tbuckley/cabot-search huggingface dataset:
Prospective multicenter study evaluating adrenal suppression after dexamethasone therapy as an antiemetic in cancer patients: a KSWOG (Korean South West Oncology Group) study.
Authors: Hye Sook Han, Ji Chan Park, Suk Young Park, Kyu Taek Lee, Sang Byung Bae, Han Jo Kim, Samyoung Kim, Hwan Jung Yun, Woo Kyun Bae, Hyun Jeong Shim, Jun Eul Hwang, Sang-Hee Cho, Moo-Rim Park, Hyeok Shim, Ki Hyeong Lee
Journal: Journal of Clinical Oncology (2015)

9605 Background: Dexamethasone has a high therapeutic index for the prevention of chemotherapy-induced nausea and vomiting; however, the chronic use of high-dose glucocorticoids is associated with adrenal insufficiency. The objective of the present study was to assess the prevalence and associated factors of adrenal suppression after antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. Methods: Patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as one of antiemetics were enrolled. Patients with a suppressed baseline adrenal response before chemotherapy and those administrated corticosteroids within 6 months of study commencement were excluded. Results: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid ACTH stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the first chemotherapy with dexamethasone as an antiemetic. Multivariate analysis revealed that the incidence of adrenal suppression was significantly associated with the duration of megestrol acetate use (P< 0.001). Adrenal suppression did not correlate with age, sex, performance status, primary tumor site, tumor stage, intent of first chemotherapy, emetic risk of first chemotherapy, chemotherapeutic agents used, or the dose and duration of dexamethasone. Conclusions: This large prospective study indicates that approximately 15% of cancer patients with a normal adrenal response showed suppressed adrenal responses after antiemetic dexamethasone therapy; this was particularly significant for patients co-treated with megestrol acetate.
A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Eric Jay Small, Raymond S. Lance, Charles H. Redfern, Frederick E. Millard, Thomas A. Gardner, Lawrence Ivan Karsh, Nancy Ann Dawson, Candice McCoy, Andrew Stubbs, Todd DeVries, Corazon P. dela Rosa, Nadeem A. Sheikh, Neal D. Shore
Journal: Journal of Clinical Oncology (2013)

5047^ Background: Sipuleucel-T and AA + P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1 st study to evaluate the combination of sipuleucel-T and AA + P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the 1 st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1 st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA + P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54 + cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2 nd and 3 rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p&gt;0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA + P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA + P. Clinical trial information: NCT01487863.
A preclinical study on the combined treatment of nimotuzumab and sirolimus in glioblastoma.
Authors: Chee Kian Tham, Paula Lam, Siewju See, Siang Hui Lai, John Thomas, Wai Hoe Ng
Journal: Journal of Clinical Oncology (2012)

2066 Background: The human epidermal growth factor receptor (EGFR) is an ideal therapeutic target for inhibiting glioblastoma (GBM) growth as the signaling pathway is highly dysregulated in GBM. However, trials so far with EGFR inhibitors have not shown clinically meaningful improvement in response rates and survival. One of the postulated mechanisms of resistance is the constitutive activation of the downstream, PI3K/AKT/mTOR pathway, independent of the upstream EGFR activation status. Hence, the dual blockage of the pathways with an anti-EGFR agent and mTOR inhibitor is postulated to have synergistic anti-tumour effects. We aim to investigate the anti-tumour effect of combined nimotuzumab (anti-EGFR monoclonal antibody) and sirolimus (mTOR inhibitor) in a GBM preclinical model. Methods: Primary human GBM cells were derived from surgical GBM specimens. The endogenous expressions of glial-fibrillary acidic proteins and EGFR were determined by IHC staining and Western Blot analysis. Cell viability assays were then carried out in these GBM cells and immortalized human normal astrocytes (iHNA) using a range of concentrations of nimotuzumab alone, sirolimus alone or combined treatment. Results: GBM cells treated with nimotuzumab showed a dose- dependent cell kill and the optimal concentration was determined to be 2 µg/ml. Treatment of the GBM cells with sirolimus showed that the drug was capable of inducing cell death at varying levels and the optimal level was determined to be 0.1 mM. Combined treatment with nimotuzumab (2µg/ml) and rapamycin (0.1 mM) showed a dose dependent cell kill in GBM cells which was not observed in iNHA cells. The combined treatment resulted in only 10% of residual gliomas at 24 h post treatment. Single treatment with rapamycin has no cytotoxic effect whereas treatment with nimotuzumab alone exerts a cytotoxicity effect of 33%. Taken together, we observed an additive effect of cell kill when rapamycin is used together with nimotuzumab in human glioma cells. Conclusions: In this study, combined treatment of nimotuzumab and sirolimus resulted in a greater cytocidal effects in GBM cells than either agent alone. We will further examine this combination regimen in a subsequent phase I clinical trial.
The impact of post transplant use of G-CSF on event free survival in AML patients undergoing allogeneic stem cell transplantation from unrelated donors and in vivo T-cell depletion with ATG
Authors: M. Schleuning, R. Thoedtmann, K. Josten, H. Baurmann, R. Schwerdtfeger
Journal: Journal of Clinical Oncology (2004)

6637 Background: Allogeneic hematopoietic cell transplantation from matched unrelated donors (MUD-HSCT) may be curative for high risk AML patients. However, it carries a considerable risk of treatment related mortality. This study was performed to identify risk factors (RF) impairing event free survival (EFS) in patients (pts) with AML undergoing MUD-HSCT and in vivo T-cell depletion with ATG. Methods: In a retrospective analysis of all pts with AML undergoing MUD-HSCT we identified RF by Log-Rank analysis and performed a multivariate analysis of all RF being significant in univariate analysis. RF included were: disease status at transplant (DS); pts age; donor sex; transplant era; stem cell source; number of cells transplanted; HLA-match; ATG source; risk of cytomegalovirus infection; acute (a) and chronic graft vs host disease (GvHD); cytogenetics (CG); post transplant application of granulocyte colony stimulating factor (G-CSF). Results: Eighty-nine pts (47 m, 42 f), median age 42 y (18 –62 y), who underwent MUD-HSCT in the period from 1996 to 2003 were included. All pts received rabbit ATG (Fresenius: n=29, Merieux/Sangstat: n=60) during conditioning. 50 pts died after HSCT. Median EFS was 186 d (9 –2125 d). As significant risk factors we identified by univariate analysis: the occurrence of aGvHD (p=0.0000), CG (p=0.0375) and use of G-CSF (p=0.0001). The only RF remaining after cox regression analysis were aGvHD (p = 0.003, RR 1,544, CI 95%, 1,160 –2,056) and use of G-CSF (p = 0,000, RR 3,401, CI 95%, 1,712 –6,757). The mortality of pts receiving G-CSF was 77% as compared to 37% in pts not receiving G-CSF. This higher mortality was due to a higher transplant related mortality but also due to a higher relapse rate. Conclusions: In this cohort the occurence of acute GvHD and the application of G-CSF were independent negative predictors for EFS. Therefore the selection of pts for use of post transplant G-CSF should be done with due care, especially in AML pts receiving MUD-HSCT and in vivo T-cell depletion with ATG. No significant financial relationships to disclose.
Impact of country-specific health economic guidelines on cost-effectiveness (CE) estimates: An illustrative study of the CE of cetuximab in the first-line (1L) treatment of <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Gerard Harty, Ronaldo Kenzou Fujii, Amrita Ostawal, Chris P Pescott
Journal: Journal of Clinical Oncology (2017)

702 Background: Adding cetuximab to conventional 1L chemotherapy (FOLFIRI or FOLFOX) improves survival outcomes in patients with RASwt mCRC. Conflicting evidence exists regarding the CE of cetuximab in mCRC, due in part to differences in country-specific health technology assessment (HTA) guidelines. Methods: CE estimates for the 1L treatment of RASwt mCRC with FOLFIRI or FOLFOX ± cetuximab were calculated for the UK (NICE), Brazil, Netherlands, and Belgium using a Markov cohort model populated with country-specific HTA requirement inputs and assumptions. Model outcomes were treatment costs, life-years (LY) or quality-adjusted LY (QALY) gained, and the incremental CE ratio (ICER). ICERs were compared against CE thresholds. Results: Country-specific HTA guidance resulted in differing CE outcomes for patients with RASwt mCRC receiving FOLFIRI or FOLFOX ± cetuximab (Table). Conclusions: We applied our Markov model to four markets, incorporating country-specific HTA requirements into our calculations. Although our analyses with similar comparators led to a varying range of CE estimates, they met the HTA threshold guidelines in the four markets. [Table: see text]
Exome sequencing of an Irish familial breast cancer family.
Authors: Judith Conroy, Sean Ennis, C. Nolan, R. M. Clarke, Eileen Berkley, Dhafir Alazawi, E. M. Connolly, Terence Boyle, M. John Kennedy, David J. Gallagher
Journal: Journal of Clinical Oncology (2015)

e12517 Background: Only a small percentage of the heritability of breast cancer is explained by high penetrance genes such as BRCA1, BRCA2, and TP53. Moderately penetrant genes, such as PALB2 and CHEK2, and low penetrance common variables, explain a minority of the remainder. We completed exome sequencing on a single Irish family with a higher than expected number of women affected by breast cancer. Methods: DNA was collected from an affected mother, 3 affected and one unaffected daughter. Exome sequencing was completed using the Agilent SureSelect exome enrichment kit. Alignment of data, data cleaning and variant identification was performed using standard procedures at NextCODE Health. Novel and rare variants (maf < 0.05%) of moderate/high impact that segregated were identified. We searched multiple databases for information on the number of heterozygous/homozygous individuals, conservation and publication of genes with cancer. Results: We identified 7 rare variants that segregated with disease. The number of variants in each individual was within normal limits. All samples passed QC. HTT, CUBN and KTN1 appear the most likely candidates for causation, with HTT the most likely. The HTT variant is completely absent in multiple population variant databases. An expanded polyQ domain in HTT has been associated with increased breast cancer risk in vitro and in mouse models. PolyQ-HTT increases EMT and pulmonary metastasis, and leads to membrane accumulation ErbB2/HER2. Trastuzumab inhibits polyQ-HTT induced HER2 accumulation and downstream effects. Conclusions: A rare, previously unreported variant in HTT segregated with breast cancer diagnosis in an autosomal dominant fashion in this family. Additional genotyping of other family members, and a functional study of this variant, are ongoing. Variants co-seg. with B.C. ESP hets ESP homs Bp PhyloP AA PhyloP Pub. Ca. Pub. B.C. CPSF3L – rs142542232 6 0 3.3 0.22 0 0 MORN1–novel (chr1:2310577) 0 0 -3.4 -2.23 0 0 CUBN – rs374652141 1 0 2.12 1.63 0 0 KTN1 – rs201224728 2 0 0.22 2.87 0 0 TCTEX1D2 – rs144257417 1 0 3.2 3.07 0 0 HTT – novel (chr4:3234961) 0 0 0.62 1.42 121 10 GCNT6 – rs146085145 0 0 2.35 -1.13 0 0 Co-seg, co-segregating; Pub., pubmed; Ca, Cancer. B.C., breast cancer; ESP, Exome Sequencing project; BP, basepair; AA; amino acid.
Long-term follow-up of patients with acute myelogenous leukemia receiving an autologous telomerase-based dendritic cell vaccine.
Authors: Hanna Jean Khoury, Robert Collins, William G. Blum, Patrick J. Stiff, Jane Lebkowski, Edward Wirth, Kevin Nishimoto, John F. DiPersio
Journal: Journal of Clinical Oncology (2015)

7007 Background: A phase II clinical trial was conducted in which subjects with AML were administered a telomerase-based dendritic cell immunotherapy (AST-VAC1; hTERT-DCs). The hTERT-DCs were prepared from leukapheresis collections from 33 subjects and were transfected with an mRNA encoding telomerase (hTERT) and the lysosomal sorting signal, LAMP-1, which enhances immunostimulatory activity. hTERT is essential for maintaining the proliferative capacity of tumor cells. Methods: AML patients were eligible to receive hTERT-DCs if they were in CR1 or CR2 with intermediate or high risk cytogenetics or if they were in early relapse with < 20% marrow blasts. The hTERT-DCs were prepared after induction therapy and before or after completion of consolidation cycles. The hTERT-DCs were administered as 6 weekly followed by 6 biweekly intradermal injections. Results: Twenty-one patients (median age: 55) in complete remission (16 CR1 and 3 CR2) and or early relapse (2) received at least 3 injections of the hTERT-DCs. Only one grade 3 or 4 adverse event, (idiopathic thrombocytopenia), possibly related to the immunotherapy was observed during the first year. The two patients who were vaccinated during early relapse progressed rapidly and did not receive the full dosing regimen of hTERT-DCs. Of the 19 patients that were in CR, 14 received all 12 doses of hTERT-DCs. Fifty-eight percent (11/19) developed cellular immune responses to hTERT as assessed by peptide ELISpot analysis. Eleven of 19 patients (median follow-up 52 mos.) are still in remission as of last follow-up; seven developed detectable cellular immune responses to hTERT. Of the 19 CR patients, 7 were ≥ 60 yo at the time of hTERT-DC immunotherapy. Four of 7 patients ≥ 60 yo remain relapse free 52-59 months post DC-hTERT immunotherapy with all four developing immune responses to hTERT. The three patients that received DC-hTERT while in CR2 were in remission as of their last follow-up of 24, 50 and 59 months with two having hTERT immune responses. Conclusions: The results suggest that immunotherapy with hTERT-DCs is safe, can stimulate an immune response to telomerase, and may provide anti-tumor immune responses even in high risk patients with AML Clinical trial information: NCT00510133.
Effect of detection of need for care on lung cancer patient-reported outcomes: A randomised controlled trial.
Authors: Olaf P. Geerse, Josette E.H.M. Hoekstra-Weebers, Marleen H. Stokroos, Harry J.M. Groen, Huib A.M. Kerstjens, Thijo Jeroen Nicolaas Hiltermann
Journal: Journal of Clinical Oncology (2015)

e20593 Background: According to the Dutch guideline, detection of need for care (DNC) is the process of completing a distress screening instrument, discussing the response pattern, and referral to a health care professional if needed/wished. DNC might be beneficial in lung cancer patients since a significant proportion reportedly experiences distress. We investigated whether standard care including DNC is associated with better patient’ outcomes, reduced healthcare utilization, or improved survival, than standard care alone. Methods: Patients starting systemic therapy for newly diagnosed or recurrent lung cancer were randomly assigned to receive standard care or standard care with DNC. Participants completed the European Organization of Research and Treatment for Cancer Quality of Life Questionnaire (EORTC-QLQ-C30), the Hospital Anxiety and Depression Scale, and the Patient Satisfaction Questionnaire at one, seven, 13, and 25 weeks after randomisation. Additionally, patients noted their healthcare use. Primary outcome was the mean change in the EORTC-QLQ-C30 global quality of life (QoL) subscale between one and 25 weeks. For a minimal clinically significant effect of 8 points on the QoL subscale and an alpha = 0.05 and 1-beta = 80%, 188 patients had to be included. Results: Of the 337 eligible patients, 223 (response rate of 66%) were randomized. At 25 weeks after randomization, 111 patients (50%) had completed all four assessments, 50 patients (44%) in the standard and 61 (56%) in the DNC group. No significant between group difference was found in mean change global QoL score (2.5, 95% CI -12·1–7·2; p=0.61), nor in the remaining EORTC-QoL subscales, depression, anxiety, patient satisfaction, healthcare utilization, or in survival. Conclusions: DNC, as implemented in the clinical care of lung cancer patients starting with a systemic therapy, does not seem to have significant beneficial effects on patient’ reported outcomes, health care use and survival. Funding This first author of this abstract received funding from the Royal Netherlands Academy of Arts and Sciences for acceptance at the American Society of Clinical Oncology General Meeting of 2015. Clinical trial information: NTR3450.
Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)
Authors: C. Tsien, M. Nyati, D. Chepeha, F. Worden, J. Helman, C. Bradford, G. Wolf, T. Lawrence, A. Eisbruch
Journal: Journal of Clinical Oncology (2009)

6077 Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation. No significant financial relationships to disclose.
Effect of clinical and biological factors on pathologic complete response (pCR) after neoadjuvant chemotherapy for patients (pts) with early-stage breast cancer (BC).
Authors: Pierre Kouchner, Jean-Philippe Spano, Eugenie Guillot, Emmanuel Touboul, Florence Renouvel, Betty Lauratet, Catherine Genestie, Loic Campion, David Khayat, jean Marc Classe, Jean-Pierre Lefranc
Journal: Journal of Clinical Oncology (2012)

e11551 Background: To evaluate predictive factors that impact pathologic complete response (pCR) after neoadjuvant chemotherapy (NC) for BC pts. The identification of such factors may improve pt selection for neoadjuvant therapy to maximize the likelihood of breast conservation surgery (BCS) Methods: A total of 279 pts treated with NC (anthracyclines and/or taxanes based chemotherapy) for BC were analyzed. Pathologic response was evaluated using Sataloff classification. Student’s test and Fisher’s test were used for statistical analysis; OS and DFS rates were estimated by Kaplan-Meier analysis and log rank test for outcome. Results: According to the TNM classification, 87.4% of pts had T2 /T3 tumors, and 45.9% of pts had a lymph node involvement before NC. HER-2 over expression was found in 23.5 % and 18.6 % of pts had triple negative tumors. Forty three (43%) of pts achieved a clinical complete response. BCS was performed in 44.8%. pCR was 26.4% in the breast primary tumor and 32.8% in the axillary nodes. Univariate analysis showed that the following variables at diagnosis were correlated with a pCR: T2 vs T3/T4 (P&lt;0.001), ductal invasive carcinoma (P=0.001), high grade (p&lt;0.007), high mitotic index (P&lt;0.001), estrogen receptor (ER) negative tumors (p=0.001), progesterone receptor negative tumors (p=0.001), chemotherapy with taxanes (p=0.0026), trastuzumab therapy (p&lt;0.001) and the number of chemotherapy cycles (p=0.002). In multivariate analysis, ER negative, high mitotic index and HER-2 overexpression were significantly associated with a pCR (P&lt;0.01). Lymph node pCR was a significant prognostic factor with 5 year RFS and DFS (respectively p&lt;0.001 and p=0.016). At a median follow-up of 53.4 months, OS and DFS at 5 years were 86.1% and 24.2% respectively. Conclusions: Our data support the hypothesis that ER negative, high mitotic index and HER2 overexpression significantly predicted pCR in pts receiving neoadjuvant therapy for early BC. These results may suggest using such factors before deciding neoadjuvant chemotherapy in order to increase eligibility for BCS.