tbuckley/cabot-search huggingface dataset:
Clinical characteristics of metastatic castration-resistant prostate cancer (mCRPC) patients with DNA repair (DNAr) defects.
Authors: Michael Kolinsky, Joaquin Mateo, Semini Sumanasuriya, Pasquale Rescigno, Diletta Bianchini, Zafeiris Zafeiriou, Raquel Perez Lopez, Nina Tunariu, Niven Mehra, Anuradha Jayaram, Suzanne Carreira, Susana Miranda, Penelope Flohr, Ruth Riisnaes, Jane Goodall, Gunther Boysen, Johann S. De Bono
Journal: Journal of Clinical Oncology (2016)

5028 Background: Recent data show that 20-30% of mCRPC patients have defects in DNAr genes. We have evaluated the clinical phenotype of these patients. Methods: Medical records of mCRPC patients treated at the Royal Marsden Hospital from 2005-2015 with deleterious DNAr defects identified by NGS were reviewed. Kaplan-Meier survival analyses and Log Rank testing were pursued. Results: Overall, 36 patients with DNAr defects were identified: 21 BRCA2, 8 ATM, 2 BRCA1, 1 HDAC2, 1 FANCA, 1 PALB2, 1 CDK12, 1 BLM. Median age at diagnosis was 61 years, with 24/34 (71%) metastatic at diagnosis, 22/29 (76%) with Gleason score ≥ 8, and median PSA at diagnosis of 86. Median follow-up was 62 (21-179) months (m), with 19 deaths. Median time to CRPC, overall survival (OS) from CRPC, and OS were 11, 67, and 111 m, respectively. Patients with BRCA2 defects were less likely to present with metastatic disease (55% vs 93%, p = 0.024), but had worse OS (69m vs 167m, p = 0.012) and OS from CRPC (50m vs 108m, p = 0.007), than patients with defects in other DNAr genes. Response to systemic therapies are presented in the table below. Conclusions: High-grade cancers and metastatic disease at diagnosis were frequent in this cohort. PSA response rates to therapy were similar to those reported in unselected mCRPC. BRCA2 aberrant cancers may have a worse prognosis and be less responsive to AR targeted therapies than patients with other DNAr defects. AR targeting pre-chemo AR targeting post-chemo docetaxel cabazitaxel carboplatin PARPi ≥50% PSA response [BRCA2 vs other] 71.4% (5/7) [75% vs 50%, p = 0.355] 36.4% (8/22) [23% vs 56%, p = 0.021†] 71.4% (20/28) [75% vs 67%, p = 0.610] 75% (12/16) [71% vs 89%, p = 0.050] 25% (1/4) [33% vs 0%, p = 0.655] 46.2% (12/26) [53% vs 33%, p = 0.205] RECIST response 16.7% (1/6) 42.9% (3/7) 33.3% (3/9) 55.6% (5/9) 0% (0/3) 42.9% (6/14) Median PFS in m 2.8 [2.8 vs 2.3, p = 1.000] 4.3 [4.1 vs 4.5, p = 0.821] 7.0 [6.0 vs 7.3, p = 0.966] 7.4 [4.5 vs 8.4, p = 0.242] 0.7 [2.1 vs 0.7, p = 0.480] 6.2 [8.9 vs 3.6, p = 0.126] Median OS from start in m [BRCA2 vs other] 24.1 [24.1 vs 8.9, p = 0.678] 33.9 [24.1 vs 41.4, p = 0.060] 43.6 [35.5 vs 43.6, p = 0.053] 22.2 [21.0 vs 38.1, p = 0.009†] 4.6 [4.6 vs 4.9, p = 0.918] 15.9 [15.4 vs 16.9, p = 0.628] †statistically significant
Long-term incidence of venous thromboembolism (VTE) among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Arin L Madenci, Brent Weil, Qi Liu, Todd M. Gibson, Yutaka Yasui, Wendy M. Leisenring, Rebecca M. Howell, Christopher Tinkle, Larissa Nekhlyudov, Lisa Diller, Gregory T. Armstrong, Kevin C. Oeffinger, Christopher Bertero Weldon
Journal: Journal of Clinical Oncology (2017)

10562 Background: This study aimed to estimate the incidence of late-occurring VTE among survivors of childhood cancer, and to identify associated demographic and clinical factors that define high-risk subgroups for potential screening and prevention. Methods: Using data from CCSS, a multi-institutional, longitudinal cohort of 5-year survivors of childhood cancer (diagnosed 1970-1999) and their siblings, the primary endpoint of self-reported late VTE (occurring ≥5 years after diagnosis) was estimated using multivariable piecewise exponential models adjusted for age, sex, and race. Generalized estimating equations accounted for potential within-family correlation where applicable. Results: Among 23,601 survivors and 5051 siblings, the incidence of VTE was 1.15 and 0.48 events per 1000 person-years, respectively. For survivors, median age at last follow-up was 28.6 years (range 5.6-58.3) and median follow-up time from diagnosis was 21.2 years (range 5.0-39.3). The adjusted rate ratio (RR) for survivors compared to siblings was 2.2 (95% confidence interval [CI] = 1.7-2.8, P&lt; 0.01). Among survivors, risk factors for VTE included BMI≥30kg/m 2 (ref. BMI 18.5-24.5; RR = 1.5, CI = 1.2-2.0, P&lt; 0.01), increasing number of severe or life-threatening (i.e. CTCAE grades 3 or 4) non-VTE chronic conditions (ref. 0 conditions; 1-2 conditions: RR = 2.5, CI = 2.0-3.1, P&lt; 0.01 ; ≥3 conditions: RR = 3.5, CI = 2.5-4.9, P&lt; 0.01), and cancer recurrence or second malignant neoplasm (RR = 3.5, CI = 2.7-4.6, P&lt; 0.01). Incidence of late VTE was associated with increased subsequent mortality, independent of non-VTE chronic conditions (RR 2.2, 95% CI = 1.7-2.8, P&lt; 0.01). Conclusions: Survivors of childhood cancer remain at increased risk for VTE across their lifespan. While typically not causal, late VTE was associated with subsequent mortality. Care providers should be aware of this increased risk and consider interventions that target modifiable co-morbidities such as obesity. Surveillance and education should be directed toward high-risk survivors.
A prospective study on neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for patients with advanced cervical cancer.
Authors: Heming Lu, Jinming Yu, Yuying Wu, Xu Liu, Hailan Jiang, Luxing Peng, Shan Deng, Jian Qin, Jinjian Cheng, Qiang Pang, Junzhao Gu, Zhiping Lu, Ping Liang, Renfeng Zhao, Changyi Chen, Xiaoxia Hu
Journal: Journal of Clinical Oncology (2017)

e17000 Background: This study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus nimotuzumab followed by surgery for advanced cervical cancer. Methods: The inclusion criteria of this study were as follows: age: 18-75 years old; ECOG 0-1; FIGO stages IB2-IIIB; not eligible for surgery. IMRT with a total dose of 50-54 Gy was delivered to the tumor and the whole uterus, and 45-48.6 Gy to the high-risk regions. Weekly cisplatin or nedaplatin was administered concurrently with IMRT. Weekly nimotuzumab was given for 6 cycles. Patients were then assessed for clinical tumor response and operability. For those who were candidates for surgery, radical hysterectomy and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Stage distributions were as follows: IB2, 3 pts; IIA, 5 pts; IIB, 16 pts; IIIA, 2 pts; IIIB, 2 pts. Twenty six (92.8%) patients completed ≥ 5 cycles of chemotherapy, and all completed ≥5 cycles of nimotuzumab. Complete clinical response and partial response were found in 8 patients (28.5%) and 20 patients (71.5%), respectively. Four patients were not eligible for surgery and 2 candidates refused surgery. They were not included in this analysis. Radical surgery was performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease. Median follow-up was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicity profiles were mainly manifested as marrow suppression, nausea, diarrhea, and loss of appetite. They were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed Conclusions: This treatment approach is highly effective and safe in advanced cervical cancer. Further studies are warranted to confirm the findings. Clinical trial information: NCT01938105.
Association between HER2 positivity by HER2/CEP17 ratio and response to neoadjuvant HER2 targeted therapy.
Authors: Katherine Cynthia Rappazzo, Heidi Chen, Tarah Jean Ballinger, Vandana Gupta Abramson
Journal: Journal of Clinical Oncology (2018)

e12632 Background: Human epidermal growth factor receptor gene 2 (HER2) amplification status in breast cancers provides prognostic information and predicts response to HER2 targeted therapies. Breast cancers undergo HER2 testing by immunohistochemistry (IHC) or florescent in situ hybridization (FISH), with a positive result by dual-probe FISH if the HER2/CEP17 ratio is ≥ 2.0. Patients who are positive for HER2 amplification respond well to HER2 targeted therapies, but no correlation has been made between the quantitative level of HER/CEP17 ratio and tumor response. We aimed to determine whether increasing quantitative levels of HER2/CEP17 ratio lead to increasing rates of pathologic response to neoadjuvant HER2 targeted therapy. Methods: Patients (n = 125) with locally advanced HER2+ breast cancer who received neoadjuvant HER2 targeted therapies including trastuzumab, pertuzumab, ado-trastuzumab, and lapatinib without cytotoxic chemotherapy were studied retrospectively. The HER2/CEP17 ratio at diagnosis was correlated to pathological complete response (pCR), residual tumor < 0.5cm (pCR0.5), and residual tumor < 1cm (pCR1) and adjusted for ER status. Results: Data from 125 patients were analyzed. Using logistic regression, there was a statistically significant nonlinear association between HER2/CEP17 ratio and pCR ( p < 0.01). Increasing HER2/CEP17 ratio positively correlated with pCR from HER2/CEP17 ratios between 2 and 11. As HER2/CEP17 ratios increased to beyond 11, the curve had a slight downward concavity. The same pattern was seen for HER2/CEP17 ratio correlating with pCR0.5 (p = 0.0055), and pCR1 (p = 0.0126). ER status was not correlated to HER2 ratio using a Wilcoxon rank sum test with continuity correction (p = 0.8505). Conclusions: Quantitative increases in HER2/CEP17 ratio are positively correlated to degree of pathologic response to neoadjuvant HER2 targeted therapies without cytotoxic chemotherapy for HER2/CEP17 ratios up to 11. Above HER2/CEP17 ratios of 11, response rates remain high, but do not have an additive benefit in response to HER2 targeted therapy.
Predictive ability of the khorana score for venous thromboembolism (VTE) in multiple myeloma (MM).
Authors: Kristen Marie Sanfilippo, Tzu-Fei Wang, Suhong Luo, Theodore Seth Thomas, Kenneth Robert Carson, Jesse W. Keller, Nicole Maria Kuderer, David Calverley, Brian Gage
Journal: Journal of Clinical Oncology (2018)

e18733 Background: Guidelines (NCCN, ASCO, ACCP) recommend thromboprophylaxis for patients with MM receiving immunomodulatory therapy who have additional VTE risk factors. No validated tool predicts VTE in this population. Khorana et al. developed a VTE risk score in patients with solid tumors and lymphoma (Blood, 2008). We aimed to evaluate the predictive ability of the Khorana score in MM patients. Methods: We identified patients diagnosed with MM within the Veterans Administration between 6/2006 and 12/2013 and followed the cohort through 12/2014. Variables of the Khorana score were assessed at baseline. We calculated VTE risk using the Khorana score by assigning 1 point each for PLT ≥ 350,000/μl, HGB < 10 g/dl, WBC ≥ 11,000/μl, and BMI ≥ 35 kg/m2. Patients with 0 points were low-risk, 1-2 points intermediate-risk and ≥3 points high-risk for VTE. We assessed the relationship between risk-group and VTE using logistic regression at 3- and 6-months. We tested model discrimination using the concordance statistic (c) with a c-statistic range of 0.5 (no discrimination) to 1.0 (perfect discrimination). Sensitivity analysis used competing risk analysis to adjust for anticoagulants and competing risk of death. Results: We identified 2874 patients with MM: 19 were high-risk, 1484 intermediate-risk and 1371 low-risk for VTE per the Khorana score. At 3-months, 115 patients developed VTE: 51 low-risk, 63 intermediate-risk, and 1 high-risk. At 6-months, there were 168 VTEs: 83 low-risk, 84 intermediate-risk, and 1 high-risk. There was no significant difference between the risk group and VTE (Table 1). The c-statistic was 0.52 at 3-months and 0.51 at 6-months. In the competing risk model, the Khorana score did not predict VTE. The independent predictors of VTE were: prior VTE, lenalidomide, and thalidomide, with a trend towards reduction in VTE with warfarin. Conclusions: In conclusion, the Khorana score did not accurately predict VTE in a MM population. There is need for a VTE risk prediction model for patients with MM. Table 1: Risk of VTE in Relation to Khorana Model Risk Score in MM 3-Month VTE OR (95% CI) 6-Month VTE OR (95% CI) Low Risk Ref Ref Intermediate Risk 1.15 (0.79-1.67) 0.92 (0.67-1.26) High Risk 1.37 (0.18-10.52) 0.82 (0.11-6.29)
Association of low serum albumin concentration with reduced overall survival for patients with metastatic head and neck cancer receiving anti-programmed death receptor-1 therapy.
Authors: Sara Kochanny, Corey Christian Foster, Arun Khattri, Rajesh Acharya, Allison Dekker, Yi-Hung Carol Tan, Elaine Klema, Ryan J. Brisson, Vassiliki Saloura, Alexander T. Pearson, Everett E. Vokes, Rom S. Leidner, Hisham Mohamed Mehanna, Tanguy Y. Seiwert
Journal: Journal of Clinical Oncology (2018)

6057 Background: Immunotherapy efficacy is modulated by immune competence which lacks well established clinical measures. Nutritional status influences immune competence and has been associated with poor outcomes with antimicrobial and oncologic therapies. The relationship between nutritional status and outcomes with anti-PD-1 checkpoint blockade has not been reported, and we examined this association in patients with metastatic head and neck (H&N) cancer. Methods: 114 patients with metastatic H&N cancer unselected for PD-ligand 1 (PD-L1) status received anti-PD-1 therapy. Low baseline serum albumin concentration was < 4.0 g/dL. Univariate logistic regression analyzed the relationship between albumin and overall response rate (ORR) measured by RECIST v1.1, and the association with body mass index (BMI) was performed with Chi-square analysis. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and Cox proportional hazard regression. Results: Median follow-up was 8.6 months. Baseline characteristics including known PD-L1+ (n = 27/48 high albumin vs. n = 27/60 low albumin, p = 0.38) were comparable between groups. ORR was 22.3%. Albumin status not associated with ORR (p = 0.41) but was associated with BMI (p = 0.04). There was a trend towards lower median PFS for the low albumin group (2.4 months, 95% confidence interval [CI]: 1.9-3.7) compared to the high albumin group (4.6 months, 95% CI: 2.6-7.5) (p = 0.1). OS was significantly reduced for the low albumin group (median: 5.4 months, 95% CI: 3.6-9.5) compared to the high albumin group (median: 12.5 months, 95% CI: 9.1-17.3) (p-0.03). On multivariate analysis, albumin was the strongest independent predictor of poor OS (p = 0.01). Conclusions: Poor nutritional status as measured by low baseline serum albumin concentration is associated with worse outcomes in patients with metastatic H&N cancer receiving anti-PD-1 therapy and is a potential measure of immune competency. Investigation of clinical measures of immune competency including albumin as a marker of nutritional status in larger patient cohorts is warranted.
Clinicopathological features and prognosis of primary GISTs with tumor rupture in the real world.
Authors: Toshirou Nishida, Haruhiko Cho, Toru Masuzawa, Gaku Chiguchi, Toshimasa Tsujinaka, Seiichi Hirota
Journal: Journal of Clinical Oncology (2017)

e22510 Background: Ruptured GIST has poor prognosis and patients (pts) with ruptured GISTs are recommended for imatinib adjuvant therapy, however, their clinicopathological features and the prognosis in the era of imatinib are unknown. Using data obtained from two different registry studies in Japan, we examined ruptured GIST patients in clinical practice. Methods: The study cohort registered 665 pts (339 male and 326 female; median age 66 yrs) with histologically-proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007. The validation cohort included 172 pts (100 and 72; median age 62.5) between 2000 and 2014. Pathological Dx was done with H&amp;E, KIT- and DOG1-IHC. Results: Disease located in the stomach (n = 506), small intestine (n = 119), large intestine (n = 26), or others (n = 14) in the study cohort and it was 120, 37, 14 or 2 in the validation, respectively. Median tumor size was 4.0 and 5.0 cm, median mitosis 2.6 and 5.0 /50HPF, and tumor rupture was seen in 21 pts (3.2%) and 5 pts (2.9%) in the study and validation cohorts, respectively. Rupture occurred preoperatively in 12 pts and intraoperatively in 9 of the study cohort. Ruptured GISTs showed high mitotic activities (median mitosis 13.0 vs 2.5 /50HPF; P &lt; 0.0001), larger tumor (median size 9.6 vs 4.0 cm; P = 0.0008), and were more symptomatic than non-ruptured in the study cohort. Ruptured GIST pts had more frequent relapses (P &lt; 0.0001) and showed shorter RFS (estimated RFS = 2.4 yrs; P &lt; 0.0001) than non-ruptured (8.4 yrs). There were no difference in age, gender, location, surgical approach, cell type, preoperative and postoperative imatinib use between two groups.These results were confirmed in the validation cohort. Ruptured GISTs showed more frequnent relapses in the peritoneum. Multivariate analysis indicated that location (HR = 1.6), size (1.07), mitosis (1.01), and rupture (4.5) were independent prognostic factors of RFS. Rupture was not always prognostic for OS, and age (1.03), gender (2.3), and mitosis (1.01) were independent prognostic factors of OS. Conclusions: Ruptured GISTs were symptomatic larger tumors with high mitotic activity and showed frequent relapses, however, it was not independently prognostic for OS in the era of imatinib.
Phase 1-2 study of TI-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies.
Authors: T.R. Jeffry Evans, Antoine Italiano, Ferry Eskens, Stefan Nicholas Symeonides, Alice Susannah Bexon, Philippa Graham, David Hinds, Pamela Manning, Sanjay Chanda, Robert Karr, Pankaj Bhargava
Journal: Journal of Clinical Oncology (2017)

TPS3109 Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.
P01.161 Neurocognitive evaluation in elderly Glioma patients
Authors: V Villani, A Tanzilli, S Telera, C Zucchella, C M Carapella, I Terrenato, R Boccaletti, A Pace
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common primary brain tumor in adults, with an increasing incidence in patients aged 75 through 85. Prognosis in these patients is particularly dismal due to more aggressive tumor biology, lower functional reserve and high prevalence of comorbidities. Many studies report cognitive impairment in GBM patients, ranging from 29 to 90%. This study was aimed at evaluating neurocognitive status and comorbidities of an elderly population with high grade glioma and the correlation with clinical and demographical variables. patients underwent an extended neuropsychological evaluation with a battery of standardized tests on 8 cognitive domains: global function (GF); verbal learning (VL); short and long-term memory (STM); executive functions (EF); abstract reasoning (AR); attention (ATT) and visuo-constructional abilities (CA). Moreover, the Cumulative Illness Rating Scale was administered to each patient for comorbidities evaluation. We assessed 69 patients with median age at diagnosis of 74 years (range 65–85). 43 patients (62%) presented multi-domain cognitive impairment, and only 8 (12%) showed no cognitive impairment. Neuropsychological deficit mainly affected executive functions (n=42), short term memory (n=28), long term memory and attention (n=22). Patients with AR deficit had a poorer PFS and OS (p<0. 001%). At the follow up, 7 out of 12 patients showed cognitive improvement, 4 resulted furtherly deteriorated and 1 patient was stable. Attention was the most affected function at follow up, while verbal learning was the most improved one. Our results highlight the high prevalence of cognitive deficits in patients with Glioma. Moreover, this study underlines the need to include cognitive functioning and comorbidities evaluation in the assessment of elderly neuro-oncological patients.