tbuckley/cabot-search huggingface dataset:
Preclinical efficacy, safety, and ADME of GRN163L, a novel telomerase inhibitor developed for the treatment of cancer
Authors: R. J. Tressler, A. C. Chin, S. M. Gryaznov, C. B. Harley
Journal: Journal of Clinical Oncology (2005)

3168 Background: Telomerase maintains telomeric DNA and plays a critical role in tumor cell immortality. Human telomerase is repressed or transiently active in normal somatic cells and telomeres gradually shorten over decades. In most cancers, telomeres are short, but maintained by telomerase. A correlation between tumor progression and telomerase activation makes the inhibition of telomerase a promising target for the treatment of cancer. GRN163L is a lipid-conjugated thio-phosphoramidate (N3’-P5’) oligonucleotide, developed as a potent and specific telomerase inhibitor for the treatment of cancer. Methods: GRN163L was administered systemically as a single agent or in combination with other chemotherapeutics in tumor models to assess activity of the molecule. IND-supporting preclinical toxicology, pharmacodynamic and ADME studies were carried out in multiple species to characterize the safety, pharmacokinetics and activity of GRN163L, and to determine the desired dose and schedule to be used in initial clinical trials for the treatment of cancer. Results: GRN163L administration in vivo inhibited telomerase activity and tumor growth in tumor xenografts. Models studied included melanoma, myeloma, hepatocellular, ovarian, and lung cancer. Combination studies of GRN63L with melphalan, Velcade, or taxol in various tumor models demonstrated increased efficacy of the combination regimens versus single agent treatment. ADME, pharmacodynamic and preclinical safety studies showed wide biodistribution and support an intermittent schedule and dose that should achieve efficacious levels of GRN163L in patients with an acceptable safety profile. Conclusions: Sufficient GRN163L has been manufactured under GLP and GMP conditions to support IND-enabling preclinical and Phase I clinical studies. The efficacy, PD, and ADME data have identified a target dose range and schedule for GRN163L, and preclinical safety studies have shown a robust safety margin that should allow attainment of this dose and schedule in the clinic. Additional studies to support the clinical development strategy are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Geron Geron
Effect of lymphovascular invasion and lymph node status on prognosis in patients with sweat gland carcinoma.
Authors: A. M. Crago, K. Busam, M. S. Brady
Journal: Journal of Clinical Oncology (2010)

e19017 Background: The rarity of sweat gland carcinoma (SGC) has made its natural history difficult to characterize. We reviewed our experience to define risk factors associated with recurrence and survival. Methods: 54 patients treated at an NCI-designated cancer center (NCI-CCC) from 1984 to 2007 were identified. Primary pathology from 22 cases was reviewed by a single dermatopathologist (KB). Results: Patients were followed for a median 3.3 years. The majority of primary tumors occurred on the head or neck (48%; 37% extremities). Improved disease free survival (DFS) was associated with clinically negative lymph nodes (LN) at presentation (median survival 10 vs. 1.5 years, p = 0.008) or a negative (-) LN biopsy (> 10 vs. 2.7 years, p = 0.006). 33 patients underwent wide excision of their primary tumor at the NCI-CCC, 3 in combination with regional nodal resection for palpable LN. The median radial margin was 0.75 cm; 3 received adjuvant radiation. One patient developed local recurrence (1/33, 3%). 30 patients had clinically localized disease. Of these, 2 patients recurred (7%; one in regional LN, one with distal metastases) and 1 died of disease. Half of 30 patients with clinically localized disease underwent LN staging at presentation. Four (4/16, 25%) had a (+)LN; 2 of these patients recurred. There were no recurrences in patients with a LN- biopsy (n = 12). Seven patients presented with palpable LN (4 at recurrence). All underwent LN dissection; 2/4 with available follow-up died of disease. On univariate analysis, pathologic features associated with decreased DFS were perineural invasion (p = 0.024), ulceration (p = 0.013), and lymphovascular invasion (LVI; p = 0.005). No recurrence was noted in the absence of LVI whereas 9/12 patients with LVI recurred (5 DOD, 4 AWD), (p = 0.005). Of 9 patients with LVI who underwent LN evaluation at first presentation, only one had a LN- biopsy; this patient later recurred in the regional LN basin. Conclusions: Patients who present with clinically localized SGC and pathologically (-)LNs have an excellent prognosis. The presence of LVI in the primary is a poor prognostic factor and is a reasonable surrogate for regional LN staging in clinically LN- patients. No significant financial relationships to disclose.
Phase I, pharmacokinetic, and pharmacodynamic evaluation of BNC105P, a novel anticancer agent that is both a vascular disrupting agent (VDA) and an inhibitor of cancer cell proliferation
Authors: J. Desai, S. Wong, G. Chong, D. Bibby, A. Leske, G. Kremmidiotis, M. Rosen, D. Rischin
Journal: Journal of Clinical Oncology (2009)

e14512 Background: BNC105P is a novel anticancer agent that inhibits tubulin polymerization and acts as a VDA. BNC105P is a phosphorylated parent compound which rapidly becomes the active agent BNC105. BNC105 exhibits 100-fold specificity for activated endothelial cells compared to quiescent endothelial cells. Methods: BNC105P (2.1 to 18.9 mg/m2) was given IV over 10 min on day 1 and 8 every 21 days to patients (pts) with advanced solid tumors (ECOG 0–2) and adequate organ function. The objectives were to determine safety, tolerability, MTD and pharmacokinetics (PK). A pharmacodynamic response was evaluated using DCE-MRI with two baseline and two post dose assessments (3–6, 24 h). DLTs were determined during the first 21 days. Results: 9 pts (7 M; 2 F), median age 60 years have been enrolled with one pt each at 2.1 and 4.2 mg/m2. At 8.4 mg/m2, one pt experienced Grade 2 (Gr 2) mucositis and a switch to a ‘3+3’ design occurred. No DLTs have been observed in 3 pts at 12.6 mg/m2 and 1 pt at 18.9 mg/m2. Notable toxicity includes one episode of Gr 1 febrile episode possibly related to infusion, two episodes of Gr 1 fatigue and one Gr 1 rash. PK data of BNC105 indicates a linear increase in plasma AUC levels (Table) and plasma half life of &lt; 0.5 h. Best observed responses were SD in 2/9 pts including one pt with mesothelioma (progression at entry) with SD up to week 22 (8.4 mg/m2). At doses ≥ 8.4 mg/m2, DCE-MRI images indicate changes in tumor perfusion post-dose. Two pts at 12.6 mg/m2 had a decrease in Ktrans values of 6 and 15 % compared to baseline. Conclusions: Pharmacodynamically active doses have been achieved with plasma drug levels correlating with active preclinical plasma exposure. To date, no excess toxicity has been observed at doses up to 18.9 mg/m2. [Table: see text] [Table: see text]
Outcome and cause of death of hepatocellular carcinoma patients with extrahepatic metastases.
Authors: Satoshi Shiba, Shunsuke Kondo, Yasunari Sakamoto, Mitsuhito Sasaki, Futa Koga, Hiroko Hosoi, Chigusa Morizane, Hideki Ueno, Takuji Okusaka
Journal: Journal of Clinical Oncology (2015)

456 Background: Sorafenib is an orally active multi-kinase inhibitor that has been approved for the treatment of advanced hepatocellular carcinoma (HCC). Advanced HCC patients often exhibit two co-existing and life-threatening factors, cancer and cirrhosis, complicating prognostic evaluations. The present study investigated the survival and causes of death of HCC patients with extrahepatic metastases in the sorafenib era. Methods: We retrospectively analyzed 72 HCC patients with extrahepatic metastases who had received sorafenib. The causes of death among the HCC patients were classified as either hepatic causes (HC) or non-hepatic causes (NHC). Each cause of death was analyzed in the two subgroups. We then compared and assessed their clinical features and outcomes using the Chi square test, the Kaplan-Meier method, and a multivariate analysis. Results: Of the 72 HCC patients (female/male, 12/60), 50 patients had died at the time of the analysis. The median age was 66 (range, 30-84) years. At the time when sorafenib was started, the number of patients with a performance status of 0, 1, or 2 was 63 (88%), 8 (11%), and 1 (1%), respectively, and the number of patients with Child-Pugh class A, and B were 67 (93%), and 5 (7%), respectively. The median survival time and the 1-year survival rate were 11.8 (95% confidence interval 5.3-18.3) months and 49.7%, respectively. The incidence of HC and NHC was 29 (58%) and 21 (42%), respectively. Differences between the HC group and the NHC group were examined according to the patient characteristics, and the following significant differences were observed: main portal vein invasion (P&lt;.05), intrahepatic tumor stage (P&lt;.05), alpha-fetoprotein (AFP) (P&lt;.05), and the des-gamma-carboxy-prothrombin level (P&lt;.05). A multivariate analysis showed that portal vein invasion (hazard ratio [HR] = 2.29, P&lt;.05), a Child-Pugh B status (HR = 7.19, P&lt;.01), and high serum levels of AFP (HR = 2.18, P&lt;.05) were independent predictors of a poor outcome, respectively. Conclusions: This study revealed differences in the clinical characteristics at the time of the start of sorafenib between patients with HC and NHC death. The present results may be useful in the design and analysis of future clinical trials.
Cognitive function, fatigue and menopausal symptoms in women following adjuvant chemotherapy for breast cancer: One and two year follow-up of a prospective controlled study
Authors: N. Tchen, H. G. Juffs, Q. L. Yi, I. Chemerynsky, F. P. Downie, K. Sabate, I. F. Tannock
Journal: Journal of Clinical Oncology (2004)

8001 Background: Previously we reported substantial fatigue and menopausal symptoms in 100 women receiving adjuvant chemotherapy (CT) for breast cancer, as compared to 100 matched normal women (p<0.0001 for both), with 16% of patients (pts) and 4% of controls experiencing moderate-severe cognitive dysfunction (p<0.008; J Clin Oncol 22, 4175–83, 2003). Here we report one and two-year follow-up. Methods: Initially pts receiving adjuvant CT nominated a female acquaintance, matched by age (+/-5yrs), as a control. Patients and controls were evaluated using the High-Sensitivity Cognitive Screen (HSCS), and the FACT-G quality of life (QL) scale, with subscales for menopausal symptoms (FACT-ES) and fatigue (FACT-F). The first evaluation was towards the end of CT, and was repeated one and two years later. Results: One year evaluations are complete (N=89 pts, 81 controls; 11/19 relapsed or withdrew) and 2-year evaluations will be complete by ASCO 2004 (currently 51pts, 51 controls). Patients showed marked improvement from baseline in cognitive function (p<0.0003), QL and fatigue (p<0.0001for both), and had fewer endocrine symptoms (p<0.03). There were still significant differences in fatigue and menopausal symptoms (p<0.0001 for both), between pts and controls, at one year. Tamoxifen was taken by 45 of 89 pts: menopausal symptoms (p<0.008) and fatigue (p=0.06) improved less, and cognitive function more (p=0.03) in pts taking tamoxifen. Conclusions: Cognitive dysfunction, is temporary in most pts; fatigue and menopausal symptoms improve rapidly but remain worse than in control subjects for at least one year. No significant financial relationships to disclose.
Phase I study of irinotecan (Iri) and cisplatin (Cp) in combination with pelvic radiotherapy for the treatment (Tt) of advanced cervical cancer (ACC): A GINECO trial
Authors: M. Fabbro, L. Gladieff, J. F. Geay, F. Guichard, C. Lemanski, F. Dalenc, D. Paraiso, M. Delannes, E. Pujade-Lauraine
Journal: Journal of Clinical Oncology (2006)

5054 Background: Chemoradiotherapy with weekly Cp has become standard for ACC treatment. Combining Cp with another active drug in ACC such as Ir may increase the activity of Tt. Methods: Treatment consisted of 6 weekly cycles with escalating dose of Ir and fixed dose of Cp (20 mg/m 2 ) administered during pelvic radiotherapy (45–50 Gy). Brachytherapy and/or surgery were allowed after pelvic chemoradiotherapy according to center policy. Cohorts of 3 to 6 pts with FIGO stage IB-IVA newly diagnosed ACC, performance status ECOG 1–2 and adequate major organ function were eligible at each dose level. Results: 15 pts were accrued at dose level I (n = 6), II (n = 3) and Intermediate (Int) (n = 6). Dose levels (DL) for Ir were 30 mg/m 2 (I), 40 (II) and 35 (Int). Dose limiting toxicity (DLT) was observed in 2/3 pts at DL II (Gr 3 asthenia in 2/3 pts including Gr 3 diarrhea and abdominal pain in one). DLT was observed in 2/6 pts at DL I (NCI-CTC Gr 3 diarrhea in 2/6 pts including Gr 3 asthenia and abdominal pain in one) and DL Int (Gr 3 asthenia in 2/6 pts including febrile neutropenia in one). However, 3/4 pts without DLT at DL Int did not complete the whole chemotherapy schedule due to pelvic mucositis and skin toxicity (dose reduction: 2pts, early stopping at 3 cycles : 1 pt). In contrast, 5/6 non-progressive pts at DL I completed their scheduled chemo-radiotherapy, with dose reduction in only 1 pt who experienced a DLT. Efficacy evaluation showed complete and partial response in 6 and 5 of the 12 evaluable patients. Conclusions: the recommended dose for future phase II study of chemoradiotherapy in ACC is irinotecan (30mg/m 2 , weekly) with cisplatin (20 mg/m 2 , weekly). No significant financial relationships to disclose.
Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies
Authors: A. M. Joshua, P. Marrano, A. Evans, T. Van der Kwast, M. Zielenska, J. Squire
Journal: Journal of Clinical Oncology (2009)

11107 Background: Many critical events in prostatic carcinogenesis appear to relate to the emergence of chromosomal instability and acquisition of genomic rearrangements. Characteristic abnormalities such as 8p loss, 8q gain, trisomy 7, PTEN microdeletions and TMPRSS2-ERG gene fusions appear to mediate mechanisms to increase neoplastic transformation in prostate cancer. Current evidence suggests that telomere dysfunction is a likely causative factor for some of these abnormalities on the basis of its relationship to mechanisms such as the break-fusion-bridge cycle that can lead to the onset of chromosomal instability. Methods: In this study, we correlated telomere length in various prostatic histologies by quantitative FISH with genomic markers of chromosomal instability by standard FISH and immunohistochemical measures of proliferation in 3 whole mount prostatectomies. Results: After analysing approximately 25,000 cells, we found that telomere shortening was correlated with an increase in the number of cells with abnormalities on chromosome 8, such as an increase in the average number of c-myc signals (r∼0.35, p∼0.02). However, there were no significant correlations with abnormalities such as trisomy 7 or abnormalities of the PTEN locus in any sample. Additional findings included; associations found with the probability of C-MYC aberrations in stroma with greater proximity to cancer (&lt;1,000 um), a correlation between telomere length in a number of prostatic histologies (normal, atrophy, HPIN and cancer) with the adjacent stroma, and a lack of correlation between the Ki67 index of various histologies and their telomere length - all suggesting the importance of microenvironmental effects on telomere maintenance in the prostate. Finally, we also report significant telomere shortening in BPH in 2 cases, a phenomenon that has not been noted previously. Conclusions: This is the first study to directly link a mechanism of chromosomal instability with specific chromosomal abnormalities in prostatic carcinogenesis and also suggests that the microenvironmental milieu is of critical importance in the evolution of in vivo telomere homeostasis. No significant financial relationships to disclose.
Follow-up of abnormal pap smear results: A population-based study.
Authors: R. Kupets, L. F. Paszat
Journal: Journal of Clinical Oncology (2010)

6076 Background: This population based study investigates the patterns of care women with high-grade cervical dysplasias receive in Ontario. Methods: The study population includes women with a first-time diagnosis of a high-grade dysplasia from 2000-2005 as identified in a centralized cervical smear database. Record linkages were then carried out to other centralized databases which include data on inpatient and outpatient procedures to characterize patterns of care provided to women with high-grade abnormal cervical smears. High-grade smears are defined ASC-H, AGUS or AGC, HSIL or diagnosis of malignancy or carcinoma on pap smear. Results: 43,712 women had a mean age of 37.6. Percent break down by diagnosis: ASC-H, AGUS, HSIL, malignancy, carcinoma: 8.9, 33, 55, 1.9, 0.17. Mean time to referral to colposcopy in weeks: ASC-H, AGUS, HSIL, malignancy, carcinoma: 16, 24, 13, 8.6, 6. Of those with a final diagnosis of cervical cancer (n = 1,195) mean time to diagnosis from index pap in weeks: ASC-H, AGUS, HSIL, malignancy, carcinoma: 26, 26, 17, 6, 3. Of those with a final diagnosis of endometrial cancer (n = 559), mean time to diagnosis from index pap in weeks: AGUS, malignancy, carcinoma: 16, 5.3, 1.5. Percentage of patients with high-grade pap smear who had no follow-up all with up to a 2-year window from index pap: ASC-H, AGUS, HSIL, malignancy, carcinoma: 16, 59, 9, 17, 28. Conclusions: Time to management of women with severe changes on pap smear is lengthy. Overall, 30% of these women are lost to follow-up and those with atypical glandular cells had the highest loss to follow up rates. Guidelines for the management of high-grade cervical smear lesions should specify time frames for reasonable follow-up of abnormal results. A consideration for revision of nomenclature used by cytopathologists should be undertaken as a strategy to reduce loss to follow-up of potentially serious cervical lesions. No significant financial relationships to disclose.
The infiltrative, diffuse pattern of recurrence in patients with malignant gliomas treated with bevacizumab
Authors: L. Potthast, S. Chowdhary, E. Pan, D. Yu, W. Zhu, S. Brem
Journal: Journal of Clinical Oncology (2009)

2057 Background: There is no standard of care for recurrent gliomas; however, bevacizumab is often used as a salvage chemotherapy regimen. A diffuse, infiltrative pattern of recurrence, as evidenced by MR imaging, was seen manifesting as multifocal disease or presumed CSF dissemination with subependymal spread. Methods: We conducted a retrospective analysis of 40 recurrent glioma patients followed at Moffitt Cancer Center from September 2006 through December 2008 treated with bevacizumab alone or in combination with irinotecan. Histologies included glioblastoma (GB), anaplastic astrocytomas (AA), anaplastic oligodendrogliomas (AO), anaplastic oligoastrocytomas (AOA), and low-grade astrocytomas. Rate of diffuse, infiltrative recurrence, progression free survival (PFS) and overall survival (OS) were analyzed and correlated with respect to specific prognostic variables. Results: 38% (15) of the patients were female and 63% (25) were male. The median (range) age was 51 (20–72) years. The median (range) KPS was 80 (50–100). Twenty-six (65%) patients had GB, 8 (20%) AA, 2 (5%) AO, and 3 (8%) AOA and 1 (3%) had LGA. Five (13%) patients had a gross total resection (GTR), 23 (58%) a subtotal resection (STR) and 12 (30%) had biopsy only. The median (range) number of prior therapies was 2 (1–7). At time of analysis 28 (70%) patients had died. Incidence of diffuse, infiltrative recurrence was seen in 8 (20%) of patients (95% CI: [9%, 36%]). This recurrence seems to be negatively associated with age: rate for age&lt;=50: 6/18 (33%); (95% CI: [13%, 59%]) while rate for age&gt;50: 2/22 (9%); (95% CI: [1%, 29%]), with an odds ratio (OR) of 5.0. Conclusions: There appears to be an increase in a diffuse, infiltrative pattern of recurrence among recurrent glioma patients treated with bevacizumab as a salvage regimen. In our experience, this appears most prevalent in patients less than 50 years of age. It is unclear why the disparity among this subset of patients occurs, however, we hypothesize that this may once again highlight the distinct tumor biology among young glioma patients. The impact of this observation on clinical decision making on whether to utilize bevacizumab in young recurrent glioma patients warrants further investigation. [Table: see text]
Enhanced immunogenicity of a nanoparticle therapeutic cancer vaccine targeting HAAH delivered intradermally using 3M's hollow microstructured transdermal system (hMTS)
Authors: Steven Fuller, Michael Lebowitz, Solomon Stewart, Susan Walker, Hossein Ghanbari, Allan Bohlke, Scott Burton, Leonard Chu, Vinh Hua
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts We are evaluating the immunogenicity and efficacy of a nanoparticle vaccine (NPV) targeting the tumor marker human aspartyl (asparaginyl) β-hydroxylase (HAAH). HAAH is an embryonic protein that is over-expressed on the surface of cancer cells, is demonstrated to be responsible
How payment reform drives innovation in interventional oncology.
Authors: Joseph Rodgers Steele, Ryan Kristopher Clarke, Elizabeth Priya Ninan, Armeen Mahvash
Journal: Journal of Clinical Oncology (2013)

276 Background: Innovation has transformed healthcare; however, our current fee-for-service payment system can actually stifle creativity. When procedures are streamlined, fewer CPT codes may be charged, resulting in lower total reimbursement. Payment reform is necessary not only to control costs, but also to support constructive innovation. We describe how an innovative, lower reimbursed, technique of catheter-directed cancer therapy failed widespread acceptance in spite of being faster, safer and cheaper than the standard of care. Methods: Retrospective patient review was performed using the radiology information system and electronic health record. Medicare Part A and Part B payments were obtained from the Hospital Outpatient Prospective Payment System (HOPPS) for Harris County, Texas, and disposable supply costs were obtained from Premier Group Purchasing Organization. Results: From May 2008 to May 2013, 292 Yttrium-90 hepatic radioembolization procedures were performed for primary and metastatic disease. Eighty patients received the innovated balloon occlusion technique. This technique resulted in less fluoroscopy dose to the patient, faster procedure times, similar clinical outcome and a disposable cost savings of $1,138.72. However, because numerous procedure steps were avoided, the total average per-patient reimbursement was decreased by $8,044.05. Conclusions: Innovation that simplifies a procedure frequently obviates process steps that correspond to specific CPT codes. Hence, in a fee-for-service payment system, a faster, safer and cheaper option may result in fewer CPT codes and lower reimbursement, a disincentive that slows adoption. Our experience resulted in lost profit of over $8,000 per case for a total exceeding $640,000. Not surprisingly, this technique has not been widely embraced since we described it nearly two years ago. Conversely, a bundled payment model would have resulted in better aligned incentives, increased profit, and cost savings shared by patients, providers, and payers.