tbuckley/cabot-search huggingface dataset:
A phase II study of pemetrexed plus carboplatin as first-line therapy of patients with locally advanced (LA) or metastatic breast cancer (MBC): Preliminary results
Authors: A. Garin, A. Manikhas, M. Biakhov, M. Chezhin, T. Ivanchenko, K. Krejcy, V. Karaseva, S. Tjuyandin
Journal: Journal of Clinical Oncology (2005)

694 Background: Pemetrexed (Alimta) is a novel, multitargeted antimetabolite that inhibits multiple folate-dependent enzymes. Phase II pemetrexed studies have shown activity in patients with breast cancer previously treated with anthracyclines or taxanes. The purpose of this study was to assess the efficacy and safety of pemetrexed plus carboplatin as first-line therapy in patients with LA or MBC. Methods: Patients ≥18 years with histologic/cytologic diagnosis of LA or MBC received pemetrexed 600 mg/m2 and carboplatin AUC 5 on day 1 every 21 days. All received folic acid and vitamin B12 supplementation. Results: From June 2003 to July 2004, 50 patients were enrolled and included in this preliminary analysis. Patient characteristics included: median age 55.5 years (range, 29–76); ECOG performance status 0/1, 30/20; pre/post-menopausal, 8/42; and stage IIIB/IV, 15/35. Fourteen patients (28%) previously received 1 adjuvant regimen; 23 (46%) had visceral metastases; and 18 (36%) had ≥3 organs involved. So far, 246 cycles have been administered (median 5 [range, 1–12]) with a relative dose intensity of 95.5% for both drugs. Twenty patients are still on study. Partial response (RECIST criteria) was achieved in 25 patients (overall response rate 50%; 95% CI, 35.5%–64.5%); 15 (30%) had stable disease; 7 (14%) progressed; and 3 (6%) were not assessable. Median response duration was 6.9 months (95% CI, 6.9–9.3 months), and median time to progression was 10.2 months (95% CI, 6.7–10.6 months). CTC hematologic toxicities were grade 3/4 neutropenia (56% of patients/24%), grade 3 thrombocytopenia (10%), and anemia (18%); 2 patients (4%) had febrile neutropenia, and 1 died. Grade 3 nonhematologic toxicities were ALT (4%), and AST, edema, pruritus, rash/desquamation, and renal (2% each). No grade 4 nonhematologic toxicities occurred. Conclusions: These preliminary results suggest that pemetrexed in combination with carboplatin has a promising efficacy and an acceptable safety profile; the results of this trial should be confirmed in the context of a phase III setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly
Comparison of transfusion rates between erythropoietic stimulating agents in gynecologic oncology patients with chemotherapy induced anemia
Authors: A. S. Case, R. P. Rocconi, M. N. Barnes, L. C. Kilgore
Journal: Journal of Clinical Oncology (2005)

5092 Objective: Chemotherapy induced anemia (CIA) commonly occurs in gynecologic oncology patients. This often leads to treatment with erythropoietic stimulating agents in order to prevent chemotherapy delays, dose modifications and transfusion of red blood cells. Our goal was to determine the subsequent transfusion rates after treatment failure with either darboetin alpha (DARB) or epoetin alpha (EPO). Methods: A single institution retrospective chart review was performed reviewing patients from January 2003 to September 2004 who received either DARB or EPO for CIA (Hgb ≤ 10.0). Data collection variables included patient demographics, cancer diagnosis, chemotherapy treatment(s), laboratory data, erythropoeisis stimulation data, and transfusions. Sample size calculations were set to detect a 20% transfusion rate difference between the two groups. Chi-square, Fisher exact test and student t-tests were used for statistical analysis. Results: 123 patients were eligible for analysis (60 DARB; 62 EPO). 93% of DARB patients received 200mg every other week, while 86% of EPO patients received 40,000 U weekly. Variables that were controlled for between the DARB and EPO groups included age, race, tumor type, histology, previous chemotherapy, number of chemotherapy agents, weeks of erythropoietic stimulation, baseline serum levels of creatinine and hemoglobin, and change in hemoglobin. Although the mean baseline Hgb and change in Hgb was similar for each group (DARB=11.2, 2.5 & EPO=11.3, 2.3), 21 (35%) of the DARB patients received a transfusion of packed red blood cells compared to 12 (19%) of EPO patients (p=0.05). Conclusions: This retrospective analysis powered to detect differences in transfusion rates revealed a statistically significant difference in transfusion rates between DARB and EPO for the treatment of CIA. Although subject to the limitations to a retrospective study, we believe this data warrants a randomized prospective trial in gynecologic oncology patients with careful attention to the timing of initiation of treatment, dosing regimens, and titration of growth factor. No significant financial relationships to disclose.
Comparative Sperm Proteomics in Mouse Species with Divergent Mating Systems
Authors: Alberto Vicens, Kirill Borziak, Timothy L. Karr, Eduardo R.S. Roldan, Steve Dorus
Journal: Molecular Biology and Evolution (2017)

Sexual selection is the pervasive force underlying the dramatic divergence of sperm form and function. Although it has been demonstrated that testis gene expression evolves rapidly, exploration of the proteomic basis of sperm diversity is in its infancy. We have employed a whole-cell proteomics approach to characterize sperm divergence among closely related Mus species that experience different sperm competition regimes and exhibit pronounced variation in sperm energetics, motility and fertilization capacity. Interspecific comparisons revealed significant abundance differences amongst proteins involved in fertilization capacity, including those that govern sperm-zona pellucida interactions, axoneme components and metabolic proteins. Ancestral reconstruction of relative testis size suggests that the reduction of zona pellucida binding proteins and heavy-chain dyneins was associated with a relaxation in sperm competition in the M. musculus lineage. Additionally, the decreased reliance on ATP derived from glycolysis in high sperm competition species was reflected in abundance decreases in glycolytic proteins of the principle piece in M. spretus and M. spicilegus. Comparison of protein abundance and stage-specific testis expression revealed a significant correlation during spermatid development when dynamic morphological changes occur. Proteins underlying sperm diversification were also more likely to be subject to translational repression, suggesting that sperm composition is influenced by the evolution of translation control mechanisms. The identification of functionally coherent classes of proteins relating to sperm competition highlights the utility of evolutionary proteomic analyses and reveals that both intensified and relaxed sperm competition can have a pronounced impact on the molecular composition of the male gamete.
Small RNA sequencing of colorectal cancer to reveal differences in microRNA expression between normal and tumor tissue.
Authors: Robin Mjelle, Wenche Sjursen, Liv Thommesen, Eva Hofsli
Journal: Journal of Clinical Oncology (2016)

506 Background: MicroRNAs (miRNAs) are promising biomarkers and therapeutic agents for colorectal cancer (CRC). However, much remains to be known about the biology of miRNAs and miRNA variants in tumor tissue and why the expression differs from normal tissue. Methods: RNA from 48 normal and 48 cancer tissue samples were sequenced using the Illumina small RNA sequencing protocol. Samples were taken from both male and female patients with tumor stage 1-4. Results: We show that almost 50% of microRNAs (miRNAs) are differentially expressed between normal and cancer tissue. When analyzing pre-miRNAs that map to genomic clusters, so-called clustered miRNAs, we show that miRNAs in the same cluster often have similar expression profiles. This shows that common changes in co-expressed miRNAs seem to explain some of the miRNA expression changes between normal and tumor samples and indicates that altered pri-miRNA transcription is the mechanism for at least some of the miRNA changes. Analyses of miRNA variants, so-called isomiRs, revealed large variations between tumor and normal samples, similar to those observed for the canonical miRNAs. Different isomiR types show different expression profiles in tumor vs normal samples, indicating that miRNA processing is altered in tumor cells. Finally, we show that several canonical miRNAs and isomiRs correlate with genetic signatures in the tumor samples, including KRAS and BRAF mutation, Microsatellite instability and MLH1 methylation, indicating that tumor subtypes have different miRNA expression. Conclusions: Our results show that miRNA expression predicts tumor subtypes with different genetic signatures. We show that some of the changes in miRNA expression are due to different transcription programs in cancer vs normal tissue.
Independent prognostic value of plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) in colorectal cancer: A prospective validation study
Authors: H. J. Nielsen, A. Ghanipour, I. J. Christensen, B. Glimelius, N. Brünner, H. Birgisson
Journal: Journal of Clinical Oncology (2008)

11072 Background: Introduction of independent prognostic markers may play a significant role in future treatment of colorectal cancer (CRC). Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a glycoprotein, which acts as an inhibitor of all active matrix metalloproteinases. TIMP-1 can be measured in plasma, and it has previously been shown to carry independent prognostic value in patients with primary CRC. The purpose of the present study was to validate TIMP-1 as a prognostic marker in patients undergoing operation for primary CRC. Methods: In the present prospective study plasma samples were collected before surgery from 323 patients with primary CRC between 2000 and 2003. After collection of all samples TIMP-1 was determined using a thoroughly validated, in-house ELISA method. Recurrence and survival were registered and the association to plasma TIMP-1 levels was studied in a Cox multivariate model including age, disease stage, differentiation, lymphatic and vascular vessel invasion calculating hazard ratios and 95% confidence intervals (HR (95%CI)) for overall survival (OS) and disease free survival (DFS). Results: Three local recurrences and 50 distant metastases were registered in stage I-III patients after a median follow-up time of 5.5 (4–7.5) years. No recurrences were observed in stage I (n=44), while 13 were recorded in stage II (n=134) and 38 in stage III (n=94). Scoring TIMP-1 as a continuous variable on a logarithmic scale, plasma TIMP-1 displayed independent prognostic information for the whole cohort in a multivariable statistical analysis: OS: HR 2.35 (1.51–3.66) and DFS: HR 1.86 (1.12–3.08). Conclusions: Plasma TIMP-1 levels carry strong independent prognostic information for patients with primary CRC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories
Inpatient integrated palliative and transplant care to improve family caregiver (FC) outcomes of patients hospitalized for hematopoietic stem cell transplantation (HCT).
Authors: Harry VanDusen, Thomas William LeBlanc, Lara Traeger, Joseph A. Greer, William F. Pirl, Vicki A. Jackson, Jason Telles, Alison Rhodes, Yi-Bin Albert Chen, Jennifer S. Temel, Areej El-Jawahri
Journal: Journal of Clinical Oncology (2016)

235 Background: As their loved ones struggle physically and psychologically with transplant toxicities, FCs of patients undergoing HCT experience substantial distress. We assessed the impact of an inpatient palliative care intervention on FC quality of life (QOL) and mood during their loved ones’ HCT hospitalization. Methods: We conducted a randomized trial of inpatient palliative care integrated with transplant care versus transplant care alone for patients hospitalized for HCT and their FCs. Eligible FCs were identified as a relative or a friend with regular in-person contact with the patient and enrolled within 72 hours of the patient’s HCT admission. The intervention entailed at least twice weekly visits between the patient and palliative care during the transplant hospitalization, and FCs were welcome but not required to be present for these visits. We used the CareGiver Oncology QOL Questionnaire (CarGOQOL) to examine QOL, and the Hospital Anxiety and Depression Scale (HADS) to assess FC mood at baseline and week-2 during HCT hospitalization. We used the two-sample t-test to assess changes in QOL and mood from baseline to week-2. Results: We enrolled 160 patients and 94 (58.8%) FCs (control n = 49, intervention n = 45) between 8/2014 and 1/2016. Study groups did not differ significantly in baseline characteristics or overall FC QOL. At 2 weeks, FCs of patients randomized to the intervention reported improvements compared to those receiving transplant care alone in some QOL domains including better coping (0.23 vs. -0.74, p = 0.02) and handling of finances (0.24 vs. -0.46, p = 0.02) and also reported lower depression symptoms (HADS-Depression: 0.25 vs. 1.80, p = 0.03). No other CarGOQOL domains or HADS-anxiety symptoms were significantly different. Conclusions: Involvement of palliative care for patients hospitalized for HCT leads to improvement in FC depression and some aspects of their QOL. These findings demonstrate the positive impact of inpatient integrated palliative and transplant care extends to FCs of patients with hematologic malignancies undergoing HCT. Clinical trial information: NCT02207322.
Randomized phase II trial of gefitinib plus anastrozole or fulvestrant in postmenopausal, metastatic breast cancer
Authors: R. W. Carlson, A. O'Neill, T. Vidaurre, H. L. Gomez, S. Badve, G. Sledge
Journal: Journal of Clinical Oncology (2009)

1013 Background: Preclinical data documents interactions between the signal transduction pathways for ER and for EGFR, and these interactions may relate to endocrine resistance in ER+ breast cancer. Limited clinical data is available. Methods: This multi-institutional, single-stage, non-comparative, randomized phase II study tested the EGFR tyrosine kinase inhibitor gefitinib 250 mg daily PO plus endocrine therapy with either anastrozole 1 mg/day PO (AG Arm) versus fulvestrant 250 mg IM every 4-weeks (FG Arm). Eligible pts were postmenopausal women with ER+ and/or PgR+ measurable metastatic breast cancer with no prior endocrine therapy for metastatic disease, no prior adjuvant AI or fulvestrant, no more than two chemotherapy regimens for metastatic disease, ECOG status 0–2, no CNS metastasis, and adequate bone marrow, liver, and renal function. Primary endpoint was RECIST determined clinical benefit (CR+PR+SD for ≥6 mos) and secondary endpoints were toxicity and interaction of biomarkers with clinical benefit. Results: 148 pts were registered, and 142 pts are eligible and analyzable, 73 to AG and 69 to FG. Treatment groups were balanced for race, age, ECOG status, and sites of disease. Median follow-up is 35 mos. Median N of 4-week cycles of treatment is 6 (range 1–42) in both groups. Treatment was terminated for disease progression in 74% v 75%, toxicity 7% v 10%, death 1% v 3%, withdrawal 8% v 1%, and other 3% v 7% in the AG v FG arms, respectively. Clinical benefit rate (95% CI) is 42% (30%-53%) v 38% (28%-52%) for AG v FG, respectively. Response rates are CR 3% v 4%, PR 21% v 17%, SD for ≥6 mos 18% v 17% for AG v FG. Median PFS is 5.7 mos v 5.2 mos and median OS is 30.2 mos v 23.8 mos for AG v FG, respectively. Overall worst toxicity grade experienced for AG is G1 and 2 = 62%; G3 = 28%; G4 = 4%, G5 = 3%; for FG was G1 and 2 = 58%; G3 = 27%; G4 = 7%; G5 = 4%. G3 + G4 + G5 toxicities occurring in ≥5% of either treatment are diarrhea (5% v 13%), SGOT elevation (7% v 8%), and infection without neutropenia (1% v 6%) for AG v FG. Conclusions: Both anastrozle and fulvestrant are active endocrine agents in combination with gefitinib and both are generally well tolerated. Anastrozole plus gefitinib appears to be the better combination to take forward for phase III comparisons. [Table: see text]
SAR302503: Interim Safety, Efficacy and Long-Term Impact on JAK2 V617F Allele Burden in a Phase I/II Study in Patients with Myelofibrosis,
Authors: Animesh Pardanani, Jason Gotlib, Catriona Jamieson, Jorge E. Cortes, Moshe Talpaz, Richard Stone, Guozhi Gao, Jenny (Yanzhen) Zhang, Frank Neumann, Ayalew Tefferi
Journal: Blood (2011)
Lenalidomide in combination with gemcitabine in patients with untreated metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial.
Authors: H. Arkenau, J. R. Infante, J. C. Bendell, H. A. Burris, M. S. Rubin, D. M. Waterhouse, G. T. Jones, D. R. Spigel, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2011)

e14640 Background: Lenalidomide is an oral Imid immunomodulatory compound with both anti-angiogenic and immunomodulatory properties. The objectives of this phase II study were to assess the safety, tolerability, and anti-tumor activity, including response rate, progression-free (PFS), and overall survivals (OS), of lenalidomide combined with gemcitabine in patients (pts) with untreated metastatic pancreas cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas (locally advanced disease excluded); ECOG PS 0-2; adequate organ function. Prophylactic anticoagulation was required (ASA, LMWH, or warfarin). Pts received lenalidomide 25mg PO days 1-21 and gemcitabine 1,000 mg/m2 IV days 1, 8, and 15 of 28-day cycles. Results: Between 5/2009 – 4/2010, 72 patients (median age 64 years; 49 [68%] male; 30 [42%] ECOG PS 0; 41 [57%] ECOG PS 1) began combination therapy at 9 sites, and received median of 2 cycles (range: 0-17+). Grade 3/4 hematologic toxicity included thrombocytopenia (15 pts, 21%) and neutropenia (12 pts, 17%), with no febrile neutropenia. Common non-hematologic toxicities were fatigue (49%), nausea (33%), anorexia (21%), constipation (19%), and rash (19%). Hematologic toxicity resulted in dose reduction of gemcitabine and lenalidomide in 33 pts (46%) and 27 pts (38%), respectively; an additional 17 and 32 patients required dosing interruption. Despite prophylactic anticoagulation (79% ASA, 13% LMWH, 5% warfarin), 13 pts (18%) developed grade 3/4 venous thromboembolic events. Three patients remain on treatment. Fifty pts (69%) have ended treatment for disease progression or death due to disease; other reasons for treatment discontinuation included: symptomatic deterioration (6), intercurrent illness (6), patient choice (6), and toxicity (1). Eight patients (11%) achieved partial response. PFS and OS were 2.5 (95% CI 1.9-3.5) and 4.73 (95% CI 3.4-6) months, respectively. Six-month OS was 38% (95% CI 27-50%). Conclusions: Compared to expected results with gemcitabine alone, the addition of lenalidomide did not improve the survival of patients with untreated metastatic pancreatic cancer.
Association of decreased peak SUV on PET after neoadjvuant therapy in patients with borderline resectable pancreatic carcinoma with pathologic response.
Authors: Evan Scott Glazer, Omar Maen Rashid, Pamela Joy Hodul, Jose Mario Pimiento, Mokenge Peter Malafa
Journal: Journal of Clinical Oncology (2016)

423 Background: Despite the use of PET scan in metastatic staging, its utility as a biomarker for borderline resectable pancreatic carcinoma (BRPC) is unclear. The peak standardized uptake value (SUV peak ) is the average SUV around the most avid portion of the tumor. We hypothesized that tumor pathologic response (PR) to neoadjuvant therapy will correlate with SUV peak changes after therapy. Methods: We reviewed our database of patients with BRPC who completed neoadjuvant chemotherapy (GTX) followed by radiation and had pre- and post- neoadjuvant PET scans. Changes in the SUV peak were calculated by subtracting the post-neoadjuvant/pre-resection PET scan from the pre-neoadjuvant PET scan. PET responders were defined as those patients whose SUV peak decreased by 4 units (the overall average decrease in SUV peak ) or more. Results: We identified 74 patients- 32 patients developed progressive disease and 42 patients underwent surgery. The average age was 66 ± 9 years; 61% of patients were male. On the final pathologic specimens, 5 patients had a complete PR to therapy while 23 patients had a moderate PR (1-49% viable tumor) and 14 patients had a minimal PR (≥ 50% viable tumor). PR is associated with a decrease in SUV peak (p = 0.02; Table). The area under the receiver operator characteristic curve for changes in SUV peak and complete PR was 0.83 ± 0.08. Of the PET responders who underwent surgery, 29% had a complete PR while none of the PET non-responders had a complete PR (p = 0.004). Of the unresected patients, PET responders had a longer overall survival compared to non-responders (18 ± 7 vs. 12 ± 7 months, p &lt; 0.05). Nodal disease was not associated with PR (p &gt; 0.3). Conclusions: PR was significantly associated with a decrease in SUV peak post-neoadjuvant therapy in patients with BRPC. Even in patients with unresectable disease, SUV peak provides useful prognostic data. We believe that pre- and post-neoadjuvant therapy PET scans may be used as a prognostic biomarker in patients with BRPC. [Table: see text]
Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain
Authors: Wei-Chao Huang, Elliott Ferris, Tong Cheng, Cornelia Stacher Hörndli, Kelly Gleason, Carol Tamminga, Janice D. Wagner, Kenneth M. Boucher, Jan L. Christian, Christopher Gregg
Journal: Neuron (2017)
Prospective analysis of <i>UGT1A1</i> promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI as the first-line setting.
Authors: Yung-Sung Yeh, Meng-Lin Huang, Chien-Yu Lu, Jaw-Yuan Wang
Journal: Journal of Clinical Oncology (2013)

491 Background: Infusional fluorouracil/leucovorin plus irinotecan-based regimen (FOLFIRI) with bevacizumab has been widely used as first-line treatment for patients with metastatic colorectal cancer (mCRC). We prospectively analyzed the influence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotyping for irinotecan dose escalation in mCRC patients treated with combination of FOLFIRI and bevacizumab as the first-line setting. Methods: A total of 65 mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab were analyzed. Genotypes were performed by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Genotype and clinical parameters were compared by univariate analysis. The irinotecan dose is escalating form 180 mg/m 2 to 260 mg/m 2 in UGT1A1 6/6 or 6/7, and from 120 mg/m 2 to 210 mg/m 2 in UGT1A17/7. Results: The response rate was observed in 44 of 60 UGT1A1 6/6 or 6/7 (73.3%) in comparison to 1 of 5 UGT1A1 7/7 (20%) patients (p=0.013). The grade III-IV adverse events (AE) was observed in 4 of 60 UGT1A1 6/6 or 6/7 (6.7%) in comparison to 3 of 5 UGT1A1 7/7 (60%) patients (p&lt;0.001), but it was not different between age of ≥ 70 and &lt; 70 (p=0.559). Fifteen of 60 (20%) patients with UGT1A1 6/6 or 6/7 could be performed with liver or lung metastaectomy in comparison to none of 5 patients with UGT1A1 7/7. In addition, the disease control rate was significantly higher in irinotecan dose of ≥ 210 mg/m 2 than irinotecan dose of &lt; 210 mg/m 2 (p=0.015). Conclusions: UGT1A1 promoter polymorphism was found to be predictive of toxicity and efficacy in mCRC patients with first-line treatment of FOLFIRI combined with bevacizumab. The higher dose of irinotecan (≥ 210 mg/m 2 ) may achieve a better disease control rate but do not increase the incidence of GR III-IV AE in mCRC patients of age ≥ 70 years.