bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor volume score (TVS), modified recist, and tissue damage score (TDS) as novel methods for assessing response in tenosynovial giant cell tumors (TGCT) treated with pexidartinib: Relationship with patient-reported outcomes (PROs).
Authors: Peterfy Charles , Ye Xin , Gelhorn Heather , Speck Rebecca M , Countryman Peter J. , Keedy Vicki Leigh , Wainberg Zev A. , Singh Arun S. , Chmielowski Bartosz , Von Hoff Daniel D. , Babiker Hani M. , Khemka Vivek , Cote Gregory Michael , Shapiro Geoffrey , Wagner Andrew J. , Healey John H. , Hsu Henry , Lin Paul S. , Tong Sandra , Tap William D. 
Published: September 2018

11048 Background: TGCT is a locally aggressive neoplasm of joint and tendon sheath synovia that may cause pain, limit joint function and destroy bone and local tissues. Measuring TGCT with RECIST is a challenge due to irregular shape and asymmetrical growth, and local tissue damage is not assessed. We reported earlier results of a longitudinal trial of pexidartinib, a selective CSF1R kinase inhibitor, using RECIST as well as novel TVS, modified RECIST and TDS. Here we examine concordance of these MRI measures with PROs. Methods: Patients (pts) with progressive TGCT in a single-arm, multi-center trial of pexidartinib (1000 mg po daily) were assessed by MRI every 2 months by 2 central radiologists (blind to visit order). For RECIST, longest measurable dimensions of up to 2 tumors per joint or tendon sheath were summed (SLD). Modified RECIST summed short axis dimensions (SSD). TVS was based on 10% increments of the estimated maximally distended normal synovial cavity or tendon sheath. TDS scored bone erosion (ERO), cartilage loss (CAR) and bone marrow edema (BME) in multiple regions of each joint. The relationship with PROs (Worst Pain numerical rating scale [NRS] and Worst Stiffness NRS) was assessed. Results: 15 pts (7 knees, 3 hips, 2 ankles, 1 elbow, 1 wrist, 1 thigh) with PRO data and evaluable MRI scans at baseline and Month 7 were assessed. All SLD, SSD and TVS scores improved with respective median changes of -25%, -39% and -50%. Baseline ERO, CAR, and BME ranged 0-19, 0-34, and 0-15, respectively. Median change for each was 0%: ERO worsened in 1 pt, CAR did not change, and BME improved in 4 and worsened in 2. Worst Pain NRS and Worst Stiffness NRS improved in 11 and 9 pts, respectively. Conclusions: TVS demonstrated the greatest pexidartinib effect size, followed by SSD and then conventional RECIST. All had good concordance with PROs. Clinical trial information: NCT01004861. [Table: see text]
Combination of pembrolizumab and metronomic cyclophosphamide in patients with advanced sarcomas and GIST: A French Sarcoma Group phase II trial.
Authors: Toulmonde Maud , Penel Nicolas , Adam Julien , Chevreau Christine , Blay Jean-Yves , Le Cesne Axel , Bompas Emmanuelle , Piperno-Neumann Sophie , Cousin Sophie , Ryckewaert Thomas , Bessede Alban , Ghiringhelli Francois , Grellety Thomas , Pulido Marina , Italiano Antoine 
Published: September 2018

11053 Background: There is a good rationale for immunotherapy in sarcoma. We report results of the first open-label multicentre phase 2 study assessing the anti-PD-1 antibody pembrolizumab in combination with metronomic cyclophosphamide (CP) in patients (pts) with advanced soft tissue sarcomas (STS) and gastro-intestinal stromal tumor (GIST). Methods: This trial included 4 cohorts of pts with advanced STS: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (Others), and GIST. All pts received CP 50 mg BID one week on, one week off, and pembrolizumab 200mg IV q21 days. The primary endpoint encompassed non-progression and objective response at 6 months per RECIST evaluation criteria v1.1 for LMS, UPS, and Others, and 6-month non-progression for GIST. Correlative studies of immune biomarkers were planned on pt’s tumor and plasma samples. Results: Between June 2015 and July 2016, 57 pts were included, and 50 were assessable for efficacy. Three pts experienced tumor shrinkage resulting in a partial response (PR) in one of them. The 6-month non-progression rate was 0%, 0%, 14.3% (95%CI 1.8-42.8), and 11.1% (95%CI 2.8-48.3) in LMS, UPS, Others, and GIST respectively. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, anemia. The only pt who experienced PR was the only one with a PD-L1-positive staining in more than 10% of immune cells on archived tumor sample. A strong macrophage infiltration was observed in tumor samples, and these macrophages largely expressed the inhibitory enzyme Indoleamine-2,3-dioxygenase-1 (IDO1). Moreover, a significant increase of the kynurenine/tryptophane ratio was observed in pts plasma samples during study treatment (p =0.0007). Conclusions: PD-1 inhibition has limited activity in advanced STS and GIST. This primary resistance may be explained by the low percent of PD-L1 positivity in these tumors, and an immune-suppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Further strategies assessing drugs such as CSF1-R inhibitors and/or IDO inhibitors combined with anti-PD-1/PD-L1 in selected sarcoma subtypes are warranted. Clinical trial information: NCT02406781.
Immune and molecular determinants of response to neoadjuvant chemotherapy in inflammatory breast cancer.
Authors: Reddy Sangeetha Meda , Wargo Jennifer Ann , Reuben Alexandre , Tetzlaff Michael T. , Roszik Jason , Reuben James M. , Woodward Wendy A. , Ueno Naoto T. , Krishnamurthy Savitri , Mittendorf Elizabeth Ann 
Published: September 2018

11501 Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer and has poor responses to standard of care neoadjuvant chemotherapy (NAC). Given there is a limited understanding of the immune microenvironment of IBC, this study aims to characterize the immune and molecular profiles of stage III and IV IBC and to identify biomarkers of response to treatment and targets for future therapies. Methods: IBC patients with available pre-treatment tumor samples and with intent to take to mastectomy were identified in the IBC tumor registry and tissue bank. Tumor infiltrating lymphocyte (TIL) infiltration in the tumor stroma was quantified on H&E slides per consensus guidelines (n = 91). On a subset of patients with available samples, deeper immune profiling was performed, including quantification of CD8 T cells by immunohistochemistry (IHC) (n = 33), PD-L1 tumor expression by IHC (n = 14), myeloid cells by multiplex IHC (n = 15), T cell clonality by T cell receptor sequencing (n = 22), and total mutational load (TML) by whole exome sequencing (n = 20). Results: Mean TIL were higher in tumors from patients that achieved a pathological complete response (pCR) to NAC than from those that did not (13.79 vs 7.24%, p = 0.019) and in patients with stage III compared to stage IV disease (11.90 vs 4.79%, p < 0.001). Though no statistically significant differences in CD8 infiltrate by response, stage, or receptor status were seen, the presence of a more clonal T cell population was predictive of pCR (13.27 vs 5.70% top 5 clone frequency, p = 0.042 among stage III patients). Myeloid cell staining revealed that tryptase staining, indicative of mast cells, was inversely associated with pCR (28.26 vs 108.0 counts/mm2, p = 0.011). Three of fourteen patient tumors displayed low PD-L1 tumor positivity (range 1-2%, 1+-2+) with the others being negative. Genomic profiling showed no statistically significant differences in TML by stage, receptor status, response, or immune infiltrate. Conclusions: Higher TIL, more clonal T cells, and lower mast cell infiltration are predictive of response to NAC in IBC. Comprehensive immune characterization of a larger cohort of pre- and post-treatment samples is currently underway.
Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC.
Authors: Streicher Katie , Higgs Brandon W. , Wu Song , Coffman Karen , Damera Gautam , Durham Nick , Greenlees Lydia , Lazdun Yelena , Cheng Li , Cooper Zachary , Ranade Koustubh 
Published: September 2018

11505 Background: Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood. We investigated the relationship between Methods: Flow cytometry and/or quantitative PCR were used to evaluate genes and proteins in five NSCLC EGFR mt cell lines and 6 wt lines. Anti-EGFR TKIs gefitinib and osimertinib were used at concentrations ranging from 0.001-100uM; EGF was used at 50 ng/mL. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 previously treated patients in CP1108 were enrolled. RNA sequencing was conducted on available tumor specimens from 97 patients in CP1108. CP1108 and TCGA were separated by EGFR status for genomic comparisons. Results: Median CD73 expression was increased 10-fold in EGFR mt NSCLC cell lines (n = 5) compared to wt cell lines (n = 6). EGF induced CD73 protein levels 5-40-fold in 3/6 EGFR wt lines. There was dose-dependent inhibition of CD73 expression (45-70 fold maximum) following treatment with gefitinib or osimertinib in 3/5 mt cell lines and 4/6 wt lines, suggesting a causal relationship between the EGFR pathway and CD73 expression. Consistent with these observations, EGFR mutant tumors had ≥2 fold increased expression of CD73 compared to wt (p < 0.05) in TCGA and CP1108 NSCLC adenocarcinoma patients. These EGFR mutants had significantly lower levels of IFNg signature, previously reported to be associated with enhanced benefit from durvalumab. Conclusions: Our findings identify a novel relationship in NSCLC between EGFR pathway activation, expression of the immunosuppressive molecule CD73 and reduced expression of IFNg mRNA signature. These results prompt the hypothesis that over-expression of CD73 in EGFR-mt NSCLC may explain, at least in part, the reduced benefit from anti-PD-1(L1) in this subset of NSCLC, and suggest evaluating anti-CD73 in combination with EGFR TKIs or anti-PD-L1 in EGFR-mt NSCLC.
CD4+ T cells in PBMC to predict the outcome of anti-PD-1 therapy.
Authors: Kagamu Hiroshi , Yamaguchi Ou , Shiono Ayako , Mouri Atsuto , Miyauchi Sachiko , Utsugi Harue , Nishihara Fuyumi , Uchida Takahiro , Murayama Yoshitake , Kobayashi Kunihiko 
Published: September 2018

11525 Background: Antibody blockade of programmed death 1 (PD-1), has led to durable responses and significant prolongation of overall survival in metastatic cancers including non-small cell lung cancer (NSCLC). However, in clinical trials, response rates were as low as 20 %, and approximately 50 % of the patients did not achieve benefits to prolong progression free survival. These results bring us a hypothesis that there are subgroups with distinct pre-existing anti-tumor immunity resulting in different responses to anti-PD-1 therapy. We reported that effector T cells, which are capable of mediating antitumor reactivity, are primed in LNs draining growing tumors and that these T cells exclusively belong to the T cells that down-regulated CD62L (CD62Llow) subpopulation. In the absence of purified tumor antigenic proteins or peptides on many tumors, the expression of the homing molecule CD62L on T cells may serve as a surrogate marker for identifying tumor-specific immune cells. Methods: We analyzed the peripheral blood mononuclear cells (PBMC) of 50 consecutive NSCLC patients who were planned to be treated with anti-PD-1 Ab, Nivolumab after obtaining written informed consent. The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. Results: The NSCLC patients who achieved partial response (PR) or stable disease (SD) had significantly (p = 4.1x10-7) more CD62Llow CD4+ T cells in PBMC than progressive disease (PD) patients. The percentages of CD62Llow in CD4+ T cells provided sensitivity 92.9 %, and specificity 96.7 % to predict the patients who had PD. Moreover, SD patients had significantly (p = 0.0067) less regulatory T cell subpopulation than PR patients, thus, it was possible to predict PR from SD. Conclusions: These results show that the major differences in pre-existing immunity among PR, SD, and PD patients to anti-PD-1 Ab existed in CD4+ T cell balance between primed effector and regulatory T cells. Further characterization of CD62Llow CD4+ T cells including mRNA microarray, checkpoint molecules, and chemokine receptors is going on.
Algorithmic prediction of response to checkpoint inhibitors: Hyperprogressors versus responders.
Authors: Gandhi Shipra , Pabla Sarabjot , Nesline Mary , Pandey Manu , Ernstoff Marc S. , Dy Grace K. , Conroy Jeffery M. , Glenn Sean , Burgher Blake , Qin Maochun , Andreas Jonathan , Giamo Vincent , Papanicolau-Sengos Antonios , Galluzzi Lorenzo , He Ji , Gardner Mark , Morrison Carl 
Published: September 2018

11565 Background: Predicting response to checkpoint inhibitors (CPIs) using biological knowledge-based decision processes with machine learning (ML) has a great potential to predict rapid progression in patients treated with checkpoint inhibitors (CPIs) (hyperprogressive disease (HPD)) as well as responders. ML models risk overfitting data and do not always evaluate the underlying biology, thus performing well in the initial training cohort but lack generalizability when extended to other cohorts. Biology-based decision may not perform as well initially due to limited understanding and a simplified rule set, but often perform equally well when extended to larger similar cohorts of patients. Methods: A custom NGS cancer immune gene expression assay compared 87 patients treated with CPIs classified as CR, PR, or SD versus 12 HPD. A ML-based polynomial regression model based on 54 immune-related genes combined with mutational burden was optimized for prediction of response. A biological 4-gene decision tree model was constructed independently based on ML. A second biological decision tree incorporated the weighted average relative rank of the expression of multiple genes in 4 different immune functions including immune cell infiltration, regulation, activation, and cytokine signaling. Bayesian model average (BMA) incorporated all three models’ results into the final prediction. Results: For87 patients classified as CR, PR, or SD the PPV >96% for responders and a NPV >90% for non-responders was achieved with the regression model, however with response indeterminate for 24% of the population. While the two biological decision tree models’ PPV were in the 70% range, they accurately revealed the critical genes’ roles in immune response with strong literature support. BMA process integrated these three models resulted in a PPV >96% and a NPV >90% and eliminated the indeterminate group. For HPD a unique biology related to priming of short term memory T-cells was identified. Conclusion: Prediction of response to CPIs is best attained by combining ML with biological knowledge. Decision tree models using a large panel of immune related genes in the context of archival samples from patients treated with CPIs can be used to better understand the biology of responders versus non-responders and provides new insights into HPD.
Restoration of tumor suppression in vivo by systemic delivery of chemically-modified PTEN mRNA nanoparticles.
Authors: Islam Mohammad Ariful , Xu Yingjie , Zope Harshal , Cao Wuji , Mahmoudi Morteza , Langer Robert , Kantoff Philip W. , Shi Jinjun , Zetter Bruce R. , Farokhzad Omid C. 
Published: September 2018

11582 Background: The onset and maintenance of cancer frequently involves gain of oncogenic function along with loss of tumor suppression. PTEN is a well-characterized tumor suppressor gene that is lost or mutated in many human cancers including ~50% of metastatic castration-resistant prostate cancer (mCRPC). Reintroduction of functional PTEN for mCRPC treatment has proven difficult. Methods: PTEN mRNA was synthesized by in vitro transcription method and modified with ARCA capping and enzymatic polyadenylation, and then substituted with Pseudo-UTP, 5’-Methyl-CTP. A robust self-assembly approach was employed to prepare PTEN mRNA nanoparticles (NPs) using cationic lipid-like compound G0-C14 and PLGA polymer coated with lipid-PEG shell. PTEN expression in tumors and PI3K-AKT pathway were confirmed by IHC and western blot, respectively. Apoptosis was checked by flow cytometry and Tunel assays. In vivo toxicity was studied by hematologic and histologic tests, and immune response. Results: We successfully restored PTEN mRNA to PTEN-null prostate cancer (PCa) cells via systemic delivery of mRNA NPs. These mRNA NPs are stable in serum, demonstrate minimal toxicity, and provide highly effective transfection in PCa cells (substantially higher HA-PTEN expression than plasmid PTEN transfection) and PCa xenograft tumors, leading to ~85% inhibition of tumor cell growth in vitro and in vivo. We also confirm mRNA NP-mediated systemic restoration of PTEN function in PTEN-null PCa and delineate its tumor suppression through inhibition of the PI3K-AKT pathway and enhancement of apoptosis. Conclusions: The work provides proof of principle for the systemic reintroduction of mRNA-based tumor suppressor genes to tumors in vivo. Because PTEN loss is frequent in late-stage PCa, this approach may have feasibility in this patient population. Considering the strong potential of mRNA therapy and the lack of systemic studies of in vivo mRNA transfection of tumors, this study sheds light on the useful application of NP-mediated mRNA delivery for validating tumor suppressors (e.g., PTEN) as a therapeutic target in cancer treatment where loss of a tumor suppressor contributes to the underlying genetic mechanism of cancer.
RASA1 and NF1 co-mutated non-small cell lung carcinomas: Cancer genomic data and evaluation of sensitivity to MEK inhibition.
Authors: Hayashi Takuo , Desmeules Patrice , Smith Roger , Drilon Alexander E. , Somwar Romel , Ladanyi Marc 
Published: September 2018

11600 Background: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. While NF1 mutations are enriched in non-small cell lung carcinomas (NSCLC) lacking KRAS alterations, they are not completely mutually exclusive. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Methods: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n = 2004), TCGA combined lung cancer dataset (n = 1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations, in RASA1 (RERFLCKJ), NF1 (LCLC103H and H1838), or both (EPLC272H). Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p = .02) and KRAS (p = .02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p < .001), suggesting selection for loss of more than one RasGAP. Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers, including KRAS. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RERFLCKJ cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK (trametinib) or PI3K (GDC0941, PI103), EPLC272H cells (with concurrent RASA1/NF1 mutations) showed notably more profound sensitivity (IC50: 0.040µM trametinib). Finally, simultaneous silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC. Patients whose tumors show this distinctive genotype should be considered for trials of MEK inhibitors.
Nanomechanical profiling of human breast tumors as prognostic marker for breast cancer.
Authors: Burian Rosemarie Anne , Appenzeller Tobias , Oertle Philipp , Raez Christian , Lim Roderick Y.H. , Forte Serafino , Dellas Sophie , Obermann Ellen , Plodinec Marija 
Published: September 2018

11618 Background: Assessment of tumor aggressiveness is crucial when making treatment decisions. Established prognostic markers may be insufficient to stratify cancer patients into treatment relevant risk groups. Emerging evidence indicates mechanical properties of cancer cells and their microenvironment play a vital role in cancer invasion and metastases. Detecting and measuring these nanomechanical changes could be a marker of cancer aggressiveness. Methods: We developed an atomic force microscope (AFM) based method: ARTIDIS (Automated and Reliable Tissue Diagnostics) for measuring nanomechanical properties of human tissue biopsies. These were performed on fresh, non-fixed tissue under physiological conditions. This novel method uses a micro-fabricated 20nm tip indenting and measuring stiffness of thousands of locations within 60-180minutes. This quantitative, biopsy-wide, nanomechanical profile strongly correlates to the tissue's biological composition. Post-AFM this biopsy is analyzed by pathology. We sought to differentiate benign from cancerous lesions based on nanomechanical properties; then link the cancerous nanomechanical profiles prospectively to the clinical outcomes. Results: Our results demonstrate the first AFM based nanomechanical profiling to detect aggressive breast cancer subtypes using fresh tissue in a clinical setting. We have shown that nanomechanical profiles of human breast cancer biopsies display stiffness profiles distinct from surrounding normal tissue. Breast cancer subtypes were distinguishable by their nanomechanical properties only. We have discovered specific nanomechanical profiles of tumor subtypes likely to metastasize. When the primary tumor displayed the same soft nanomechanical profile as adjacent tissue, this was associated with positive nodal status. Conclusions: Our results demontrate nanomechanical profiling is a fast and sensitive method to stratify malignant biopsies into relevant subgroups in a clinical setting. Relative stiffness and distribution values provide a nanomechanical profile indicating cancer aggressiveness. This will help optimize specific cancer diagnosis, orientate therapy choice and support patient follow up.