tbuckley/cabot-search huggingface dataset:
Preclinical profile of ASPH_0047, a potent and selective antisense oligonucleotide targeting transforming growth factor beta 2 (TGF-β2).
Authors: Michel Janicot, Katja Wosikowski, Frank Jaschinski, Hanna Korhonen, Stephan Braun, Kathy Hasenbach, Eugen Leo
Journal: Journal of Clinical Oncology (2014)

11088 Background: Transforming Growth Factor beta (TGF-β) proteins are members of a large family of related cytokines comprised of at least 33 members in mammals encoded by different genes, and which regulate a host of activities ranging from embryonic development to tissue homeostasis. The three bona fide TGF-β isoforms (TGF-β1, -β2 and -β3) play critical, pleiotropic roles in the pathophysiology of various human diseases. In cancer, correlations between TGF-β expression, disease stage and clinical parameters have been reported and linked to poor clinical outcome. TGF-β has been associated with a wide range of tumor-promoting processes, including tumor cell invasion and migration, angiogenesis, immunosuppression, as well as tumor stem cell maintenance and protection. More specifically, the TGF-β2 isoform has been reported to be a key molecular determinant of immunosuppression and invasiveness, and consequently playing a major role in metastasis. Therefore, inhibiting TGF-β2 appears as an attractive therapeutic intervention in Oncology. Methods: Based on the sequence of the human TGF-β2 mRNA, we have identified and engineered ASPH_0047, a LNA-modified antisense oligodeoxynucleotide gapmer, which shows potent and selective target mRNA and protein downregulation in various tumor cell-based assays, and promising anti-tumor activity in animal models. Results: In preclinical species, ASPH_0047 features plasma and tissue pharmacokinetics profile similar to previously reported profiles for LNA gapmers, strong metabolic stability and long-lasting tissue distribution with marked tissue penetration in liver, kidney and spleen. Preliminary safety assessment of ASPH_0047 in rats and Cynomolgus monkeys upon repeated 30-min infusion consistently points at dose-related stimulation of the immune system in several organs, including accumulation of distended macrophages in lymph nodes, and degenerative renal and liver changes at high doses. Conclusions: Key preclinical features of ASPH_0047 supporting rapid advancement to clinical development will be presented.
IV-HCC: Clinical and prognostic implications of plasma IGF-1 and VEGF in patients with hepatocellular carcinoma.
Authors: A. O. Kaseb, J. Morris, M. Hassan, E. Lin, L. Xiao, E. K. Abdalla, J. Vauthey, J. L. Abbruzzese
Journal: Journal of Clinical Oncology (2011)

155 Background: Hepatocellular carcinoma (HCC) is a vascular tumor, derived mainly by vascular endothelial growth factor (VEGF)-mediated angiogenesis. It is always associated with chronic liver disease (CLD) and cirrhosis, which directly affect survival of HCC patients. Insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, and therefore, CLD is associated with low levels of IGF-1. Methods: 288 new consecutive patients with HCC were eligible for the study between 2001 and 2008 at M. D. Anderson Cancer Center. Baseline clinicopathologic features, CLIP and BCLC staging, plasma IGF-1 and VEGF levels were available and multivariate Cox regression models and median survival were calculated. Kaplan-Meier curves were used to estimate overall survival and the log-rank test was used to compare survival probabilities in patients with different IGF-1 and VEGF levels. Recursive partitioning was used to determine the optimal cut point for IGF-1 and VEGF, using repeated training/validation samples, each using 2/3 of the data to determine the best cut point and the remaining 1/3 to validate it. Prognostic ability of different molecular staging systems was compared using C-index. Results: Lower plasma IGF-1 and higher plasma VEGF levels significantly correlated with advanced clinicopathologic parameters and poor overall survival, with an optimal cut point of 26 pg/mL and 450 pg/mL respectively. The combination of low IGF-1 and high VEGF predicts median OS of 2.7 months compared with 19 month for patients with high IGF-1 and low VEGF (p-value=&lt;0.0001), and further refines the prognostic ability of BCLC and CLIP HCC staging systems (p&lt;0.0001). Conclusions: Molecular classification of HCC using baseline plasma IGF-1 and VEGF significantly correlated with clinical features and survival of HCC patients. Furthermore, integrating IGF-1 and VEGF into HCC staging systems, CLIP and BCLC, significantly enhanced their ability to predict prognosis. It may prove to be useful in designing strategies to personalize treatment approaches to these patients. No significant financial relationships to disclose.
Codon 12 K-ras mutations in plasma DNA are not an indicator of disease in non-small-cell lung cancer (NSCLC) patients
Authors: P.-G. Betta, S. Trombino, C. Angelini, M. Neri, R. Puntoni, R. Filiberti, M. Loprevite, S. Orecchia, R. Libener, P. Russo
Journal: Journal of Clinical Oncology (2005)

7204 Background: Overexpression or mutational activation of the K-ras gene, mostly in codon 12, has been found in 30–80% of NSCLCs. Cell-free circulating DNA genetically identical to that of the primary tumor has been detected in the plasma of cancer patients. K-ras mutations were examined in plasma DNA and paired tumor tissue specimens of patients with NSCLC and also in plasmas from a different cohort of NSCLC patients and healthy control subjects. Methods: An overall number of 48 NSCLC patients and 40 controls participated in the study, after written consent. Peripheral blood was collected in EDTA-coated Vacutainers. The DNA was purified from plasma aliquots of 12 NSCLC and the corresponding tumor tissue samples. The plasma DNA was isolated using both the Qiagen method and the modified Guanidine/Promega Resin (G/R) method according to Wang et al. (Kopreski et al. J Natl Cancer Inst 2000; 92:918–23; Wang et al. Clin Chem 2004; 50:211–3). The DNA was also isolated by the Qiagen method from an additional 76 plasma samples (36 NSCLC and 40 controls, respectively). The isolated DNA was amplified by means of a PCR method that enriches for mutations in codon 12 of the K-ras gene. The assay employs simultaneous restriction enzyme digestion and PCR amplification and is similar to previously reported assays described by Kopreski et al. All amplification assays included a K-Ras mutation-positive control. Results: The presence of K-ras mutations in cancer tissue showed no correlation with the corresponding plasma sample, either extracted by the Qiagen or by the G/R Method: Codon 12 K-ras mutations were present in 2 out of 12 tissue samples, while no mutation or two mutations different from those identified in the corresponding tumor tissue were detected in the plasma using the Quiagen and G/R methods, respectively. K-ras mutations were detected in 15 plasma samples collected from the additional 36 NSCLC patients (41.7%) as well as from 12/40 controls (30.0%). Conclusions: Our results do not support the use of codon 12 K-ras mutations in plasma DNA as a diagnostic marker in NSCLC. (This study was funded by the Assessorato Sanità Regione Piemonte - Progetti Ricerca Sanitaria Finalizzata 2003) No significant financial relationships to disclose.
Dexamethasone inhibits MEK1-related epithelial tumours in vivo
Authors: R. Lal, F. Watt
Journal: Journal of Clinical Oncology (2005)

9546 Background: The ras/MEK/ERK pathway is implicated in the progression of epithelial carcinomas. In our transgenic mouse model, constitutively active MEK1 is expressed in keratinocytes in the suprabasal layers of the epidermis. We have characterised a T-cell rich, dense inflammatory infiltrate, in the dermis of MEK1 mice and observed benign epidermal tumours at suspected sites of injury. Punch-biopsy wounding induced benign tumours in 38 of 92 (41.3% 95% confidence interval (CI) 32%–52%) MEK1 mice and no tumours occurred in 44 transgene negative mice. We investigated a possible interaction between the inflammatory infiltrate and keratinocyte proliferation by comparing the proportion of MEK1 mice that developed tumours after wounding only against wounding and dexamethasone treatment, a potent anti-inflammatory agent. Methods: Age-matched, wounded, MEK1 transgenic mice were allocated to either a no treatment control group or a treatment group of dexamethasone 100mcg (3mg/kg/day by sub-cutaneous injection) for 30 days from the day after wounding. Mice were observed daily for 60 days for tumour development. The time to tumour development was recorded. Results from 2 independent experiments have been pooled. Results: Tumours developed in 15 of 37 (40.5% 95% CI 26%–57%) MEK1 mice in the no treatment group and in 4 of 38 (10.5% 95% CI 4%–25%) MEK1 mice in the dexamethasone group (Fisher’s exact test, two-sided p-value=0.0035). The difference in proportions of the 2 groups developing tumours is 0.3 (95% CI 0.11–0.49). The relative risk of wound-induced tumours with no treatment is 3.85 (95% CI 1.4–10.5). The mean time to tumour development was 22.6 days (95% CI 19.9–25.6 days) in the no treatment group and 50 days (95% CI 39.4–60.6 days) in the dexamethasone group (Mann-Whitney test, two-sided p-value=0.0005). The earliest tumour in the dexamethasone group developed 10 days after treatment ceased. Conclusion: Dexamethasone inhibits wound-induced, benign epidermal tumours in MEK1 transgenic mice. Tumours can occur after dexamethasone withdrawal. This anti-proliferative effect may be through suppression of the dermal inflammatory infiltrate. Further investigation will include the use of anti-inflammatory agents with a more specific activity profile. No significant financial relationships to disclose.
Mortality trends in female breast cancer from 1973 to 2007 in urban Shanghai.
Authors: P. Bao, C. Wu, K. Gu, C. Wang, Z. Huang, P. Peng, Y. Gong, Y. Xiang, W. Dong, W. Lu, Y. Zheng
Journal: Journal of Clinical Oncology (2011)

e12015 Background: There is limited published information describing the disease burden of breast cancer in urban Shanghai. Such information is important for planning cancer control and prevention activities. The objective of this analysis was to examine the long-term mortality trends in breast cancer in women from 1973 to 2007 in urban Shanghai. Methods: Female breast cancer deaths and number of women at risk were collected respectively by the Vital Statistics Registry of the Shanghai Center for Disease Control and Prevention and by the Municipal Bureau of Public Security of Shanghai. Time trends in the age-standardized mortality rate of breast cancer in women in urban Shanghai were analyzed using Joinpoint regression modeling including annual percentage change (APC) for both the entire period and for the time segments. Results: A total of 13 285 female breast cancer deaths were registered from 1973 to 2007 in urban Shanghai. The 5-year crude mortality was 18.3 per 100 000 person-years (py) and the age-adjusted mortality was 8.9 per 100 000 py. Breast cancer ranked the fourth leading cause of cancer death among women. From 1973 to 2007, the age-adjusted female breast cancer mortality rate increased consistently in urban Shanghai, with an overall increase of 9.0% and an APC of 0.72% (P<0.001). Conclusions: The observed increasing trend in female breast cancer mortality in urban Shanghai may reflect underlying changes in cancer related risk factors. Currently, risk factors are still widely prevalent. The cancer prevention and control strategies should continue to focus on both common measures for reducing individual exposures and environmental measures.
ROR1 Negative Chronic Lymphocytic Leukemia (CLL) Have a Distinctive Gene Expression Signature and May Represent an Indolent-Disease Subtype
Authors: Emanuela M. Ghia, Laura Z. Rassenti, Liguang Chen, Bing Cui, Christopher Deboever, Kelly A. Frazer, Thomas J. Kipps
Journal: Blood (2015)
CHIR-258: first-in-human phase 1 dose escalating trial of an oral, selectively targeted tyrosine kinase inhibitor in patients with solid tumors
Authors: D. Sarker, J. Evans, I. Judson, P. Butzberger, C. Marriott, R. Morrison, J. Vora, C. Heise, A. Hannah, J. de Bono
Journal: Journal of Clinical Oncology (2005)

3044 Background: CHIR-258 is an orally active small molecule that exhibits potent inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC50≤10 nM for VEGF, FGF, PDGF and c-KIT receptor kinases; 37nM for CSF-R1). Methods: CHIR-258 was administered as intermittent therapy (single daily doses for 7 days followed by 7-d washout, repeated) to adult patients with advanced solid tumors enrolled in groups of 3–6. The starting dose was < 1/10STD10 in the rat upon 28 days dosing. The protocol was later amended to explore continuous dosing. PK and PD (phospho-ERK in PBLs) are serially performed. Results: 20 pts (median age 60 yrs; 8F/12M; median ECOG performance status 1; median prior regimens 1, range 0–5) were treated in 4 intermittent dosing cohorts (25, 50, 75 and 100 mg/day) and 1 continuous dosing cohort (100 mg/d). DLT, consisting of grade 3 hypertension in 1 pt with pre-existing HTN, was seen upon continuous dosing; this group will be expanded. Other drug-related toxicity includes mild-to-moderate nausea/vomiting, diarrhoea, fatigue, anaemia, headache and transient pruritic rash. Plasma exposure (AUC0-24) and Cmax increase proportionally across the dose range (R2= 0.97 and 0.98, respectively) and were lower on Day 7 compared to Day 1; reduction in exposure appears to reach nadir after 7 days of dosing. Elimination half-life ranged from 10–16 hours. Trough CHIR-258 concentrations at all doses ≥ 50 mg/d were above the concentrations known to inhibit target receptor activation in vitro. Consistent with the preclinical observation that the drug preferentially accumulates in tumors, inhibition of p-ERK at 100 mg/d was observed in 2 out of 3 evaluable patients at 4 and 24 hours following the dose, despite time-dependent reduction of plasma exposure. Signs of antitumor activity included 3 pts with stable disease 4+ months (parotid, renal and imatinib-refractory GIST; the GIST pt showed a reactive increase in metabolic uptake in the PET obtained after the 7-d washout compared to that after 7-d dosing). Conclusions: Biologic activity of CHIR-258 at tolerable doses has been noted; accrual to the continuous dosing group continues to define the recommended dose. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron Chiron
Asthma remission: Predicting future airways responsiveness using an miRNA network
Authors: Michael J. McGeachie, Joshua S. Davis, Alvin T. Kho, Amber Dahlin, Joanne E. Sordillo, Maoyun Sun, Quan Lu, Scott T. Weiss, Kelan G. Tantisira
Journal: Journal of Allergy and Clinical Immunology (2017)
Acute pain management in radiation oncology: Quality of care and the impact of an integrated palliative oncology service.
Authors: Michael A Garcia, Tracy A. Balboni, Steve E. Braunstein, Shannon E. Fogh, Wendy Anderson, Steve Pantilat, Allison Taylor, Alexander Spektor, Monica Shalini Krishnan, Daphne A. Haas-Kogan, Lauren Michelle Hertan
Journal: Journal of Clinical Oncology (2016)

195 Background: Radiotherapy (RT) effectively palliates bone metastases, but relief may take weeks, frequently necessitating acute pain management (APM). NCCN Guidelines for Adult Cancer Pain (V2.2015) recommend initiation/titration of analgesics for patients with pain scale value (PSV) ≥ 4. We sought to evaluate how often symptomatic patients have analgesic regimens assessed and intervened upon at radiation oncology (RO) consult for bone metastases, and the impact of a dedicated palliative RO service on APM. Methods: We reviewed consult notes for 217 bone metastases patients treated with RT at Dana Farber Cancer Institute/Brigham &amp; Women’s Hospital (DFCI/BWH) and University of California, San Francisco (UCSF) during June-July 2008, Jan-Feb 2010, Jan-Feb 2013, and June-July 2014, time periods before and after implementation in 2011 of a dedicated palliative RO service at DFCI/BWH. For symptomatic patients, rate of assessment of analgesic regimen was recorded. Among patients with PSV ≥ 4, rate of pain intervention was recorded. The impact of a palliative RO service on these rates was evaluated. Results: Median age was 63 and median KPS was 70. Median PSV for painful bone metastases was 5 (IQR 2-7); 51% had PSV ≥ 4. Among symptomatic patients, analgesic regimen was assessed for 44.5% (51.7% at DFCI/BWH and 28.1% at UCSF). Among patients with PSV ≥ 4, pain intervention occurred for 17.2% (20.5% for DFCI/BWH, 0% for UCSF). At DFCI/BWH, consultation by a dedicated palliative RO provider was associated with higher rate of assessment of analgesic regimen (82.4% vs 47.7%, p = 0.007). At DFCI/BWH, consultation by a palliative RO provider was associated with higher rate of pain intervention (31.2% vs 7.9%, p = 0.012). There was no difference in analgesic regimen assessment or intervention between non-dedicated palliative RO providers at DFCI/BWH and UCSF (p = 0.07 and 0.09, respectively). Conclusions: At two cancer centers, half of bone metastases patients seen for RT have PSV ≥ 4, yet a minority have analgesic assessment and intervention, indicating need for APM quality improvement in RO. An integrated palliative RO service was associated with improved assessment and management of acute pain per NCCN guidelines.
Novel jumping translocations (JT) associated with genetic instability and aggressive disease in chronic lymphocytic leukemia (CLL).
Authors: C. Miller, F. Racke, G. Lozanski, A. McFaddin, J. C. Byrd, N. A. Heerema
Journal: Journal of Clinical Oncology (2011)

6533 Background: JT is a rare cytogenetic aberration involving translocation of the same fragment of donor chromosome (Chr) onto two or more recipient Chrs in different cell lines. Their presence is considered to indicate genetic instability and an aggressive disease state. While JT has been reported in hematologic tumors, there have been no reports of their occurrence in CLL. Methods: Records of CLL patients were reviewed for karyotypes containing JTs. Conventional cytogenetic analysis was performed using mitogens including pokeweed mitogen, phorbol 12-myristate 13-acetate, and CpG oligodeoxynucleotides (ODN). Fluorescence in situ hybridization (FISH) studies were also performed analyzing common recurrent aberrations in CLL. Results: We identified 8 patients who had evidence of JTs at some period during their care. Donor Chr segments exhibited 4 breakpoints (bp) from centromeric regions. Recipient bp showed no preference for a particular Chr and showed 15/32 bp in the telomeric regions, while centromeric bp occurred in 4/32. The remainder of the bp (13/32) occurred between the pericentromeric and subtelomeric regions. Of these, 11/13 were located in the same vicinity as fragile sites. Complex karyotypes were found in all cases at the time of JT formation. Importantly, FISH analysis showed a deletion of Chr 17p (TP53) in 7 of 8 cases. Although most patients carried low to intermediate Rai clinical stages at the time of diagnosis, all patients required therapy within 4 yrs of diagnosis with a median time to treatment of 4-9 months. Conclusions: The use of CpG ODNs to increase mitotic activity in CLL has led to increased sensitivity to detect Chr abnormalities in CLL using metaphase analysis. Since the institution of this method at OSU, we have begun to identify JTs occurring in our CLL population. Patients exhibiting JTs had complex karyotypes, and 7 of 8 had deletion of Chr 17p. Patients with a TP53 deletion exhibit a greater number of Chr abnormalities and an aggressive clinical course. While numbers are small, patients with JTs appear to have a clinical course as aggressive if not more so than those with TP53 deletions. To our knowledge, these represent the first cases of JTs identified in CLL.
Controlled attenuation parameter for detection and stratification of hepatic fibrosis in alcoholic and non alcoholic fatty liver disease
Authors: Antonia Lepida, Francesco Puleo, Delphine Degré, Laurine Verset, Pieter Demetter, Thierry Gustot, Massimo Bocci, Jonas Schreiber, Michael Adler, Eric Trepo, Christophe Moreno
Journal: Hepatology (2013)
Adjuvant activated T-cell (ATC) therapy for patients with non-metastatic or resected metastatic renal cell carcinoma
Authors: J. S. Treisman, R. Morris, N. Garlie, A. Lefever, J. P. Hanson
Journal: Journal of Clinical Oncology (2008)

5041 Background: Activated T cells (ATC) have the ability to kill tumor in vitro and have been used in the treatment of renal cell carcinoma (RCC). The use of ATC may have the greatest potential in the adjuvant setting with minimal residual disease. This phase II study evaluated ATC infusions in patients who had initial nephrectomy and complete surgical resection of any metastatic disease with the goal of determining toxicity, disease recurrence and survival of the treated patients. Methods: One hundred patients with completely resected RCC, ECOG 0–2 were enrolled. Mononuclear cells were collected from each patient with a single apheresis, activated with interleukin-2 and anti-CD3 monoclonal antibody (OKT3) and expanded to a total of 120 x 10 ⌃9 cells and cryopreserved. Patients had reinfusion of 10 x 10⌃9 cells monthly for 6 months, and then every 3 months for 18 months. Patients were then followed closely for evidence of recurrence and compared to a control group of patients from the same institution that had not participated in the study. Results: Of the 100 patients enrolled, 80 had Stage 3 or 4 disease. Of the 543 control patients, 92 had Stage 3 and 248 had Stage 4 disease (including 60 patients with resected disease). Cell infusions were tolerated well with most patients (82%) having no cell-related toxicities. There were no Grade 4 cell- related toxicities and Grade 1–3 toxicities consisted of transient chills, fever, headache and fatigue. Patients with Stage 3 disease treated with ATC (N=46) exhibited 64% survival at 5 years, vs. 45% for control patients (N=92) (p=.05). Patients with resected Stage 4 disease treated with ATC (N=34) exhibited 75% survival at 5 years compared 20% for controls (N=60) (p=.0008). Similarly, 38% of Stage 4 patients treated with ATC exhibited no recurrence at 5 years compared to only 20% for the controls (p=.01). Conclusions: The data suggests that ATC infusions were associated with improvement in survival for RCC patients with Stage 3 and completely resected stage 4 disease, with a decrease in recurrence rate in patients with resected stage 4 disease. A multi-center randomized trial is needed to further validate the approach. No significant financial relationships to disclose.