tbuckley/cabot-search huggingface dataset:
A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies
Authors: Drew W. Rasco, Kyriakos P. Papadopoulos, Michael Pourdehnad, Anita K. Gandhi, Patrick R. Hagner, Yan Li, Xin Wei, Rajesh Chopra, Kristen Hege, Jorge DiMartino, Kent Shih
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma. Patients and Methods: Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide. Results: DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg. Conclusions: Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.
Amenorrhea in lung cancer patients.
Authors: Elizabeth Jane Cathcart-Rake, Kathryn Jean Ruddy, Ruchi Gupta, Ann Partridge, Elizabeth A. Stewart, Celine Vachon, Ping Yang
Journal: Journal of Clinical Oncology (2017)

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1 st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.
Combined Immunosuppressive Therapy Induces Remission in Patients With Severe Type B Insulin Resistance: A Prospective Cohort Study
Authors: Joanna Klubo-Gwiezdzinska, Maria Lange, Elaine Cochran, Robert K. Semple, Cornelia Gewert, Rebecca J. Brown, Phillip Gorden
Journal: Diabetes Care (2018)

OBJECTIVE Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism, and a high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes. RESEARCH DESIGN AND METHODS We performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, monitored for median 72 months (25th, 75th interquartile range 25, 88), and treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia. RESULTS All data are given as median (25th, 75th interquartile range). Twenty-two patients aged 42 (25, 57) years, 86.4% women, fulfilled inclusion criteria. At baseline, fasting glucose was 307 (203, 398) mg/dL, HbA1c was 11.8% (9.7, 13.6), total testosterone (women) was 126 (57, 571) ng/dL (normal 8–60), and daily insulin requirement was 1,775 (863, 2,700) units. After 5 (4, 6.3) months, 86.4% (19 of 22) of patients achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 (76, 92) mg/dL, HbA1c of 5.5% (5.2, 6), and testosterone (women) of 28 (20, 47) ng/dL. During follow-up of 72 (25, 88) months, 13.6% (3 of 22) of patients developed disease recurrence, occurring 24 (22, 36) months after initial remission, which responded to repeated therapy. None of the patients died. CONCLUSIONS Combined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes and, as such, should be recommended in patients with type B insulin resistance.
O(6)-methyl-guanine-DNA promoter methyltransferase methylation and IDH1/2 mutation in small cell lung cancer.
Authors: Hongyang Lu, Jing Qin, Haimiao Xu, Na Han, Fajun Xie, Weimin Mao
Journal: Journal of Clinical Oncology (2016)

e20103 Background: Small cell lung cancer (SCLC) is sensitive to first-line chemotherapy and radiotherapy, but it is easy to recurrence. Temozolomide is suitable for relapsed SCLC particularly with brain metastases. Response to temozolomide may correlate with O(6)-methyl-guanine-DNA methyltransferase(MGMT) methylation in SCLC. Isocitrate dehydrogenase (IDH) mutation is an independent prognostic factor of good outcome in gliomas, and appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. The purpose of this study is to know MGMT promoter methylation and IDH1/2 mutation in SCLC. Methods: 33 SCLC specimens which received surgery were retrospectively collected in Zhejiang Cancer Hospital, China, between 2008 and 2014. High-resolution melting (HRM) analysis and methylation specific polymerase chain reaction (MSP) was used to detect MGMT promoter methylation, and PCR amplification and Sanger sequencing was used to detect IDH1/2 mutation. Results: Of the 33 examined SCLC specimens, MGMT promoter methylation was detected in seventeen patients (51.5%), and no IDH1/2 mutation was detected. Conclusions: IDH1/2 mutation may be not ideal marker in SCLC treated with temozolomide. It is urgency to carry out one research about the predictive value and prognosis of MGMT promoter methylation in relapsed SCLC treated with temozolomide in China.
Abstract 12886: The Relationships Among Sleep Apnea, Brain Volumes, and Cognition in Individuals With Heart Failure
Authors: Chooza Moon, Kelsey Melah, Sterling C Johnson, Lisa C Bratzke
Journal: Circulation (2015)

Introduction: Approximately 25% to 75% of heart failure (HF) patients have sleep apnea (SA), which may contribute to brain changes that are associated with decreases in attention, memory, and executive function. Unfortunately, there is a dearth of research that explores how SA may contribute to brain changes and cognition within the HF population. Thus, the purpose of this study is to examine the relationships between the apnea-hypopnea index (AHI), grey and white matter brain volumes, and neuropsychological test scores of attention, memory and executive function. Hypothesis: HF patients with higher AHI would have decreased brain volumes and neuropsychological test scores. Methods: Using a cross-sectional design, we sampled 28 HF patients; 13 HF patients had AHI ≥ 10 and 15 HF patients had AHI &lt;10. Eighty percent were male (n=12) and their mean age was 68 (SD = 5). We evaluated AHI with a portable multichannel sleep-monitoring device, brain volumes with voxel-based morphometry method T-1 weighted images from 3.0 T magnetic resonance imaging, and cognition with a neuropsychological test battery. We used multiple regression analysis to examine proposed relationships. For analysis of AHI and brain volumes, we controlled for age, sex, education, left ventricular ejection fraction , and intracranial volume. Results: In regression models adjusting for covariates, AHI was significantly related to reduced grey matter volume in areas including the inferior temporal gyrus, fusiform gyrus, cingulate gyrus, and superior frontal gyrus (p &lt;0.001). In white matter volume, AHI was related inversely to white matter volume in areas such as superior temporal gyrus and superior frontal gyrus (p&lt;0.001). However, AHI was not correlated with any of the neuropsychological test scores. Conclusion: AHI was associated with reduced grey and white matter volumes in the brain. These are areas associated attention and memory. However, AHI was not related to any of the cognitive test scores. In dementia literature it has been shown that brain changes precede changes in cognition by months to years. Therefore, longitudinal, prospective studies are recommended to determine whether brain volume changes that are associated with sleep apnea precede cognitive decline in individuals with HF.
Pre-screening test for clinical trials of Autologous γδ T lymphocyte therapy for advanced cancer.
Authors: Michael D. Leek, Angela Scott, Kathryn Campbell, Adele Hannigan, Karen J. Williams
Journal: Journal of Clinical Oncology (2016)

e14527 Background: A sub-set of T lymphocytes, the γδ T lymphocytes, play an important role in cancer suppression and modulation of tumour growth, however, the capacity for these cells to proliferate is different between individuals. The authors are developing an autologous γδ T cell therapy, which involves cleanroom-based expansion of γδ T lymphocytes over a two/three week period, which is aimed to be a treatment for a wide-variety of different tumour types. An assay has been created for the identification of the proliferative capacity of γδ T cells as part of a pre-screening test for patients ahead of enrolling into clinical trials with the autologous product. Methods: Patients provide a 10ml blood sample from which peripheral blood mononuclear cells are extracted and used directly in the assay. Cells are expanded over 10 days, during which time they are counted and assessed for viability. Flow cytometry based phenotyping is used to assess the percentage of γδ T cells prior to, and following ex vivo expansion. This permits the calculation of the γδ T cell enrichment factor. This factor is used to determine whether a patient’s cells are capable of meeting the levels of γδ T cell expansion required to provide a single γδ T cell dose (1-10x109cells). Results: Flow cytometry based phenotyping is used to assess the percentage of γδ T cells prior to, and following ex vivo expansion. This permits the calculation of the γδ T cell enrichment factor. This factor is used to determine whether a patient’s cells are capable of meeting the levels of γδ T cell expansion required to provide a single γδ T cell dose (1-10x109cells). Conclusions: Including this pre-screening test in clinical trials with the autologous γδ T lymphocyte therapy will avoid unnecessary procedures for patients being considered for the trials.
Clinical, radiological and genetic features, associated with the histopathologic response to neoadjuvant chemotherapy (NAC) and outcomes in locally advanced soft tissue sarcoma (STS) patients (pts).
Authors: Sophie Cousin, Amandine Crombe, Eberhard Stoeckle, Véronique Brouste, Francois Le Loarer, Carlo Lucchesi, Michèle Kind, Maud Toulmonde, Paul Sargos, Audrey Michot, Guy Kantor, Isabelle Soubeyran, Jean Michel Coindre, Antoine Italiano
Journal: Journal of Clinical Oncology (2017)

11014 Background: Two large phase III studies have shown an improved overall survival in soft-tissue sarcoma (STS) pts treated with neoadjuvant chemotherapy. The prognostic impact of pathologic response is not known neither the clinical, radiological and genetic features associated with response. Methods: Data from pts with localized STS of the extremities or trunk wall and treated with anthracyline-based NAC at Institut Bergonie (Bordeaux, France) were reviewed. Central pathology (diagnosis, histological response) and radiology (MRI, DCE-MRI) reviews were performed for all the cases. A good histological response (GR) was defined as &lt;10% residual viable tumor. Exome and RNA sequencing of pre-treatment tumor samples was performed in order to identify genetic aberrations predictive of response. Results: 150 patients (88 male) were included in the study. Median age was 60 years (17-84). 40 pts (26.7%) were good responders. GR was associated with undifferentiated pleomorphic sarcomas and very large tumors (&gt; 20 cm). Median OSwas 10.3 year [IC95 : 5.8 ; 14.9]. On multivariate analysis, only GR (HR= 0.36, 95%CI 0.184-0.703, p=0.0028) and performance status (PS) (HR= 3.799, 95%CI 1.72-8.387, p=0.001 for PS=2-3) were prognostic factors for OS. Early DCE- MRI parameters (after 2 cycles of treatment) such as, area under the contrast concentration vs. time curve for 90 seconds after contrast injection ( IAUC90) were strongly associated with histological response (p=0.027) whereas RECIST 1.1 was not. Conclusions: As for bone sarcomas, histological response to NAC is a crucial prognostic factor in STS. Multiparametric MRI parameters obtained post-2 nd cycle of NAC are predictive of histological response and should be considered to adjust the therapeutic strategy. Genetic features (including the CINSARC signature) associated with response to NAC will be presented at the meeting.
Intensification of induction chemotherapy before chemoradiotherapy improves progression-free survival in patients with locally advanced pancreatic cancers.
Authors: Nicolas Williet, Thomas Di Bernardo, Lea Saban-Roche, Nicolas Magne, Jean Marc Phelip
Journal: Journal of Clinical Oncology (2018)

e16221 Background: Aim of our study was to assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer Methods: All patients with locally advanced pancreatic cancer treated between February 2010 and November 2016 with CRT (total dose: 50 Gy; Capecitabine: 830 mg/m2 twice daily) were included in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT such as Folforinox or GemOx (group I). Data were collected retrospectively. The primary endpoint was progression-free survival (PFS) defined as the time between start of CRT and tumor progression. This study was approved by local ethical committee (IRBN632017/CHUSTE) Results: Before CRT, 30 patients had intensive ICT (Folforinox: n = 24; GemOx: n = 6) and 16 had Gemcitabine: median age 64 and 70.5 years, respectively (p = 0.02). Groups were balanced regarding median duration of ICT (4 months; IQR: 3-6; p = 0.98), median total radiation dose, and baseline prognostic factors such as performance status (median: 0), CA19.9 level (median: 40 and 40.2, respectively), degree of differentiation (p = 0.34), and tumor response at 3 months of ICT (20% vs 18.8%; p = 0.86). Median PFS was statistically better in group I (11.7 months; 95%CI%: 8.9-27.6) compared to group G (6.7 months; 95%CI: 4.2-NA): HR = 0.42; 95%CI: 0.20-0.90; p = 0.02. After uni- and multivariate analyses adjusting for age, performance status and baseline CA19.9 level > 100IU/L, only ICT intensification was prognostic. OS tend to be better in group I (19.4 months vs 14.9 months; p = 0.10; HR = 0.45; 95%CI: 0.17-1.19). No prognostic factor was identified by uni- and multivariate analyses. Grade III toxicities were reported only with intensive ICT (overall: 30.4%; diarrhea: 12.5%; alopecia: 10%; neurologic: 8.7%; fatigue: 4.2%; nausea: 4.2% and neutropenia: 4.2%). Conclusions: This study shows ICT intensification before CRT is a promising strategy in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.
Association of risk of clinical recurrence (CR) and prostate cancer death (PCD) with a 17-gene genomic prostate score (GPS) value <20.
Authors: Phillip G. Febbo, Michael Crager, Emily Burke, H. Jeffrey Lawrence, Jennifer Cullen, Eric A. Klein
Journal: Journal of Clinical Oncology (2017)

5074 Background: Over-treatment of localized prostate cancer (PC) can result from over-estimation of a patient’s risk of CR and PCD. GPS (scale 0-100) has been validated to predict adverse pathology, biochemical recurrence, metastasis, and PCD and provides a more accurate overall assessment of patient risk than clinical risk factors alone. A recent validation study found that no patients with AUA Low- or Intermediate-risk disease and a GPS of &lt;20 developed PC metastases or PCD. Here, 2 large longitudinal PC cohorts were analyzed to estimate the risk of CR and PCD for GPS &lt;or &gt;20 units. Methods: Data from Klein et al. European Urology (EU) 2014 and Cullen et al. EU 2014 were analyzed to establish the risk of CR and PCD associated with a pre-established GPS cut-point of 20. Patients were divided based on the value of GPS (≤20, &gt;20). Cox regression analyses accounted for cohort sampling weights. Since GPS was developed using Klein et al, standardized hazard ratios (std HR, HR for 1 SD change in the covariate) for GPS and CR and PCD survival curves for the 2 groups were estimated correcting for regression to the mean (RM). Results: Of the 402 patients in Cullen et al. (median follow up 5.2 years), only 5 patients developed metastases; all 5 had GPS &gt;20. For Klein et al., of 426 patients with a median follow up of 6.6 years, there were 109 CR (metastasis and local recurrence) and 39 PCD; only one patient with events had a GPS &lt;20. Overall 28% of patients had GPS &lt;20. GPS was a significant predictor for both CR (std HR 2.50 (95%CI 1.99, 3.15, p &lt;0.001, RM-corrected std HR 2.16, FDR &lt;0.1%) and PCD (std HR 2.90 (95% CI 2.06,4.06, p&lt;0.001, RM-corrected std HR 1.96, FDR &lt;0.1%) after adjustment for AUA group. Men with intermediate risk prostate cancer and a GPS score of &lt; 20 have a 2.6% and 0.7% 10-year RM-corrected risk of CR and PCD, respectively (Table 1). Conclusions: GPS strongly predicts risk of CR and PCD in men with AUA Low- or Intermediate-risk PC. Patients with a GPS score &lt;20 have a very low risk of CR or PCD and should be considered for AS. [Table: see text]
Information Transparency in the Drug Approval Process
Authors: Brian I. Rini, Harold J. Burstein, Daniel J. George
Journal: JAMA Oncology (2018)

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Randomised phase-III-trial of concurrent chemoradiation (CRT) for locally advanced head and neck cancer (stage III-IVB): Comparing dose reduced radiotherapy (63,6 Gy) with paclitaxel/cisplatinum to standard radiotherapy (70,6 Gy) with fluorouracil/cisplatinum.
Authors: Rainer Fietkau, Heinrich Iro, Markus Hecht, Benjamin Hofner, Olaf Gefeller, Panagiotis Balermpas, Claus Roedel, Matthias Hautmann, Oliver Koelbl, Horst Leber, Attila Salay, Christian Ruebe, Peter Breinl, Waldemar Krings, Stephan Gripp, Barbara Wollenberg, Rainer Keerl, Ulrike Schreck, Birgit Siekmeyer, Gerhard Grabenbauer
Journal: Journal of Clinical Oncology (2017)

6016 Background: Concurrent CRT with 70.6 Gy is the standard treatment for locally advanced head and neck cancer (LA-SCCHN). There exist no prospective data on safety and efficacy of a reduced radiation (RT) dose. Methods: Pts with stage III-IVB LA-SCCHN were randomized 1:1 to receive 70.6 Gy with concurrent cisplatinum (20mg/m²/d IV on days 1-5 and 29-33) and fluorouracil (600 mg/m²/d CIV on days 1-5 and 29-33) (standard arm A) versus 63,6 Gy with intensified chemotherapy using concurrent cisplatinum (20mg/m²/d IV on days 1-4 and 29-32) and paclitaxel (20mg/m²/d IV on days 2, 5, 8, 11 and 25, 30, 33, 36) (experimental arm B). After a planned interim analysis recruitment was stopped due to statistical reasons. Results: Between 06/2010 and 02/2015 a total of 221 pts were randomized with 105 pts receiving treatment in arm A and 112 in arm B (4 pts dropped out). Median follow-up was 38 months. Pts’ characteristics: Oral cavity (15%), oropharynx (54%), hypopharynx (28%), larynx (14%); 17 pts had more than one primary site; tumor stage: III (14%), IV (86%); HPV-status (p16) was positive in 20%, negative in 38%, currently pending in 42%. A total of 96 PFS-related events occurred. 3-year PFS (ITT) was 58% in the standard arm A and 48% in experimental arm B (p = 0.454). 3-year OS (ITT) was 64% in arm A and 59% in arm B (p = 0.688). 3-year rates of distant metastases, loco-regional recurrences and death were 10% vs 12%, 17% vs 21% and 15% vs 19% for pts in arm A and B, respectively. As for the p16-positive subgroup, 3-year PFS/OS were 77%/76% in arm A (n = 21) and 69%/80% in arm B (n = 22), respectively. Grade 3+ hematologic adverse events during therapy (arm A/arm B): Anemia 11%/4% (p = 0.038); neutropenia 40%/16% (p &lt; 0.001); thrombocytopenia 8%/3% (p = 0.130). Conclusions: These preliminary results indicate that pts receiving concurrent CRT for LA-SCCHN did not benefit from a lower total RT dose of 63.6Gy despite intensified chemotherapy. However, in the subgroup of p16-positive pts a reduced RT dose may be sufficiently effective. Clinical trial information: NCT01126216.