tbuckley/cabot-search huggingface dataset:
Abstract P402: Serum Magnesium and the Risk of Ischemic Stroke among Women
Authors: Sally N Akarolo-Anthony, Monik C Jimenez, Stephanie E Chivue, Walter C Willett, Kathryn M Rexrode
Journal: Circulation (2013)

Background: Low magnesium levels may be associated with higher blood pressure as well as endothelial dysfunction. Results from studies examining the association between serum magnesium and risk of stroke are inconsistent, with some studies suggesting a protective association with higher levels. Methods: Among 32,826 participants in the Nurses’ Health Study who provided blood samples in 1989-1990, ischemic strokes were identified and confirmed by medical records through 2006. We conducted a nested case-control analysis of 460 cases, matched to controls (1:1) on age, menopausal status, use of postmenopausal hormones, ancestry, date of blood draw, fasting status and smoking status. Magnesium quintiles were created based on the distribution of serum magnesium levels among controls, and a dichotomous variable was also created, based on prior data: low magnesium (&lt;2.0 mg/dL) and high magnesium (≥ 2.0 mg/dL). Conditional logistic regression models were used to estimate the multivariable adjusted association of serum magnesium and the risk of ischemic stroke and unconditional analyses were used to assess effect modification. Results: In univariate analysis, median magnesium levels did not differ between stroke cases and controls (median=2.1 in each, p-value=0.16). Conditional on matching factors, women in the lowest magnesium quintile had a relative risk (RR) of 1.34 (95% confidence interval [CI]: 0.85-2.09) for ischemic stroke, compared to those in the highest quintile. Additional adjustment for potential confounders (alcohol intake, body mass index [BMI], physical activity, aspirin use, thiazide diuretic use, history of diabetes, history of coronary heart disease, glycosylated hemoglobin and the ratio of total to HDL-cholesterol) did not substantially alter the risk estimates (RR=1.34; 95% CI: 0.82-2.17). However, women with magnesium levels &lt;2.0mg/dL had a significant increase in the risk of ischemic stroke, compared to women with magnesium levels ≥2.0 (RR= 1.66; 95% CI: 1.18 - 2.34. Controlling for potential confounders (as above) did not significantly alter this risk (RR= 1.63; 95% CI: 1.13 - 2.36). No significant effect modification was observed by age, BMI, hypertension or diabetes. Conclusions: Serum magnesium levels &lt;2.0 are associated with increased risk of ischemic stroke among this population of women.
Hyperprogression after immunotherapy: Clinical implication and genomic alterations in advanced non-small cell lung cancer patients (NSCLC).
Authors: Youjin Kim, Chu Hyun Kim, Hong Sook Kim, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee, Ho Yun Lee, Keunchil Park
Journal: Journal of Clinical Oncology (2018)

9075 Background: Hyperprogressive disease (HPD) emerges as a new subset of patients treated with immune-oncology (IO) agent. The definition of HPD is not yet clearly established, and it is unclear which patient is rapidly progressing after IO treatment. We investigated clinical features and potential genomic markers associated with HPD after IO therapy. Methods: We performed a retrospective clinical and radiological analysis of advanced NSCLC patients treated with single IO at Samsung Medical Center(July 2014 to December 2017). CT scans were quantitatively analyzed in terms of tumor volume and tumor growth rate (TGR) by comparing prior vs upon IO. We extracted tumor volume for each metastatic organ, classifying into HPD and non-HPD by volume-based growth kinetics. We also performed deep targeted sequencing of 375 of genes. Results: Of 220 evaluable patients37 patients (17%) were classified as HPD. 26 (70%) were male, 24 (65%) smoker, 25(68%) ≧ 65 years, 10 (27%) ECOG PS ≧ 2, 31(84%) adenocarcinoma. Compared to non-HPD population, HPD was not associated with higher tumor burden at baseline, nor with gender, smoking status, PD L1 status, line of chemotherapy, prior radiotherapy. With median follow up of 20 months(m), mPFS and mOS were 4.4m (95% CI: 2.8-6.0), 12m (95% CI: 9.4, 16.0), respectively. HPD patients had significantly lower mPFS (1.2 vs 4.1m, p = < .000), mOS (7.1 vs.15.9m, p = 0.09). Further details with genomic profiling will be presented. Conclusions: HPD(defined by tumor growth kinetics) occurs in 17% of 220 advanced NSCLC patients after single-agent checkpoint inhibitors. Genomic profiles may help to identify patients at risk for HPD on IO.
Update of the EORTC questionnaire for assessing quality of life in patients with lung cancer: Introducing the new EORTC QLQ-LC29.
Authors: Michael Koller
Journal: Journal of Clinical Oncology (2016)

e18096 Background: The EORTC QLQ-LC13 was the first module developed to be used in conjunction with the core questionnaire C30. Since the publication of the LC13 in 1994, major advances have been made in the treatment of lung cancer as well as in assessing quality of life. Therefore, the EORTC decided to support a project to update the LC13. Methods: The study design followed the Phase I to III approach described in the EORTC Module Development Manual. Phase I generates relevant quality of life issues using a mix of sources, including patient involvement. Phase II transforms issues into questionnaire items. An international multi-center study investigated the feasibility of the provisional module (Phase III). Patients had to fill in the EORTC QLQ-C30 and a 78-item provisional lung cancer module generated in Phases I and II. Patients rated each of the items regarding perceived importance, comprehensibility, and acceptance. The 78 items were assessed against a set of pre-specified statistical criteria comprised of distribution properties of the items and patient ratings. Biometrical methods primarily included descriptive statistics and basic psychometric analyses (Cronbach’s alpha). Results: A total of 12 centers from Cyprus, Germany, Italy, Israel, Spain, Norway, Poland, Taiwan, and UK participated in the Phase III study. 200 patients with histologically confirmed lung cancer were enrolled. Mean age was 64 years (range 39−91). 59% of the patients were male, 82% had NSCLC, and 56% were treated with a palliative approach. 29 out of the 78 items met the pre-specified statistical. Initial psychometric analyses suggested a five multi-item scale structure (coughing, shortness of breath, side effects, tumor progression related to existential issues, surgery-related symptoms; all Cronbach’s alphas > .70). Conclusions: The updated module retained 12 of the 13 original LC13 items and contains new items that assess therapy side effects of targeted therapy, radio-chemotherapy, and thoracic surgery. A large-scale international multi-center Phase IV study will be conducted to fully assess the psychometric properties of the updated lung cancer module. Clinical trial information: NCT01434784.
Outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with different new agents (NAs) sequence in post-docetaxel (DOC) setting: Final analysis from a multicenter Italian study.
Authors: Orazio Caffo, Emilio Bria, Ugo De Giorgi, Marcello Tucci, Luca Galli, Lucia Fratino, Sabrina Rossetti, Roberto Iacovelli, Giovanni Lo Re, Claudia Mosillo, Donatello Gasparro, Pamela Francesca Guglielmini, Azzurra Damiani, Giuseppe Procopio, Delia De Lisi, Fiorella Ruatta, Sarah Scagliarini, Maddalena Donini, Isabella Sperduti, Umberto Basso
Journal: Journal of Clinical Oncology (2017)

5030 Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) may prolong survival in mCRPC pts progressing after DOC, although it is not clear how to use NAs to best exploit their efficacy and avoiding their possible cross resistances. In 2015, we reported the outcomes of a series of 260 mCRPC pts, receiving at least 2 NAs, after DOC progression in routine clinical practice (Eur Urol. 2015;68:147-53). In the present study we updated the analysis with longer follow-up and by assessing a larger series of pts. Methods: Based on a multi-institutional collaboration, we collected data of pts who received at least 2 NAs after DOC: we assessed biochemical (bRR) and objective response rates (oRR) and progression free survival (PFS) of each NA by treatment line; moreover, we evaluated the overall survival (OS) from the second line start by sequence strategy. For the OS analysis we differentiated three different types of NAs sequences after DOC: one new hormone agent (AA or ENZ) followed by CABA (NHA→CABA); CABA followed by AA or ENZ (CABA →NHA); one NHA followed by the other NHA (NHA →NHA). Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All received NAs as 2 nd and 3 rd line after DOC. The outcomes by both treatment lines and NAs are detailed in the table. We observed a statistically significant difference in terms of OS when compared the three sequence strategies: the median OS of pts treated with NHA→CABA, CABA→NHA, and NHA→NHA was respectively 12.9 mos, 14.2 mos, and 8.8 mos, respectively (p = 0.01). Conclusions: At our knowledge this retrospective study reports the highest number of pts treated post-DOC with at least 2 NAs. Our data confirmed that the activity of NAs decreased in the 3 rd line compared to the 2 nd line and suggested a cumulative OS advantage when CABA is used in the sequence. [Table: see text]
Association of a specific innate immune response to DNA damage with DNA repair deficient colorectal cancers.
Authors: Petros Tsantoulis, Laura A. Hill, Steven M. Walker, Pratyaksha Wirapati, Donna M. Graham, Richard H. Wilson, Victoria Coyle, Mauro Delorenzi, D. Paul Harkin, Richard D. Kennedy, Sabine Tejpar
Journal: Journal of Clinical Oncology (2016)

3035 Background: We previously described a molecular subtype of tumors that presents an innate immune response to intrinsic DNA damage. The associated gene expression pattern is mediated by the STING viral response pathway within the cancer cell and is defined by up-regulation of cytokines that drive lymphocytic infiltration and up-regulation of immune checkpoint such as PD-L1 and IDO1. We have developed a 44-gene signature, the DNA damage response deficient (DDRD) assay that can prospectively identify this molecular subtype (Mulligan et al 2014). We now apply this assay to colorectal cancer (CRC) to look for associations with DNA repair deficiency. Methods: We applied the DDRD assay to 72 stage I, 448 stage II, 836 stage III and 90 stage IV CRC patients with gene expression and exome sequencing data from the TCGA, Marisa and PETACC3 datasets (Kucherlapati et al., 2012, Marisa et al., 2012, Bosman et al., 2009). The association between DDRD positivity and MSI (microsatellite instability) status was tested using Chi-squared testing. A further analysis was performed within the TCGA cohort to determine if DDRD positivity is associated to general mutational burden in CRC, including evaluation of mutations in known DNA repair genes. Results: Approximately 35% of CRC were DDRD positive. Consistent with a loss of DNA repair capacity, the mean mutational burden was significantly higher in high DDRD score samples (Spearman's correlation P = 0.0008). A strong association was found between MSI and DDRD positivity in all datasets (T-test P < 0.001) where around 80% of tumors known to be MSI positive were DDRD positive. Significantly 25% of MSS (microsatellite stable) tumors were DDRD-positive. Gene mutations associated with the MSS DDRD positive group included ATM, ATR, BRCA1/2 and other components of the Fanconi Anemia(FA)/BRCA pathway (P < 0.001 ). Conclusions: The DDRD assay is detected in patients with DNA repair deficiencies, particularly MSI or mutations in components of the FA/BRCA pathway. As this molecular subgroup is defined by an innate immune response and activation of immune checkpoint genes such as PD-L1, we hypothesize that DDRD positive CRC patients may benefit from therapies that specifically target immune biology.
Use of immunotherapy (IO) supplied free of charge to cancer patients.
Authors: Rajiv Agarwal, Andrew S. Epstein, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2018)

e18914 Background: IO has increased both hope and uncertainty for patients (pts) with cancer. Many pts with off-label indications not qualifying for trials have received IO from the manufacturer free of charge (“compassionate use” or “free drug”). We describe the first data on this utilization pattern of IO at Memorial Sloan Kettering Cancer Center (MSK). Methods: Pharmacy dispensing logs from March 2017 to January 2018 were reviewed to identify pts who received off-label ipilimumab, nivolumab, or pembrolizumab at MSK’s main outpatient clinic and in-patient hospital. Confirmation of use of “free drug” was achieved through review of clinical documentation. Descriptive analysis was performed to characterize IO administration among cancer type and its use relative to the end of life. Results: Outpatient: a total of 173 pts: median age 62 (range 22-92); 72 women and 101 men received 758 doses of off-label IO (68 ipilimumab, 280 nivolumab, 410 pembrolizumab). 170/173 (98%) of pts had metastatic, locally advanced, or recurrent disease; 3 melanoma pts received adjuvant off-label IO. Pt distribution of use across cancer type: gastrointestinal (101), neuro-oncology (22), sarcoma (18), thoracic (13), gynecologic (11), melanoma (5), and merkel cell carcinoma (3). Of 65 known pt deaths, 15 received off-label IO in last 30 days of life and 46 received off-label IO in last 90 days of life. Inpatient use (limited to pts medically unable to receive treatment as an outpatient): a total of 13 pts: median age 56 (range 22-78); 7 women and 6 men received 25 doses of off-label IO (1 ipilimumab, 9 nivolumab, 15 pembrolizumab). Pt cancer type: genitourinary (4), neuro-oncology (2), thyroid (2), breast (1), lymphoma (1), sarcoma (1), thoracic (1), and unknown primary (1). None of these 13 pts were alive and progression free at 3 months after starting IO. Of 10 known pt deaths, 8 received off-label IO in last 30 days of life. Conclusions: With growing expectations for potential benefit, a substantial number of cancer pts are receiving off-label IO free of charge. To further inform our clinical practice, ongoing analyses will examine the safety and efficacy, healthcare-associated costs, and relationship to key end-of-life outcomes of off-label IO.
TCT-148 An international analyses of 122,610 NSTEMI patients with 5 year outcomes: assessing the influence of age and comorbidities on invasively vs medically managed patients between 2004 and 2014.
Authors: Majd Protty, Karam Al-zuhairi, None Tim Kinnaird, Mamas Mamas, Christian Torp-Pedersen, Dave Smith, Philip Freeman
Journal: Journal of the American College of Cardiology (2018)
Factors predicting learning curve, morbidity, mortality, and outcomes: A prospective phase III study of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancy—First Indian study.
Authors: S.P. Somashekhar, Ramya Yethadka, Ashwin K Rajgopal, Amit Rauthan, Shabber Zaveri, Vijay Ahuja, Poonam Patil, Nithya Ramadurai, Rohit C Kumar
Journal: Journal of Clinical Oncology (2018)

e17512 Background: The risk of morbidity associated with CRS & HIPEC is substantial enough to make any surgeon think twice before adopting it. Knowing the factors that will predict morbidity would help us in deciding which patients to push forward for HIPEC after CRS.This study is an attempt to find such factors that predict morbidity. Methods: Patients diagnosed of peritoneal surface malignancy from ovary, colorectal, appendicular, stomach, mesothelioma and other rare variety were included in the study. The study period was from March 2012 to December 2017. After cytoreductive surgery HIPEC was done with Performer HT (RanD) machine. All data prospectively entered in the HIPEC registry was analyzed with main focus on morbidity and factors predicting morbidity . Results: Of the 163 cases, primary organ of origin were ovary, colorectal, stomach, mesothelioma and others ( 110,27,8,14,4) respectively. 20 were upfront, 94 interval and 49 recurrent cases. Mean duration of surgery was 9.5hours, blood loss 1250ml and PCI 17. Total , upper quadrant , pelvic, peritonectomy, glissons capsulectomy, mesenteric stripping was done in 42.5%,68.1%,69.3%,14.7% & 4.3% respectively. Multivisceral ,diaphragmatic & bowel resection was done in 20.9%,40.5% and 57.5%. More than one anastomosis was done in 13.4%. 44.7%were extubated on table, 14.7%required prolonged ventilation, mean ICU stay 2.5 days. G3-G5 morbidity was noted in 40%, major being surgical 30%, hematological 20%, electrolyte imbalance 19%. Performance status, mean PCI > 14, duration of surgery > 10 hours, multivisceral resection, total peritonectomy, upper quadrant peritonectomy , more than one anastomosis were found to be significant factors predicting morbidity. The learning curve to reach technical proficiency in CRS + HIPEC is about 60 cases for a center with high volume cases . Conclusions: Analysing our journey of CRS & HIPEC we would want to tell that doing HIPEC for patients with above mentioned risk factors would be double edged sword and so one should weigh the benefits against morbidity when considering such patients for CRS & HIPEC.
Landscape of somatic mutations in different subtypes: Advanced breast cancer with circulating tumour DNA analysis.
Authors: Zongbi Yi, Fei Ma, Yanfang Guan, Fang Li Yuan, Xiaoying Sun, Xiuwen Guan, Chunxiao Li, Xin Yi, Haili Qian, Binghe Xu
Journal: Journal of Clinical Oncology (2017)

e23039 Background: It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of gene expression. Yet the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely undetermined. Methods: Overall, 100 blood samples were obtained from 100 advanced female breast cancer patients who underwent therapy at Cancer Hospital, Chinese Academy of Medical Sciences from March 2015 to September 2016. Mutations in 1021 tumor-related genes in ctDNA was assayed by gene-panel target-capture next-generation sequencing. Results: Somatic genomic alterations in ctDNA including copy number variants and point mutations were identified in 96 of 100 patients (96.0%). The number of somatic mutations varied markedly between individual patients (mean 2.9, range1-31). No difference was found between four subtypes for the number of somatic mutations. However, the mean number of somatic mutations was higher in age at 40-50 year than patients over age 60 ( p= 8.46 vs 3.88; p= 0.01). Results from multivariate analyses showed that the number of somatic mutations was increased with the number of endocrine therapy line ( p= 0.007). TP53 and PIK3CA were two most frequently mutated genes detected in ctDNA of 100 patients which were recurrently detected in 43 (43.0%) and 32 (32.0%) patients, respectively. ESR1/PIK3CA were more prevalent in HR+ cancers ( p= 0.007, 0.025 respectively). NOTCH1 are more frequently detected in HER2- group than in HER2+ patients (15.63% vs 2.94%; p= 0.033). In multiple logistic regression analysis indicated that pathological grade, tumour size at diagnosis and PR statue were positive associated with PIK3CA mutations. Multiple regression analysis also revealed that ki-67, metastatic at diagnosis, number of metastatic sites, number of endocrine line were associated with ESR1 mutations. Conclusions: The results revealed that different subtypes ABC have their own genetic alterations features. Certain gene mutations may be related to clinical treatment especially endocrine therapy.
Do elderly and young patients derive similar relative survival benefits from novel oncology drugs? A systematic review and meta-analysis.
Authors: Vanessa Sarah Arciero, Sierra Cheng, Erica McDonald, Mahin Iqbal Qureshi, Ronak Saluja, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2017)

10029 Background: Elderly patients are commonly believed to derive less benefit from cancer drugs, even if they fulfil clinical trial eligibility. We aim to examine if novel oncology drugs provide differential treatment outcomes for elderly and young patients on clinical trials. Methods: A systematic review of randomized control trials (RCTs) cited for clinical efficacy evidence in novel oncology drug approvals by the Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and 2015 was conducted. Studies reporting age-based subgroup analyses for overall or progression free survival (OS/PFS), were considered. Independent reviewers extracted survival hazard ratios (HRs) and confidence intervals (CIs) for age-based subgroups. Meta-analyses based on an inverse variance random effects model were performed to examine patient subgroups &lt; 65 and ≥ 65 years separately, and pooled HRs were compared to examine if differences in relative survival benefits existed between patient subgroups. Sensitivity analyses were conducted specific to cancer type, primary endpoint, and the type of systemic treatment. Results: Eighty-five RCTs, including 55,512 patients, reported age-based survival outcomes and were included. One study reported age-based toxicity and no studies age-based quality of life results. Pooled HRs [95% CIs] for patients &lt; 65 and ≥ 65 years were 0.60 [0.56-0.65] and 0.66 [0.61-0.72], respectively with no difference between the two subgroups ( P= 0.08). All sensitivity analyses revealed similar results. Conclusions: Our results suggest that elderly and young patients derive similar relative survival benefits from novel oncology drugs. In settings where there is no other direct high-level evidence of elderly patients deriving less benefit than younger patients, it is reasonable to consider offering novel oncology drugs to elderly patients who fulfil trial eligibility. There is, however, a need to report age-based toxicity and quality of life results to support patient discussions regarding the balance of treatment benefit and harm, to encourage informed individualized decision-making.