tbuckley/cabot-search huggingface dataset:
A first-in-human, multicenter, open label, phase I study in patients with advanced and/or refractory solid malignancies to evaluate the safety of intravenously administered ATOR-1015.
Authors: Jeffrey Yachnin, Gustav J Ullenhag, Ana Carneiro, Dorte Nielsen, Kristoffer Staal Rohrberg, Anne Månsson Kvarnhammar, Anna Dahlman, Erika Bågeman, Camilla Wennersten, Charlotte Astrid Russell
Journal: Journal of Clinical Oncology (2019)

TPS2653 Background: ATOR-1015 is a human bispecific IgG1 antibody targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and the tumor necrosis factor receptor superfamily member 4, OX40 (also known as CD134). Both in vitro and in vivo, ATOR-1015 induces activation of cytotoxic T cells and depletion of regulatory T cells (1). In syngeneic tumor models, using human OX40 transgenic mice cross-reacting with both targets, ATOR-1015 is demonstrated to localize to the tumor. Further, the effects of ATOR-1015 are shown to occur in the tumor area and not in the spleen (1). Treatment with ATOR-1015 also reduces tumor growth and improves survival in several tumor models in mice, including bladder, colon and pancreatic cancer (1). The non-clinical safety profile and the pharmacokinetics were established in cynomolgus monkeys and the data were used for the dosing schedule. Methods: This is a multicenter, open-label, dose escalation study enrolling patients with advanced and/or refractory solid malignancies (NCT03782467). The primary objective of the study is to determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) and to establish the safety profile of ATOR-1015. ATOR-1015 is administered intravenously biweekly as a single agent until confirmed progressive disease, unacceptable toxicity or withdrawal of consent. The study will start with single patient cohorts until grade 2 toxicities are observed, thereafter the study follows a modified 3+3 design. At the MTD/RP2D, or a lower dose, up to 20 patients are planned for additional safety and efficacy evaluation. Study enrollment was initiated in January 2019. A total of up to 53 patients are estimated to be enrolled in the study. (1) Månsson Kvarnhammar et al. Journal for ImmunoTherapy of Cancer 2018; 6(Suppl 1):115. Abstract P683. Clinical trial information: NCT03782467.
Case 47-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Z. Myron Falchuk, Lynn F. Butterly, Theodore A. Stern
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 60-year-old woman was admitted to the hospital because of chronic diarrhea and weight loss.She was in a stable state of health until six months earlier, when her usual intermittent mild constipation was replaced by diarrhea that worsened progressively. Her stools were watery, sometimes contained blood, and occurred mainly after eating solid food. Cramps developed and occurred primarily in the lower quadrants, but she sometimes experienced upper abdominal pain as well and reduced her food intake. She noticed increased thirst and a decrease in urinary volume and observed that stools were not provoked by drinking coffee . . .
PD-L1 detection using 89Zr-atezolizumab immuno-PET in renal cell carcinoma tumorgrafts from a patient with favorable nivolumab response
Authors: Joseph Vento, Aditi Mulgaonkar, Layton Woolford, Kien Nham, Alana Christie, Aditya Bagrodia, Alberto Diaz de Leon, Raquibul Hannan, Isaac Bowman, Renee M. McKay, Payal Kapur, Guiyang Hao, Xiankai Sun, James Brugarolas
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Programmed death-ligand 1 (PD-L1) expression in metastatic renal cell carcinoma (RCC) correlates with a worse prognosis, but whether it also predicts responsiveness to anti-PD-1/PD-L1 therapy remains unclear. Most studies of PD-L1 are limited by evaluation in primary rather than metastatic sites, and in biopsy samples, which may not be representative. These limitations may be overcome with immuno–positron emission tomography (iPET), an emerging tool allowing the detection of cell surface proteins with radiolabeled antibodies. Here, we report iPET studies of PD-L1 in a preclinical tumorgraft model of clear cell RCC (ccRCC) from a patient who had a favorable response to anti-PD-1 therapy. <h3>Case presentation</h3> A 49-year-old man underwent a cytoreductive nephrectomy in 2017 of a right kidney tumor invading into the adrenal gland that was metastatic to the lungs and a rib. Histological analyses revealed a ccRCC of ISUP grade 4 with extensive sarcomatoid features. IMDC risk group was poor. Within two hours of surgery, a tumor sample was implanted orthotopically into NOD/SCID mice. Consistent with an aggressive tumor, a renal mass was detected 18 days post-implantation. Histologically, the tumorgraft showed sarcomatoid differentiation and high levels of PD-L1, similar to the patient's tumor. PD-L1 was evaluated in subsequently transplanted mice using iPET and the results were compared to control mice implanted with a PD-L1-negative tumor. We labeled atezolizumab, an anti-PD-L1 antibody with a mutant Fc, with zirconium-89. iPET revealed significantly higher <sup>89</sup>Zr-atezolizumab uptake in index than control tumorgrafts. The patient was treated with high-dose IL2 initially, and subsequently with pazopanib, with rapidly progressive disease, but had a durable response with nivolumab. <h3>Conclusions</h3> To our knowledge, this is the first report of non-invasive detection of PD-L1 in renal cancer using molecular imaging. This study supports clinical evaluation of iPET to identify RCC patients with tumors deploying the PD-L1 checkpoint pathway who may be most likely to benefit from PD-1/PD-L1 disrupting drugs.
Study of a smartphone-based symptom assessment (OurBrainBank) for subjects with glioblastomas.
Authors: Jessica Morris, Bruce Hellman, Kelli Duprey, Jacob Ellen, Lakshmi Nayak, Fabio Iwamoto
Journal: Journal of Clinical Oncology (2019)

e13574 Background: Self-reports from patients done monthly or every few months in the doctor’s office have several limitations, including poor recall, under- or over-reporting of events, among other biases. Methods: We developed a glioblastoma specific app (OurBrainBank) using a platform designed by uMotif, which was previously used in other conditions but has been customized for glioblastoma. All data are sent to a HIPPA compliant database. The subject can view or export their own data as well and create data reports to their medical team. Inclusion criteria included age 18 years or older, diagnosis of glioblastoma, English-speaking subject, and availability of a smartphone or tablet. After electronic informed consent, patients completed baseline questionnaires about their treatment and validated surveys (EORTC-QLQ, EORTC-BN20). Certain parameters such as sleep quality, exercise, mood, and fatigue were captured for all patients. In addition, patients picked 6 additional symptoms most relevant to their clinical condition. Results: Since the study was IRB-approved and the app made available free of charge on app stores, there have been 305 individual patients who registered on this app. Recruitment has relied heavily on social media and patient run online support groups. The most commonly tracked symptoms were exercise, fatigue, mood, sleep quality, appetite, memory and concentration. Patients were alerted to capture symptoms at least weekly and more than 5,000 datapoints were captured. The median age was 48 (18-83). 53% of patients had received the GBM diagnosis &lt; 1 year and 25% between 1-2 years. Most patients found symptom tracking useful (average rating of 7 in 0-10 scale). Conclusions: At this initial stage, OurBrainBank has shown that it can efficiently collect glioblastoma patients’ symptoms. In the next steps, we plan to collect passive data from smartphones and other device trackers. Additionally, OurBrainBank will enable patients to donate their medical records to a national and international database. The goal over the next few years is to create an unprecedented database of high quality and granularity with tens of thousands of de-identified glioblastoma patients, with open-access to qualified academic researchers. In addition, this powerful ‘real world experience’ database will be useful for pharma/biotech companies.
The Idylla MSI Test (CE-IVD) multi-center concordance study: Microsatellite instability detection in colorectal cancer samples.
Authors: Patrick Pauwels, Torben Steiniche, Muriel Gazin, Jan Van de Velde, Ellen Bellon, Evelien Rondelez, Liesbeth Vandenbroeck, Karen Zwaenepoel, Koen De Winne, Tine Meyer, Julie Mejer, Magnus Stougaard, Klaas Decanniere, Benoit Devogelaere, Geert G. Maertens, Bram De Craene
Journal: Journal of Clinical Oncology (2019)

e15112 Background: To validate the Idylla MSI Test to detect microsatellite instability (MSI) in colorectal cancer (CRC) samples in comparison with Promega MSI Analysis System v1.2 (Promega MSI) and in conditions similar to normal use. Methods: The study was performed on residual formalin-fixed and paraffin-embedded (FFPE) samples obtained from routine diagnostics by two centers, University Hospital Aarhus and University Hospital Antwerp. Samples originated from CRC patients (all stages). Both centers performed the Idylla MSI Test (with 7 novel homopolymer deletion markers) at their premises on 150 and 180 samples, respectively. The comparator method, Promega MSI, was performed for all 330 samples by University Hospital Antwerp. Results: Seven (n=7) of 330 samples were excluded from the concordance analysis due to invalid or error (failed) results for Idylla MSI Test and/or Promega MSI. For the 323 valid results, overall, positive and negative percentage agreement were 99.7% (98.3%-100%;), 98.7% (92.9%-99.8%) and 100% (98.5%-100%), respectively. A higher number of invalids was observed for Promega MSI (2.1%) compared to the Idylla MSI Test (0.6%) taking into account per protocol retesting (18 retests for Promega MSI (6%) and 3 for Idylla MSI Test (1%)). Conclusions: This study validated the Idylla MSI Test with high performance and low invalid rate to discriminate MSI-H from MSS status on a clinical routine set of CRC samples.
Development of a radiomics nomogram based on the CE-CT features to predict the survival of upfront resectable patients with pancreatic head cancer and suspected venous invasion.
Authors: Yinan Shen, Tianyu Tang, Xueli Bai, Tingbo Liang
Journal: Journal of Clinical Oncology (2019)

e15760 Background: Pancreatic head adenocarcinoma is commonly diagnosed at an advanced stage when adjacent vascular invasion is present. This study aimed to establish a radiomics nomogram by integrating radiomics signature and clinical predictors to estimate overall survival(OS) in patients who underwent attempted curative resectional surgery for pancreatic head cancer with suspected peri-pancreatic venous invasion. Methods: Data on patients with pancreatic head adenocarcinoma and suspected peripancreatic invasion who underwent pancreatic resection with venous reconstruction were retrospectively collected from 2012 to 2016 at two academic institutions. A total of 396 radiomics features were extracted from pretreatment CE-CT images of each patient. Least absolute shrinkage and selection operator (LASSO) regression was applied to select optimal features and generate a radiomics signature. The radiomics nomogram was developed by integrating the radiomics signature and clinical predictors. The performance of radiomics nomogram validated in the cohort of patients of second institution. Results: Radiomics signatures were significantly associated with pancreatic head adenocarcinoma patients' survival time. The radiomics nomogram combined with clinical predictors(CA-199 value, Peripancreatic venous abnormalities and Lymph node staging) provided good predictive accuracy of survival on calibration curves. The C-index of the model in predicting overall survival (OS) was 0.836 for the validation cohort. Conclusions: The nomogram accurately predicted OS in patients with pancreatic head cancer with suspected peripancreatic venous invasion after attempted curative pancreatic resectional surgery. These findings might aid clinicians with treatment decision-making and improve precise medicine.
HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 TRIAL.
Authors: Julia Dianne Wulfkuhle, Denise M. Wolf, Christina Yau, Rosa Isela Gallagher, Lamorna Brown Swigart, Gillian L. Hirst, Douglas Yee, Paula Raffin Pohlmann, Anthony D. Elias, Stacy L. Moulder, Debu Tripathy, Angela DeMichele, Laura Esserman, Donald A. Berry, Laura van 't Veer, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2019)

3133 Background: T-DM1 (T), a conjugate of the anti-HER2 therapeutic antibody trastuzumab and the microtubule assembly inhibitor emtansine, was administered in combination with pertuzumab (P), an anti-HER2 therapeutic antibody, to HER2+ breast cancer patients in the I-SPY 2 TRIAL, and graduated in all HER2+ subtypes. Pre-specified biomarker analysis was performed to identify candidate biomarkers associated with pCR within the HER family and cell proliferation pathways in patients treated with T+P. We hypothesized that quantitative measurement and activation of HER2 and activation of its major dimerization partner, EGFR would predict response to T+P. Methods: In the T+P treatment arm, 49 had RPPA and pCR data. 40 RPPA endpoints including 14 total/phospho-proteins in the HER family were assessed for association with pCR using logistic regression (likelihood ratio test; p &lt; 0.05). Analysis was also performed adjusting for HR status and within HR subsets. Markers were analyzed individually; multiple comparison correction (Benjamini-Hochberg) was applied to all p-values. Our statistics are descriptive and do not adjust for multiplicities of other biomarkers outside this study. Results: Of the endpoints tested, only quantitative total HER2 expression, phospho-HER2 (Y1248 and Y877), phospho-EGFR (Y1173 and Y1068), and phospho-SHC Y317 had a positive association with response in the population as a whole, and in a model adjusting for HR status (BH p &lt; 0.05). In HR subset analysis, these 5 analytes had uncorrected p &lt; 0.05 regardless of HR subtype but only survived p-value correction in HR+ tumors. Conclusions: Quantitative measurement of HER2 protein positively associates with response to T+P in patients already identified as HER2+ by central IHC and FISH testing. Activation of HER2 and its dimerization partner, EGFR, also associate with response to T+P in HR+ patients. While our results need to be validated in larger prospective trials, they indicate that new approaches to measure more quantitatively the amount and activation state of HER2 and activated EGFR may more effectively identify patients that respond to HER2 targeted therapies than HER2 IHC and FISH alone.
Quality of life after preoperative radio-/chemotherapy in locally advanced breast cancer patients.
Authors: Christiane Matuschek, Carolin Nestle-Kraemling, Sylvia Wollandt, Vanessa Speer, Edwin Boelke, Stephan L. Roth, Werner Audretsch, Balint Tamaskovics, Guido Lammering, Freddy Joel DjiepmoNjanang, Wilfried Budach, Jan Haussmann
Journal: Journal of Clinical Oncology (2019)

e12083 Background: Preoperative radiotherapy and chemoradiotherapy (PRT/PCRT) represents an increasingly used clinical strategy in different tumor sites. However, concerns regarding a possible unfavorable influence on the clinical outcome still exist. The aim of the current study was to examine the long-term global health status in our series of LABC patients treated with PRT/PCRT followed by breast-conserving surgery (BCS) or mastectomy (ME). Methods: Of the 315 patients treated with PRT/PCRT in the years 1991 and 1999, 203 patients were still alive at long-term follow up of mean 17.7 years (range 14-21). Thirty-seven patients were lost to follow up and 58 patients refused to be contacted, which resulted in 107 patients (64 patients after BCS and 43 after mastectomy) being available and willing to undergo further clinical assessment. PRT/PCRT consisted of external beam radiation therapy (EBRT) with 50 Gy (5 × 2 Gy/week) to the breast and the supra-/ infraclavicular lymph nodes combined with a consecutive electron boost or (in case of BCS) a 10-Gy interstitial brachytherapy boost with Ir-192 prior to EBRT. Overall, chemotherapy was administered either prior to RT or concomitantly in the majority of patients. Quality of life (QoL) was assessed by EORTC QLQ-C30 questionnaires for overall QoL and EORTC QLQ-BR23 for breast-specific QoL. Results are reported using functional scales (body image, sexual functioning, sexual enjoyment, and future perspective) and symptom-related items (systemic therapy side effects, breast symptoms, arm symptoms, and upset by hair loss). The results were compared to a published reference cohort of n=2028 healthy adults (16-92 years), including n=1139 women (age 16-92 years). EORTC QLQ-C30 functional scales were also analyzed between different subgroups including an age-matched analysis with a two sided paired t-test. Results: In comparison with this healthy control group of 1139 women, we did not detect any significant differences for the functional scales measured by physical function, emotional well-being, cognitive, and social function as well as the symptom scales: fatigue, nausea, vomiting, pain, diarrhea and financial difficulties for both groups. However, significant inferior scores were found in the present study group regarding obstipation (p=0.013), loss of appetite (0.038), sleeping disorder (p=0.01) and dyspnoe (p=0.01). Conclusions: Taken together, retrospective as well as prospective data underline the feasibility of preoperative radiotherapy in breast cancer.
Correction to: Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T-cell immunity
Authors: Elena E. Tchekneva, Mounika U. L. Goruganthu, Roman V. Uzhachenko, Portia L. Thomas, Anneliese Antonucci, Irina Chekneva, Michael Koenig, Longzhu Piao, Anwari Akhter, Maria Teresa P. de Aquino, Parvathi Ranganathan, Nicholas Long, Thomas Magliery, Anna Valujskikh, Jason V. Evans, Rajeswara R. Arasada, Pierre P. Massion, David P. Carbone, Anil Shanker, Mikhail M. Dikov
Journal: Journal for ImmunoTherapy of Cancer (2019)

Following publication of the original article [1], the author reported the wrong version of Figs. 5 and 7 have been published. The correct version of the figures can be found below.
Increasing potency and safety of anticancer drugs through sortilin receptor-mediated cancer therapy: A new targeted approach for the treatment of ovarian cancer.
Authors: Borhane Annabi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Cyndia Charfi, Richard Béliveau
Journal: Journal of Clinical Oncology (2019)

e17068 Background: The development of personalized therapies against ovarian cancer remains highly challenging in current modern oncology. One strategy to achieve greater selectivity and better anticancer drug delivery into cancer cells is to conjugate cytotoxic agents to specific peptide ligands that selectively target receptors abundantly and/or exclusively expressed on these cells. Increased expression of Sortilin, a scavenging receptor, has been clinically observed in invasive ovarian cancer biopsies, and correlated with tumor grades. In light of this, we developed a peptide conjugation platform and a new Sortilin receptor-mediated vectorization strategy to increase cell targeting selectivity and cell delivery efficacy of anticancer agents. Methods: As a proof-of-concept, Doxorubicin was conjugated to a Sortilin binding peptide (KA-peptide). In vitro, intracellular delivery of the Doxorubicin-KA-peptide conjugate (DoxKA) was assessed in ES-2 and SKOV-3 ovarian cancer cell line models using flow cytometry and fluorescent microscopy. Sortilin gene silencing was performed with specific siRNA. DoxKA efficacy and safety were evaluated in vivo using ES-2 (CD1 nude mice) and SKOV-3 (athymic mice) subcutaneous xenograft models. Results: Uptake of DoxKA was observed in both Sortilin-positive ovarian cancer cell lines tested and was reduced when Sortilin expression was specifically silenced or upon competition with the Sortilin ligands Neurotensin and Progranulin. Results indicate that the uptake of DoxKA occurs via Sortilin-mediated endocytosis in contrast to simple diffusion for Doxorubicin. DoxKA was found to bypass the P-glycoprotein (P-gp) efflux pump in MDCK-MDR1 cells overexpressing P-gp as the uptake of DoxKA was unaffected by the P-gp inhibitor Cyclosporin A. In vivo, DoxKA showed lower potential side effects than Doxorubicin alone did, with decreased accumulation in healthy tissues such as heart and ovary. DoxKA caused a more potent inhibition of human ovarian tumor xenografts growth in mice and was better tolerated (absence of leukopenia and neutropenia) than the unconjugated Doxorubicin at an equivalent dose. Conclusions: These results strongly support the future clinical use of this platform to generate novel personalized therapeutics with specific targeting of Sortilin-positive tumors in the next stage of development in phase 1 clinical trial.
Characterization of tumor mutation burden, PD-L1 and hepatitis B virus in Chinese hepatocellular carcinoma patients.
Authors: Junjie Xu, Xiao Liang, Lingxiang Liu, Haibo Mou, Zhe Wan, Shi Jiang, Zhe Yang, Daobing Zeng, Xiaoqian Chen, Junping Shi, Ming Yao, Zhonghai Chen, Kai Wang
Journal: Journal of Clinical Oncology (2019)

e15666 Background: Hepatocellular carcinoma (HCC) has a high mortality rate and is the fourth most common cancer in China. Immunotherapy of immune checkpoint inhibitors (ICI) is a promising novel treatment strategy, but the response rate is generally low and it is not clear which patients will benefit from ICI immunotherapy. Methods: Deep sequencing targeting 450 cancer genes was done on FFPE and matched blood samples from 601 Chinese HCC patients (pts). Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations (CNV), gene rearrangements and fusions were analyzed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house, PD-L1 expression was done by immunohistochemistry staining and Hepatitis B Virus (HBV) by target capture. Results: Patients, median age 55 years old, had TMB values in a range of 0.7 to 69.6 Muts/Mb. The 1 st Quartile, median and 3 rd Quartile TMB values were 3.8, 5.4 and 7.8 Muts/Mb, respectively. Comparing 155 pts with TMB-H (≥3 rd Quartile) to 181 TMB-L (≤1 st Quartile) pts, the mutant frequencies of TERT (49% vs 38%, p= 0.044), CTNNB1 (32% vs 11%, p&lt; 0.001), LRP1B (14% vs 5%, p= 0.004) and ARID1A (12% vs 5%, p= 0.014) were higher. The mutant frequency of TP53 was lower (57% vs 68%, p= 0.035). TMB-L had younger pts (median age 50y vs 60y, p&lt; 0.001) and CNV (382 vs 232, p&lt; 0.001). PD-L1 expression was detected seen in 222 pts, including 152 pts of Dako 28-8 Ab and 70 pts of Dako 22C3 Ab with no preference. The PD-L1 positive rate (TPS ≥1%) was 7% and 34% in 28-8 group and 22-C3 group, respectively. Eleven pts were both TMB-H and PD-L1 positive. HBV probe signal was detected in 285 pts, 262 of which were positive (≥10 reads). TMB, PD-L1 expression and HBV were not found to be significantly correlated. Conclusions: In our study, 37% of Chinese HCC pts with PD-L1 positive or TMB-H may benefit from immunotherapy. TMB-H HCC pts were older, had more common TERT, CTNNB1, LRP1B and ARID1A mutations, and fewer TP53 mutations and CNV. In our current cohort, TMB and PD-L1, TMB and HBV, and PD-L1 expression and HBV were not correlated significantly.