and KDR+CD133+ cell fractions were lower. There were differences in relative EPC fractions between the groups: KDR+ cells were the largest fraction in GBM while CD133+ cells were the largest fraction in MI. An increase in glioma malignancy grade coincided with an increase in the KDR+ fraction while the CD133+ cell fraction decreased relatively. Most plasma angiogenic factors were higher in GBM than MI patients. In both MI and GBM, the ratio of CD133+ HPCs correlated significantly with elevated levels of MMP9. In the GBM patients MMP9 correlated strongly with levels of all HPCs. CONCLUSION In conclusion, the data demonstrate that EPC traffic in patients with glioma is different from that in normal tissue regeneration. Therefore, the effects of glioma extent beyond the brain, and future therapies aimed at lowering KDR+ cells and HPCs may add to effective treatment.
Getting the Right Patient to the Right Place in the Right Amount of Time—A Role for Both Mobile Stroke Units and Prehospital Clinical Scales
Authors: Jason McMullan, Pooja Khatri
Journal: JAMA Neurology (2019)

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PL3.5 Efficacy and safety of selinexor in recurrent glioblastoma
Authors: A B Lassman, P Y Wen, M van den Bent, S R Plotkin, A Walenkamp, A Green, X Huang, K Karla Rodriguez-Lopez, M G Kauffman, S Shacham, M Mau-Soerensen
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68). MATERIALS AND METHODS This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method. RESULTS 76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7) At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%). CONCLUSION Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.
P04.12 Characteristics of IDH-mutant gliomas with non-canonical IDH mutations
Authors: L Poetsch, C Dehais, J Frénel, A Siegfried, S Lacomme, R Seizeur, D Larrieu-Ciron, D Cappellen, D Loussouarn, C Ferec, S Eimer, C Carpentier, M Sanson, J Delattre, D Figarella-Branger, F Ducray, C Bronnimann
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND About 10% of IDH-mutant gliomas harbor non-canonical IDH mutations (non-R132H IDH1 and IDH2 mutations). The aim of the present study was to analyze the characteristics of these gliomas in comparison to those of IDH1 R132H mutant gliomas. MATERIAL AND METHODS We retrospectively analyzed the characteristics of a multicentric series of 161 gliomas with non-canonical IDH mutations and compared them to those of consecutive series of 109 IDH1 R132H mutant gliomas. Medical, radiological and pathological were reviewed. RESULTS Median age at diagnosis was 35 years in gliomas with a non-canonical IDH1 mutation, 42 years in those with an IDH2 mutation and 44 years in those with an IDH1R132H mutation. A familial history of cancer was more frequent in gliomas with a non-canonical IDH mutation than in those with an IDH1 R132H mutation (22,3% vs 5,5%, p&lt;0.05). In both IDH1 R132H-mutant and non-canonical IDH-mutant gliomas the most frequent location was the frontal lobe. Yet, compared to IDH1R132H-mutant gliomas those with a non-canonical IDH mutation had more frequently an infratentorial location (5,5% vs 0% p&lt;0,05) and were more frequently multicentric (4,9%, versus 0.9%, p&lt;0.05). Compared to IDH1R132H-mutant gliomas, gliomas with a non-canonical IDH1 mutation were more frequently astrocytomas (65.7% vs 45%, p&lt;0.05) while those with an IDH2 mutation were more frequently oligodendrogliomas (82% vs 55%, p&lt;0.05). The median overall survival in IDH1 R132H-mutant and non-canonical IDH-mutant gliomas was similar (122 versus 120 months). CONCLUSION Gliomas with non-canonical IDH mutations are associated with distinct clinical, radiological and histological characteristics. Their prognosis, however, is similar to that of gliomas with canonical IDH mutations.
P14.69 Evaluation of electric field intensity delivered by Tumor-Treating Fields therapy to PET-defined metabolic volumes in recurrent glioblastomas
Authors: S Mittal, F John, A Naveh, Z Bomzon, G R Barger, C Juhasz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Tumor-Treating Fields (TTFields) therapy is a clinical treatment option for patients with newly-diagnosed and recurrent glioblastomas. Electric field intensities (EFIs) delivered to the tumor mass may affect treatment responses. In this study, we used the patients’ neuroimaging data to create realistic head models and evaluate: (i) the magnitude of EFIs delivered to the tumor mass; (ii) factors affecting the EFI values; and (iii) factors affecting treatment responses as assessed by amino acid PET. MATERIAL AND METHODS Fourteen recurrent glioblastomas in 9 patients were evaluated with α-[11C]-methyl-L-tryptophan (AMT)-PET before and up to 3 months after TTFields therapy (mean follow-up: 2.3 months). Individual MRI and CT scans were used to create patient-specific realistic head models and simulate TTFields delivery to the tumors. For each direction of treatment (antero-posterior, left-right), two 9-disk transducer arrays were simulated using disks placed according to the patients’ NovoTAL System™ based treatment plan. To generate TTFields, an alternating voltage difference (200V peak-to-peak, 200 kHz) was imposed on the outer surfaces of the disks. The simulations were performed using the Sim4Life V3.0 (ZMT-Zurich) quasi-electrostatic solver. The field intensities were normalized to simulate 2A peak-to-peak current supplied by the device. 3D EFI maps were created and fused with the pre- and post-TTFields PET images to measure EFIs delivered to the PET-defined metabolic tumor volume. Interval changes of static AMT uptake and kinetic PET variables were also evaluated. RESULTS The mean EFI delivered to the tumors varied between 1.34–2.43 V/cm (mean: 1.86 V/cm). Fronto-parietal tumors received higher mean EFI than temporal lobe tumors (p=0.05). Most tumors showed decreasing (n=9) or stable (n=4) AMT uptake on follow-up PET imaging after TTFields therapy. Higher EFIs delivered to the tumors (r=-0.56, p=0.04) and concomitant bevacizumab treatment (n=7, p=0.01) were associated with a greater PET response. On tracer kinetic analysis, the AMT uptake responses correlated with transport rate changes (p=0.04). CONCLUSION TTFields treatment of recurrent glioblastomas delivers variable EFIs to the metabolic tumor volume. Treatment responses on PET are driven by decreased amino acid transport rates, whose magnitude is associated with higher EFIs delivered to the tumor mass and also with concomitant antiangiogenic treatment in those with combined therapy. (The cost of the PET scans was supported by a grant from NovoCure Ltd., Haifa, Israel)