tbuckley/cabot-search huggingface dataset:
Multistage phase II design for mixed tumor response and time-to-event endpoints: An application for screening new drugs in hepatocellular carcinoma (HCC).
Authors: Benny C. Y. Zee, Xin Lai, Ann Sing Lee, Maria Lai, Marc Chong, Chloe Kwok, Jacques Jolivet
Journal: Journal of Clinical Oncology (2012)

e14706 Background: Phase II trials aim to assess the anti-tumor activity of investigational therapies, and consider if they warrant further study. In some instances such as a study treatment added to standard therapy in HCC, tumor response alone may not provide a clear picture on its effectiveness (e.g. biologics and targeted therarpy). Other endpoints such as progression-free survival (PFS) in addition to conventional tumor response would increase the chance of detecting useful treatment and also be able to terminate a study earlier if the treatment was deemed ineffective. Methods: Following a similar rationale for multinomial endpoints in phase II trials by Zee (1999), we have developed a multi-stage phase II stopping rule for "mixed tumor response and time-to-event endpoints". We used a study entitled, “Randomized Phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced HCC” as an illustration. We applied this multi-stage stopping rule for mixed endpoints in a randomized phase II setting, where the control arm was being used here as a way to set up the null hypothesis. We defined the null hypothesis by a mixture of response rate of 5% and PFS of 2.6 months versus an alternative hypothesis of response rate of 20% and PFS of 5.2 months. Results: The stopping rule was such that the null hypothesis would be rejected at a correlation of 0.5 for the mixed endpoints and conclude that the treatment is effective if we have 0-1 responders and a PFS&gt;=4.0 months, or 2 responders and PFS&gt;=3.8 months, or 3 responders and a PFS&gt;=3.6 months, or 4 responders and a PFS&gt;=3.0 months, or 5 responders with any PFS. Conclusions: In the AEG35156 study, we had 3 responders (based on Choi’s criteria), and 1 responder even if we used RECIST criteria. A PFS of 4.0 months. Therefore, we concluded that the study treatment in combination with sorafenib has a positive effect and warrants further investigation. This methodology would greatly improve the efficiency for phase II screening especially on new biologics on top of a standard or for diseases where tumor response alone does not reflect the full effectiveness of the new treatment.
Abstract 207: Left Ventricular Assist Device (LVAD) Reverses Inhibition on Beta-adrenergic Receptor Resensitization
Authors: Elizabeth E Martelli, Arunachal Chatterjee, Randall Starling, Christine Moravec, Sathyamangla V Naga Prasad
Journal: Circulation Research (2015)

Beta-adrenergic receptor (βAR) down-regulation and desensitization are hallmarks of heart failure. Agonist occupied βAR undergo desensitization through phosphorylation by G-protein coupled receptor kinases leading to βAR internalization. Phosphorylated βAR becomes resensitized following dephosphorylation by protein phosphatase 2A (PP2A) in the endosomes and we have shown previously shown that PP2A activity is regulated by phosphoinositide3-kinaseγ (PI3Kγ). Traditionally, it has been considered that increased desensitization mechanisms underlie βAR dysfunction in heart failure but it is not known whether resensitization of βARs is altered and an integral contributor to heart failure. To test whether resensitization mechanisms are altered in heart failure and could play a role in recovery of βAR function post-LVAD, we used paired pre- and post-LVAD human heart samples along with non-failing hearts. Since resensitization occurs in endosomes, plasma membranes and endosomes were isolated from these human heart samples and assessed for PI3K activity, PP2A activity, β2AR phosphorylation and adenylyl cyclase (AC) activity as a measure of recovery in βAR function by G-protein coupling. Significant PI3Kγ activity was observed in the endosomes of pre-LVAD compared post-LVAD and non-failing human heart samples while plasma membrane PI3K activity remained similar across all samples. Similarly, AC activity was markedly reduced in plasma membranes and endosomes of pre-LVAD samples compared to post-LVAD and non-failing showing reduced ability of receptors to couple to G-proteins indicating reduced recovery of receptor function in post-LVAD heart samples. Consistent with the reduced recovery in βAR function in pre-LVAD samples, significant β2AR phosphorylation was observed in the endosomes and plasma membranes of pre-LVAD compared to post-LVAD and non-failing. Correspondingly, we observed significant reduction in endosomal PP2A activity in the pre-LVAD samples which was remarkably reversed in post-LVAD samples similar to the activity in non-failing. These studies suggest that resensitization is inhibited in end-stage human heart failure and may critically contribute to cardiac remodeling and hypertrophic response upon cardiac stress.
Changing trend of HIV-associated PCNSL over 15 years: A single-center experience.
Authors: Andrew Bayat, Jeremy Clifton Jones, Harris V. K. Naina
Journal: Journal of Clinical Oncology (2014)

2049 Background: Primary central nervous system lymphoma (PCNSL) is a rare form of extra nodal non Hodgkin lymphoma, accounting for approximately 3-4% of primary brain tumors and approximately 1% of all NHL. HIV is one of the leading risk factors for PCNSL. Though whole brain radiation is used often, there is no standard of care available for HIV associated PCNL. In this single center retrospective study we report the survival data of patients with biopsy-proven PCNSL with and without HIV between 1998-2013. Methods: We identified patients with PCNSL between 1998 and 2013 through our institution’s tumor registry. After patient identification, the medical records were reviewed for the following patient data: age at diagnosis, ethnicity, sex, HIV status, CD4 cell count, HIV viral load, neuroimaging, treatment (radiation therapy and/or chemotherapy), date of death and date of last contact. Survival data and date of death were obtained from our tumor registry, chart reviews, and social security death index searches. Results: A total of 128 patient were identified as having biopsy-proven PCNSL: 41 HIV-positive and 87 HIV-negative. Average age at diagnosis was 60.8 for HIV-negative patients and 38.9 HIV-positive. The HIV-positive cohort was 80% males while only 54% in HIV-negative. Median survival for the two groups was 4.6 and 15.9 months respectively. Amongst HIV-negative patients: those who received MTX + WBRT had median survival of 25.7 months whereas those who received MTX alone had a median survival of 10.9 months although this difference did not meet statistical significance. HIV-positive patients who were diagnosed between 2009 and 2013 had significantly longer median survival than those diagnosed between 2004-2008 as well as 1998-2003 timeframes. Conclusions: Our current data confirm that there remains a marked gap in median survival among HIV-negative and HIV-positive patients diagnosed with PCNSL. It would also suggest that there is no significant difference in median survival among HIV-negative patients who receive WBRT versus those who receive MTX alone. We also confirm that median survival for HIV-positive patients has improved over the last decade coinciding with improvements in antiretroviral therapy.
Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates
Authors: Christopher Sundling, Mattias N.E. Forsell, Sijy O'Dell, Yu Feng, Bimal Chakrabarti, Srinivas S. Rao, Karin Loré, John R. Mascola, Richard T. Wyatt, Iyadh Douagi, Gunilla B. Karlsson Hedestam
Journal: The Journal of Experimental Medicine (2010)
Circulating endothelial cells (CECs), progenitors (CEPs), and circulating tumor cells (CTCs) for prediction of response in patients with advanced breast cancer (ABC) receiving metronomic oral vinorelbine (oV): Preliminary results
Authors: F. Nole, E. Munzone, F. Bertolini, M. T. Sandri, G. Petralia, L. Adamoli, D. Radice, D. Cullura, A. di Pietro, A. Goldhirsch
Journal: Journal of Clinical Oncology (2009)

e14572 Background: Metronomic administration of chemotherapy given once or more per week with no extended gaps was shown to be effectively anti-angiogenic, causing growth arrest or apoptosis of endothelial cells in tumor neo-vessels. Preclinical and clinical studies indicate that ultra-low concentrations of various microtubule inhibitors inhibit proliferation or migration of endothelial cells. We investigated in a phase II study the activity of metronomic administration of oV in ABC, kinetics and response prediction of CECs, CEPs, CTCs and of other biomarkers of angiogenesis (soluble VEGF, VEGFr2, TSP1, bFGF). CT perfusion scans were also performed. Methods: From February 2008, 47 pts with ABC received oV (50 mg/die TTW). Currently 20 pts are evaluable for both activity and biomarker assessment. Baseline levels of biomarkers of angiogenesis were correlated with clinical response. Results: Shown in Table . Conclusions: We found that the baseline value of apoptotic cells (expressed as % of total cells) was significantly correlated with outcome. The baseline total, viable, and apoptotic CEC count and CTCs might provide an indirect measure for angiogenic turnover and an indicator of better response to anti-angiogenic therapy, supporting the use of metronomic treatments in patients expressing high levels of baseline CECs. Updated results will be presented together with correlation with perfusion CT scan and levels of CTCs. [Table: see text] No significant financial relationships to disclose.
A phase II, multicenter, single-arm study of eribulin mesilate as first-line therapy for HER2-negative locally advanced or metastatic breast cancer.
Authors: Seika Tei, Tsutomu Takashima, Shinichiro Kashiwagi, Hidemi Kawajiri, Shinya Tokunaga, Shigehiko Nishimura, Shigehito Yamagata, Takeo Nishimori, Yoko Mizuyama, Tsuyoshi Sunami, Kenji Tezuka, Satoru Noda, Katsumi Ikeda, Yoshinari Ogawa, Naoyoshi Onoda, Tetsuro Ishikawa, Shinzoh Kudoh, Minoru Takada, Kosei Hirakawa
Journal: Journal of Clinical Oncology (2015)

e12017 Background: Eribulin mesilate, one of the tubuline inhibitors, is usually used for metastatic breast cancer (MBC) as a third or later-line chemotherapy. Eribulin showed survival benefit equivalent to capecitabine with good quality of life in upfront line chemotherapy. We conducted this single arm phase II trial to evaluate efficacy of eribulin as first-line treatment. Methods: The patients with HER2-negative unresectable locally advanced or MBC with measurable lesion who never received chemotherapy. They received 1.4 mg/m2 of eribulin intravenously on day1 and 8 of each three-week cycles until disease progression or intolerable toxicity occured. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression free survival (PFS), time to treatment failure (TTF), overall survival, and safety. Mandatory efficacy evaluation was performed every six weeks. A total of 32 assessable patients were required to test the null hypothesis that the true confirmed response rate is at most 20% versus the alternative at least 40% in 5% alpha-error level and 80% power. Results: Thirty-five patients were enrolled and received eribulin. Patients’ median age was 64 years (range 40–75). Twenty-eight (80%) had estrogen receptor-positive disease and seven (20%) were triple-negative. Ten patients (28.6%) received peri-operative chemotherapy including anthracycline and/or taxane, and eighteen patients (51.4%) received adjuvant endocrine therapy. The median duration of the treatment was eight cycles (range 1-21). The ORR was 54.3% (CR 2: PR 17) and clinical benefit rate was 62.9%. Median PFS was 25 weeks and median TTF was 23 weeks. Although grade 3/4 neutropenia occurred in 22 patients (63%), febrile neutropenia was observed in only two patients (5.7%). Non-hematological toxicities were generally mild and grade 3/4 events were rarely seen. Hair loss, fatigue, sensory neuropathy, and fever were frequently observed. Conclusions: Our data showed that Eribulin had excellent clinical response with mild non-hematological toxicity as a first-line chemotherapy against advanced or MBC. Clinical trial information: 000006086.
Ipilimumab in the real world: The U.K. expanded access programme (EAP) experience in advanced melanoma.
Authors: Saif Ahmad, Wendi Qian, Sarah Gabrielle Ellis, Muhammad Adnan Khattak, Avinash Gupta, Kiruthikah Thillai, Ruth E. Board, Jenny Nobes, Angus Dalgleish, Simon Aird Grumett, Anthony Maraveyas, Sarah Danson, Toby Talbot, Maria Marples, Ruth Plummer, Satish Kumar, Mark R. Middleton, James M. G. Larkin, Christian Ottensmeier, Philippa Corrie
Journal: Journal of Clinical Oncology (2013)

3018 Background: Since publication of the registration trial in 2010 (Hodi et al, NEJM 2010;363:711-23), real world use of ipilimumab (Ipi) in previously treated advanced melanoma patients has extended beyond the specific trial entry criteria of ECOG PS 0-1. We undertook a review of UK patients (pts) treated in the international EAP prior to European licensing of Ipi in August 2011, to compare real world survival outcomes. Methods: UK clinicians registered in the EAP provided anonymised data using pre-specified variable fields for all pts. The EAP stipulated pts should have previously treated, unresectable stage III or IV metastatic melanoma and receive Ipi 3 mg/kg, 3 weekly IV, for up to 4 cycles. Response using RECIST criteria was assessed 12 weekly. Grade ≥3 adverse events (AEs) using CTCAE v3.0 were collected. Results: To date, information on 162 pts has been received from 16 UK sites. Primary sites were: 78% cutaneous, 4% ocular, 1% mucosal, 17% unknown. 78% pts had M1c disease, 14% had brain metastases. N o prior therapies ranged from 0-4, 72% pts received 1 prior therapy. Median age was 60 years, men&gt;women (1.6:1). ECOG PS was: 38% 0, 47% 1, 14% 2, 1% 3. BRAF status was known in 38% cases and WT in 75% of these. 19% pts were on steroids at baseline. N o cycles delivered was 4 in 52%, 3 in 13%, 2 in 16%, 1 in 17% pts. Most frequent reason for stopping early was clinical evidence of disease progression (71%), death (16%) or unacceptable AE (12%). 32% pts experienced a grade ≥3 AE, the most common being diarrhoea (13%) and fatigue (8%). Complete and partial responses were reported in 1% and 21% of treated pts. At median follow-up of 17 months, median progression free survival and overall survival (OS) were 2.8 and 5.7 months, 1 year OS was 30%. Comparing outcomes of various pt subgroups, the strongest prognostic factor for OS was ECOG PS at the start of treatment (p&lt;0.0001). For pts with PS 0 or 1, median OS was 8.8 months (compared with 10 months in the registration trial). More detailed safety and efficacy data on pt subgroups will be presented. Conclusions: This review, representing the largest Ipi EAP UK dataset, reports overall poorer survival outcomes than in the registration trial, but pts with similar characteristics to the trial population lived longer.
In Vitro Chemotactic Index and Response to CXCR4 Antagonist AMD3100 Correlate with CD34+ Cell Yield from Leukapheresis Products: Implications for Poor Mobilizers.
Authors: Leah A. Marquez-Curtis, Jencet Montano, Doris Quinn, Loree M. Larratt, A. Robert Turner, Mariusz Ratajczak, Anna Janowska-Wieczorek
Journal: Blood (2006)
Characterization of patients who received further adjuvant endocrine therapy after 5 years of aromatase inhibitors (AIs): NCIC CTG MA 27.
Authors: Steven E. Vogl, Abdullah Khalaf Altwairgi, Judy-Anne W. Chapman, Liting Zhu, Lois E. Shepherd, Paul Edward Goss
Journal: Journal of Clinical Oncology (2012)

e11005 Background: MA.27 examined the efficacy of 5 yrs of adjuvant aromatase inhibitors (AI), exemestane and anastrozole. Long term outcomes of AI trials may be influenced by unspecified subsequent hormonal therapy so we enquired about its frequency. Methods: Clinical trials (NCIC CTG MA.17R, NSABP B-43) are exploring &gt;5 yrs AI; neither efficacy nor toxicities are known. MA.27 enrolled 7,576 patients June 2003 to July 2008: 5526 (73% in US), 1301 (17% in Canada), 749 (10% outside North America). Clinical cut-off for final follow-up and analysis was April 15 2010: median 4.1 yrs follow-up. Receipt of concomitant medications was routinely reported throughout the trial. Only 345 patients (median age, 64.2 years) completed protocol-specified 5 yrs AI, without breast cancer (BC) relapse, development of contralateral BC, or other second malignancies. Patients were classified by extended endocrine therapy: off trial, physician prescribed specific endocrine therapy; randomized trial endocrine therapy; or no endocrine therapy. Differences in baseline patient and tumor characteristics for these classifications were compared with Fisher’s exact test. Results: From the total group of 345 patients, 320 (93%) received no further endocrine therapy, and 25 (7%) received subsequent therapy. Among the 25, 18 (72%) entered trials and were assigned to endocrine therapy or placebo. Physicians prescribed endocrine therapy to the other 7 (28%). Fourteen (78%) of those who received trial assigned and 7 (100%) of those who received specific additional endocrine therapy were below 70 years of age. Of the 25 patients who received subsequent therapy, only 2 (8%) had &gt;2 cm tumor, and 6 (24%) had node positive tumors. None of the characteristics were significantly different for women who did or did not receive additional therapy. Conclusions: MA.27 is closed to further follow-up, so these results represent the totality of trial information about further endocrine therapy from clinical practices of those who enrolled MA.27 patients. It appears that subsequent hormonal therapy was uncommon (7% of women) after 5 yrs of an AI.
Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness
Authors: Ruben Casanova, Daniel Xia, Undine Rulle, Paolo Nanni, Jonas Grossmann, Bart Vrugt, Reto Wettstein, Rafael Ballester-Ripoll, Alberto Astolfo, Walter Weder, Holger Moch, Marco Stampanoni, Andrew H. Beck, Alex Soltermann
Journal: Cancer Research (2017)

Accurate stratification of tumors is imperative for adequate cancer management. In addition to staging, morphologic subtyping allows stratification of patients into additional prognostic groups. In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation (TF), a measure of tumor invasiveness of lung squamous cell carcinoma (LSCC). In two independent clinical cohorts from tissue microarrays (TMA: n = 208 patients) and whole sections (WS: n = 99 patients), TF was associated with poor prognosis and increased risk of blood vessel infiltration. A third cohort from The Cancer Genome Atlas (TCGA: n = 335 patients) confirmed the poor prognostic value of TF using a similar human-based score on hematoxylin-eosin staining. Integration of RNA-seq data from TCGA and LC-MS/MS proteomics from WS revealed an upregulation of extracellular matrix remodeling and focal adhesion processes in tumors with high TF, supporting their increased invasive potential. This proposed histologic parameter is an independent and unfavorable prognostic marker that could be established as a new grading parameter for LSCC. Cancer Res; 77(10); 2585-93. ©2017 AACR.
Menopausal hormone therapy and breast cancer by body mass index (BMI) and African ancestry.
Authors: Rowan T. Chlebowski, Garnet L Anderson, Aaron K Aragaki, Ross L Prentice, Wendy Demark-Wahnefried
Journal: Journal of Clinical Oncology (2014)

1503 Background: In the Women’s Health Initiative (WHI) randomized, placebo-controlled clinical trials, estrogen plus progestin (E+P) increased breast cancer incidence while estrogen alone (E alone) decreased incidence. Nonetheless, some observational studies report breast cancer findings combining these approaches and additionally suggest breast cancer safety for ”HRT” use in obese and African American women. Methods: We examined E+P and E alone influence on breast cancer incidence by BMI and race/ethnicity in the WHI trials (with 16,608 in the E+P trial, 5.6 yrs intervention and 10,739 in the E alone trial, 7.2 yrs intervention ) with 13 yrs of cumulative follow-up. Hazard ratios (HRs) were estimated using Cox proportional hazards models. Additionally, HRs were estimated in a case-only analysis incorporating African admixture, measured for self- identified African Americans using genetic ancestry information from 656,852 markers. Results: Both for the previously reported overall results (E+P HR 1.28 95% CI [1.11-1.48], p < 001; E alone HR 0.79 [0.65-0.97], p = 0.02) (JAMA 2013; 310:2) and by BMI and race/ethnicity, E+P and E alone had opposite effects on breast cancer incidence. There was no interaction with BMI for either E+P (p = 0.58) or E alone (p = 0.86). For Black women in the E+P trial, breast cancer results were similar to White women regardless of % African Ancestry. For Black women in the E alone trial, a somewhat greater reduction in breast cancer incidence for E alone use was seen (HR 0.47 [0.26-0.82]) compared to White women (HR 0.84 [0.67-1.05]). In the case-only analysis, HRs for Black women 0.45 [0.24-0.87]), Black women with < 79% African ancestry (0.62 [0.26-1.48]) and Black women with ≥ 79% African ancestry (0.32 [0.12-0.86]) suggest CEE effect modification on breast cancer risk by African ancestry (p-trend = 0.04). Conclusions: Observational study analyses of hormone therapy influence on breast cancer should separately consider E+P and E alone. Current randomized trial findings do not support breast cancer safety for E+P use in obese or African American women. The suggestion that greater African ancestry is associated with greater reduction in breast cancer incidence with E alone use warrants further study. Clinical trial information: NCT00000611.