tbuckley/cabot-search huggingface dataset:
Use of BLOCker sequencing (blocking oligonucleotide cycle sequencing) after ice COLD-PCR for detection of K-RAS mutations.
Authors: G. Wu, B. J. Legendre, J. Scott, S. Peterson, K. Echtenkamp, P. Eastlake, K. Richardson
Journal: Journal of Clinical Oncology (2011)

e13547 Background: The epidermal growth factor receptor (EGFR) antagonists, cetuximab and panitumumab, can be effective in colorectal cancer treatment. However, activating K-RAS mutations in codons 12 and 13 are associated with a poor EGFR antagonist response. As these mutations are seen in ~40% of CRC, high sensitivity assays for detection of these mutations will aid in patient treatment and disease monitoring. Methods: Ice COLD-PCR (Improved and Complete Enrichment CO-amplification at Lower Denaturation temperature PCR) uses a reference sequence oligonucleotide (RS-oligo) to enhance detection of all low level mutations during PCR. The RS-oligo is complementary to one wild-type strand, so only one wild-type strand but both mutant DNA strands are amplified. This results in linear WT sequence amplification but exponential mutant sequence amplification. Ice COLD-PCR methods used in these studies can detect 0.05 – 0.01% K-RAS mutant DNA. For low level mutation confirmation we added BLOCker-oligos to sequencing reactions to block wild-type and allow mutant DNA sequencing (BLOCker-Sequencing). For blocking to occur, additional hybridization and denaturing steps are added to the cycle sequencing program. This insures that the BLOCker-oligo:WT DNA remains intact but the BLOCker-oligo:Mutant DNA is denatured. A sequencing primer overlapping the BLOCker-oligo 5’ end anneals to the mutant strand that is subsequently extended. Results: BLOCker sequencing was used to confirm presence or absence of low level K-RAS mutations after Ice COLD-PCR. When a K-RAS mutation is present at 0.05%-0.01%, the mutant peak may appear as baseline noise. When BLOCker Sequencing of these samples is performed, the presence of a mutation at this low level is enhanced in the BLOCker Sequencing electropherogram. There is no enhancement if the sample does not contain a mutation. Conclusions: Following Ice COLD-PCR amplification, BLOCker sequencing was able to confirm the presence or absence of very low levels of K-RAS mutations in the starting samples. BLOCker Sequencing is a novel method to confirm low level mutation presence when there is a uncertain DNA sequencing electropherogram result following Sanger sequencing.
Peritoneal carcinomatosis from colorectal cancer: Not a lost cause.
Authors: Y. E. Kier, A. S. Aulakh, M. Furman, L. A. Lambert
Journal: Journal of Clinical Oncology (2011)

592 Background: Patients who present with peritoneal carcinomatosis (PC) from colorectal cancer are considered terminal, with an expected median survival of 6-8 months. Therapy is often considered palliative and aggressive treatments are nihilistically ignored. This study investigates the clinicopathologic characteristics and clinical outcomes of CRC patients who present with PC. Methods: This is a retrospective review of all patients who presented with stage IV CRC from 1/2000-12/2008 to a single, tertiary care institution. Patients with PC at the time of presentation were identified. Demographic data, clinicopathologic characteristics, treatment and survival data were collected and analyzed. Results: 591 patients who presented with stage IV colorectal cancer were identified. Complete data was available on 216 patients. PC was confirmed in 106 patients (17.9%). PC was the only site of metastatic disease in 40 patients (6.7%). Compared with patients who did not have PC, patients with PC had significantly more right-sided primary tumors (28% vs 47%) and more mucinous tumors (7% vs 22%). The median overall survival for patients with isolated PC was 11.1 months as compared with 9.1 months for PC patients with extraperitoneal metastases (p = 0.5). Conclusions: Patients with right-sided and mucinous primary colon cancers are at increased risk of developing PC. Despite a lack of aggressive therapy, patients with isolated PC achieved a 11 month median survival. Treating PC patients and patients at-risk for PC with optimal oncologic therapy, including cytoreduction and intraperitoneal chemotherapy, will improve survival and should be considered early in the management of PC patients. No significant financial relationships to disclose.
A review of the quality of evidence in oncology studies.
Authors: K. J. Hogan, S. H. Karbowicz, L. M. Nishida, H. I. Sherman
Journal: Journal of Clinical Oncology (2011)

e16635 Background: Evaluating the quality of evidence in clinical trials helps to identify flaws which may affect the reliability of study outcomes. Reliable evidence more accurately predicts the likelihood and extent of benefit of medications and their comparative effectiveness. Methods: A review of evidence was conducted for fourteen oncology medications approved by the FDA between 2006 and 2010. The review included a total of 31 clinical trials identified in the PubMed database and unpublished clinical trials identified in manufacturer dossiers and on the FDA website. Evidence was appraised by systematically evaluating study components defined in the CONSORT (Consolidated Standards of Reporting Trials) Statement guideline. Characteristics of the trials were catalogued along with any major flaws that have the potential to impact the reliability of the trial. A trial was considered reliable when there were no major flaws identified that could bias or confound the primary outcome. The analysis included the proportion of reliable studies, the incidence of major flaws in individual trials, and average flaws per study. Results: All 31 of the clinical trials reviewed had flaws which could impact the reliability of the reported outcome. Major flaws identified included use of an unvalidated surrogate endpoint (77% of trials), lack of blinding (74% of trials), lack of comparator (58% of trials), a high proportion of non-completers or missing data points (41% of trials), use of confounding medications (16% of trials), a relatively large differential loss between treatment groups (13% of trials), lack of an intent-to-treat analysis (10% of trials), and unbalanced baseline characteristics (3% of trials). The mean number of major flaws per trial was 2.9. Trial design accounted for 94% of trials appraised as unreliable, while flaws due to execution of the trial accounted for 6%. Conclusions: A review of evidence for a cross section of recently approved oncology medications shows that there is a great opportunity for improving the quality of oncology studies.
Efficacy and safety of weekly paclitaxel combined with cetuximab in the treatment of pretreated recurrent/metastatic head and neck cancer patients.
Authors: B. Jimenez, J. M. Trigo Perez, M. I. Saez Medina, C. Quero Blanco, B. Pajares, A. Rueda, E. Alba
Journal: Journal of Clinical Oncology (2011)

5594 Background: The addition of cetuximab to weekly paclitaxel have shown high efficacy in the first-line treatment of patients with recurrent /metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidate to platinum-based CT. Methods: We have retrospectively analyzed the efficacy of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who were not candidate to platinum-based CT or those who present disease progression after platinum schedules. Patients received weekly paclitaxel 80 mg/m2 and cetuximab 250 mg/m2 (initial dose of 400 mg/m2) till progression or unacceptable toxicity. Results: Twenty-one patients were included. Median age was 56 (43-72), ECOG PS (0/1/2): 6/10/5, 18 patients had received prior platinum-based treatment (9 patients were platinum-sensitive and 9 were platinum-refractory). With a median follow-up of 6.18 months (1.3-29.7), overall response rate (ORR) was 47.6% (95% IC 26.3-69%): 1 (4.7%) complete response and 9 (42.9%) partial responses. Median duration response was 10.23 months. There were no differences in response according to platinum sensitivity (55% sensitive vs. 45% refractory; P=0.74). Median progression free survival (PFS) and overall survival (OS) were 4.17 and 9.17 months, respectively. The main toxicity consisted of rash in 70% of patients (55% grade 2-3), with an association between rash severity and ORR (grades 0-1: 33% vs. grades 2-3: 55%; P=0.03) and a trend to better PFS and OS. Conclusions: Weekly paclitaxel in combination with cetuximab is a well tolerated and high active treatment in patients with R/M-SCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. The efficacy of this combination is apparently higher than the published data on single agent cetuximab in this setting.
Adjuvant chemotherapy for gastric cancer: Less drug, same efficacy.
Authors: T. Liu, W. Li, Y. Sun, K. Shen
Journal: Journal of Clinical Oncology (2011)

114 Background: Adjuvant chemotherapy is proved to improve survival in gastric cancer by meta-analyses. However, no evidence showed the best regimen. We conducted a retrospective analysis to compare triplets with doublets in the adjuvant setting. Methods: We collected data from January 2004 to December 2008 from patients performed radical surgery and adjuvant chemotherapy. Doublets were defined as 5-FU 750 mg/m 2 (d1- 5) or capecitabine 1,000 mg/m 2 (d1-14) plus cisplatin 60 mg/m 2 (d1) or oxaliplatin 130 mg/m 2 (d1), while triplets had epirubicin 50 mg/m 2 (d1) added. Chemotherapy was initiated within 6 weeks after surgery, repeated every three weeks and planned for 6 cycles. Patients were followed up in the outpatient clinic until death or April 30, 2010. Cox proportional-hazard model and chi-square test were used to test statistical difference. Results: A total of 316 patients (210 in doublets, 106 in triplets) had a median follow-up time of 47 months. 77 patients died at the end of follow-up (3-year survival of 67.4%).Two groups were well balanced except age (median age of 57 in doublets, 51 in triplets, p &lt; 0.001). All the patients tolerated well, with few grade 3/4 side effects (21.9% in doublets, 30.2% in triplets, p = 0.107). Two groups had similar disease-free survival (median DFS, 16 months vs. 23 months, p = 0.656) and overall survival (3-year survival rate, 59.6% vs. 64.8%, p = 0.293). Subgroup analysis showed the same benefit on survival between the two groups. Conclusions: Our study suggested doublets and triplets had the same efficacy as the adjuvant chemotherapy. Furthermore, doublets seem more cost-effective. [Table: see text] No significant financial relationships to disclose.
The impact of histological variants on bladder cancer survival: A population-based analysis.
Authors: Francisco Gelpi-Hammerschmidt, Dayron Rodriguez, Ilker Tinay, Christopher Brian Allard, Michael Blute, Adam S. Kibel, Steven Lee Chang, Quoc-Dien Trinh, Mark A Preston
Journal: Journal of Clinical Oncology (2016)

458 Background: We evaluated the clinical and prognostic impact of bladder cancer histologic variants (BCHV) using a large population-based cancer database. Methods: Using the Surveillance, Epidemiology, and End Results database (SEER), we identified bladder cancer patients from 2001-2012, and categorized them according to histological differentiation. 5 year disease-specific survival (DSS) was calculated using the Kaplan-Meier method. Cox proportional hazards regression model was used to predict association with disease-specific mortality (DSM). In addition, we fitted multivariate logistic regression models to predict the impact of histological variants on muscle-invasive status (MI), nodal involvement (NI), and metastatic disease (MD). Results: The cohort included 175,544 urothelial (96.3%) and 6,714 non-urothelial (3.7%) cancers. The latter were divided into: 2,382 squamous cell carcinoma, 1,648 adenocarcinoma, 888 small cell, 912 sarcomatoid, 292 signet-ring cell, 314 neuroendocrine and 278 micropapillary bladder tumors. Urothelial cancers overall had the best 5-year DSS. Of the non-urothelial variants, micropapillary and squamous had the best and worst DSS respectively (p &lt; 0.001). On multivariable analysis predicting DSM, micropapillary and squamous variants had the best and worst prognosis respectively (HR 0.79, p = 0.102 and HR 2.63, p &lt; 0.001), compared to urothelial tumors. On multivariable analysis predicting MI, NI, and MD: squamous (OR 22.76, p &lt; 0.001), micropapillary (OR 3.17, p &lt; 0.001) and adenocarcinoma (OR 4.14, p &lt; 0.001), had higher likelihood respectively, compared to urothelial tumors. Conclusions: Despite accounting for a minority of bladder cancers, BCHV are associated with worst outcomes. It is essential to recognize the potential implications of these variants when deciding treatment. Additional studies are warranted to better characterize the clinical impact of these variants.
Phase I study of vorinostat in combination with temozolomide in patients with malignant gliomas.
Authors: P. Y. Wen, V. K. Puduvalli, J. G. Kuhn, J. M. Reid, K. Lamborn, T. F. Cloughesy, S. M. Chang, J. Drappatz, W. K. A. Yung, M. R. Gilbert, H. I. Robins, F. S. Lieberman, A. B. Lassman, R. M. McGovern, S. Desideri, X. Ye, M. M. Ames, I. J. Espinoza-Delgado, S. A. Grossman, M. Prados
Journal: Journal of Clinical Oncology (2011)

2032 Background: Vorinostat (V) is an oral histone deacetylase inhibitor. In preclinical studies it inhibits growth of glioblastoma (GBM) lines and has additive activity when combined with temozolomide (TMZ) or radiotherapy (RT). Methods: The Adult Brain Tumor Consortium conducted a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG) who had received RT and had not progressed on TMZ, > 18 yrs old, KPS 60 or greater, adequate marrow reserve and organ function. Patients received 150-200 mg/m2 of TMZ on days (d) 1-5 every 28 d. V was administered either on d 1-14, or on d 1-7 and 15-22, every 28 d. Dose-limiting toxicities (DLT), were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. An additional 10 patients was added to the MTD dose. Results: To date, 59 patients have been enrolled (39 GBM; 16 AG; 4 others). Median age 51 yrs (25-81); median KPS 90 (60-100). The MTD of vorinostat is 300 mg/d on d 1-14 every 28 d in combination with TMZ 150mg/m2 for 5 d every 28 d. No DLTs were seen in 16 patients receiving this dose of V. TMZ pharmacokinetic data (PKs): (n=16) Cmax 5.2 (+/- 1.55) mcg/ml; AUC 20.1 (+/-4.66) mcg x hr/ml; t1/2 2.0 (+/-0.32)/hr]. Vorinostat PKs (n=16) (300mg dose level): Cmax 267 (+/-174)ng/ml; AUC0-8 603 (+/-197) ng x hr/ml]. The t1/2 for vorinostat and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Because the exposure of V was low on this schedule, an alternative schedule of V administered on days 1-7 and 15-22 with TMZ was examined. The MTD of V was 500mg/d with TMZ 150mg/m2 for 5 d every 28 d. The MTD of V was 400mg/d with TMZ 150mg/m2 for 5d in cycle 1 and 200mg m2/d for subsequent 5/28 d cycles. The most common DLTs were fatigue and thrombocytopenia. Conclusions: Vorinostat is well tolerated in combination with TMZ. Updated PK, efficacy and toxicity data will be presented. These results led to an ABTC and NCCTG phase II trial of vorinostat with RT and TMZ in newly-diagnosed GBM
Phase I study of neoadjuvant S-1 plus cisplatin with concurrent radiation for biliary tract cancer (KOBTC02).
Authors: Osamu Itano, Takuya Minagawa, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2016)

353 Background: Although surgery plays a key role in the curative treatment for biliary tract cancer (BTC), the prognosis is not satisfactory because of frequent postoperative recurrence. Multimodal treatment has been warranted in order to improve this situation. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of cisplatin as neoadjuvant chemoradiotherapy with S-1 and external beam radiation for BTC. Methods: Patients with resectable BTC at initial diagnosis were eligible for inclusion. The planned dosages of cisplatin (mg/m2)/S-1 (mg/m2/day) were as follows: 40/80 (level 0); 50/80 (level 2); 60/80 (level 3). S-1 was orally administered twice daily from day 1 to 14 and day 29 to 42. Cisplatin was administered intravenously over 2 hours in each dosage of level at day 1 and 29. Radiation was delivered as a total dose of 50.4 Gy (28 fractions to 1.8 Gy). Dose-limiting toxicity (DLT) was a delay factor of the schedule due to incomplete recovery. (Response rate (RR) was evaluated according to the RECIST version 1.0.). Results: Twelve patients were enrolled, and level 1 was chosen as the starting dose. One of six patients developed DLTs at level 1, and the dose was escalated to level 2. DLTs occurred in two of six patients at level 2. As the MTD were determined as over 60 mg/m2, the RD were confirmed as level 2 for a subsequent phase II study. Conclusions: We determined the MTD and RD of cisplatin with concurrent S-1 and external beam radiation as neoadjuvant chemoradiotherapy for resectable BTC. Although further clinical trials are warranted to evaluate efficacy, this new regimen is potentially expected to become a standard neoadjuvant treatment for resectable BTC. Clinical trial information: 000009028.
Oral and intravenous vinorelbine plus trastuzumab for 1st-line treatment of HER2-overexpressing metastatic breast cancer (MBC). A trial of the german AIO breast cancer group
Authors: D. Laessig, U. Vehling-Kaiser, H. D. Harich, A. Welt, B. Heinrich, R. Pihusch, C. Ziske, G. Deutsch, S. Hegewisch-Becker, V. Heinemann
Journal: Journal of Clinical Oncology (2008)

1061 Background: High activity of intravenous vinorelbine (VNR) plus trastuzumab (T) has been demonstrated in previous clinical trials performed in HER2-overexpressing MBC patients (pts). The present phase II study evaluates a new regimen investigating the combination of oral and intravenous vinorelbine plus trastuzumab. Methods: This phase II trial investigated HER2-overexpressing MBC pts (IHC 3+ or FISH+) who received VNR at an intravenous dose of 25mg/m2 on day 1 followed by oral VNR applied at a dose of 60mg/m2 on days 8 and 15 of a 3-week cycle. Trastuzumab was given at 3-week intervals with a starting dose of 8mg/kg on day 1 of the first cycle, and a maintenance dose of 6mg/kg in all subsequent cycles. Overall response rate was evaluated as a primary endpoint, while progression-free survival (PFS), overall survival (OS), and safety were analysed as secondary endpoints. Results: 42 pts were recruited. Median age was 60 years (range 34 - 75 years), and median baseline Karnofsky performance status was 100% (range 70–100%). 67% of pts were hormone receptor positive. A HER2 IHC score of 3+ was determined in 95% of pts, while 5% of pts had an IHC score of 2+, but were FISH positive. 27 pts (64%) had received previous (neo)-adjuvant therapy (21 anthracycline-based, 8 taxane-based). Visceral metastasis was evident in 69% of pts. A median of 8 cycles (range 1–18) were applied. Hematological toxicity was generally low with grade 3–4 neutropenia of 19%. Complete remission was observed in 8 pts (19%), partial remission in 18 pts (43%), and stable disease in 8 pts (19%) for an ORR of 62%. Median remission duration was 7.5 months, median PFS was 7.9 months. The median of OS has not been reached so far. Conclusions: The combination or oral plus intravenous vinorelbine and trastuzumab has shown high antitumor efficacy and excellent tolerability in 1st-line treatment of HER2 overexpressing MBC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pierre Fabre Pharma Pierre Fabre Pharma
The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights
Authors: J. Wesley Pike, Mark B. Meyer, Seong-Min Lee, Melda Onal, Nancy A. Benkusky
Journal: Journal of Clinical Investigation (2017)

The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.
Inclusion criteria for cancer cachexia clinical trials: CT-defined skeletal muscle loss versus body weight loss.
Authors: Eric Roeland, Sandahl H Nelson, Ashleigh Campillo, Sean Heavey, Joseph D. Ma, Carolyn Revta, Andrea Gallivan, Vickie E Baracos
Journal: Journal of Clinical Oncology (2015)

67 Background: Cancer cachexia is defined by skeletal muscle loss, with or without fat loss (Fearon et al 2011); however, inclusion criteria for cachexia clinical trials requires a defined weight loss over time rather than muscle loss. We hypothesized that cross sectional imaging may reveal the presence of cachexia otherwise obscured by fat mass changes. Methods: A retrospective analysis of longitudinal CT scans was performed in metastatic colorectal cancer (mCRC) patients screened for a cancer cachexia trial, which required ≥5% weight loss in the prior 6 mos. De-identified CT images were analyzed for total muscle, subcutaneous, and visceral fat cross-sectional areas (cm 2 ) at the 3rd lumbar vertebra at baseline and up to 12 mos prior (Lieffers et al 2009). Logistic regression was used to test differences between patients with &lt;5% vs ≥5% weight loss. Random intercept regression was used to evaluate significant trends in CT measures over time. Results: 42 mCRC patients were screened and 3(7%) enrolled. Patients were excluded for comorbidity/contraindication 14 (33%), excessive [&gt;20%] weight loss 4 (9.5%), and insufficient [&lt;5%] weight loss 19 (45%). For the &lt;5% weight loss subset, there was a mean of 6.7 CT scans (SD=2.67) and of 9% (SD=5.4, min=0%, 25th percentile=4.9%) mean max muscle loss. Notably this group was simultaneously losing muscle (p=0.002) and gaining visceral adipose (p=0.007). For the ≥5% weight loss subset, there was a mean of 7.5 CT scans (SD=4.5) and 20% (SD=10.0, min=5.2%, 25th percentile =10.6) mean max muscle loss. Greater max muscle loss increased the odds of being in the ≥5% weight loss subset (OR=1.19, 95% CI: 1.06,1.33). This group also had a significant decrease in visceral adipose over time (p&lt;0.001). Redefined inclusion criteria of ≥5% muscle loss would have included 14 of the 19 patients excluded because of &lt;5% weight loss. Conclusions: Defining cancer cachexia as weight loss over time may be limited as it does not capture body composition changes and hinders trial accrual. Cross-sectional CT body composition analysis may improve early detection of muscle loss and improve trial accrual.