tbuckley/cabot-search huggingface dataset:
Association of chemotherapy induced neutropenia at 1-month mark (CIN-1-month) and overall survival in patients receiving TAS-102 for refractory metastatic colorectal cancer: A Cohort study.
Authors: Pashtoon Murtaza Kasi, Daisuke Kotani, Michael Cecchini, Kohei Shitara, Atsushi Ohtsu, Ramesh K. Ramanathan, Howard S. Hochster, Axel Grothey, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2016)

e15124 Background: TAS-102 (tri-fluoro-thymidine and tipiracil hydrochloride; a novel combination oral nucleoside anti-tumour agent) was recently approved for patients with refractory metastatic colon cancer (mCRC). Internal review of data at a single-institution showed a trend towards better overall survival (OS) for patients who had chemotherapy-induced neutropenia after one cycle (one month) of therapy (CIN-1-month). To explore this finding further, a cohort study was designed based on outcome data from 3 centers in United States and 1 from Japan. Methods: CIN-1-month after starting TAS-102 was defined by the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 as a neutrophil count decrease of ≥ grade 2 (absolute neutrophil count < 1500/mm3). Patient demographics and clinical characteristics were compared between patients with CIN-1-month (exposed) versus those who did not have CIN-1-month (unexposed); with the median progression-free survival (PFS) and OS were calculated using the Kaplan-Meier method, and differences evaluated using the Log-rank test. Results: Our cohort study had a total of 149 patients with data regarding their neutrophil assessment at 1 month mark. Patients who developed ≥ grade 2 CIN-1-month had a both longer PFS (median 3.0 months versus 2.4 months; Log-rank P-value = 0.01), as well as OS (14.0 versus 5.6 months; Log-rank P-value < 0.0001). Only CIN-1-month (adjusted HR: 0.21 (95% CI: 0.11-0.38) and higher baseline CEA levels (adjusted HR: 2.00 (95% CI: 1.22-3.35) were noted to be independent predictors of OS. Furthermore, neutropenia at 1-month mark was noted to be a statistically significantly predictor of OS over a wide range of cutoffs. Conclusions: Our observations are hypothesis generating. Neutropenia after starting TAS-102 was associated with better prognosis in patients with refractory mCRC. One can postulate that the dosage of TAS-102 potentially may need to be increased to achieve better outcomes in patients not experiencing any neutropenia. Further pharmacologic investigations should help elucidate these issues.
Clinical validation of an ultra-deep next generation DNA sequencing approach for the detection of bladder cancer in the urine.
Authors: Jason Ablat, Theresa M. Koppie, Trevor Levin, Carly King, Kevin Phillips, Martha Evans-, James E. Korkola, Peter C. Black
Journal: Journal of Clinical Oncology (2018)

e16515 Background: Currently available bladder cancer (BCa) urine tests suffer from poor sensitivity, specificity and limited insight on disease classification. We have developed an assay to identify bladder tumor associated mutations in urine using broad and ultra-deep next generation DNA sequencing of over 100,000 genomic loci. In a cohort of patients from a variety of urologic practice settings, we aimed to describe the sensitivity and specificity of this assay in the detection of BCa. Methods: Urine samples and clinical data for 114 patients were collected from three outpatient urology practices and two academic urology centers. Of the 114 patients, 48 patients had active BCa, and 66 did not. Tumor grade distribution was 33 high grade, 13 low grade, and 2 unknown. Stage distribution among the 48 BCa patients was Ta (n = 19), TIS (n = 1), T1 (n = 5), > T2 (n = 20), Tx (n = 3). Of the 66 patients without BCa, most had GU diagnoses and previous cancer histories (non-BCa), including BPH, hematuria, urinary tract symptoms, kidney stones and prostatitis. Twenty patients had previous or concurrent cancer diagnoses (non-BCa). DNA was extracted and sequenced on a HiSeq 2500. Sequencing data was run through a previously validated algorithm, which classified samples as positive or negative. Results: In this patient cohort, our assay achieved a sensitivity of 93%, specificity of 89%, and an incidence adjusted negative predictive value of 99% for detection of BCa. Interestingly, false positives were most common in patients with concurrent or previous cancer histories. Mutational profiles predicted tumor grade with 80% accuracy. In a select cohort of longitudinally tracked patients, 9 of whom ultimately developed BCa, our test demonstrated a 3-9 month lead time over cystoscopy in 5 patients with minimally residual or occult disease. Conclusions: We describe the clinical validation of a urine-based, next generation DNA sequencing assay in the detection of bladder BCa. Our data further demonstrate potential utility in molecular grading, as well as the prediction of future BCa recurrence. Multiple retrospective and prospective studies are underway to further validate clinical validity and utility in other GU cancers.
Influence of KRAS exon 2 mutation variants as well as NRAS- and BRAF-mutations on outcome of patients with metastatic colorectal cancer (mCRC) receiving combination chemotherapy with or without bevacizumab.
Authors: Dominik Paul Modest, Ingrid Ricard, Volker Heinemann, Susanna Hegewisch-Becker, Wolff H. Schmiegel, Rainer Porschen, Sebastian Stintzing, Ullrich Graeven, Dirk Arnold, Ludwig Fischer Von Weikersthal, Clemens Giessen-Jung, Arndt Stahler, Hans-Joachim Schmoll, Andreas Jung, Thomas Kirchner, Andrea Tannapfel, Anke C. Reinacher-Schick
Journal: Journal of Clinical Oncology (2016)

3551 Background: To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients (pts.) with mCRC receiving first-line combination chemotherapy with or without bevacizumab. Methods: 1239 pts. from 5 randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was retrospectively evaluated by Kaplan-Meier method, log rank tests and cox regression. Results: In 664 tumors no mutation was detected, 462 tumors were diagnosed with KRAS mutation, 39 tumors with NRAS mutation and 74 tumors with BRAF mutation. This categorization was associated with significant differences in progression-free (PFS) (P<0.01) and overall survival (OS) (P<0.01). Furthermore, KRAS exon 2 mutation variants were associated with heterogeneous OS (p=0.01). In particular G12D and G12V subtypes that occur with high frequency among KRAS exon 2 variants were associated with rather favourable OS, whereas other less frequent subtypes (G12C, G13D, G12S) correlated with less favourable outcome. Outcome data are summarized in table 1. Multivariate analyses will be presented at the meeting. Conclusions: In this retrospective evaluation, KRAS exon 2 mutation variants G12D and G12V were associated with rather favourable OS while KRAS G12C, G12S and G13D mutant tumors were associated with less favourable OS. Expectedly, any mutations in KRAS and NRAS were associated with inferior OS of mCRC patients compared to patients with tumors not being mutated in any of these genes. Subgroups Progression-free survival months (95% CI) Overall survival months (95% CI) No mutation (n=664) 10.3 (9.7-10.8) 26.9 (25.2-28.5) KRAS mutation (n=462) 9.5 (8.9-10.1) 21.0 (18.5-23.5) G12D (n=152) 10.5 (9.0-11.9) 25.2 (22.2-28.2) G12V (n=92) 9.5 (8.2-10.8) 23.5 (16.7-30.3) G13D (n=71) 8.8 (7.6-10.0) 17.6 (13.3-21.9) G12S (n=34) 9.3 (7.1-11.4) 19.1 (15.2-23.0) G12C (n=28) 10.1 (6.4-13.8) 16.8 (15.6-18.0) G12A (n=22) 9.8 (7.7-11.8) 24.0 (16.4-31.5) NRAS mutation (n=39) 9.5 (8.3-10.7) 21.3 (14.9-27.8) BRAF mutation (n=74) 7.4 (6.2-8.5) 11.7 (9.7-13.6)
Risk of hematological toxicities in patients with advanced breast cancer treated with everolimus: A meta-analysis of phase 3 randomized controlled trials.
Authors: Anita Sultan, Kyaw Zin Thein, Sriman Swarup, Ruth D’Cunha, Fred L. Hardwicke, Catherine Jones, Sanjay Awasthi
Journal: Journal of Clinical Oncology (2018)

e13087 Background: Aberrant signaling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway was shown to involve in endocrine and trastuzumab resistance in breast cancer. Everolimus (E) is an oral mTOR inhibitor and showed clinical benefit in these population with noteworthy safety concerns. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of hematological toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2018 were queried. Phase 3 RCTs that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase 3 RCTs with a total of 1992 patients with advanced breast cancer were eligible for analysis. Studies compared E+ paclitaxel(P) + herceptin(H) vs P+H, E+ exemestane(Ex) vs Ex, E+ vinorelbine(V)+ H vs V+H. The RR of all-grade side effects were as follows: anemia, 2.07 (95% CI: 1.45-2.96, p < 0.001); neutropenia, 1.30 (95% CI: 0.97-1.73, p = 0.07); leukopenia, 1.27 (95% CI: 1.06-1.52, p = 0.009); thrombocytopenia, 6.19 (95% CI: 3.25-11.77, p < 0.001); and febrile neutropenia (FN), 4.27 (95% CI: 2.33-7.85, p < 0.001). The RR of high-grade side effects were as follows: anemia, 3.55 (95% CI: 2.33-5.42, p < 0.001); neutropenia, 1.36 (95% CI: 0.92-2.00, p = 0.11); leukopenia, 1.31 (95% CI: 1.04-1.63, p = 0.01); thrombocytopenia, 5.49 (95% CI: 1.82-16.54, p = 0.002); and FN, 4.33 (95% CI: 2.30-8.18, p < 0.001). Conclusions: Our meta-analysis demonstrated that patients on everolimus experienced a significant increase in all grades of anemia, leukopenia and thrombocytopenia. Everolimus-based regimens also contributed to a significant increase in all grades of FN with a relative risk of 4.33 for grade 3 and 4 FN. FN remains a major cause of morbidity, mortality and drug dosing inconsistencies among patients with cancer and proper supportive care is required.
A unique MRI-based radiomic signature predicts hypermutated glioma genotype.
Authors: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya-Matsuoka, Kristin Alfaro-Munoz, Nabil Elshafeey, Nancy Attia Ahmed El Shafei, Pascal Zinn, John Frederick De Groot, Rivka R. Colen
Journal: Journal of Clinical Oncology (2018)

2022 Background: Hypermutation is defined as the excessive accumulation of DNA mutation in cancer cells and is reported in several forms of cancer including low and high grade gliomas. Incidence of hypermutated genotype was associated with failure of DNA repair machinery such as mismatch repair (MMR) or disruption of DNA fidelity due to mutations in DNA polymerase genes (POLE and POLD).Hypermutated gliomas (mainly glioblastoma (GB)) are largely seen at recurrence with associated resistance to temozolomide therapy. Herein, we sought to identify an imaging-based signature for hypermutated gliomas using a radiomics-based approach. Methods: In this IRB-approved retrospective study, we analyzed a total of 101 patients with primary gliomas from the University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS) platforms (T200 and Foundation 1) were used to determine the Mutation burden status in post-biopsy (stereotactic/excisional). Patients were dichotomized based on their mutation burden; 77 hypomutated ( < 30 mutations) and 24 hypermutated ( > = 30 mutations or < 30 with MMR gene or POLE/POLD gene mutations). Radiomic analysis was performed on the conventional MR images (FLAIR and T1 post-contrast) obtained prior to tumor tissue surgical sampling; and a total of 2480 rotation-invariant radiomic features were extracted using: (i) the first-order histogram and (ii) grey level co-occurrence matrix. The Maximum Relevance Minimum Redundancy technique was used to select the most relevant radiomic features. ROC analysis and leave-one-out cross-validation (LOOCV) were used to assess the performance of the Support Vector Machine (SVM) classifier as and AUC, Sensitivity, Specificity, and p-value were obtained. Results: We found 100 radiomic features that can discriminate between hypermutated versus hypomutated gliomas, AUC 96.3% (CI: 90.2%-98.9%), Sensitivity 100%, Specificity 95%, p-value = 3.769e-6. Conclusions: Hypermutated gliomas has a unique radiomic quantitative signature that can be used to predict mutation burden regardless of tumor grade or histopathology.
Using GeneReader NGS system to identify mutations in BRCA 1/2 genes in matched FFPE and blood samples.
Authors: Vishal Kapoor, Nathan Dennison, Adam Burke, Alexander Burton, Richard Dyson, Lea Thoegerson, Dietrich Lueerssen, Bodil Oester, Andrew Robb, Leif Schauser, Kyriakos Ttavas, Juergen Lauber, Simon Hughes
Journal: Journal of Clinical Oncology (2018)

e17536 Background: Supported by strong clinical evidence, testing for germline mutations in BRCA1 and BRCA2 in suspected familial breast cancer cases has gradually become common practice, especially in countries like the US. However, while less widely known and much harder to detect, somatic aberrations in these genes also play a critical role in cancer evolution, outcome and management. Methods: In order to enable full investigation of mutations in BRCA 1/2 genes, we have developed the GeneRead QIAact BRCA Advanced UMI Panel that is compatible with a range of clinical samples. To provide a fully integrated solution enabling any laboratory to adopt the test, we used the GeneReader NGS System, combining wet bench sample processing, target sequence enrichment, and optimized bioinformatics for BRCA 1/2 gene analysis. The performance of this assay has been demonstrated by running a set of matched FFPE and Blood samples harbouring BRCA 1/2 mutations. Results: The assay, which was designed to cover the entire coding regions of both genes +/- 20bp flanking intronic sequences, in combination with a specifically designed bioinformatics pipeline can detect both single nucleotide variants (SNVs) as well as Insertion/Deletions (InDels) in challenging real-world patient samples from both breast and ovarian tumour types. For sequencing, samples were pooled and run in a 8-plex (FFPE) or 12-plex (Blood) configuration per flowcell, which yielded sequencing results with an average coverage of ≥300x unique molecular index (UMI) across all target regions. For FFPE and blood samples > 95% and > 99% of the target regions showed sufficient uniform amplification and sequencing coverage, to detect mutant alleles at a minimum 5% and 50% allele frequency, respectively. Mutational status was correctly confirmed in all matched samples, resulting in 100% concordance with an alternative testing technology. Conclusions: These results support the use of the GeneReader NGS System to detect BRCA 1/2 mutations relevant to both germline and somatic cancers. This fully integrated workflow together with an optimized BRCA pipeline enables an easy implementation of the test by any molecular cancer research laboratory.
Peter George Reed Dawe
Authors: John Dawe
Journal: BMJ (2018)

Peter George Reed Dawe was born in Bangalore, India, where his father was serving in the Indian Army. On his father’s retirement, the family moved to Tauranga, New Zealand. Peter Dawe attended King’s School in Auckland and Wanganui Collegiate School before studying to become a doctor at Otago University in Dunedin. He was a keen oarsman, at both high school and university, and he represented Otago University from 1950 to 1953, as captain of the …
P01.159 elderly glioblastoma 5-ALA guided resection
Authors: P Oppido, C Carapella, A Pace, V Villani
Journal: Neuro-Oncology (2018)

The prognosis of patients with glioblastoma (GBM) aged 65 years or older is universally poor: their median survival ranges from 4 to 9 months. The main reason is that older patients are often treated more conservatively than younger; this less aggressive treatment is a result of reluctance to offer aggressive treatment for fear of postoperative complications. Several series report that the 5-ALA fluorescence-guided resection increases the extension of tumour removal, improving survival. The aim of this study is to evaluate the impact of the 5-ALA on outcome in elderly GBM. 44 patients age ranged from 65 to 83 years (median 71 yrs.), affected by GBM (38 newly diagnosed and 6 recurrent tumours) underwent preoperative and early postoperative MRI, showing contrast enhancing lesions. All patients with KPS>70 and resectable lesions were selected for the 5-ALA fluorescence-guided microsurgical removal. Only 22 patients (all MGMT positive) received, as first line treatment, focal RT plus concomitant daily temozolomide (TMZ), followed by adjuvant chemotherapy with TMZ; other 16 patients received RT fractionated focal irradiation; six patients received temozolomide only due to neurological disabilities. In this population second and in some cases third line treatments were utilized in recurrent cases. The relevance of co-morbidities (CM) in this clinical setting was evaluated in all patients utilizing a slightly modified Cumulative Illness Rating Scale (CIRS). All patients had a median follow-up of 15 months (6–82). in more than 90% of patients tumour tissue yielded red 5-ALA-fluorescence with different intensity; mainly in recurrent GBM, the 5-ALA-fluorescence allowed a better definition of active tumour, with a clear border. Postoperative KPS improved in the majority of patients. In the present experience the procedure did not determine any relevant additional neurological deficit, nor CM. Early postoperative MRI confirmed gross total resection without contrast enhancement in 80 % of patients. In newly diagnosed GBM patients median OS was 18 months, with a rate of survival at 2 years of 35%. Univariate analysis of the whole cohort showed that age greater than 75 years, intermediate or high CIRS-CI, and the presence of >3 comorbidities were associated with shorter survival. In multivariate analysis the predictive role on OS for ages greater than 75 years, intermediate and high CIRS-CI was confirmed. Elderly GBM patients are suitable for the 5-ALA-removal, improving the probability of achieving maximal tumour resection, when feasible. It improves tumour detection and allows extended resection of GBM. This surgery improves survival in elderly patients, without any further additive neurological deficit. Furthermore, the evaluation of CM should drive the therapeutic decisions in elderly GBM.
Concomitant use of antiacids in patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib therapy.
Authors: Razwan Abd Razak, Victoria Kunene, Yuk Ting Ma
Journal: Journal of Clinical Oncology (2016)

e14103 Background: There are reports suggesting that concomitant use of tyrosine kinase inhibitors (TKIs) and gastric acid suppression reduces overall survival. This single centre study is looking at the impact of acid suppression on survival in patients with inoperable hepatocellular carcinoma (HCC) receiving sorafenib therapy. Methods: Retrospective study of patients with inoperable HCC receiving sorafenib treated at Queen Elizabeth hospital Birmingham between January 2006 and April 2015. Data was collected from electronic patient archives. Primary objective was progression free survival (PFS) and secondary objective was overall survival (OS). Results: One hundred and ninety seven (197) patients were identified and 182 patients were included in the analysis. 77 patients received concomitant acid suppression therapy with PPIs (omeprazole or lansoprazole) or ranitidine and 105 did not receive acid suppression. Demographics: Median age was 66 years (range 19-85 years). There were 149 males and 33 females. Child-Pugh scoring in no acid suppression group was: A (31.3%), B (10.4%) C (0.5%) vs A (39.7%), B( 17.6%) and C (0.5%)in acid suppression group. Median PFS was 7.6 months (95% CI: 5.9-9.2 months),vs 1.9 months (95% CI: 1.4-2.3 months, p < 0.0001) in favour of the no acid suppression group. Median OS was 8.7 months (95% CI: 7.3-10.2 months) vs of 5.7 months (95% CI: 4.5-7.0 months) in favour of no acid suppression. (p< 0.0001). Further analysis on patients with no acid suppression group with well-preserved liver functions showed a median OS of 10.9 months (95% CI: 7.2-14.6 months, p< 0.0001). Conclusions: Although this is a retrospective study with small numbers, the results show better disease control and survival in patients with no acid suppression group compared to continuous acid suppression group. Prospective multicentre studies are required to analyse the impact of antacids in patients receiving sorafenib.
Effect of pharmacogenetic-based selection of first-line chemotherapy on response rate and R0 surgery in metastatic CRC patients.
Authors: Albert Abad, Jose M Vieitez, Vicente Alonso, Pilar Garcia Alfonso, Jose Luis Manzano, Bartomeu Massuti, Manuel Benavides, Alfredo Carrato, Jordi Remon, Javier Gallego Plazas, Veronica Conde, Cristina Gravalos Castro, Manuel Valladares, Mariano Provencio, Ramon Salazar, Manuel Gallen, Fernando Rivera, Javier Sastre, Enrique Aranda, Eva Martinez-Balibrea
Journal: Journal of Clinical Oncology (2016)

3530 Background: In a previous work we demonstrated that pts harboringTYMS-3’UTR+6 bp/+6 bp and ERCC1-118 C/T or C/C genotypes may better receive capecitabine instead of 5FU in an OXA-based first-line treatment. The objective of the present work was to demonstrate that prospective selection of first-line treatment according to these genetic variants could improve the outcome of metastatic CRC pts. Methods: We designed a phase II comparative clinical trial (SETICC, SElected Treatment In Colorectal Cancer; NCT01071655) in which 195 CRC pts with initially unresectable metastasis were randomized 2:1 to receive XELOX plus bevacizumab in a control arm or, based on our previous results, chemotherapy according to their TYMS-3’UTR and ERCC1-118 genotypes plus bevacizumab in in the experimental arm (table 1). Results: In 161 evaluable pts the overall best objective response (Complete +Partial response) was 47% (95 CI: 33.9-61.1) in the control arm and 65% (95 CI: 55.2-73.9) in the experimental arm (p = 0.04). In the Per Protocol (PP) population (N = 180), 20% (N = 37) were converted to resectable, 16 pts in the control arm and 21 in the experimental arm. The R0 surgery was 43% (N = 7) in the control arm and 86% (N = 18) in the experimental arm (p = 0.018). Median PFS (10 months; 95 CI: 8.5-11.6 vs 9.4 months; 95% CI: 6.7-12.1 months) and overall survival (19.3 months; 95% CI: 15.5-23.1 vs. 16.5 months; 95% CI: 13.5-19.5.) was better for pts in the experimental arm (p:NS). Conclusions: This study shows for the first time that prospective selection of first-line treatment according to TYMS-3’UTR and ERCC1-118 polymorphisms significantly improves the ORR and R0 liver metastasis resection of CRC pts with non-initially resectable liver metastases. This approach should be taken into account in this kind of pts in order to increase the probability of R0 surgery success rate. Clinical trial information: NCT01071655.ITT Treatments’ assignment according to genotypes (Martinez-Balibrea et al, Eur J Cancer 2008). Genotypes Treatment TYMS-3’UTR ERCC1-118 XELOX +6bp/+6bp T/T XELIRI +6bp/+6bp C/T or C/C FUOX +6bp/-6bp or -6bp/-6bp T/T FUIRI +6bp/-6bp or -6bp/-6bp C/T or C/C
Assessing the Effects of Psychotherapy
Authors: R Sandell
Journal: Psychotherapy and Psychosomatics (1987)

The use of the difference between pre- and posttherapy status as an estimate of change and of the regression transformation as an adjustment for initial status variation is discussed in reliability and scaling terms. Also, the quantitative view of psychotherapeutic change implied by difference scores is set in contrast to a qualitative view of change as inner (re)structuring. Further, it is argued that psychotherapeutic goals should be conceived in terms of metapsychology rather than as the acquisition of desirable surface traits. Finally, the therapeutic and research consequences of testing and interviewing are compared.