bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitor-related endocrinopathies: A nationwide population-based study.
Authors: Elantably Dina , Al Armashi Abdul Rahman , Hammad Faris , Alkrekshi Akram 
Published: June 2022

2653 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, unleashing the body’s immune system against cancer is not without consequences and may trigger immune-related adverse events (irAEs), such as endocrinopathies. Real-world data of these endocrinopathies is lacking. This study aims to obtain the prevalence of endocrine irAEs and identify possible underlying demographic risk factors or disparities. Methods: A cross-sectional study was performed using a US-based population database (Explorys) that aggregates records from 26 healthcare systems and includes over 79 million patients. Our sample included all patients on an ICI, and we further identified patients who developed endocrinopathies while on different ICI regimens. The demographic data extracted was categorical, hence presented as counts and percentages. The odds ratio (OR), standard error, and 95% confidence interval were calculated with the use of SPSS software version 28.0 (IBM). Results: There were 20,950 patients on an ICI; 58% males, 83% Caucasians, 10% African-Americans (AA), 38% aged between 18-65, and 63% were over 65 years. The prevalence of the studied endocrinopathies is listed in the table. The most prevalent ICI-induced endocrinopathy was hypothyroidism (7.9-13%). Combination therapy with ipilimumab and nivolumab showed the highest prevalence of ICI-induced endocrinopathies, followed by durvalumab. The odds of developing ICI-induced endocrinopathy were significantly higher with combination therapy than nivolumab monotherapy (OR 1.6; 95% CI 1.4-1.9). There was no statistically significant difference in endocrinopathy prevalence when comparing Caucasians to AA and adults18-65 years to seniors over 65 years. Conclusions: This is the largest epidemiological study of ICI-related endocrinopathies. We find an intriguing divergence from endocrinopathy prevalence reported in the literature and real-world data we are presenting here. Over diagnosis of overt hypothyroidism, as opposed to subclinical hypothyroidism, is concerning as the former necessitates levothyroxine therapy. More alarming is the under diagnosis of hypopituitarism and PAI, in which delay in treatment can be fatal. The diagnosis of these conditions can be challenging. Raising awareness, setting protocols for testing, and involving endocrinologists are crucial. Further studies are needed to clarify our findings. [Table: see text]
Evaluating survival following severe immune-related adverse events requiring hospitalization.
Authors: Wright Francis , Kim Daniel Myung , Silverstein Jordyn , Wang Michelle , de Dios Kimberly , Young Arabella , Quandt Zoe E. , Brondfield Sam 
Published: June 2022

2666 Background: As immune checkpoint inhibitors (CPI) are increasingly approved for the treatment of multiple cancer types, hospitalizations related to severe immune-related adverse events (irAE) will increase in tandem. Here, we identify patients hospitalized due to irAEs and describe survival outcomes across irAE, CPI, and cancer type. Methods: We identified patients exposed to CPIs who were hospitalized from 1/2012 to 12/2020 at our tertiary care hospital by computationally extracting data from the electronic health record. We then performed manual chart review to include only confirmed irAE-related hospitalizations. Survival outcomes were analyzed using Kaplan-Meyer survival curves with log-rank tests. Results: Of 3137 patients treated with CPIs, 117 were hospitalized for irAEs (cumulative incidence 4%). Of these, 36% had melanoma, 15% had lung cancer, 9% had renal cell carcinoma (RCC), and the rest were distributed across other cancers. The average number of irAE-related hospitalizations per patient was 1.25 (ranging from 1-3). Among 153 irAEs requiring hospitalization, 39% were gastrointestinal (GI) (including hepatitis), 12% endocrine, 12% pulmonary, 12% neurologic, 12% musculoskeletal, 7% cardiovascular, 6% dermatologic, and the rest affected other organs. Across all patients hospitalized for irAEs, median survival following hospitalization was 980 days. Patients with GI and endocrine irAEs had longer median survival (1474 days and median not reached [NR], respectively), while patients with pulmonary irAEs had shorter median survival (64 days) [p=0.002]. Patients with melanoma and RCC had longer median survival (2796 days and NR, respectively), while patients with lung cancer had shorter median survival (165 days) [p=<0.001]. Survival was not significantly different across CPI type [p=0.20]. Conclusions: Although hospitalization for severe irAE was rare, these findings suggest that among these patients, survival differs by irAE and cancer type. This real world data can contribute to clinical models that predict the risk of hospitalization and the risk of death due to severe irAEs, which may inform patient counseling and treatment decision-making. [Table: see text]
A multicenter, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.
Authors: Hu Xiaojie , Zeng Kang , Xu Zhongyuan , Li Wenbin , Li Changxing , Kang Zhuang , Li Shenglan , Hui Ai-Min , Wu Zhuli , Huang Xin , Han Pu , Li Ben , Lin Xiaoxi 
Published: June 2022

3011 Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of > 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.
Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, PD-1/PD-L1, and TIM-3 are markedly increased in basal cell carcinoma.
Authors: Rapoport Bernardo Leon , Malinga Nonkululeko , Siwele Shalete , Steel Helen C. , Kwofie Luyanda LI , Meyer Pieter , Smit Teresa , Anderson Ronald , Kgokolo Mahlatse 
Published: June 2022

3043 Background: Although co-inhibitory immune checkpoint proteins are primarily involved in promoting inhibitory cell-cell interactions in adaptive immunity, especially tumor immunity, the soluble cell-free variants of these molecules are also detectable in the circulation of cancer patients where they retain immunosuppressive activity. Nevertheless, little is known about the systemic levels of these soluble co-inhibitory immune checkpoints in patients with various subtypes of basal cell carcinoma (BCC), which is the most invasive and treatment-resistant type of this most commonly occurring malignancy. Methods: In the current study, we have measured the systemic concentrations of five prominent co-inhibitory immune checkpoints, namely CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3, as well as those of C-reactive protein (CRP) and vitamin D (VD), in a cohort of patients (n = 40) with BCC, relative to those of a group of control participants (n = 20), using the combination of multiplex bead array, laser nephelometry and ELISA technologies, respectively. Results: The median systemic concentrations of CRP and VD were comparable between the two groups; however, those of all five immune checkpoints were significantly elevated ( P= 0.0184 - P£0.00001), with those of CTLA-4 and PD-1 being highly correlated (r = 0.87; P< 0.00001). Conclusions: This seemingly novel finding not only identifies the existence of significant systemic immunosuppression in BCC, but also underscores the therapeutic promise of immune checkpoint targeted therapy, as well as the potential of these proteins to serve as prognostic/predictive biomarkers in BCC.
Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer.
Authors: Rapoport Bernardo Leon , Steel Helen C. , Benn Carol , Nayler Simon , Smit Teresa , Heyman Liezl , Theron Annette J. , Hlatswayo Nomsa , Kwofie Luyanda LI , Meyer Pieter , Anderson Ronald 
Published: June 2022

3044 Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells can up-regulate or down-regulate these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) relative to those of a healthy control group. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data was prospectively obtained and levels compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Pre-treatment levels of the soluble stimulatory molecules viz. GITR (p<0.0001), GITRL (p< 0.020), CD27 (p< 0.024), CD40 (p< 0.021), ICOS (p< 0.009), as well as the inhibitory molecules PD-L1 (p< 0.0001), CTLA-4 (p< 0.005), TIM-3 (p< 0.0004), HVEM (p< 0.0004) were significantly lower in early BC pts compared to controls. Post-treatment, there were significant increases in most ICM levels (Table), with the exception of CTLA-4, which decreased significantly following treatment. On the other hand, pre-treatment plasma concentrations of CCL5 (RANTES) (84.22 vs. 48.72 pg/mL, p<0.0001), M-CSF (84.41 vs 13.34 pg/mL, p<0.0001), FGF-21 (24.36 vs. 8.64 pg/mL, p<0.001) and GDF-15 (806.82 vs. 430.03 pg/mL, p<0.0001) were significantly increased in the breast cancer pts compared to healthy controls. A pathological complete response (pCR) was documented in 65% of pts (mostly TNBC). There were no correlations between pre-treatment ICM levels, CCL5, M-CSF, FGF-21 and GDF-15 and pCR. Conclusions: We identified low levels of stimulatory and inhibitory ICMs in newly-diagnosed, non-metastatic BC pts compared to healthy controls. Following treatment, with the exception of CTLA-4, most of these pre-treatment abnormalities of systemic ICM levels corrected. NAC is associated with upregulation of sPD-L1 and most other ICMs. These results indicate that early BC is associated with down-regulation of soluble stimulatory and inhibitory ICMs. Newly-diagnosed early BC pts appear to have generalized immune-suppression independent of subtype and stage. To our knowledge, this is the first study to describe the effect of treatment on systemic ICMs in early BC pts. [Table: see text]
Circulating tumor DNA (ctDNA) in HER2 exon 20 insertion mutations and responses in NSCLC HER2 exon 20 insertion treated with poziotinib.
Authors: Thiagalingam Arunthi , Lakshmikanthan Sribalaji , Mak Allysia , Shell Scott A. , Leu Sharon , Sun Sophie , Bertino Erin Marie , Haura Eric B. , Washington Rocky , Bhat Gajanan , Lebel Francois M. , Barrett John A. 
Published: June 2022

3051 Background: ctDNA levels in plasma samples permits temporal assessment of tumor mutational status and tumor burden during therapy. Poziotinib is an oral HER2 TKI in development for NSCLC patients harboring HER2 exon 20 insertion mutations. We assessed serial plasma samples for changes in HER2 exon 20 insertion mutations and other driver mutations in first- and second-line patients comparing to clinical response per RECIST1.1. Methods: NSCLC patients harboring HER2 exon 20 insertion mutations were enrolled into the poziotinib ZENITH20 using tumor tissue based NGS. Serial plasma samples were collected at baseline, at C3D1, at Day 1 of every other cycle until disease progression. The Guardant360â 74-gene liquid biopsy assay was used to assess changes in tumor-associated somatic variants including the target variant HER2 exon20 insertion as well as other emergent driver mutations in ctDNA as expressed as percent variant allele frequency (%VAF). Results: 23 first- and second-line NSCLC patients were evaluable with tumor tissue confirmation of HER2 exon 20 insertion mutations. 22 of 23 (96%) had baseline plasma samples with detectable ctDNA. 21 of 22 samples had detectable HER2 exon 20 insertion mutations (mean % VAF 20±5) resulting in a concordance of 95% versus tissue based NGS. 7 patients had serial testing through C7D1 permitting assessment of ctDNA dynamics and comparison to clinical responses. 5 of 7 (71%) serially tested patients treated with poziotinib at 16mg QD had undetectable HER2 exon 20 insertion at C3D1 which was associated with a tumor response PR. Tumor escape (PD) was observed in 2 of the 5 patients which correlated with increases in target HER2 exon 20 insertion VAF in the plasma with the remaining 3 patients ≥PR. Notably, the rise in HER2 exon 20 in ctDNA occurred prior to tumor escape. In one patient treated with poziotinib at 16 mg QD we observed undetectable levels of the HER2 exon 20 insertion in ctDNA at C3D1 which continued through C16. This patient’s responses correlated with patient tumor response of SD at C2 which then became PR through C9 and CR through C17. Conclusions: Poziotinib treatment resulted in reductions in HER2 exon 20 insertion mutations in ctDNA preceded and correlated with the clinical tumor response. Increases in ctDNA HER2 exon 20 insertion mutations were observed prior to confirmation of tumor escape. Serial monitoring of ctDNA is a potential predictive biomarker for treatment response and disease progression. Future evaluation in a larger population is required to confirm the impact of these findings.
The HERPET study: Imaging HER2 expression in breast cancer with the novel PET tracer [18F]GE-226, a first-in-patient study.
Authors: Kenny Laura M. , Gilbert Fiona J , Gopalakrishnan Gosala , Aravind Preetha , Barwick Tara , Patel Neva , Hiscock Duncan ROBERT , Boros Istvan , Kealey Steven , Aigbirhio Franklin I , Lozano-kuehne Jingky , Cleator Susan Jane , Fleming Ben , Riddle Pippa , Ahmad Rizvana , Chua Sue , Johnston Stephen R.D. , Mansi Janine , Cook Gary J. , Aboagye Eric O. 
Published: June 2022

3069 Background: Over-expression the human epidermal growth factor receptor-2 (HER2) is seen in 20% of breast cancers; this is an adverse prognostic factor and used to guide therapy selection. At present HER2 expression can only be determined using biopsy material using immunohistochemistry or fluorescence in situ hybridisation. Heterogeneous expression of HER2 is now being recognised as a cause of treatment resistance but is difficult to characterise. A non-invasive method for determining HER2 expression could have several advantages and help select appropriate therapy for patients. GE-226 is a novel radiolabelled GE-Affibody radioligand which binds to the HER2 receptor with high affinity at a different epitope than trastuzumab. Methods: Patients with locally advanced or metastatic breast cancer were recruited and scanned for 65 mins after iv injection of 200MBq of GE-226 (mean activity injected for each patient 202MBq (range 164-223MBq, mean radiochemical purity 94%) of radioligand, over one bed position for dynamic imaging, followed by a half-body scan. Blood sampling was used to measure metabolism of the tracer. Safety was assessed. HER2-extracellular domain (ECD) domain was measured in blood. Tumoural uptake was quantified by semi-quantitative and fquantitative parameters in HER2 positive and HER2 negative tumours. Patients had routine baseline FDG imaging. Results: Twenty patients completed the study. GE-226 scans were well tolerated. There were no serious adverse events. GE-226 was slowly metabolised into a single metabolite in the liver; 97% of parent remained at 60 minutes post injection (range 82-100). There was a significant difference in tumoural radioligand uptake between biopsy proven HER2 positive and HER2 negative tumoural patients as measured by SUVmean and SUVmax (p < 0.001). Comparing HER2 positive to HER2 negative cases, there was also a significant difference between tumour to normal tissue uptake ratios SUVmean. Heterogeneous uptake was observed in three patients, two with interlesional uptake variation and one with intralesional heterogeneity. Tumoural uptake increased over time. Normal physiological uptake in salivary glands and the thyroid gland was noted. GE-226 was able to differentiate between lymphadenopathy due to sarcoidosis and cancer in one patient and was superior to FDG which had shown widespread uptake in the benign and malignant nodes. Conclusions: [18F]GE-226 imaging is well tolerated and shows promise for imaging of HER2 positive breast cancer. Further studies with this agent are now planned. Clinical trial information: NCT03827317.
Image-based detection of FGFR3-fusion in urothelial bladder cancer.
Authors: Peled Nir , Zalach Jonathan , Gazy Inbal , Hayun Ido , Avinoam Assaf , Nataf Daniel , Paz-Yaacov Nurit 
Published: June 2022

3072 Background: Fibroblast growth factor receptor-3 (FGFR3) is a transmembrane protein, somatically altered in a large spectrum of cancer types. Chromosomal rearrangement resulting in FGFR3 gene fusions leads to a constitutively active tyrosine kinase, mediating tumorigenesis. FGFR3-fusion is a prognostic and predictive marker as well as a validated therapeutic target in urothelial bladder cancer. Both FISH and RT-PCR assays can be used for the detection of FGFR3 rearrangements while immunohistochemistry lacks sufficient sensitivity and specificity. In recent years advances in next-generation sequencing improved their ability to detect these alterations in clinical settings. However, systemic screening of these alterations is still expensive, time-consuming, and requires expertise personnel for data analysis and interpretation. In this study, we aimed to develop and validate an alternative machine learning (ML) based method for the detection of FGFR3-fusions directly from routine pathology hematoxylin and eosin (H&E) slides. Methods: A cohort of 388 H&E whole slide images of bladder urothelial carcinoma samples, obtained from the TCGA Research Network ( https://www.cancer.gov/tcga ) was used. Cases were randomly divided into training (n = 238) and testing (n = 150) sets. Advanced Convolutional Neural Network (CNN) was used to generate the FGFR3-fusion classifier on the training set following validation on the testing set. Results: Validation of the FGFR3-fusion classifier was performed on a cohort of 150 cases from 19 different centers, including three positive cases of FGFR3-TACC3 fusions and 147 negative cases. The AI-classifier performance was measured in comparison to the TCGA dataset. The model demonstrated 100% sensitivity and 94% specificity, with an Area Under the Curve (AUC) of 0.96. Conclusions: Herein, we demonstrate a real-time ML-based genomic testing solution for FGFR3-fusion detection in bladder cancer directly from H&E stained slide images. Utilization of such an alternative method can facilitate fast, accurate, and systemic screening of patients if integrated within the routine pathological pipeline supporting targeted therapy treatment for these patients.
Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study.
Authors: Ribrag Vincent , Wainberg Zev A. , Iglesias Docampo Lara , Ramkumar Thiruvamoor , Barys Louise , Chen Shuqi , Raccuglia Marc , Wilbaux Mélanie , Beltz Karen , Luyt Amy , Fan Yu Yun , Suenaga Naoko , Luo Fangjun , Dai Xuan , Lai Clinton , Chen Jia 
Published: June 2022

3083 Background: Polycomb Repressive Complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Its dysregulation and over-expression are associated with tumorigenesis in several conditions. MAK683 is a potent oral inhibitor of PRC2 activation, allosterically targeting the EED–H3K27me3 binding site. Methods: NCT02900651 is an ongoing first-in-human dose-escalation study of MAK683 in adults with advanced malignancies. MAK683 was administered fasted once (QD) or twice daily (BID) on a continuous schedule in 28-day treatment cycles. The pharmacokinetic (PK) profile of MAK683 was assessed in sequential blood samples on Days 1, 8 and/or 15 of Cycles 1–6. MAK683 pharmacodynamic activity in Cycle 1, measured by change in H3K27me3, was evaluated in peripheral blood monocytes on Days 1, 8, and 15 by flow cytometry and in tumor biopsies at baseline and Day 15 by H-score. Results: As of Aug 30, 2021, 125 patients had received MAK683 at doses of 10–800 mg QD or 60–450 mg BID. MAK683 was well absorbed with a median Tmax of ̃1-4 hours across cohorts. PK exposure (Cmax, AUC) increased generally with dose over the entire dose range with no major deviation from dose proportionality, taking into account the sample size and PK variability. Apparent terminal half-life (geometric mean) was 2.5–6.6 hours across cohorts and constant over time. MAK683 accumulation of ̃0.9-2.2-fold (QD) or ̃1.3-2.0-fold (BID) was seen with repeat dosing. Peripheral monocytes showed substantial on-treatment reductions from baseline in the H3K27me3/H3 ratio across doses. Maximum percentage reduction was proportional to cumulative MAK683 AUC, with a trend towards greater reductions at higher baseline H3K27me3. H3K27me3 H-score reductions from baseline > 40 were observed in 7/10 patients with diffuse large B-cell lymphoma (n = 4) or epithelioid sarcoma (n = 6) and paired baseline–Day 15 biopsies. RNA-seq characterization of biopsy samples is ongoing. Conclusions: MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683. Clinical trial information: NCT02900651.