tbuckley/cabot-search huggingface dataset:
A phase Ib study of IMU-131 HER2/neu peptide vaccine plus chemotherapy in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Yee Chao, Thomas Yau, Marina Maglakelidze, Iurie Bulat, Suebpong Tanasanvimon, Chaiyut Charoentum, Wichit Arpornwirat, Jedzada Maneechavakajorn, Arunee Dechaphunkul, Teerapat Ungtrakul, Chia-Jui Yen, Li-Yuan Bai, Wen-Chi Chou, Ursula Wiedermann, Anthony J Good, Nick Ede, Leslie Mi Ok Chong
Journal: Journal of Clinical Oncology (2019)

4030 Background: Gastric cancer is the 5th most common cancer and the 3rd leading cause of cancer deaths. HER2/neu is overexpressed in 15% - 25% of patients with gastric cancer. Monoclonal antibodies against HER2/neu are effective but alternatives are needed due to cost and global availability. IMU-131 is a B-cell peptide vaccine composed of a fusion of 3 epitopes from the extracellular domain of HER2/neu conjugated to CRM197 with the adjuvant Montanide. Polyclonal antibodies against IMU-131 peptides elicit antitumor activity in vitro and a phase I study demonstrated safety and immunogenicity in Her-2 +/++ breast cancer patients. Methods: IMU-131 was given to patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma in an international open-label Phase 1b dose escalation trial performed in 14 Asian and Eastern European sites assessing safety, tolerability, and immunogenicity. Each patient received IMU-131 on Days 0, 14, and 35, accompanied by cisplatin and 5-fluorouracil or capecitabine every 21 days. Results: 14 patients were enrolled with advanced stage IIIb or IV with 10 HER2 overexpressing tumors (7 x HER2+++, 3 x HER2++ FISH positive) and 4 HER2++ expressing tumors. Mean age was 57 yo (range of 21 - 79) with ECOG scores of 0 or 1 in 7 patients each. There were 9 Asian and 5 Caucasian patients with 5 females and 9 males. Dose levels were 0.1, 0.3 and 0.5 mg with 3, 6, and 5 patients receiving those dose levels each. 11 patients received all 3 doses with 3 patients who received only 2 doses due to disease progression and 2 patients received a dose on day 182. Of the 14 patients dosed 11 were evaluable for tumor progression at day 56 and later. Of those patients, the best response was 1 CR, 4 PR,5 SD and 1 PD. In the 0.1 mg dose group the best response was 1 CR and 2 SD, with 2 PR, 2 SD and 1 PD in the 0.3 mg group and 2 PR and 1 SD in the 0.5 mg group. In patients with HER2 overexpression there was 1 CR, 4 PR, 2 SD and 1 PD, and in patients with HER2++ expression there was 3 SD. There were no SAEs related to IMU-131 and 1 patient had a mild injection site reaction. Conclusions: IMU-131 is a promising B-Cell vaccine against HER2. Further work in a controlled phase 2 trial is ongoing. Clinical trial information: NCT02795988.
Demographic characteristics of smoldering multiple myeloma patients: A hospital-based study including 11,643 patients.
Authors: Kamal Chamoun, Ravi Kumar Kyasaram, Leland L. Metheny, Molly Gallogly, Paolo Fabrizio Caimi, Stanton L. Gerson, Marcos J.G. De Lima, Ehsan Malek
Journal: Journal of Clinical Oncology (2019)

e13064 Background: SMM is the requisite asymptomatic phase that precedes Multiple Myeloma (MM). Observation until progression to MM has been the standard of care. However, the improvement in risk assessment and utility of chemoprevention strategies stemmed from large trials (e.g. QUIREDEX and E3A06) is beginning to shift the paradigm toward early detection of SMM by implementing screening strategies (e.g., PROMIS study). Lack of specific ICD code for SMM has been a major problem in epidemiologic studies aiming at characterizing the demographics and temporal dynamics of SMM. Here, we used the National Cancer Data Base (NCDB), which covers more than 70% of cancer pts in the USA, for this purpose. Methods: NCDB data from year 2010 to 2014 was analyzed. We defined SMM as pts with ICD-O 9732 that were placed on active surveillance or did not receive any therapy in the first 3 months (m) after diagnosis (Ravindran et al. Blood Cancer J. 2016). Institution size was categorized as small, medium and large if they reported &lt; 10, 10-50, and &gt; 50 cases per year, respectively. Results: Out of a total of 68234 MM pts, we identified 11643 (17%) with SMM. Median follow up was 32 m (0 - 85). Median age was 65 years (26 - 90), 52% were males, 71% were white and 24% were black. Median survival was 77.7 and 49.8 m for pts with SMM and MM, respectively ( p= 0.001). Median age at diagnosis of SMM was 62 and 66 years in blacks and whites, respectively ( p= 0.01). Over 87% of pts were diagnosed in small and medium size institutions (38% and 49%, respectively). Medicare was the main insurance payer (57%), followed by private insurance (32%) and Medicaid (5%), and 3% were not insured. The majority of pts (59.5%) lived in areas where the median income is less than $46K/year. Median distance traveled to treatment facility was 8.5 miles. During the first two years from diagnosis 18% needed treatment which is compatible with known estimated 10% per year risk of progression from SMM to MM. Conclusions: This large study of over 11,000 SMM pts highlights the national demographics of SMM diagnosed between years 2010 and 2014. Our results indicate that targeting small and medium size facilities should be an essential part of SMM screening strategies.
Regorafenib-associated adverse event management in colorectal and gastrointestinal stromal cancer patients: A systematic review and meta-analysis.
Authors: Ganfeng Xie, Yuzhu Gong, Shuang Wu, Chong Li, Songtao Yu, Zhe Wang, Jianfang Chen, Quanfeng Zhao, Jianjun Li, Houjie Liang
Journal: Journal of Clinical Oncology (2019)

e15181 Background: Adverse events (AEs) observed in regorafenib treated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST) often require treatment modification. However, due to dearth of literature reporting AE management, we performed a systematic review and meta-analysis to assess the success of different methods of managing regorafenib-associated AEs and also determined risk factors of the AEs. Methods: A comprehensive search was conducted in PubMed, Embase and Cochrane Library, to retrieve RCTs and observational studies published from inception to May 2018, discussing the management methods of AEs with rate of improvement and risk factors of the AEs. The success rate for each method was evaluated as percentage and compared using chi 2 -test. Risk factors were presented using Pearson correlation. Results: We identified 28 studies for this analysis (N = 3120 patients; 305 GIST and 2,815 mCRC). Methods used for management included intermittent dose withdrawal (66.7%), delayed treatment schedules (54%), dose reductions (41%), complete drug withdrawal (19%) and preventive measures like dexamethasone and lactose administration or surgery (63.7%). Reduction or improvement in AEs was observed in 57%, 17% and 100% patients after lowering the initial dose, intermittent withdrawal of regorafenib and using other preventive measures, respectively. Patients aged &lt; 65 years had significantly higher occurrence of AEs compared with patients aged ≥65 years (27.6% vs. 71.3%, p = 0.001). A significant positive correlation was observed between the occurrence of all and grade 3AEs with 160mg dose (r = 0.967 and 0.746 respectively; p = 0.001 for both) with no significant correlation observed for 120-mg and 80-mg doses and any gender. Conclusions: Initiating dose of 160mg is a major risk factor for regorafenib associated AEs in mCRC and GIST patients; with intermittent dose reduction, withdrawal, and delayed treatment being the commonly used management strategies. To allay the risk of AEs and maintain the efficacy, 120mg initial dose is recommended for mCRC and GIST patients. However, further studies are required to confirm the results.
Trifluridine/tipiracil plus bevacizumab in elderly patients with previously untreated metastatic colorectal cancer (KSCC1602): A multicenter, phase II clinical trial.
Authors: Eiji Oki, Akitaka Makiyama, Yuji Miyamoto, Masahito Kotaka, Hirofumi Kawanaka, Keisuke Miwa, Akira Kabashima, Masahiro Hamanoue, Takafumi Ohchi, Tomomi Kashiwada, Mototsugu Shimokawa, Hiroshi Saeki, Yoshito Akagi, Hideo Baba, Masaki Mori
Journal: Journal of Clinical Oncology (2019)

3548 Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable patients. We aimed to assess the efficacy and safety of trifluridine/tipiracil plus bevacizumab in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. Treatment consisted of trifluridine/tipiracil (35 mg/m 2 orally a day on day 1-5 and day 8-12) with bevacizumab (5mg/kg intravenously on day 1 and day 15), given every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate (ORR), Overall survival (OS) and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients were enrolled in this study. The characteristics of patients were male/female : 17/22, median age : 77.5 (range: 70-88) and PS: 0/1 : 31/8. The ORR of 37 patients were assessed by the central review committee. The best response was 40.5(15/37) % (95% CI: 24.8-57.9), and the disease control rate was 86.5 (32/37) % (95% CI: 71.2–95.5). The AEs which were frequent as grade 3 or 4 were leucopenia (71.8 %), neutropenia (48.7 %), anorexia (12.8 %), febrile neutropenia (10.3 %) and fatigue (10.3 %). No treatment related death was reported. Conclusions: The combination of trifluridine/tipiracil plus bevacizumab is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Hematological adverse events were need for caution. The primary endpoint of PFS will be presented in the end of this year. Clinical trial information: UMIN000025241.
Defining real-world criteria for immune-related adverse events (irAEs).
Authors: PRABHSIMRANJOT SINGH, Amanda Brito, Raja-Elie E Abdulnour, Shilpa Grover, Eric Yenulevich, Sherri Oliver Stuver, Kenneth L. Kehl, Nicole R. LeBoeuf, Joseph O. Jacobson, Osama E. Rahma
Journal: Journal of Clinical Oncology (2019)

e14172 Background: Management of Immune checkpoint inhibitors (ICIs) associated irAEs requires accurate diagnosis and severity measurement. However, outside of clinical trials, there is no clear definition of irAEs to guide treatment. Methods: We established a dedicated immune toxicity inpatient service (ITox) for patients admitted with irAEs using institution-developed guidelines adapted from NCCN and ASCO. We developed definitions for ICI associated hepatitis, colitis and pneumonitis and created algorithms for defining an irAEs as definite, likely, possible, or unlikely. Algorithm fields were completed twice, by two independent reviewers including medical oncology specialists and toxicity specialists (a pulmonologist or gastroenterologist) to evaluate the accuracy of the algorithm in defining irAEs. Results: From June to November 2018, 65 patients were admitted to iTox with suspected irAEs. Various cancers patients treated with ICI were included; with lung and head and neck cancers the most common (36.9%). Pembrolizumab was the most common ICI (47.7%). ICI in combination with non-checkpoint inhibitor treatment was used in 23 (37.7%) and concurrent radiation therapy in 5 patients (7.7%). Forty (71.4%) patients discontinued ICI due to toxicity. Fifty-one patients were evaluable with irAEs: colitis (19); pneumonitis (24) and hepatitis (8). Multiple irAEs were reported in 17 patients. When applied to clinical cases, our algorithms generated a toxicity definition in 63% of cases, with which reviewers agreed most of the time (84-100%) (Kappa 0.7-1.0). Concordance between the two reviewers was 75-87% (Kappa 0.55-0.82) (Table). Conclusions: Our algorithms generated irAEs definitions with fair inter-rater reliability. These findings have real-world implications; accurate diagnosis of irAEs is essential for proper management. Defining irAEs outside the clinical trial context remains an important challenge. [Table: see text]
Circulating PD-L1-exosomes to monitor tumor response in melanoma patients.
Authors: Charlee Nardin, Marine Cordonnier, Gaetan Chanteloup, Valentin Derangere, Marie Paule Algros, Guillaume Marcion, Laurent Arnould, Carmen Garrido, Francois Aubin, Jessica Gobbo
Journal: Journal of Clinical Oncology (2019)

9517 Background: In the era of effective molecular targeted treatments and immunotherapies, there is an urgent need to implement the use of circulating biomarkers in the clinic to facilitate personalized therapy and predict treatment response. We conducted a retrospective study to demonstrate the involvement of circulating PD-L1 exosomes in melanoma patients. Methods: One hundred melanoma patients were included. Exosomes were isolated by ultracentrifugation and evaluated by nanoparticle tracking analysis using a NS300 Instrument (Nanosight, Amesbury, UK). Isolated exosomes were tested for the expression of exosomes markers such as TSG101. PD-L1 expression in plasma and in melanoma plasma-derived exosomes (ExoPD-L1) was measured using an enzyme-linked immunosorbent assay (PD-L1 Human ELISA Kit, Invitrogen). Results: First, ExoPD-L1 was assessed in melanoma cell lines. Exosomes may have a role in cancer immunosuppression mediated by T-cells since they were as efficient as cancer cells to inhibit T-cells activation. In melanoma patients, ExoPD-L1 (median 64,26 pg/mL) was significantly higher than free PD-L1 in the plasma which was barely detectable (0,1 pg/mL). Furthermore, ExoPD-L1 was detected in all patients whereas only 67 % were PD-L1 positive in tumor. Although baseline ExoPD-L1 levels were not associated with clinicopathologic characteristics and tumour burden, ExoPD-L1 variations (ΔExoPD-L1) after treatment correlated with tumor response and survival. A ΔExoPD-L1 cut-off of &gt; 100 was defined, yielding a 83% sensitivity, a 70% specificity, a 91% positive predictive value and a 54% negative predictive values for disease progression. The use of this cut-off allowed stratification in two groups of patients statistically different in terms of overall survival and progression free survival. Conclusions: PD-L1 level in circulating exosomes may be a more reliable marker than PD-L1 expression in the tumor tissue. Monitoring of circulating exosomal PD-L1 may be a promising biomarker to predict tumor response and correlate with survival.
A multi-institutional investigation assessing prevalence of germline genetic alterations in Chinese patients with gastric carcinoma.
Authors: Yinjie Zhang, Xicheng Wang, Changbin Zhu, Xiaotian Zhang, Qing Wei, Lvzhi Ren, Di Shao, Jing Gao, Yan Yan Li, Jingdong Zhang, Xiao-Bing Chen, Chaojie Wang, Qiu Meng, Xin Wang, Baorui Liu, Lin Shen
Journal: Journal of Clinical Oncology (2019)

e13020 Background: Gastric carcinoma is one of the most common malignancies in east asian. Previous studies demonstrated around 10% of patients with gastric cancer were found to have pathogenic germline variants. While, predisposition genes of gastric cancer in Chinese patients are still largely unknown. Thus, we aim to delineate prevalence of deleterious germline mutations in Chinese gastric patients with hereditary high-risk familial cancer history. We also aim to analyze clinical relevance of deleterious germline mutations. Methods: Forty index cases were recruited from 7 institutions in China. DNA samples extracted from blood specimens were captured using a 171-cancer predisposition gene panel and then sequenced by MGI-SEQ 2000 platform. Germline variants were determined to be deleterious according to the ACMG 2015 guidelines. Pathogenic and Likely pathogenic germline variants were further validated by Sanger sequencing. Results: 12 of 40 (30%) probands had 13 pathogenic/likely pathogenic germline variants involving 11 different genes: CHEK2 (n = 2), SPINK1 (n = 2), BLM (n = 1), CDH1(n = 1), EXT2 (n = 1), MLH1 (n = 1), MSH2(n = 1), MUTYH (n = 1), PALB2 (n = 1), NF1 (n = 1), ERCC2 (n = 1). For patients with multiple primary cancers, pathogenic germline alterations were exclusively presented (5 out of 12) (P=0.003). Besides,27 germline variants (like EPCAM, RAD54B, FANCD2, FANCA) with uncertain significance in 15 patients were predicated to be deleterious via in silico predictors. Conclusions: This multi-institutional study identified 30% (12/40) of Chinese gastric cancer patients with family history to have deleterious germline alterations. And potential deleterious variants were also identified. Our data illustrates a significantly distinguished spectrum of germline variants compared with Caucasian ones. This may indicate unique carcinogenesis of gastric cancer in Chinese patients. Since patients with pathogenic or likely pathogenic germline variants have dismal clinical outcome and higher rate of multi-cancer occurrence, genetic counseling of gastric cancer should be considered for individuals with family history at their early age.
Evaluation of tumor infiltrating lymphocites (TILs) and survival in patients with resected non-small cell lung cancer.
Authors: Nuria Cárdenas Quesada, Ana Laura Ortega Granados, Bélgica Márquez Lobo, Carmen Rosa Garrido, Pedro Sanchez Rovira, María Isabel Núñez Torres
Journal: Journal of Clinical Oncology (2019)

e20010 Background: Due to the prognosis of non-small cell lung cancer (NSCLC), even at initial stages we need to characterise better our patients in order to know their prognosis. The purpose of our study is to find some prognostic factors to help us to choose the best therapeutic approach. We found some data about histology and tumor lymphocytic infiltration. Methods: We followed outcome of 94 patients diagnosed of initial stage NSCLC that underwent surgery in our institution between 2010-2013, for more than 5 years, and related survival with findings in tumor samples. Results: Tumor samples were classified in order to establish 4 variables related to tumor lymphocitic inflltration (TILs, as it was established by Brambilla et al): absent, mild, moderate and intense. 20 (21.3%) patients were considered TILs intense, 36 (38.3%) moderate, 33 (35.1%) mild and 5 absent (5.3%). We found some significative differences in disease free survival (DFS, more favorable for TILs absent group), but none for overall survival (OS). Conclusions: TILs and tumor stage could be part of an immunoscore to classify initial stage NSCLC, this score should be validated in future studies [Table: see text]
B- and T-lymphocyte attenuator stimulation protects against atherosclerosis by regulating follicular B cells
Authors: Hidde Douna, Jacob Amersfoort, Frank H Schaftenaar, Mara J Kröner, Máté G Kiss, Bram Slütter, Marie A C Depuydt, Mireia N A Bernabé Kleijn, Anouk Wezel, Harm J Smeets, Hideo Yagita, Christoph J Binder, I Bot, Gijs H M van Puijvelde, Johan Kuiper, Amanda C Foks
Journal: Cardiovascular Research (2019)

The immune system is strongly involved in atherosclerosis and immune regulation generally leads to attenuated atherosclerosis. B- and T-lymphocyte attenuator (BTLA) is a novel co-receptor that negatively regulates the activation of B and T cells; however, there have been no reports of BTLA and its function in atherosclerosis or cardiovascular disease (CVD). We aimed to assess the dominant BTLA expressing leucocyte in CVD patients and to investigate whether BTLA has a functional role in experimental atherosclerosis.We show that BTLA is primarily expressed on B cells in CVD patients and follicular B2 cells in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. We treated Ldlr-/- mice that were fed a western-type diet (WTD) with phosphate-buffered saline, an isotype antibody, or an agonistic BTLA antibody (3C10) for 6 weeks. We report here that the agonistic BTLA antibody significantly attenuated atherosclerosis. This was associated with a strong reduction in follicular B2 cells, while regulatory B and T cells were increased. The BTLA antibody showed similar immunomodulating effects in a progression study in which Ldlr-/- mice were fed a WTD for 10 weeks before receiving antibody treatment. Most importantly, BTLA stimulation enhanced collagen content, a feature of stable lesions, in pre-existing lesions.Stimulation of the BTLA pathway in Ldlr-/- mice reduces initial lesion development and increases collagen content of established lesions, presumably by shifting the balance between atherogenic follicular B cells and atheroprotective B cells and directing CD4+ T cells towards regulatory T cells. We provide the first evidence that BTLA is a very promising target for the treatment of atherosclerosis.
A phase I dose-finding and pharmacokinetics study of CPC634 (nanoparticle entrapped docetaxel) in patients with advanced solid tumors.
Authors: Florence Atrafi, Herlinde Dumez, Ron H.J. Mathijssen, Catharina Wilhelmina Menke, Jo Costermans, Cristianne J.F. Rijcken, Rob Hanssen, Ferry Eskens, Patrick Schoffski
Journal: Journal of Clinical Oncology (2019)

3026 Background: CPC634 is a novel product with docetaxel temporarily entrapped within stabilized CriPec nanoparticles. We performed the first-in-human study with CPC634 (NCT02442531). Methods: Patients (≥18 years) received CPC634 intravenously either 3-weekly (Q3W) (part 1, 15-100 mg/m 2 ), 2-weekly (Q2W) (part 2, 45 mg/m 2 ) or Q3W with dexamethasone premedication (part 3) following a 3+3 design. Primary objectives were to assess safety, establish the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and to evaluate the pharmacokinetic (PK) profile of CPC634. Results: Thirty-three patients (part 1; n = 24, part 2; n = 3, part 3; n = 6) were treated. Skin toxicity was dose limiting at doses &gt; 60 mg/m 2 in part 1, and at a 45 mg/m 2 dose in part 2. Skin toxicity was cumulative but resolved after ceasing treatment. The MTD in part 1 was set at 70 mg/m 2 . In part 3, the 60 mg/m 2 was explored which resulted in improved skin tolerability even after repeated administrations without dose limiting toxicities. The RP2D was therefore set at 60 mg/m 2 with dexamethasone premedication. Grade ≥3 adverse events (CTCAE version 4.03) were skin toxicity (21%), fatigue (8%), neutropenia (6%), peripheral sensory (8%) and motor neuropathy (4%), stomatitis (4%), infections (4%) and hypomagnesemia (3%). Alopecia grade 1 was reported in 15% of patients. CPC634 exhibited a dose-proportional PK profile. One partial response and sixteen cases of stable disease (RECIST 1.1) were confirmed in part 1 and in part 3 as best response. Conclusions: CPC634 could be administered safely but showed cumulative, though reversible skin toxicity at high doses. The RP2D was set at 60 mg/m 2 Q3W with dexamethasone premedication. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) is currently ongoing. Clinical trial information: NCT02442531.