tbuckley/cabot-search huggingface dataset:
A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced hepatocellular carcinoma (HCC).
Authors: Masafumi Ikeda, Takuji Okusaka, Hiroshi Ishii, Osamu Yokosuka, Naoshi Yoshida, Yasuo Yanagihara, Kiwamu Okita
Journal: Journal of Clinical Oncology (2014)

2616 Background: OPB-31121 is an orally administered novel STAT3 inhibitor. STAT3 is found to be activated in the majority of HCC with poor prognosis. Following phase I studies for solid tumors, this multicenter phase I study was performed to evaluate the safety, recommended dose (RD), pharmacokinetics, and antitumor activity of OPB-31121 in patients (pts) with advanced HCC. Methods: HCC pts with Child-Pugh A or B who progressed on or were intolerant to sorafenib were eligible. A standard 3 + 3 dose-escalation design was used with a 28-day cycle. The tested dose levels were 50, 100, 200, and 400 mg/day. Tumor response was assessed by modified RECIST. Results: Twenty-three pts were enrolled. All pts had previously received median 2 different regimens (range, 1-5) of chemotherapy. Median age was 65 (range, 45-79) and 20 pts were male. ECOG PS 0/1=15/8, HBV/HCV=8/7, Child-Pugh A/B =22/1. The most common toxicities of all grades were nausea (87%), vomiting (83%), diarrhea (70%), fatigue/malaise (57%), and peripheral sensory neuropathy (26%). These toxicities were predominantly grade 1 or grade 2. The dose-limiting toxicities were persisting grade 2 nausea which needed a drug withdrawal at 200 mg and grade 3 nausea, diarrhea, peripheral sensory neuropathy and gait disturbances at 400 mg. The RD for OPB-31121 in advanced HCC pts was determined to be 200 mg. PK analysis showed that T1/2 was approximately 30 h and Tmax was around 8 h at 200 mg. Both Cmax and AUC exhibited dose proportionality. The mean Cmax value at 200 mg was 2-3 times higher than IC50 values for inhibitory effect against cell proliferation and phosphorylated STAT3 in human HCC cell lines in vitro. In 200 mg, 3 pts (44%) had stable disease among 7 pts. Conclusions: A 200mg/day of OPB-31121 was well-tolerated in pts with advanced HCC and toxicities were manageable. Further clinical development of OPB-31121 will be considered after getting results from an ongoing phase I study of another novel, chemically related compound with similar pharmacologic activities. Clinical trial information: NCT01406574.
KRX-101, a Novel FLT3 Inhibitor, Potently Active Against Resistant FLT3-ITD/FLT3-TKD Mutant AML in Vitro and In Vivo
Authors: Herman O Sintim, M. Javad Aman, Frederick Holtsberg, Ashkan Emadi, Rena G Lapidus
Journal: Blood (2018)
Effect of delaying chemotherapy on survival outcomes in the treatment of stage IV non-small cell lung cancer.
Authors: Mohammad Mozayen, Mohamed Farouq Alsharedi, Inderjit Mehmi, Todd W. Gress, Maria R. B. Tria Tirona
Journal: Journal of Clinical Oncology (2014)

e19092 Background: Whether a delay in the initiation of systemic chemotherapy for advanced non-small cell lung cancer (NSCLC) can affect overall survival (OS) is not well studied. In this study we aim to evaluate the effect of time interval between initiation chemotherapy and diagnosis on overall survival in stage IV NSCLC. Methods: A retrospective review of the tumor registry records of stage IV NSCLC patient who received chemotherapy between 1995 to 2012 at Cabell Huntington Hospital, WV was conducted. Age at diagnosis, gender, histology, performance status and site(s) of metastases of patients were reviewed. The time interval between the date of diagnosis and starting systemic chemotherapy was calculated in days. The patients were divided based on the time interval into two groups. Group A <46 days and group B 46 days or more. Primary end point was the difference in OS between the two groups. Results: A total of 172 patients were reviewed. Median time interval from diagnosis to start of treatment was 46 days. Each group had 86 patients. Median age was 61 years for A and B groups with a male to female ratio of 1:1.2 and 1:0.70, respectively. The most common histology was adenocarcinoma in group A and B (43% and 45%, respectively). The rate of metastases in groups A and B were as follows: brain -25% and 28%, liver-20% and 9%, bone -30% and 30%, respectively. Performance status of ECOG (0, 1) was 82% and 76% in group A and B, respectively .The median OS for group A was 7 months versus 12 months for group B (p=0.04). Conclusions: In our single institution retrospective review, delayed systemic chemotherapy for advanced stage IV NSCLC more than 46 days did not have a detrimental effect at OS and suggested a better outcome. Further larger and prospective studies are warranted to validate these findings.
Pre-Clinical Efficacy of CD123-Targeting Antibody-Drug Conjugate IMGN632 in Blastic Plasmacytoid Dentritic Cell Neoplasm (BPDCN) Models
Authors: Qi Zhang, Tianyu Cai, Lina Han, Vinitha Mary Kuruvilla, Sharlene Adams, Sloss M Callum, Karine Harutyunyan, Andrew A. Lane, Yelena Kovtun, Naval G. Daver, Naveen Pemmaraju, Patrick Zweider McKay, Marina Y. Konopleva
Journal: Blood (2018)
Facing Opioids in the Shadow of the HIV Epidemic
Authors: Caroline M. Parker, Jennifer S. Hirsch, Helena B. Hansen, Charles Branas, Silvia S. Martins
Journal: New England Journal of Medicine (2019)

Facing Opioids in the Shadow of the HIV Epidemic In combating the opioid epidemic, we can learn from failures in the response to HIV as well as from the successes. The failure of equity in prevention and treatment points to the importance of social factors in shaping who benefits from effective biomedical therapies.
Phase 3 trial of APF530 versus palonosetron (PALO) in preventing chemotherapy-induced nausea and vomiting (CINV): Efficacy in breast cancer patients (pts) receiving moderately (MEC) or highly (HEC) emetogenic chemotherapy.
Authors: Ralph V. Boccia, William Cooper, Erin O'Boyle
Journal: Journal of Clinical Oncology (2014)

9645 Background: APF530 provides controlled, sustained release of granisetron for preventing acute (0-24 h) and delayed (24-120 h) CINV. In a phase 3 trial measuring complete response (CR; no emesis or rescue medication), APF530 was noninferior to PALO in preventing acute and delayed CINV in MEC pts and acute CINV in HEC pts (defined by Hesketh, J Clin Oncol. 1997). We report data from 608 breast cancer pts in this trial. Methods: Pts receiving single-dose MEC or HEC were randomized to APF530 250 or 500 mg SC (granisetron 5 or 10 mg) or PALO 0.25 mg IV prior to cycle 1 (C1). In C2-4, PALO pts were randomized to APF530 250 or 500 mg; APF530 pts continued their C1 APF530 dose. Between-group comparisons used Fisher’s exact test. Results: In C1, 78% of 423 MEC pts and 75% of 185 HEC pts received cyclophosphamide + doxorubicin or epirubicin. CRs with APF530 250 or 500 mg in C1 were not significantly different from those with PALO in preventing acute and delayed CINV with MEC or HEC (Table). There were no significant differences in within-cycle CRs between APF530 doses for acute and delayed CINV in MEC or HEC in C2-4. Both APF530 doses combined elicited high CRs during acute CINV in C2 (72%, 78%), C3 (75%, 84%), and C4 (82%, 85%) for MEC and HEC, respectively, trending toward higher CRs in later cycles. High CRs occurred in C2-4 during the delayed phase and overall risk period. Conclusions: APF530 has substantial activity in preventing CINV in first and subsequent cycles of chemotherapy in breast cancer pts receiving MEC or HEC. Clinical trial information: NCT00343460. CINV APF530 250 mg APF530 500 mg PALO Between-treatment P MEC N = 149 N = 140 N = 134 Acute CR, n (%) 106 (71) 102 (73) 91 (68) .661 P* .605 .427 95% CI* -7.6, 14.0 -5.9, 15.8 Delayed CR, n (%) 69 (46) 67 (48) 69 (52) .677 P* .406 .629 95% CI* -16.8, 6.6 -15.4, 8.3 Overall CR, n (%) 63 (42) 63 (45) 61 (46) .847 P* .632 1.0 95% CI* -14.8, 8.4 -12.4, 11.4 HEC N = 60 N = 67 N = 58 Acute CR, n (%) 46 (77) 49 (73) 38 (66) .398 P* .224 .436 95% CI* -6.1, 27.4 -9.2, 24.0 Delayed CR, n (%) 35 (58) 42 (63) 30 (52) .465 P* .579 .277 95% CI* -11.9, 24.4 -6.6, 27.9 Overall CR, n (%) 31 (51.7) 37 (55.2) 24 (41.4) .288 P* .275 .152 95% CI* -7.9, 28.1 -4.1, 30.8 *P and 95% CI vs PALO.
Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine after surgery for NSCLC.
Authors: Steffen Filskov Sorensen, Andreas Carus, Peter Meldgaard
Journal: Journal of Clinical Oncology (2014)

e18501 Background: Randomized trials have demonstrated an improvement in overall survival by the use of adjuvant cisplatin-based doublet chemotherapy after surgery for stage II or III NSCLC; the benefit for stage IB remains controversial. Cisplatin can only be administered intravenously (iv.) and is often combined with vinorelbine, which can be administered either iv. or orally. Studies have demonstrated patient preference for oral administration; however, the efficacy of oral administration of vinorelbine compared to iv. in adjuvant treatment of NSCLC is unknown. This retrospective study assessed the baseline characteristics, overall and disease-free survival of patients treated with either adjuvant iv. vinorelbine/cisplatin or oral vinorelbine/cisplatin. Methods: We reviewed 265 consecutive patients referred to the Department of Oncology at Aarhus University Hospital (Denmark) from 2005–2012 for adjuvant chemotherapy after surgery for NSCLC. Survival was estimated by the Kaplan-Meier method. Results: The median age (range) of all patients was 63 years (35–80). 56% were males and 61% were in WHO performance status (PS) 0. Adenocarcinoma histology was observed in 55%. Pathological stage was IB, IIA, IIB, IIIA, IIIB, IV in 13%, 29%, 13%, 36%, 4%, and 4% of patients, respectively. 126 patients received iv. and 139 received oral vinorelbine/cisplatin; 55% received full dose of chemotherapy. The two groups were comparable with respect to baseline characteristics, but significantly imbalanced by type of surgery and median follow-up time. Median overall survival (OS) for all patients was 79.0 months (95% CI 58.3–99.7) and the median disease-free survival (DFS) was 35.0 months (16.4–53.6). Significant predictors of survival in univariate analysis were gender, N-stage, pathological stage, and PS. No statistically significant difference in OS or DFS for patients treated with iv. or oral vinorelbine was detected (p=0.90 and p=0.10, respectively). Conclusions: Intravenous or oral administration of vinorelbine in adjuvant treatment with vinorelbine/cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival.
Incidence and survival of dermatofibrosarcoma protuberans in the United States.
Authors: Kathryn L Kreicher, David E Kurlander, Haley R Gittleman, Jill Barnholtz-Sloan, Jeremy S Bordeaux
Journal: Journal of Clinical Oncology (2014)

9037 Background: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma of intermediate malignancy. Information on risk factors, incidence, and survival of DFSP is limited. We sought to describe the incidence of and survival from primary DFSP in the United States. Methods: We used data from the 18 registries of the Surveillance, Epidemiology, and End Results (SEER) Program from 2000-2010 to calculate the incidence of and survival from primary DFSP. Results: 6,817 cases of primary DFSP were reported from 2000-2010. Overall incidence was 0.41 per 100,000 person years. Incidence remained steady over the study period. The trunk was the most common anatomic site for all age groups except for men over the age of 80. Incidence among women was 1.14 times higher than men (95% CI of rate ratio: 1.07-1.22). Incidence among blacks was almost 2 times the rate among whites (95% CI of rate ratio: 1.8-2.1). 10-year relative survival of DFSP was 99.1% (95% CI: 97.6% - 99.7%). Increasing age, male sex, and black race were associated with higher all-cause mortality. Anatomic location of the upper limb, lower limb, and head were associated with higher mortality as compared to the most common location of the trunk. Conclusions: The epidemiology of DFSP differs from most skin cancers. Our data show that incidence of DFSP has not changed over the last decade. Incidence among blacks is almost twice that of whites. This is the first report showing statistically higher incidence among women than men. Worse survival is associated with increased age, male sex, black race and anatomic location of the limbs and head.
Evaluation of possible prognostic factors in patients with acute myeloid leukemia (univariate and multivariate analysis).
Authors: Mohamed Abdelfatah, Ahmed Elkhanany, Ali Al-Ameri, Rabih Nayfe, Zeyade Kanaan, Aref Al-Kali
Journal: Journal of Clinical Oncology (2014)

e18015 Background: Malnutrition is a common complication in critically ill and in-patients with malignancy, associated increase the hospital stay and adding more financial burden to the health care system. Prealbumin is a hepatic protein that had been used, as a marker for malnutrition; it is sensitive and cost-effective method in assessing the severity of illness resulting from malnutrition. Prealbumin levels have been shown to correlate with patient outcomes and are an accurate predictor of patient recovery. Methods: A total of 188 adult pts (98 male) with AML between 2002-2012 were enrolled. Retrospective data included demographics, insurance status, labs, cytogenetics. Outcome, complete remission (CR), overall survival (OS) and relapse free survival (RFS) were obtained. Serum Prealbumin was defined as <18mg/dl. 25-30 was defined as overweight, while >30 as obesity. On the other DM severity were evaluated by measuring Hemoglobin A1c, Kidney function was classified by measuring GFR. Results: In univariate line regression, definitive correlation exists between survival in weeks and age (r=-0.34, P<0.0001). However, BMI did not exhibit such correlation. In univariate Overall Survival, when compared across groups, significant correlation was found with low PreAlbumin (p< 0.0001), where median survival for low versus normal levels were 21 and 352 weeks respectively, and Complex Cytogenetics (p=0.03) with median survival 126 versus 150 weeks. However, other parameters of the cohort were mostly non significant, including Insurance status (0.07), DM control (p=0.39), BMI subcategories (p=0.4), GFR status (p=0.1), BM Fibrosis (p=0.71), Presence of trisomy 8 (p=0.37) and concomitant diagnosis of Osteoporosis (p=0.76). In multivariate analysis using Cox regression, adjusting for age, sex, BMI, prealbumin, cytogenetics, there were significant impact of both Age (Unit HR 1.024, P <0.0001) and PreAlbumin level (OR=3.86 compared with normal level, P=0.0004) on survival. Conclusions: Old age, complex cytogenetics and low PreAlbumin are seem to have statistically significant effect on survival in AML patient's, larger sample study needed to confirm our results
Survival after Hematopoietic Stem Cell Transplantation in an Older, Fit Cohort of Patients with Advanced Myelodysplastic Syndromes: The MDS-TAO Study
Authors: Gregory A. Abel, Haesook T. Kim, David P. Steensma, Richard M. Stone, Angel M. Cronin, Anand R. Habib, Vincent T. Ho, Martha Wadleigh, Areej El-Jawahri, Edwin P. Alyea, Daniel J. DeAngelo, John Koreth, Joseph H. Antin, Robert J. Soiffer, Corey S. Cutler
Journal: Blood (2018)
A phase I trial of dabrafenib (BRAF inhibitor) and pazopanib in<i> BRAF-</i>mutated advanced malignancies.
Authors: Sigurdis Haraldsdottir, Filip Janku, Cynthia Dawn Timmers, Susan Michelle Geyer, Larry J. Schaaf, Jennifer L. Sexton, Jennifer Thurmond, Vivianne Marie Velez Bravo, Vanda M. T. Stepanek, Erin Marie Bertino, Kari Lynn Kendra, Amir Mortazavi, Vivek Subbiah, Ming Poi, Mitch A. Phelps, Manisha H. Shah
Journal: Journal of Clinical Oncology (2014)

TPS2628 Background: BRAF inhibitor therapy is associated with an impressive albeit short-lived response rate in the treatment of malignant melanoma. Mechanisms of resistance include upregulation of the MAPK pathway through mutations in NRAS, MEK and BRAF alternate splicing; furthermore upregulation of PDGFR-β can cause resistance. Some malignancies, such as thyroid malignancies, have upregulation of VEGF pathways and also carry a BRAF mutation. Combination of therapies targeting VEGF and MAPK pathways could enhance the effects of both agents as well as target potential pathways of resistance. We are conducting a NCCN-sponsored phase I trial combining both agents in the treatment of advanced BRAF mutated malignancies. Methods: This is a phase I dose-escalation trial with a conventional 3+3 approach. Dose escalation of pazopanib preceeds escalation of dabrafenib doses as dabrafenib is a CYP3A4 inducer and might therefore cause more rapid metabolism of pazopanib, a CYP3A4 substrate. Inclusion criteria include any advanced malignant tumor carrying a mutation in the BRAF gene. Prior use of dabrafenib or pazopanib is not allowed and only 3 prior tyrosine kinase inhibitor regimens are allowed. Patients with a history of BRAF mutated malignancies within 5 years of study enrollment are allowed on the study. Starting doses on dose level 1 are 50 mg bid for dabrafenib and 400 mg qd for pazopanib, escalating to 150 mg bid for dabrafenib and 800 mg qd for pazopanib on dose level 5. Both agents are given continuously on a 28 day schedule. Cohorts 1 and 2 have been completed without dose-limiting toxicities. Enrollment to cohort 3 began in November 2013. Correlative studies include quantification of the copy number of the BRAF V600E mutant allele in circulating plasma. Clinical trial information: NCT01713972.
Pretreatment neutrophil to lymphocyte ratio may be an useful tool in predicting survival in early triple-negative breast cancer patients.
Authors: Mirco Pistelli, Mariagrazia De Lisa, Zelmira Ballatore, Miriam Caramanti, Alessandra Pagliacci, Nicola Battelli, Alfredo Santinelli, Tommasina Biscotti, Rossana Berardi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2014)

1111 Background: There is a growing body of evidence that immune response plays a large role in cancer outcome. The neutrophil to lymphocyte ratio has been used as a simple parameter of systemic inflammation in several tumors. The purpose was to investigate the association between pre-treatment NLR, disease-free survival and overall survival in patients with early triple negative breast cancer (TNBC). Methods: We reviewed the records of patients with stage I-III TNBC at our Institution from 2006 to 2011. Patients were divided into two groups, according to a pre-treatment NLR cut off value was 3. The difference among variables was calculated by chi-square test. DFS and OS were estimated using Kaplan-Meier method. Cox analysis was performed to analyze clinical parameters for their prognostic relevance. Results: A total of 90 patients were eligible for analysis: 18,7% of patients showed higher pre-treatment NLR (group B). Median age at diagnosis was 53 years (range 28-79). The median follow-up time was 53.8 months (13.1-195.2). There was no significant correlation among pre-treatment NLR and various clinical pathological factors, including age, menopausal status, tumor size, lymph nodes status, grading, Ki-67, necrosis, lympho-vascular invasion. At univariate analysis patients with higher pre-treatment NLR (group B) showed significantly lower DFS (p<0.01; HR=0.21, 95% CI 0.01-0.39) and OS (p<0.01; HR=0.16, 95% CI 0.007-0.37). Multivariate analysis revealed that pre-treatment NLR was an independent prognostic factors influencing DFS (p=0.006; HR=5.12, 95% CI 1.6-16.38) and OS (p=0.008; HR=6.84, CI 1.6-28.5). Conclusions: Our study suggests that pre-treatment NLR may be associated with DFS and OS of patients with early TNBC and can be easily introduced in clinical practice in order to identify TNBC patients with poor prognosis. Prospective studies are needed to assess the potential role of NLR in guiding treatment decisions, patient selection, and clinical trials design.
Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study.
Authors: Pamela T. Soliman, Russell Broaddus, Shannon Neville Westin, David A. Iglesias, Jennifer K. Burzawa, Qian Zhang, Mark F. Munsell, Rosemarie Schmandt, Lois M. Ramondetta, Karen H. Lu, Victoria Lin Bae-Jump
Journal: Journal of Clinical Oncology (2014)

5510 Background: Metformin reduces cancer incidence and improves overall survival in diabetic patients. Preclinical studies have shown that metformin decreases endometrial cancer (EC) cell growth by activation of AMPK and mTOR inhibition. The purpose of this study was to determine the effects of short-term metformin on serum and tumor biomarkers in women diagnosed with EC. Methods: In this IRB approved, prospective trial, women with newly diagnosed EC underwent a pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850 mg daily for a minimum of seven days, and then underwent post-treatment blood draw/definitive surgery. Pre- and post- serum analyses were performed. Immunohistochemical analyses on tumor tissue from the pre- and post-treatment samples were compared to evaluate molecular changes in the PI3K/AKT pathway, apoptosis, proliferation, and AMPK activity. Results: Twenty patients completed the study. Median age and BMI were 54 years (range 27-68) and 36.0 kg/m2 (range 21.9-50.0), respectively. Median waist circumference was 113 cm (range 80-156). Median duration of metformin treatment was 10 days (range 7-24). A majority of women had endometrioid adenocarcinomas (86.7%) and were early stage (93%). Two patients were noted to have KRAS mutations. After treatment with metformin, there were significant decreases in serum IGF-1 (p=0.046), omentin (p=0.007), insulin (p=0.012), C-peptide (p=0.018), and leptin (p=0.0035). Comparison of pre- and post-treatment tissue samples showed decreased levels of phospho-AKT (90%, p=0.0002), phosphor-S6rp (70%, p=0.057), and phosphor-p44/42MAPK (83.3%, p=0.0038). There was no difference in Ki67, phosphor-ACC, or caspase 3 staining in pre- and post-treatment samples. These changes did not correlate with BMI. Conclusions: In this prospective phase 0 study we demonstrate that relevant serum and molecular changes occur in patients with newly diagnosed EC after a short course of low dose metformin. Decreased circulating insulin and down regulation of the PI3K/AKT pathway signaling at the tissue level likely results in mTOR inhibition and a decrease in cell growth. Clinical trial information: NCI-2012-01796.