tbuckley/cabot-search huggingface dataset:
Rates of survival throughout the years in soft tissue sarcoma with synchronous metastases: Results of a population-based study.
Authors: Melissa Vos, Vincent K.Y. Ho, Astrid W. Oosten, Cornelis Verhoef, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2017)

11068 Background: Roughly 10% of patients with soft tissue sarcoma (STS) present with synchronous metastases and generally cannot be cured anymore. With the registration of trabectedin, pazopanib and the identification of other agents exerting activity against STS, the treatment of these patients in the Netherlands has changed considerably in the last decade. The aim of this population-based study is to examine whether the overall survival (OS) of patients with STS and synchronous metastases has improved over the years. Methods: All patients diagnosed with adult-type STS and synchronous metastases between 1989 and 2014 were queried from the Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan Meier method and log rank test in different timeframes based on year of registration of trabectedin ( &lt; 2007 vs. ≥2007) and pazopanib ( &lt; 2012 vs. ≥2012). A multivariable Cox regression analysis was performed to identify relevant characteristics prognostic for OS. Results: In total, 1,393 patients with adult-type STS and synchronous metastases were identified. Over the whole time period, median OS did not improve significantly (5.8 months in 1989-1994 to 8.1 months in 2010-2014, p = 0.095), but median OS &lt; 2007 compared to ≥2007 did improve significantly (5.8 months to 7.3 months, p = 0.035). This was particularly apparent in the liposarcoma subgroup, where median OS doubled (5.2 months to 11.5 months, p = 0.020). Median OS &lt; 2012 compared to ≥2012 did not increase significantly (6.1 months to 7.6 months, p = 0.062), though there was a relatively short follow-up of 2 years while the survival curve seems to reach a plateau phase. Aside from not receiving (any type of) treatment, elderly age, STS subtype other than lipo- or leiomyosarcoma, high or unknown grade and nodal involvement were significant negative predictors for OS, whereas primary tumor site in the extremity and surgery in an academic center had a favorable effect on OS. Conclusions: OS of STS patients with synchronous metastases has not improved significantly over the years, except for the subgroup of liposarcomas after 2007. A longer follow-up period is needed to clarify the impact of pazopanib on OS in patients with metastatic STS.
Efficacy and toxicity of HLX07 as a new anti-EGFR monoclonal antibody for epithelial cancers.
Authors: Hsingjin Eugene Liu, Chi-Ling Tseng, Scott Liu, Weidong Jiang
Journal: Journal of Clinical Oncology (2017)

e14078 Background: EGFR is a validated target for anti-cancer drug development. Several anti-EGFR monoclonal antibodies (mAb) are used in clinics, but associated with a variety of toxicities. A new anti-EGFR mAb might offer better efficacy with less toxicities. Methods: we have developed a new humanized anti-EGFR mAb, HLX07, through engineering of Fab portion and improvement of glycosylation profile and tested in in vitro assays, in vivo xenograft animal models and primate pharmacokinetic (PK) and toxicokinetic (TK) studies. Results: HLX07 exerted potent antibody-dependent, cell-mediated cytotoxicity in vitro. It specifically binds to monkey and human but not rodent EGFR. HLX07 has better binding affinity to human EGFR, compared with cetuximab (K D 1.43x10 -10 vs. 2.62x10 -10 ). HLX07 completely inhibited the phosphorylation of EGFR in H292 cells at ≥0.1 nM, The IC50 of HLX07 for DiFi and H292 cells were 54.2 and 23.9 ng/mL, respectively, compared with 63.7 and 37.2 ng/mL by cetuximab, respectively. In vivo xenogenic studies also demonstrated that HLX07 significantly inhibited the growth of H292, A432 and WiDi cells in a dose-dependent manner. Xenogenic studies also showed that HLX07 used with gemcitabine and/or cisplatin was more active than either agent alone. HLX07 was more effective than cetuximab in inhibiting the growth of FaDu cells when used with local radiotherapy in vivo. Single-dose and 13-week repeat-dose GLP pharmacokinetic and toxicokinetic studies in cynomulgus monkeys up to 60 mg/kg/wk shows minimal-to-mild toxicities (see table). Conclusions: The detailed preclinical characterization indicates that HLX07 has better efficacy and less toxicity than cetuximab. A phase 1 first-in-human study is ongoing (NCT02648490). [Table: see text]
Treatment patterns of malignant melanoma in the United States in 2011-2016: A retrospective cohort study.
Authors: Leon Raskin, Shweta Shah, Megan Braunlin, Jacqueline Buchanan, David Cohan
Journal: Journal of Clinical Oncology (2018)

e21633 Background: Novel therapies have changed melanoma treatment since 2011, but real world clinical practice has not been well studied. Our study described advanced melanoma treatment changes from 2011 to 2016. Methods: This retrospective cohort study used MarketScan claim database to find ≥ 18 yr old patients with first skin melanoma in Jan 01, 2011 - Sept 30, 2016, one inpatient/two outpatient claims, no other cancers, and treated with checkpoint or BRAF/MEK inhibitors, other targeted therapies, cytokine, or chemotherapy. Descriptive statistics compared treatment in 2011-13 (vemurafenib, ipilimumab) and 2014-16 (new checkpoint and BRAF/MEK inhibitors) in neoadjuvant, adjuvant, and line of therapy (LOT) for recurrent/metastatic disease. Results: 1,891 melanoma patients (mean follow-up 3.4 yrs) were treated with 2.8% neoadjuvant, 20.8% adjuvant, 80.7% LOT 1, 20.1% LOT 2, 6.4% LOT 3, and 2.2% LOT 4. Most adjuvant and LOT 1 were monotherapies; from 2014, combination use of dabrafenib/trametinib and ipilimumab/nivolumab significantly increased in LOT 1-3. Chemotherapy use decreased (26% vs. 14%) and checkpoint inhibitor use increased (29% vs. 41%) in all therapy settings. Increased checkpoint inhibitor use was related to ipilimumab in neoadjuvant/adjuvant, pembrolizumab in LOT 1-2, nivolumab in LOT 1-4, and ipilimumab/nivolumab in LOT 1-3. BRAF/MEK inhibitor use declined in neoadjuvant (14% vs. 6%) and LOT 3-4 (35% vs. 26%, 41% vs. 14%). Vemurafenib use decreased (8% vs. 1%) in all therapy settings, while dabrafenib/trametinib use increased (5% vs. 9%) in neoadjuvant, adjuvant, and LOT 1-2. Other targeted therapy use including bevacizumab increased in neoadjuvant (11% vs. 35%) and adjuvant (17% vs. 23%) but decreased in LOT1 (10% vs. 8%) and significantly decreased in LOT 2-4. Cytokine use declined (36% vs. 28%), mainly in neoadjuvant/adjuvant (56% vs. 18%, 54% vs. 36%). Conclusions: Immune checkpoint inhibitors have largely replaced cytokines and chemotherapy in most lines of melanoma treatment. Advanced melanoma treatment, initially dominated by monotherapies, now includes more drug combinations. Overall, the melanoma therapeutic landscape has been transformed since 2011 and continues to change.
Primary Aldosteronism
Authors: James Brian Byrd, Adina F. Turcu, Richard J. Auchus
Journal: Circulation (2018)

Primary aldosteronism (PA) is the most common form of secondary hypertension. In many cases, somatic mutations in ion channels and pumps within adrenal cells initiate the pathogenesis of PA, and this mechanism might explain why PA is so common and suggests that milder and evolving forms of PA must exist. Compared with primary hypertension, PA causes more end-organ damage and is associated with excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation. Screening is simple and readily available, and targeted therapy improves blood pressure control and mitigates cardiovascular morbidity. Despite these imperatives, screening rates for PA are low, and mineralocorticoid-receptor antagonists are underused for hypertension treatment. After the evidence for the prevalence of PA and its associated cardiovascular morbidity is summarized, a practical approach to PA screening, referral, and management is described. All physicians who treat hypertension should routinely screen appropriate patients for PA.
Therapeutic benefit of empiric drug sequencing in metastatic renal cell carcinoma.
Authors: Viola Chen, Cynthia Gong, Christian R Hoerner, Chiyuan A Zhang, Sandy Srinivas, Alice C. Fan
Journal: Journal of Clinical Oncology (2018)

e16569 Background: Multiple targeted therapies (TT) against the VEGFR, mTOR and PD-1 pathways exist to treat metastatic renal cell carcinoma (mRCC). Due to a lack of biomarkers, current practice relies on empiric sequencing. Patients can experience periods of clinical benefit from TT interspersed with periods of TT failure. In our single institution experience, we elucidate patterns of TT benefit in patients occurring after previous periods of TT failure. Methods: Using the Stanford RCC Database, we identified patients with clear cell RCC receiving systemic TT (sunitinib, pazopanib, axitinib, sorafenib, cabozantinib, everolimus, temsirolimus or nivolumab) from 1/1/2003 to 10/1/2017. Overall survival (OS) was captured by patients with a confirmed death date. Clinical benefit was assigned to therapy duration of ≥3 months, while failure was assigned to therapy duration of ≤3 months. We analyzed the frequency that patients underwent treatment without clinical benefit by identifying periods of clinical response interspersed with periods of clinical failure. Results: 195 patients in the cohort received a total of 471 independent lines of TT (median 2 TTs per patient, range 1-8). Median age at diagnosis and mOS were 62 and 2.04 years, respectively. Median duration of TT per patient was 3.7 mos (Range: 0-71 mos). 59% of patients experienced clinical benefit in consecutive lines of therapy before experiencing failure and 15.9% of patients received clinical benefit in at least three consecutive lines of TT. Despite failure in a previous line, 31.4% of patients derived clinical benefit in a later line of TT. Of note, 7.3% (n = 14) patients experienced their first clinical benefit in as late as the third line of therapy. Conclusions: Our study indicates that failure of clinical benefit in any particular line of TT does not preclude benefit in a later line. It will be important to determine whether patients discontinued treatment ≤3 months due to toxicity or disease progression. Considering the low median number of TTs per patient and the ability to derive clinical benefit in the third line or beyond, there remains a critical need for early biomarkers of TT response to minimize side effects and improve quality of life.
Mutations related to hematopoietic malignancies in circulating cell-free DNA of healthy individuals.
Authors: Jun Liu, Xi Chen, Chunli Wang, Yuhang Cai, Yong Liu, Renhua Wu, Hongmei Zhu, Shida Zhu, Xiaochun Zhang, Zhaoyang Qian
Journal: Journal of Clinical Oncology (2016)

7070 Background: Somatic SNVs/indels and clonal mosaicism in blood of individuals free of hematological malignancies has been previously characterized, but were reported with a low frequency ( < 3%), presumably attributed to the limited power of those methods used. Methods: We sequenced and analyzed circulating cell-free DNA of 150 healthy individuals using an ultrasensitive method on a 508 cancer gene panel. Results: We detected aberrations in previously described driver genes of hematopoietic system cancer and myelodysplastic syndrome in 43(28.7%) individuals. Frequently mutated genes included DNMT3A(10.7%), TET2(3.3%), JAK2(2.7%), SETD2(2%), CBL(1.3), MLL2(1.3%), MYD88(1.3%), ATM(1.3%), and NFE2L2(1.3%). Conclusions: The results suggested that mutation-induced clonal hematopoietic expansion is more prevalent than previously described. Comparison of the mutation spectrum of our study with that of myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML) identified genes that may play roles in malignancy transformation. Our study provided a baseline view for liquid biopsy based on circulating cell-free DNA.
Inotuzumab ozogamicin (InO) treatment in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL): Analysis from INO-VATE by bone marrow blast percentage (BMB%).
Authors: Anjali S. Advani, Daniel J. DeAngelo, David I. Marks, Matthias Stelljes, Michaela Liedtke, Wendy Stock, Nicola Gökbuget, Susan Mary O'Brien, Elias Jabbour, Akil Abid Merchant, Tao Wang, Erik Vandendries, Alexander Neuhof, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2018)

7028 Background: InO is a calicheamicin-conjugated antibody targeting CD22 on ALL blast cells. Here we report outcomes in R/R ALL patients (pts) receiving InO or standard of care chemotherapy (SC) in the phase 3 INO-VATE trial according to baseline BMB%, an indicator of disease burden. Methods: Adults with CD22+ ALL due to receive salvage treatment were randomized 1:1 to InO (n = 164) or SC (n = 162). Dosing and methods were published previously (Kantarjian et al, NEJM 2016). BMB% was defined as low ( < 50%), moderate (50–90%), and high ( > 90%) at start of treatment. Results: At baseline, characteristics across all groups were balanced and median BMB% was 28%, 78%, and 95% in the low, moderate, and high disease burden subgroups. Complete remission rates were significantly higher in InO vs SC pts, with 74% vs 46%, 75% vs 48%, and 70% vs 17% achieving CR/CRi in low, moderate, and high BMB% subgroups. Significantly more pts in the InO arm achieved minimal residual disease negativity: 29/53 (55%), 52/79 (66%), and 16/30 (53%) for low, moderate, and high BMB% compared with 10/48 (21%), 11/83 (13%), and 2/30 (7%) for SC, respectively. InO-treated pts also had improved progression-free survival vs SC, with hazard ratios of 0.44 (97.5% CI, 0.26–0.74, 1-sided P= 0.0001) for low, 0.50 (97.5% CI, 0.34–0.75, P< 0.0001) for moderate, and 0.33 (97.5% CI, 0.16–0.69, P= 0.0002) for high BMB%. Overall survival (OS) was favored in the InO arm across groups (Table) with potentially the greatest difference seen in pts with high BMB% (HR = 0.60 [97.5% CI 0.32–1.129, 1-sided P= 0.03]). Clinical trial information: NCT01564784. Conclusions: InO treatment resulted in superior efficacy over SC across all BMB% subgroups out to 2 years follow-up, particularly in patients with the greatest disease burden by BMB%. BMB% OS Probability, Mos (95% CI) 6 12 24 Low InO (n = 53) 56.6 (42.3–68.7) 34.0 (21.7–46.6) 30.0 (18.3–42.5) SC (n = 48) 59.5 (43.7–72.3) 38.8 (24.6–52.8) 2.4 (0.2–11.0) Moderate InO (n = 79) 61.7 (50.0–71.4) 35.6 (25.1–46.2) 21.1 (12.8–30.8) SC (n = 83) 51.3 (39.7–61.8) 34.0 (23.7–44.6) 15.0 (8.0–24.0) High InO (n = 30) 53.3 (34.3–69.1) 26.7 (12.6–43.0) 13.3 (4.2–27.8) SC (n = 30) 32.6 (16.4–49.8) 12.2 (3.2–27.8) 8.1 (1.4–22.6)
Structure-activity relationships (SAR) and mechanistic analysis of clinical-stage anti-cancer small molecule ONC201 analogues.
Authors: Jessica Wagner, Gary Olson, Bhaskara Rao Nallaganchu, Richard Pottorf, Martin Stogniew, Lee Schalop, Wolfgang Oster, Mathew Garnett, Ultan McDermott, Cyril Benes, Rohinton Tarapore, Joshua E. Allen, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2016)

e23161 Background: We previously screened for small molecules that could stimulate anti-tumor immunity within tumor cells through p53-independent TRAIL upregulation. TRAIL initiates apoptosis selectively in cancer without toxic side-effects. We identified ONC201, which upregulates an integrated stress response (ISR) through induction of ATF4/CHOP/DR5 and acts as a dual inhibitor of Akt/ERK, leading to TRAIL gene activation. After completing a first-in-human phase I clinical trial with encouraging results, ONC201 is being evaluated in several phase II trials in select advanced cancers. Methods: We synthesized ONC201 analogues with distinct therapeutic properties. After performing detailed SAR studies, we evaluated ONC201 analogues in several tumor cell lines. ONC212 was selected for animal studies that included toxicity, maximum tolerated dose (MTD), pharmacokinetic (PK), and efficacy evaluations. Results: Among the subset of ONC201 analogues that exhibited potency improvements we noticed more rapid kinetics of activity and lowered GI50 values in some human cancer cell lines relative to the parent compound. Based on pronounced in vitro potency improvements, ONC212 was selected for further in vitro and in vivo studies. ONC212 tumor type sensitivity profiling in > 1000 genetically annotated cell lines from the Genomics of Drug Sensitivity in Cancer collection corroborated its significant improvement in potency in select tumor types. Furthermore, ONC212 possesses a high MTD in mice that significantly exceeds its efficacious dose, acceptable PK profile, and oral activity in mice. Compelling in vivo efficacy against several tumor types, including colon and triple negative breast cancer, has been demonstrated with no evidence of toxicity at therapeutic doses. In vitromechanism studies have demonstrated overlap between ONC201- and ONC212-mediated signaling in tumor cells that includes activation of the ISR. Conclusions: The wide safety margin, distinct PK, and robust potency of ONC212 has prompted its development as the next drug candidate from the new class of compounds defined by the novel pharmacophore of ONC201 in indications that complement the parent compound.
Risk of chronic comorbidities in survivors of adolescent and young adult cancer (AYA).
Authors: Chun Chao, Lanfang Xu, Kimberly L. Cannavale, F. Lennie Wong, Po-Yin S Huang, Robert Michael Cooper, Smita Bhatia, Saro Armenian
Journal: Journal of Clinical Oncology (2018)

10015 Background: Data needed to develop age-appropriate survivorship care guidelines for AYA cancer are lacking. Using a retrospective cohort design, we described risk of chronic comorbidities in AYA cancer survivors. Methods: 6,778 two-year survivors of cancers diagnosed at age 15-39y at Kaiser Permanente Southern California between 2000-2012 were included. A non-cancer comparison group (N = 87,737) was matched to cancer survivors (1:13) on age, sex and calendar year. New onset of comorbidities listed in Table 1 was ascertained using ICD-9 diagnosis codes, laboratory values, medication prescription and cause of death in the electronic health records through end of 2014. Incidence rate and incidence rate ratio (IRR) from Poisson regression adjusting for age, sex, race/ethnicity were derived for each comorbidity. Within cancer survivors, multivariable Poisson regression was used to evaluate the associations between chemotherapy exposures (mutually adjusted) and risk of selected comorbidities. Results: Median age at cancer diagnosis was 33y; 35% were male; 42% were non-Hispanic white. The most common cancer types were thyroid (16%), breast (16%) and melanoma (10%). Comparison with non-cancer subjects: see Table 1. Within cancer survivors: chemotherapy exposure was associated with multiple comorbidities. The largest IRR was found for methotrexate use and avascular necrosis (AN) (IRR = 15.5); followed by ifosfamide and chronic kidney disease (IRR = 8.3); and bleomycin and pulmonary fibrosis (IRR = 4.7). Conclusions: These data provide basis for identifying high-risk individuals for population-based targeted surveillance. IRR for cancer survivors in reference to non-cancer comparisons. IRR 95% Confidence Interval Heart Failure 2.6 1.8 3.8 Coronary Artery Disease 1.6 1.1 2.3 Stroke 3.2 2.4 4.3 Dyslipidemia 1.3 1.2 1.4 Hypertension 1.4 1.2 1.5 Premature Ovarian Failure 2.9 1.6 5.3 Diabetes 1.5 1.3 1.7 Thyroid Disorders 2.1 1.8 2.4 Hearing Loss 1.7 1.3 2.1 Vision Loss 1.4 0.7 2.5 Asthma 1.2 1.0 1.4 COPD 2.3 1.3 4.2 Severe Depression/Anxiety 1.4 1.2 1.6 Chronic Liver Disease 2.4 2.0 2.8 Renal Failure 2.5 2.1 3.0 Avascular Necrosis 8.3 4.6 14.9 Fractures 2.1 1.6 2.8 Joint Replacement 3.9 2.4 6.2 Osteoporosis 5.8 3.7 8.9
A phase 1, first-time-in-human study of MEDI9197, a TLR7/8 agonist, administered intratumorally in subjects with a solid tumor cancer.
Authors: Shilpa Gupta, Fatemeh Tavakkoli, Serguei Soukharev, Guozhi Gao, Shannon R. Morris, Jeffrey S Miller
Journal: Journal of Clinical Oncology (2016)

TPS3095 Background: Toll-like receptors (TLRs) are proteins in the innate immune system that, once bound to their ligands, directly activate innate immune cells, including myeloid dendritic cells, plasmacytoid dendritic cells, monocytes/macrophages, and B cells. This activation may result in immune modulation such as activation of co-stimulatory molecules, production of antitumor and antiviral cytokines, and stimulation of cell-mediated NK and T cell immune responses involved in eradicating tumors. MEDI9197 is a small molecule imidazoquinoline agonist for human TLR7 and TLR8 that is designed to be water-insoluble, a property that confers a long-lasting depot effect. This agent is being developed as a potential anticancer therapy for intra-tumoral injection in patients with solid tumors. Methods: This is a phase 1, multicenter, open-label, dose-escalation, first-time-in-human study to evaluate the TLR7/8 agonist MEDI9197 delivered by intratumoral injection (to minimize systemic exposure and systemic immune activation but still stimulate targeted immune activation within the tumor). Subjects have metastatic/locally advanced solid tumors that have progressed on, are refractory to, or for which there is no standard of care therapy. Subjects must have a minimum of one lesion that is easily accessible (cutaneous or subcutaneous mass that is palpable and/or visualized by ultrasound for local injection). The study uses a 3 + 3 design to investigate a range of dose levels; subjects in each cohort will receive up to 4 doses of MEDI9197. The primary objective is to evaluate the safety and tolerability of MEDI9197 as determined by the primary endpoints of dose-limiting toxicities, adverse events, and laboratory parameters. Secondary objectives are to evaluate pharmacokinetics, changes in intratumoral pharmacodynamic (PD) biomarkers (lymphocyte populations and gene expression profiles), changes in systemic PD biomarkers, and antitumor activity (objective response, duration of response, disease control rate). Response will be determined using Response Evaluation Criteria in Solid Tumors (RECIST). Recruitment is ongoing, with a target enrollment of approximately 45 subjects. Clinical trial information: NCT02556463.
The effects of a functionally-graded scaffold and bone marrow-derived mononuclear cells on steroid-induced femoral head osteonecrosis
Authors: Masahiro Maruyama, Akira Nabeshima, Chi-Chun Pan, Anthony W. Behn, Timothy Thio, Tzuhua Lin, Jukka Pajarinen, Toshiyuki Kawai, Michiaki Takagi, Stuart B. Goodman, Yunzhi Peter Yang
Journal: Biomaterials (2018)