tbuckley/cabot-search huggingface dataset:
Combined use of methylated reprimo cell-free DNA and pepsinogens for noninvasive detection of early gastric cancer.
Authors: Alejandra Alarcon, Wilda Olivares, Maria Jose Maturana, Andres Rodriguez, Oslando Padilla, Ignacio Alberto Wichmann, Alfonso Calvo, Alejandro Corvalan
Journal: Journal of Clinical Oncology (2015)

27 Background: Gastric cancer (GC) has been described as a multistep cascade of precursor lesions such as non-atrophic chronic gastritis (NACG), multiphocal atrophic gastritis (MAG), intestinal metaplasia (IM), low grade dysplasia (LGD) and high grade dysplasia (HGD) leading to early stages of GC (EGC). Currently, no non-invasive biomarkers for this progression are clinically available. We have previously identified a potential biomarker based on methylated Reprimo (RPRM) cell-free DNA (cfDNA) (Clin Cancer Res 2008;14:6264-9). In a cross-sectional study of 1,076 patients, we showed a sensitivity of 70.8% (95% CI: 60.3 to 81.3) and specificity of 74.3% (95% CI: 71.5 to 77) for methylated RPRM cfDNA, to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC (Digestive Disease Week 2014 #108). However, the crude detection rate of EGC was only 46.6%. Here, we aim to explore the role of the combined use of methylated RPRM cfDNA and well stablished atrophy biomarkers such as pepsinogens, for non-invasive detection of EGC. Methods: A case-control study was performed including 237 patients (NACG:40; MAG:94; IM:55; LGD:11; HGD:5: EGC:15; AGC:17) scheduled for upper gastrointestinal endoscopy (UGIE). A heparinized venous blood sample was collected and methylated RPRM cfDNA and Immunoassays for Pepsinogen I and II were performed. Positive value was considered if methylated RPRM cfDNA &gt; 0 copies/mL and PG I/II ratio &lt;3.0 were found. Results: Overall sensitivity and specificity for the combined use of methylated RPRM cfDNA and PGI/II to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC was 67.5% (95% CI: 50.2% to 81.9%) and 63% (95% CI: 55.9% to 69.7%), respectively. Positive and negative predictive values were 25.2% (95% CI: 17% to 34.9%) and 91.3% (95% CI: 85.3% to 95.4%), respectively. Importantly, crude detection rate for EGC increased from 46.6% to 86.7%. Conclusions: The combined use of methylated RPRM cfDNA and PGI/II reached similar sensitivity and specificity compared to methylated RPRM cfDNA alone to distinguish NACG+MAG+IM+LGD vs HGD+EGC+AGC. However, combined use of methylated RPRM cfDNA and PGI/II significantly improved the detection rate of EGC, a lesion with a curability rate over 95%.
Tart cherry juice as a treatment for chemotherapy-induced peripheral neuropathy.
Authors: Cindy Alberts Carson
Journal: Journal of Clinical Oncology (2016)

153 Background: CIPN is believed to affect up to 30% of cancer patients, particularly recipients of platinum compounds, plant alkaloids, and taxanes. Conventional treatments, such as antiepileptics, antidepressants, NSAIDs, and narcotics, usually provide only partial relief, and may have significant adverse effects. Tart cherries have a long history as a treatment for arthritides. It is believed that acanthocyanin pigments found in tart cherries modulate cytokines, decrease capillary permeability, and inhibit cyclooxygenase, which would be expected to reduce inflammation and pain. Methods: The study group consisted of 17 primary care patient volunteers with painful CIPN. This is a subset of a larger ongoing study of tart cherry juice as a treatment for PN generally. All study patients had carried a diagnosis of PN for 1-5 years, and had no symptoms of PN prior to cancer treatment. All patients described 7-10/10 pain more than 50% of the time. All study patients were allowed to remain on their prescribed doses of AEDs and antidepressants during the study. The patients agreed not to use NSAIDs, steroids, lidocaine, and narcotics during the study. There were no other restrictions. 12 patients had received platinum compounds and/or taxanes, 4 had received plant alkaloids, and 1 bortezomib. All patients drank 4 oz. of tart cherry juice BID for 14 days. The juice was a combination of 4 species imported from the Caucasus and sold commercially as “100% Cherry Juice from Concentrate.” Results: After 14 days of treatment, the patients were questioned regarding pain level. Three patients (carboplatin+taxol) reported no improvement. Seven patients (platinum, taxanes, alkaloids, and bortezomib) reported a decrease of maximum pain to 5-6/10. Five patients (alkaloids, platinum) reported a decrease of maximum pain to 3-4/10. Two patients (alkaloids) reported a decrease of maximum pain to 0-2/10. Overall, greater than 70% of the patients reported a greater than 25% reduction in maximum pain. Conclusions: While there are significant limitations to this study, a 14 day course of tart cherry juice appeared to improve CIPN in the majority of patients, with no reported adverse effects.
Induction chemotherapy with gemcitabine-carboplatin-paclitaxel (GEMCAP) in stage III non-small cell lung cancer (NSCLC).
Authors: G. L. Banna, H. Lipari, C. Buscarino, A. Seca, A. Basile, M. Ippolito, G. Novello, R. Condorelli, S. Cavallaro, G. Squadrito, M. D'Arrigo, V. Gebbia, A. Terminella, S. Saita
Journal: Journal of Clinical Oncology (2011)

7063 Background: The addition of gemcitabine (G) to doublet chemotherapy with carboplatin (C) and paclitaxel (P) has demonstrated to improve clinical outcome of advanced stage IIIB and IV NSCLC in a phase II-III study, albeit with significant hematologic toxicity. In a previous dose finding study, we identified a safe GEMCAP regimen based on dose-limiting toxicities. Methods: Patients aged 18-75 years, with ECOG PS 0-1, and unresectable clinical stage IIIA NSCLC, or stage IIIB suitable for definitive radiation treatment were treated in a phase II study with C AUC 5 i.v., P 175 mg/m2 i.v. on day 1, and G 800 mg/m2 i.v. on days 1 and 8, every 3 weeks for 3 cycles. Patients with stage IIIA disease in response following GEMCAP were reassessed for surgery; those with unresectable stage IIIA disease and stage IIIB, were treated with radiotherapy. Primary endpoint was response rate. Secondary endpoints included: toxicity, progression-free survival (PFS), resection rate, and overall survival (OS). Results: Of the 53 enrolled patients, 42 were males, 11 females, 29 (55%) had stage IIIA, 24 (45%) stage IIIB NSCLC, 47 (89%) had a PS 0. Forty partial responses and one complete response were observed, for an overall response rate of 80%. G3-4 and G2 toxicities, occurring in ≥ 5% of patients, included: neutropenia (19-8%), hypertransaminemia (11-2%), diarrhoea (6-0%), G3-4 toxicities; neutropenia (34%), asthenia (25%), diarrhoea (15%), peripheral neuropathy (13%), osteomialgya (11%), hypertransaminemia (6%), nausea/vomiting (9%), G2 toxicity. With a median follow-up of 20 months (range, 6-77) PFS was 10.5 months (95% CI, 9.9-11.4); OS was 21.1 months (95% CI, 19.6-22.9). Thirteen patients were operated, for a resection rate of 44%. Conclusions: The GEMCAP regimen at the dose employed produced high response and resection rate, with acceptable toxicity, as induction chemotherapy for clinical stage III NSCLC. PFS and OS compared favourably with that expected for clinical stage III disease.
A phase II study with decitabine, low-dose cytarabine and G-CSF priming in high-risk myelodysplastic syndromes, refractory/relapsed acute myelogenous leukemia or acute myeloid leukemia in patients with significant comorbidities.
Authors: J. Butera, E. Winer, C. Wang, J. J. Castillo, A. G. Thomas, H. Safran, A. E. Mega, G. A. Colvin, B. Rathore, P. J. Quesenberry
Journal: Journal of Clinical Oncology (2011)

6537 Background: The incidence of AML increases with advancing age; the median age of presentation for AML is 69 years. At present, there are limited treatment options available for elderly patients with AML or those with refractory disease. Both cytarabine and decitabine exert their cytotoxic effect on leukemic cells in the S phase. G-CSF priming has the ability to move leukemic cells into S phase. Methods: We evaluated the use of low-dose cytarabine 20 mg/m2 SC, decitabine 20 mg/m2 IV and G-CSF 5 mcg/kg days 1-5 every 4 weeks in patients with high risk MDS or refractory/relapsed AML or elderly AML patients with significant co-morbidities. Between 04/2009 and 02/2010, 9 of a planned 12 patients were enrolled in the trial. 5 patients had AML, 4 had high-risk MDS. Median age was 72 years (range 60-89). ECOG performance status was 0-1. 1 AML patient had failed allogeneic hematopoietic stem cell transplantation, and 1 patient had relapsed after induction with multiple chloromas. All high-risk MDS patients were previously only treated with supportive care. Results: 1 of 5 patients with AML had complete remission (CR), 2 had progressive disease, and 2 were not evaluable. The only patient with CR was a newly diagnosed AML M5 elderly patient. 1 of 4 patients with high-risk had partial clinical response defined by significant hematologic improvement in 2 cell lines. Median number of cycles given was 2 (range 1-6). The median overall survival was 30 days (range: 14-234 days). Grade 3-4 toxicities included: mucositis (n=1), pulmonary infiltrates/infection (n=2), ANC decrease (n=5), thrombocytopenia (n=6), anemia (n=6). Conclusions: Although this is a small pilot study, the combination of decitabine, low-dose cytarabine with G-CSF priming does not demonstrate improvement over the current standard of care for this high-risk, refractory patient population.
Association of single-nucleotide polymorphisms (SNPs) in sodium channel, voltage-gated, type I, alpha subunit (SCN1A) with toxicity in metastatic colorectal cancer (mCRC) patients (pts) in a phase I study of patupilone (EPO906) and celebrex (C).
Authors: H. Lenz, Y. Ning, W. Zhang, D. Yang, S. Cole, R. D. Agafitei, X. Menendez, P. Cheng, S. Iqbal, A. B. El-Khoueiry
Journal: Journal of Clinical Oncology (2011)

e14039 Background: EPO906 is an epothilone that stabilizes microtubules leading to cell cycle arrest and apoptosis. Preclinical models reveal activity in 5FU resistant colon cancer. C was added to EPO906 based on preclinical data suggesting a decrease in risk of diarrhea. SCN1A polymorphisms T1067C (rs2298771) and IVS5_91(rs3812718)] have been associated with outcome and toxicity in mCRC pts treated with oxaliplatin-based chemotherapy. Methods: A standard 3+3 design was used to determine the MTD. Dose of C was fixed while EPO906 was escalated to a maximum of 13 mg/m2. Genomic DNA was extracted from peripheral whole blood or dissected from formalin fixed paraffin embedded tumor tissue. The polymorphisms were analyzed using a direct sequencing method. Results: 43 pts were accrued; male/female 19/24; median age 58 (35-84); median number of prior therapies 4 (1-9). The MTD was 12 mg/m2. All cycles grade 3/4 toxicities: diarrhea 44%, fatigue 23%, anorexia 16%, nausea 16%, sensory neuropathy 9%, vomiting 9%, hypokalemia 7%. Response was evaluable in 37 pts: 3 (8%) PR, 21 (57%) SD. Median PFS was 3.4 mo (95% CI: 1.6-5.7) and median OS was 6.6 mo (95% CI: 4.9-10.1). Grade 3/4 diarrhea was 52% in pts carrying the SCN1A 1067 T/T alleles versus 39% in pts with C/T and 17% with C/C (p=0.0118, Fisher’s exact test). There was no statistically association between SCN1A polymorphisms and response or survival. Conclusions: The combination of EPO906 and C is well tolerated with promising activity. A phase II study of the combination is on-going. The preliminary association of the SCN1A T1067C SNP with toxicity is consistent with our findings in a study of EPO906 in pts with ovarian cancer. Prospective validation of this association is warranted. Toxicity EPO 906 Dose level mg/m2 N Not evaluable for DLT DLTs 7 3 0 0 8 4 1 0 9 7 1 1 diarrhea, nausea, vomiting 10 8 2 1 nausea, anorexia 11 7 1 1 diarrhea, vomiting 12 9 3 1 diarrhea 13 5 1 2 diarrhea, vomiting 43 diarrhea, anorexia
Surveillance imaging following colon cancer resection: Universal or risk-based?
Authors: Christina Edwards Bailey, Chung-Yuan Hu, Amanda Cuddy, Y. Nancy You, George J. Chang
Journal: Journal of Clinical Oncology (2014)

307 Background: Current colon cancer surveillance guidelines recommend annual imaging for all patients following curative resection. The primary aim of this study is to evaluate variation in surveillance practices following colon cancer resection. Methods: A retrospective cohort study of patients ≥ 66 years old with stage I-III colon cancer that underwent surgical resection in the Surveillance, Epidemiology, and End Results-Medicare linked database (July 2001 through December 2007) with at least 3 years of follow-up was performed. Medicare claims for PET and CT scan of the chest, abdomen and pelvis performed after surgical resection were recorded and analyzed. In order to evaluate the use of definitive treatment (DT) for presumed recurrent disease, we identified patients who had undergone lung, liver, or colorectal resection during follow-up. Results: Of 22,544 patients who underwent primary resection of colon cancer, 13,753 (61.0%) underwent PET and/or CT after resection and 1,109 (4.52%) underwent at least 1 DT. The mean number of imaging performed for patients who did not undergo DT was 1.68. Within this group, the utilization of PET and/or CT varied by stage, with 14.1%, 22.4%, and 42.2% of patients with stage I, II, and III disease undergoing imaging, respectively. The most significant factor associated with PET and/or CT was tumor stage with an odds ratio of 1.86 (95% CI 1.70-2.02, P&lt;0.001) for stage II disease and 4.56 (95% CI 4.17-4.99, P&lt;0.001) for stage III disease compared to stage I disease. Additional factors significantly associated with PET and/or CT included year of diagnosis and SEER region. Among patients who did undergo DT, the mean number of PET and/or CT performed was 5.37 but the majority of imaging studies were performed 4 months prior to DT (mean 2.95). Conclusions: There is a high degree of variation in the use of surveillance imaging among elderly patients with localized colon cancer although some of this variation appears to be associated with stage at presentation. Our findings highlight discordance between clinical practice and surveillance guidelines. Further study is needed to understand the basis and appropriateness of clinical decision making that departs from guideline-based care.
A dual stable isotope method by LC-MS/MS to define patterns of androgen metabolism in localized versus advanced prostate cancer.
Authors: Charles Dai, Yoon-Mi Chung, Eric A. Klein, Nima Sharifi
Journal: Journal of Clinical Oncology (2016)

40 Background: Prior work has shown that androstenedione (AD) rather than testosterone (T) is the preferred substrate of 5α-reductase for dihydrotestosterone (DHT) synthesis in castration-resistant prostate cancer. However, patterns of metabolism in hormone-naive prostate cancer are still poorly defined. Previously, we reported on the utility of dual radioisotope labeling of steroid precursors to characterize androgen metabolism in localized prostate tissue. We now describe an alternative approach via stable isotope labeling and analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which has unique advantages over the former method. Methods: LNCaP cell lines and prostate tissue from patients undergoing radical prostatectomy for localized cancer were incubated in serum-free media, spiked with 13 C-labeled AD and 2 H-labeled T. Media was collected at 7, 24, and 48 hours of incubation. Steroids were extracted, separated, and then analyzed by way of LC-MS/MS to identify labeled metabolites of AD and T. Results: Incubation of labeled AD and T resulted in conversion over time to both 13 C-labeled and 2 H-labeled downstream metabolites, 5α-dione and DHT. Although both precursors contributed to 5α-dione and DHT formation, the steroid of origin could be determined on the basis of differential labeling. In ex-vivo tissue incubations, unlabeled 5α-dione was also observed, which was distinguishable from its stable isotopic form and most likely represents endogenous steroid. Conclusions: Both cell lines and tissue appear to metabolize labeled AD and T, and formation of DHT occurs through both precursors. Furthermore, the presence of endogenous 5α-dione suggests that alternative pathways of DHT synthesis, which bypass T, may be naturally accessible in the hormone-naïve setting. We propose a robust ex-vivo technique to readily track simultaneous pathways of DHT synthesis in prostate cancer. Future work will focus on defining metabolic phenotypes of localized prostate cancer and specific patterns of flux under different hormonal and pharmacologic conditions.
Dose-intensified daunorubicin induction and consolidation plus combined modality maintenance therapy for children with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Study C9710.
Authors: J. H. Feusner, J. Gregory, B. K. Moser, V. Hars, C. L. Willman, B. L. Powell, R. A. Larson
Journal: Journal of Clinical Oncology (2010)

9510 Background: Children aged <15 yrs with newly diagnosed APL were enrolled on study to evaluate the benefit of dose intensified daunorubicin (DNR) with tretinoin (ATRA) and cytarabine during induction, the addition of ATRA to DNR during consolidation, and mercaptopurine (6MP) and methotrexate (MTX) added to ATRA for maintenance. Methods: Patients were enrolled with morphologically diagnosed APL, but confirmation by molecular detection of PML/RARa was required for study eligibility. During induction, DNR was given at 50 mg/m2/d × 4 days (1.5 mg/kg/d if <3 yrs old). Two cycles of consolidation utilized DNR (50 mg/m2/d) × 2 days (or 1.5 mg/kg/d) plus ATRA (45 mg/m2/d) for 7 days. Maintenance was randomized to either intermittent ATRA (7 days every other week) or the same ATRA plus 6MP (60 mg/m2 daily) and MTX (20 mg/m2 weekly) for one year (Powell et al. Proc ASCO, 2007, abstr 2). Results: Sixty-four children were enrolled; 7 were ineligible (6 were PCR negative; 1 withdrew consent). Induction responses for the 56 pts with data were: 47 CR, 4 PR (all attained CR during consolidation), 1 NR, 3 intracranial hemorrhagic (ICH) deaths within the first 5 days on study, and one death from CVA on d 27 of induction. The CR rate was 84% for all pts (CR+PR 91%), 93% for Sanz low and intermediate risk, and 54% for Sanz high risk. The 3 yr DFS, EFS, and OS was 63%, 53%, and 87%, respectively. There were 9 deaths on study: 4 during induction (3 with ICH, one with CVA), 3 due to relapse, 1 from CHF in CR during maintenance, and 1 at 4 yrs off therapy due to a previously diagnosed brain tumor. Outcomes for the prior US intergroup trial (Pediatr Blood Cancer 2009; 53: 1005) which used less DNR, no ATRA during consolidation, and either ATRA alone or observation for maintenance were 81% CR, 5 yr DFS of 41%, and OS of 69%. Conclusions: Compared to the 53 children on the prior Intergroup trial E2491, the current treatment approach appears to have improved the OS, and especially the DFS. Future studies need to evaluate the role of arsenic trioxide in newly diagnosed children with APL, as well as methods to reduce early deaths, especially in Sanz high risk pts during induction. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cephalon
Cell-free <i>DNA</i>, <i>KRAS</i>, and <i>BRAF</i> mutations in plasma from patients with metastatic colorectal cancer treated with third-line cetuximab and irinotecan.
Authors: N. Pallisgaard, K. G. Spindler, I. S. Vogelius, A. K. M. Jakobsen
Journal: Journal of Clinical Oncology (2011)

3599 Background: The possible clinical importance of circulating cell-free DNA (cfDNA) in metastatic colorectal cancer (mCRC) remains to be elucidated. This especially applies to tumor specific mutations. The aim of the present study was to investigate the importance of cfDNA in relation to third line treatment. Furthermore, we wanted to investigate the quantitative relationship of cell free DNA with specific mutated DNA in the plasma. Methods: Inclusion criteria were; histopathologically verified chemotherapy resistant mCRC, adequate PS and organ function. Treatment consisted of irinotecan 350 mg/m2 q3w and weekly cetuximab 250 mg/m2 until progression or unacceptable toxicity. Mutational status in tumor was assessed by a commercial kit. A quantitative PCR method was developed and used to asses the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline and prior to each cycle. Results: The study included 108 patients. The majority of KRAS mutations detected in the tumor was also found in the plasma (32/41 [78%]). Two of the 3 BRAF mutations in tumor were detected in the plasma. Plasma cfDNA and KRAS levels (pKRAS) were strongly correlated (r = 0.968, p<10-4). The disease control (DC) rate was 77% in patients with low cfDNA (<25 percentile) and 30% in patients with high (>75% percentile [p=0.009]). Patients with pKRAS levels higher than the 75% percentile had a DC rate of 0% compared to 42% in patients with pKRAS below (p=0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pKRAS and high levels were clear indicators of a poor outcome. Off note, at least one patient harboured a different mutation in the primary tumor compared to the metastasis and plasma samples, and in 4 patients without mutation in the tumor and baseline plasma samples, a KRAS (n=4) or BRAF (n=1) mutation appeared at time of progression. Conclusions: KRAS and BRAF analysis in plasma is an alternative to tissue analysis. Quantitative levels of cfDNA and pKRAS were strongly correlated to clinical outcome of third-line treatment of mCRC, and mutational status may change during the course of treatment. Quantification of plasma cfDNA holds promise of clinical application.
Outcomes in patients with brain metastasis from esophageal carcinoma.
Authors: Nadia Saeed, Nishi Kothari, Eric Albert Mellon, Sarah E. Hoffe, Jessica M. Frakes, Ravi Shridhar, Jose Mario Pimiento, Ken Lee Meredith, Nam D. Tran, Khaldoun Almhanna
Journal: Journal of Clinical Oncology (2016)

159 Background: Brain metastases from esophageal carcinoma have historically been rare. With improvements in systemic therapy, patients are living longer and the incidence of brain metastasis (mets) is expected to rise. However, there is no consensus on management. We present our single institution experience with brain mets from esophageal cancer. Methods: We retrospectively identified 49 patients (pts) with brain mets from primary esophageal cancer who were treated at our tertiary referral center between 1998 and 2015. Medical records were reviewed to collect demographic and clinical information. Results: Median age at diagnosis of the primary esophageal cancer was 60 years. 41 pts were male. 39 pts had adenocarcinoma, 4 had squamous cell carcinoma, 4 had poorly differentiated carcinoma, and 1 had neuroendocrine carcinoma. Stage at diagnosis ranged from I-IV. 7pts had synchronous brain mets, defined as occurring within 3 months of diagnosis. The remaining pts were found to have brain mets more than 3 months after diagnosis. 27 pts had a solitary met, 12 had two lesions, and the rest had multiple lesions. For primary treatment, 12 pts had surgery only, 8 had stereotactic radiosurgery (SRS) as a definitive treatment, and the remainder had a combination of surgery, SRS, and whole brain radiation therapy. Median survival following esophageal cancer diagnosis was 24 months (range 3-71), and median survival after the identification of brain mets was 5 months (range 1-52). Using the recursive partitioning score (RPA), 15 pts had class I disease and 28 had class II, and 6 had class III disease. Those with class I or II disease had significantly improved overall survival (p &lt; 0.001). Conclusions: Brain metastases from esophageal cancer are rare with overall poor prognosis. However, some pts can have prolonged survival. In the largest series to date, we found that pts with controlled systemic disease and limited number of brain lesions who had definitive therapy (surgery or SRS) had better outcome. Aggressive treatment may improve outcomes.