tbuckley/cabot-search huggingface dataset:
Rate of occult metastases in patients (pts) with biochemically-recurrent prostate cancer (BRPC) from a phase 2 trial of sipuleucel-T and androgen deprivation therapy (STAND).
Authors: Adam S. Kibel, Charles G. Drake, Evan Y. Yu, Nicholas J. Vogelzang, John M. Corman, Lawrence Ivan Karsh, Aymen Elfiky, Neal D. Shore, Frederick E. Millard, Nancy N. Chang, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2017)

e16516 Background: Identifying occult metastases in men with BRPC is critical, as treatment depends on disease state (biochemical recurrence vs oligometastatic disease). It is prudent to investigate pts for metastases, even men with low prostate-specific antigen (PSA) levels, to select appropriate salvage, local or systemic treatments. We evaluated baseline parameters of BRPC pts with occult metastases identified during screening for STAND (phase 2, NCT01431391). Methods: STAND eligibility criteria included prostate cancer primary therapy and PSA doubling time (PSADT) ≤12 months. Pts with metastases were excluded. We compared pts with and without metastases. Results: Of 99 screened pts, 68 entered STAND with non-metastatic BRPC, 11 (11%) failed screening due to metastases and 20 (20%) due to other reasons. In this small sample, no baseline parameters were identified that clearly distinguished between pts with or without metastases. For pts with metastases vs STAND pts, median age was similar (66 vs 65 y); all were Caucasian. Baseline median (range) PSA levels were numerically higher (4.3 [1.7–141.7] vs 2.4 [0.3–47.8] ng/mL) and PSADT values were numerically shorter (3.5 [1.1–7.6] vs 5.1 [1.0–16.4] months) for pts with metastases vs STAND pts, respectively. The proportion of pts with PSA &gt; 10 ng/dL was 29% vs 19%, or PSADT &lt; 6 months was 80% vs 59% for pts with metastases vs STAND pts, respectively. Baseline lactate dehydrogenase, alkaline phosphatase and hemoglobin levels were similar between groups. Conclusions: A substantial proportion (11%) of BRPC pts with presumed non-metastatic disease had undiagnosed occult metastases at low PSA levels. Such pts may benefit from closer monitoring with improved imaging technology, continuous androgen deprivation therapy or potentially docetaxel. While more rigorous screening (even at low PSA levels) may be advantageous, identifying such pts is challenging as their baseline parameters may not differ significantly vs BRPC pts with no metastases. In the future, detection of oligometastatic disease is likely to increase due to more sensitive imaging modalities, thus, the BRPC state will be reduced. Clinical trial information: NCT01431391.
Phase ib/2a study of PLX51107, a small molecule BET inhibitor, in subjects with advanced hematological malignancies and solid tumors.
Authors: Amita Patnaik, Richard D. Carvajal, Kimberly Mayumi Komatsubara, Carolyn D. Britten, Robert Wesolowski, Glenn Michelson, Oscar Alcantar, Chao Zhang, Ben Powell, Paul Severson, Eric Martin, Marlana M. Orloff
Journal: Journal of Clinical Oncology (2018)

2550 Background: PLX51107 is an orally active small molecule inhibitor that exhibits low nanomolar potency in blocking interactions mediated by the four BET family proteins and a unique pharmacokinetic (PK) profile. Methods: We conducted a first-in-man 3+3 dose escalation study of PLX51107 in adult patients with relapsed or refractory solid tumors (lymphomas included) and AML to determine the recommended phase II dose (RP2D) (NCT02683395). Secondary endpoints included safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). Enrollment through Cohort 7 (160 mg QD) is ongoing as of January 2018. Results: 36 subjects with advanced solid tumors (median age 60.5 years) received PLX51107 in escalating doses from 20mg to 160mg QD and 60mg BID. Uveal Melanoma (n = 11) was the most common tumor type followed by sarcoma (n = 6), and NSCLC, Breast and CRPC (n = 2 each). Most common toxicities in ≥ 15% of pts: fatigue (33%), vomiting (25%), diarrhea (25%), nausea (19%), bilirubin increase (17%), and INR increase (17%). Most were grade (G) 1-2. There were 3 treatment-related serious AEs (1 each of G3 nausea, G2 vomiting, and G2 kidney injury). Subjects with extensive hepatic metastases ( > approx. 50% of the liver) demonstrated higher exposure and more AEs. Dose limiting toxicity (DLT) was observed at 20mg (1 G3 thrombocytopenia), 120mg QD (1 G3 nausea) and 160mg QD (1 G2 kidney injury). PK was dose proportional with t1/2 < 2.5hr. Sixty mg BID dosing yielded same AUC as 120mg QD. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent induction of HEXIM1/WDR47 and reduction of CCR1/CCR2 gene expression within 3 hours of dosing. Eight pts achieved stable disease by RECIST (2 uveal melanoma, 3 sarcoma, 1 CRPC, 1 NSCLC), ranging from 4-14 months, and one subject with uveal melanoma demonstrated stable disease for 14 months. Conclusions: PLX51107 continues to enroll in dose escalation; patients with extensive hepatic metastasis are excluded going forward. Based on preclinical toxicology data, the expected Maximum Tolerated Dose will be in the 200-300 mg range. The BID dosing schedule will not move forward due to no increase in exposure observed. Clinical trial information: NCT02683395.
A prospective study to evaluate outcomes of AIDS-related lymphomas at a tertiary referral cancer centre.
Authors: Aruna Alahari Dhir, Sheela Sawant, Manju Sengar, Anuprita Daddi, Blossom Damania, Surya Mishra, Dirk Dittmer, Tanuja Shet
Journal: Journal of Clinical Oncology (2017)

e19012 Background: AIDS related non Hodgkin’s Lymphoma (ARL) remains a major cause of morbidity and mortality .There are limited prospective studies on ARLs in Indian population. We studied the clinical profile and outcome of patients with ARL . Methods: Consecutive patients diagnosed with ARL in the period February 2014-march 2016 who were treatment naïve were included in the study. Details of HIV and ARL, treatment details , complications and outcome were recorded. The primary objective was overall survival(OS), secondary objectives were response rates correlation of overall survival with CD4 count, IPI, duration of HIV, histopathology and stage of NHL. Survival was described with the Kaplan-Meier method, and effect of predictor variables was tested with the log-rank test. Results: 42 patients(28 males) with a median age 45.5 years were included in the study . The commonest types of NHL were DLBCL 22 (52.38 %) and plasmablastic lymphoma 14 (33.33%). HIV infection was detected at the time of lymphoma diagnosis in 21 (50%). The median CD4+ T cell count was 137 cells/mm3 . 32 (76.19%) had stage III/IV disease and and 35(83.3%) had extranodal involvement. IPI score was &gt;2 in 20/40(50%). 30/42 patients received chemotherapy of these 21 received atleast 4 cycles. 19 patients received CVEP regimen , 8 REPOCH and 3 others . NNRTI plus 2 NRTI combination was the HAART regimen in 26/30(86.6%) patients. Grade 3-5 febrile neutropenia was seen in 17/30 (56.6%) . Response was assessed using PET-CT scan in 22 patients ,16 (72.7%) had complete response .16/30 patients expired , 8 of these were due to infections . Median survival was 10 months (0.0-20.4 months). The estimated 2 year overall survival is 43.6 % . Patients with early stage disease had better overall mean survival (p=0.01). Type of NHL, IPI, CD 4+ T cell count, HAART prior to NHL treatment did not affect overall survival . Conclusions: Patients of ARL present at a younger age ,with higher grade and advanced disease. Higher proportion of plasmablastic lymphomas were seen in our study as compared to western data. Though most patients achieve complete response the overall survival is low . Myelosuppression and associated infections continues to be a challenge in the management of ARL.
Targeting NFE2L2 mutations in advanced squamous cell lung cancers with the TORC1/2 inhibitor TAK228.
Authors: Paul K. Paik, Besnik Qeriqi, Linda Su Hyun Ahn, Michelle S. Ginsberg, Nidhi Tandon, Daniel McFarland, L. Austin Doyle, Elisa de Stanchina, Charles M. Rudin
Journal: Journal of Clinical Oncology (2018)

9098 Background: Despite efforts over the past decade, no targeted treatments exist for pts w/ SQCLC. Analyses by TCGA and others (Paik Cancer Disc 2015) have identified a heretofore untargeted, frequently mutated oncogene (NFE2L2)/tumor suppressor (KEAP1) pair, each mutated in ~20% of pts w/SQCLC. NFE2L2 encodes Nrf2, a transcription factor involved in the oxidative stress response which is targeted for degradation by Keap1. NFE2L2 mutations occur exclusively in an exon 2 hotspot that encodes the Neh2 domain (aa.1-86), which is the binding site for Keap1. Mutations in this region disrupt Keap1 binding, leading to Nrf2 nuclear translocation and increased mTOR signaling through regulation of RagD (Shibata Cancer Res 2010). We now report translational studies and prelim results from a phase 2 trial of the oral TORC1/2 inhibitor TAK228 in SQCLC pts with these mutations. Methods: Cytotoxicity, signaling, and xenograft experiments were performed using LK-2 SQCLC cells harboring an NFE2L2 E79K mutation treated with TAK228, everolimus, rapamycin, or deforolimus. Pts w/ prev treated stage IV SQCLC w/ NFE2L2 mutations are eligible for an NCI CTEP single-institution phase 2 study of TAK228 3mg po qd (continuous 28 day cycles; NCT02417701). 10 endpoint: ORR. 20 endpoint: PFS. The study utilizes a Simon 2-stage design with H0 = 5% (N≥1/5 responses), HA = 40% (N≥2/10 responses). Results: TAK228 exhibited significantly increased anti-tumor activity over TORC1 rapalogs in LK-2 cells. TAK228 alone was cytotoxic at sub-[μM] (IC50 68nM); all other rapalogs had IC50s > 10μM. This was assoc with an 80% decrease in downstream pS6 . Tumor response (-55% shrinkage) was also seen in an LK-2 xenograft treated with TAK228. No anti-tumor/growth inhibitory response was seen with any other rapalog. N = 4 pts have been treated on the clinical trial (exon 2 del, D29H, F37V, W24C). 2 related-SAEs (G3 hyperglycemia, G3 confusion) were seen; no other > G2 AEs reported. ORR = 25% (1 PR, 3 SD, 0 PD). Prolonged response is present, with DOR = 11mo, 8mo, 5.5mo, and 1mo, all ongoing. Conclusions: TAK228 is well-tolerated w/ evidence of pre-clinical and clinical activity in NFE2L2 mutant SQCLC. The trial has met its first-stage endpoint and has expanded to N = 10 patients. Clinical trial information: NCT02417701.
Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation
Authors: Kumar Vaibhav, Molly Braun, Mohammad Badruzzaman Khan, Sumbul Fatima, Nancy Saad, Adarsh Shankar, Zenab T. Khan, Ruth B.S. Harris, Qiuhua Yang, Yuqing Huo, Ali S. Arbab, Shailendra Giri, Cargill H. Alleyne, John R. Vender, David C. Hess, Babak Baban, Md Nasrul Hoda, Krishnan M. Dhandapani
Journal: The Journal of Experimental Medicine (2018)

Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation-deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
Prognostic value of CD73 expression in resected colorectal cancer liver metastasis.
Authors: Nouredin Messaoudi, David Henault, David Stephen, Isabelle Cousineau, Pierre-Antoine St-Hilaire, Franck Vandenbroucke-Menu, Michel Dagenais, Richard Letourneau, Marylene Plasse, Andre Roy, Real W. Lapointe, Bich Nguyen, Dominique Trudel, Elizabeth Arslanian, Genevieve Soucy, Anne-Marie Mes-Masson, John Stagg, Simon Turcotte
Journal: Journal of Clinical Oncology (2018)

3584 Background: As approximately 80% of patients recur and die of their cancer after undergoing curative-intent resection of colorectal cancer liver metastasis (CRLM) combined with systemic chemotherapy, novel prognostic biomarkers and therapeutic targets are needed to improve outcomes. We investigated in CRLMs whether the expression of the cell-surface enzyme CD73, rate limiting for the degradation of extracellular AMP into immune-suppressive adenosine, could define a subset of patients with distinct prognosis. Methods: A tissue microarray-based analysis of 391 CRLMs resected in 214 patients (2011-2014) and followed prospectively until 10/2017. Each CRLM was arrayed with six 0.6 mm intratumoral punch biopsies, with automated quantification of CD73, cytokeratins 8/18 (CK) and DAPI expression measured by multiplex immunofluorescence. We tested associations between CD73 and pathological variables, time to recurrence (TTR) and disease specific survival (DSS). Results: The mean patient age was 62.7 years, 78.5% received pre-operative chemotherapy (mean of 6 cycles), and a median of 2 CRLMs/patient were resected. The median TTR and DSS of patients was 15.4 and 56.7 months, respectively. CD73 expression was similar whether patients received or not pre-operative chemotherapy, but was higher in patients with larger CRLMs ( > 5cm vs. ≤5cm, p = 0.01), poor pathologic response to pre-operative chemotherapy (Rubbia-Brandt TRG score 4-5 vs. 1-2-3, p = 0.01), and more necrosis ( > 25% vs. ≤25% surface necrosis, p = 0.004). In patients who received pre-operative chemotherapy, those with CD73high CRLMs (n = 62, 38.3%) had significantly shorter median TTR (11 vs. 18 months, p < 0.001) and DSS (47 vs. 58 months, p = 0.007) than CD73low patients. Pathologic response to chemotherapy was only associated with TTR, not DSS. By multivariate analysis, CD73high CRLMs was a poor prognostic factor independent of clinicopathological features for both TTR and DSS. Conclusions: Our results support that CD73 expression in CRLMs may identify a subset of patients with poor prognosis after exposure to systemic chemotherapy, providing insights to guide now-designed trials targeting CD73 with antibodies or the adenosine A2A receptor with inhibitors.
Definitive local therapy for oligo-recurrence in patients with completely resected non-small cell lung cancer.
Authors: Haruhisa Matsuguma, Rie Nakahara, Ikuma Wakamatsu, Tomohide Sugiyama, Yoichi Nakamura, Takashi Kasai, Yukari Kamiyama, Nobuo Hoshi, Koichi Inoue, Susumu Katano, Kohei Yokoi
Journal: Journal of Clinical Oncology (2018)

8527 Background: The aim of this study was to elucidate a curable subgroup among patients with non-small cell lung cancer (NSCLC) who experienced post-operative recurrence. Methods: Between 1986 and 2012, among the 1,408 patients who underwent complete resection for NSCLC with anatomical lung resection at our institution, 420 experienced recurrence. After excluding 14 patients with insufficient information about recurrence, 406 patients were included in this retrospective study. We investigated the association between several clinicopathological factors and post-recurrence survival (PRS) and post-recurrence progression-free survival (PR-PFS). Results: The 5y-PRS and PR-PFS rates were 13.8% and 5.5%, respectively. By multivariate analysis, sex, disease-free interval (DFI), specific targeted therapy, time of recurrence, number of recurrent foci, and definitive-local therapy (DLT) were found to be independent prognostic factors for both PRS and PR-PFS. These 6 prognostic factors were classified into two types according to the 5 year PR-PFS rate difference. Among the 6 prognostic factors, Sex, DFI, and Specific targeted therapy were not associated with long term improvement of PR-PFS. Conclusions: We found that recent medical practice, a small number of recurrent foci (oligo-recurrence), and DLT treatment, were associated with cure of post-operative recurrence. Variable Univariate Multivariate 5y PR-PFS rate(%) MST(months) HR P-value Sex Female/Male 3.0 / 7.1 6.8 / 5.5 1.33 0.018 DFI (months) < 12 / ≥12 5.7 / 4.7 4.4 / 8.3 0.69 0.001 Time of recurrence 1987-1996 / 1997-2005 / 2006- 4.5 / 2.0 / 11.2 5.0 / 5.3 / 8.9 - / 0.95 / 0.71 - / 0.737 / 0.016 DLT No / Yes 1.2 / 14.0 4.7 / 8.4 0.51 < 0.001 Specific targeted therapy No / Yes 5.3 / 5.4 5.7 / 22.4 0.50 0.005 Number of recurrences ≥4 / 2 - 3 / 1 1.6 / 4.4 / 12.7 5.1 / 6.1 / 7.9 - / 0.82 / 0.64 - / 0.177 / 0.005
A pharmacodynamic biomarker study of vistusertib (AZD2014), an mTORC1/2 inhibitor, given prior to radical prostatectomy (CANCAP02).
Authors: Simon Pacey, Nimish Shah, Barry Davies, Ola Bratt, Anne Warren, Richard D. Baird, Vincent Gnanapragasam, Susan Ingle, Sara Stearn, Andrea Machin, Wendi Qian, Wanfeng Zhao, Elizabeth Harrington, Elisabeth Maria Oelmann, Mirela Hategan, Sanjeev Srinivas Kumar, Javier Garcia Corbacho
Journal: Journal of Clinical Oncology (2018)

5081 Background: The effect of novel drugs can be studied in primary prostate cancer (PC), if given prior to radical prostatectomy (RP). Altered PI3K/AKT/mTOR signalling is associated with aggressive primary PC and progression. CanCap02 investigated the effects of vistusertib (AZD2014), an oral, dual mTORC1/mTORC2 inhibitor in men with PC. Methods: Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy, attempted intra-operative biopsy and RP tissue were collected for IHC analysis. Adverse events (AE) were graded using CTCAE v4. Blood was collected to determine plasma vistusertib concentrations. The primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and vistusertib plasma pharmacokinetics. Exploratory objectives included interrogating biological pathways related to mTOR and anti-cancer effects. Results: Median age 62 (50 – 69) yrs, 48% intermediate and 52% high risk recurrence. 20/23 pt were evaluable for primary endpoint analysis. The majority of AEs (67%) were Gr1 includin: mucositis, diarrhoea, thrombocytopenia, rash, transaminitis, lymphopenia and hyperglycaemia. Two pts discontinued vistusertib due to AEs (mucositis, thrombocytopenia, raised liver enzymes/ bilirubin) which resolved prior to RP. RP was only delayed in one pt to allow resolution of AE (Gr 1 thrombocytopenia). Vistusetib inhibited mTOR1/2 (pS6, 4EBP1 and NDRG1 were reduced). PSA declined in 3 pt (15%, range -48 to +332%) over two week dosing period. Analysis of tumour PTEN status, tumour infiltrating lymphocytes and Ki67 are ongoing. Mean plasma vistusertib concentration during RP was 738 ± 287 ng/mL. Mean fasting plasma glucose was 4.88 ± 0.56 mmol/L at baseline and rose after vistusertib to 6.16 ± 0.78 mmol/L, correlated with plasma vistusertib levels. Conclusions: Vistusertib (50mg bd) is feasible for a two week course prior to RP, mTORC1/ 2 were inhibited in tumour tissue as well as surrogate tests (ie plasma glucose) and in some pt (15% pt) a fall in PSA occurred. The AE profile might be improved by an intermittent dosing schedule. Clinical trial information: NCT02064608.
Pre-treatment neutrophil to lymphocyte ratio (NLR) association with curative intent metastasectomy (MSX) in metastatic renal cell carcinoma (RCC).
Authors: Aline Fusco Fares, Daniel Vilarim Araujo, Eliza Dalsasso Ricardo, Marcelo Corassa, Maria Nirvana Cruz Formiga, Walter Henriques Costa, Gustavo Cardoso Guimaraes, Stenio C. Zequi, Isabela Cunha
Journal: Journal of Clinical Oncology (2017)

e16051 Background: NLR is a marker of inflammation and when elevated is associated with poor outcome in many tumors, including RCC. Hereby we evaluate the association of NLR with the likelihood of curative intent MSX. Methods: We retrospectively studied 846 patients diagnosed with metastatic RCC between 2007 and 2016. 116 patients fulfilled inclusion criteria: previous nephrectomy, no sarcomatoid features and available tumor specimens from metastatic site. Regression tree for censored data method was used to find the best NLR cut-off value. NLR was examined baseline – prior to MSX or targeted therapy. Chi-square test was used to evaluate associations between variables. We estimated overall survival (OS) using Kaplan-Meier curves. Cox proportional hazards regression models were fitted to evaluate the prognostic significance of NLR in univariable and multivariable analysis. Results: The median OS for the whole cohort was 45 months (95% CI, 27.6 to 62.4 months), and the median follow-up was 78.2 months. The best cut-off NLR value was 4.07. Higher NLR was associated with shorter OS when compared to the lower NLR cohort (11.5 months vs 68.3 months HR = 0.26, 95% CI: 0.15 – 0.97, p ≤ 0.0001, respectively). Univariate analysis revealed that bone metastasis and poor IMDC criteria were associated with worse OS and that MSX and lower NLR were associated with better OS. On multivariate analysis MSX, lower NLR and favourable/intermediate group on IMDC criteria were associated with a decreased risk of death (HR = 0.41, 95% CI 0.19-0.85, p = 0.018 and HR = 0.45, 95% CI 0.22-0.90, p = 0.025, HR = 0.35, 95% CI 0.16-0.79, p = 0.012, respectively). We found a positive association of lower NLR and curative intent MSX (p = 0.002). Conclusions: NLR is a prognostic marker in metastatic RCC and a ratio ≤ 4,07 is associated with a higher likelihood of curative intent MSX.