tbuckley/cabot-search huggingface dataset:
A randomized double-blind phase II evaluation of the cyclooxygenase-2 protein inhibitor celecoxib in treating severe dysplasia of the cervix
Authors: J. H. Farley, V. Truong, J. McBroom, E. Goo, W. Larsen
Journal: Journal of Clinical Oncology (2005)

5106 Background: We evaluated the efficacy of daily Celecoxib in the regression of moderate and severe cervical dysplasia, when compared to placebo. Methods: All women, over the age of 18, with the histologic diagnosis of CIN II or III were entered onto the IRB approved study. Women who were pregnant, breast feeding, had a medical history of stomach bleeding, history of allergic reaction after taking NSAIDs, severe kidney or liver problems, positive dysplasia on ECC, cervical cytology diagnosis of, AGUS, CIS, AIS, invasive carcinoma, or severe clinical immunosuppression, were excluded. Women were randomized to receive either Celecoxib 200mg twice a day or placebo. Both examining physician and patients were blinded to treatment option. Follow-up colposcopy with cervical cytology was obtained at 2 months intervals for six months. Results: From November 2002 until October 2003 a total of 25 patients were enrolled in this Randomized Phase II study. 5 patients self terminated the study early but were included in the final statistical analysis. All of the Celecoxib patients tested positive by HC II for high risk HPV while only 85% of placebo patients were positive for high risk HPV. 92%, of the Celecoxib group had CIN II while, 15%, of the placebo group had CIN III. There was no statistical difference in the distribution of any of the clinical variables between the Celecoxib and placebo groups to include entry histology and cytology. 56% of patients enrolled had an overall response in the trial. The mean time to response was 69 days. 84% of patients who received Celecoxib had a clinical response. This was significantly higher than the 31%, of the placebo patients that had a clinical response, p< 0.025. 1 patient, 8%, of the Celecoxib group had progression of disease while three, 23%, of the placebo group had progression of disease at a mean time of 65 days. Conclusions: We have demonstrated that Celecoxib has significant activity in the treatment of high-grade cervical dysplasia. Those patients taking Celecoxib were 75% more likely to have a decrease in the severity of cervical dysplasia on therapy. Further trials with larger numbers are needed to assess duration of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
<i>KRAS</i> gene amplification to define a distinct molecular subgroup of gastroesophageal adenocarcinoma.
Authors: Les Henderson, Peng Xu, Emily O'Day, Fabiola Cecchi, Adele Blackler, Wei-Li Liao, Todd A. Hembrough, Daniel V.T. Catenacci
Journal: Journal of Clinical Oncology (2016)

74 Background: KRAS mutation is rare ( &lt; 5%) in gastroesophageal cancer (GEC). However, the incidence of KRAS gene amplification (amp+), consequent protein levels, and prognostic and/or therapeutic implications are unknown. Methods: 410 GEC samples and 30 cell lines were assessed for KRAS gene copy number (GCN) by fluorescence in situ hybridization (FISH) (n = 90), Kras expression by selected reaction monitoring mass spectrometry (Kras-SRM-MS) (n = 393), and Kras-SRM level evaluated for correlation with KRAS amp+ status (n = 73). Survival analysis was performed comparing KRAS amp+ versus non-amp+ patients. When possible, concurrent 315 gene next-generation sequencing was also performed. Four KRAS-amplified xenograft lines (CAT-2,12,14,15) were established from malignant effusions. Tumorigenic activity of KRAS amp+ lines (CAT lines, MKN-1) were assessed using MTT and soft agar assays in vitro and subcutaneous xenograft models, compared to non-amp+ lines. Inhibitory assays were performed using KRAS siRNA and CRIPSR, and commercial inhibitors targeting downstream effectors MEK and/or PIK3CA. Results: KRAS FISH revealed clustered gene amp+ in 28.9% (26/90); these patients had worse prognosis than non-amp+ patients. GCN significantly correlated with Kras expression. All KRAS amp+ cell lines significantly overexpressed Kras protein and were tumorigenic in xenograft subcutaneous models. KRAS siRNA and KRAS CRISPR of KRAS amp+ cell lines demonstrated inhibition in MTT viability and soft agar assays, compared to appropriate controls, and demonstrated significant and durable xenograft growth reduction. Conversely, inhibition using MEK and/or PI3K inhibitors demonstrated only transient growth reduction in vivo. Conclusions: KRAS gene amp+ was observed in a large subset (26%) of GEC patients, which correlated with extreme expression by mass spectrometry. Established xenograft lines serve as models to investigate therapeutic strategies for KRAS amp+ patients. Inhibition using MEK/PIK3CA inhibitors provided transient benefit for KRAS amp+ tumors while durable inhibition was observed with Kras protein knockdown, suggesting potential benefit from novel siRNA therapeutics currently in development.
Multicenter phase II study of trastuzumab (H) and capecitabine (X) as first- or second-line treatment in HER2 over-expressing metastatic breast cancer (Japan Breast Cancer Study Group: JBCSG-003)
Authors: D. Yamamoto, S. Iwase, K. Kitamura, H. Odagiri
Journal: Journal of Clinical Oncology (2005)

802 Background: H and X are active in MBC and are synergistic in pre-clinical models. Methods: We are conducting a multi-center phase II trial to evaluate the safety and efficacy of capecitabine (1657 mg/m2/day in 2 divided doses from day 1 to day 21 of each 28 days cycle) combined with H (2 mg/kg/wk IV after an initial 4 mg/kg loading dose) as 1st- or 2nd-line Rx in HER2 over-expressing (2+ or 3+) MBC. Results: 27 Patients (pts) with MBC receiving prior chemotherapy Rx for MBC, taxane, and adriamycin were enrolled. Pt characteristics are as follows: 7 pts HER2 2+, 20 pts HER2 3+, median age 54 (range: 42–70), median number of disease sites 2.2 (range: 1–4), visceral dominant disease 16 (59.3%), no prior adjuvant treatment only 5 (18.5%), prior treatment for MBC 22 (81.5%). Three pts experienced G2 hand-foot syndrome, 15 pts had G1 hand-foot syndrome, 7 pts had G1 nausea/vomiting, 5 pt had G1 fatigue, 3 pt had G1 diarrhea, 1 pt had G1 infection, 1 pt had hypersensitivity reaction. Eleven PR’s (40.7 %) were observed and 9 NC’s (33.3%) were observed in 27 pts. ORR was 28.6% (2/7) in HER2 2+ pts and 45% (9/20) in HER2 3+ pts. Median TTP was 5.2 months.OS was 16.1 months. Conclusions: Therefore, based on these data, H and X is a well tolerated, effective regimen in HER2 overexpressing MBC. No significant financial relationships to disclose.
High frequency irreversible electroporation (H-FIRE) as a novel method of targeted cell death.
Authors: Imran A Siddiqui, Russell C. Kirks, Erin H Baker, Eduardo Latouche, Matt Dewitt, Jacob Swet, Dionisios Vrochides, David A Iannitti, Rafael Davalos, Iain Mckillop
Journal: Journal of Clinical Oncology (2016)

277 Background: Irreversible electroporation unlike ablation is excellent in inducing cell death via apoptosis. It, however, has disadvantages of electrical conduction via cardiac and nervous tissue. This results in requiring cardiac monitoring and general anesthesia and paralytics while performing electroporation. We hypothesized a novel high-frequency IRE (H-FIRE) system employing ultra-short bipolar pulses would obviate the need for cardiac synchronization and paralytics while maintaining measurable effect on cell death. Methods: Female swine (55-65Kg) were used. Two H-FIRE electrodes were inserted into the liver (1.5-cm spacing). In the absence of paralytics H-FIRE pulses were delivered (2250V, 2-5-2 pulse configuration) at different on times (100 vs. 200μs) or number of pulses (100 vs. 300). Next electrodes were placed across major hepatic vascular structures and H-FIRE performed. At conclusion tissue was resected and analyzed histologically. Results: 24 H-FIREs were performed (mean ablation time 275 secs). No EKG abnormalities or changes in vital signs were measured during H-FIRE procedures. In 1/24 H-FIREs minor twitching of the rectus abdominis was recorded coinciding with pulse delivery. Histologically, tissues had effective electroporation as evidenced by cell death and caspase activity. Blinded scoring was performed for necrosis and apoptosis. Areas of cell death were predictable. No significant vascular damage or coagulated/thermally-desiccated blood was detected within major vessels following H-FIRE. Conclusions: H-FIRE is a novel way of liver electroporation. It produces predictable cell apoptosis without the requirement of paralytics and alteration of electrocardiographic signals as compared to traditional electroporation, while preserving underlying vascular integrity. Its application in cancer cell death needs to be further studied, but it has a potential for clinical use in targeting tumors with minimal morbidity and associated cardiac and neurologic side effects.
Feasibility of adjuvant cisplatin and gemcitabine in patients who have undergone complete resection of stage IB-IIIA non-small cell lung cancer (NSCLC): Preliminary report of a feasibility trial in Japanese patients
Authors: M. Yamaguchi, S. Takeo, R. Suemitsu
Journal: Journal of Clinical Oncology (2008)

18503 Background: Adjuvant cisplatin-based chemotherapy has been shown to improve survival in patients with completely resected NSCLC. To evaluate the feasibility and safety of combination of cisplatine (C) and gemcitabine (G) as adjuvant chemotherapy in Japanese patients with completely resected NSCLC. Methods: Patients with completely resected NSCLC with ECOG PS 0–1 and preserved renal, hepatic, and bone marrow function were enrolled. Therapy was initiated within 8 weeks from surgery and consisted of 4 cycles of intravenous C (50 mg/m2) and G (1,000 mg/m2) on days 1 and 15 every 4 weeks. The primary endpoint was the feasibility. An “adequate exposure” was defined as receiving 4 cycles within 16 weeks of initiating therapy. A two-stage optimal Simon design was used: to proceed beyond the first stage, 5 of the first 7 treated patients had to have reached completion. We hypothesized that if the threshold successful execution rate was 55% and the expected successful execution rate was 80%, 16 patients would be required for this analysis. Results: Twenty patients were enrolled, and 10 have completed. The patient characteristics are median age: = 65.8 years (range 41–73); gender: 2 females and 8 males; race: all Japanese; all performance status: 0; procedure: 9 lobectomies and 1 pneumonectomy. The stage distribution was stage II (70%) and stage IIIA (30%). To date, 6 of 10 patients (60%) have completed 4 cycles with a full dose, and 2 patients each have completed 3 and 2 cycles, respectively. One patient who discontinued the protocol at 2 cycles required dose reduction. With regard to hematologic toxicity, there were 3 grade 3 and 1 grade 4 neutropenias and 1 grade 3 and 2 grade 4 anemias. No grade 3/4 nonhematologic toxicity was observed. Treatment was discontinued due to withdrawal from treatment (n=1) and grade 4 anemia (n=2), and no treatment-related deaths were observed. Conclusions: Preliminary results indicate this adjuvant therapy is safe and feasible as adjuvant chemotherapy for Japanese patients with completely resected NSCLC. A Phase III trial with this regimen is warranted to assess its impact on survival. No significant financial relationships to disclose.
Geriatric subgroup of AGITG MAX trial: International randomized phase III trial of capecitabine (C), bevacizumab (B), and mitomycin C (M) in first-line metastatic colorectal cancer (CRC).
Authors: T. J. Price, D. Zannino, K. Wilson, J. Simes, G. A. Van Hazel, B. A. Robinson, A. Broad, V. Ganju, S. P. Ackland, N. C. Tebbutt
Journal: Journal of Clinical Oncology (2011)

510 Background: In an aging population a greater proportion of geriatric patients will be considered for systemic chemotherapy. CRC is a common cancer and will be a major health issue in geriatrics. Methods: MAX, a three arm study of C v CB v CBM, found an improvement in PFS with addition of B (± MMC) to C (Tebbutt NC et al. JCO 2010; 28(19): 3191–3198). This analysis assesses effect of adding B (± MMC) to C on PFS, OS, RR and toxicity in geriatric patients (age &gt;75y). Results: 99 patients (21%) were &gt;75y. Number/Median age: C 37/78.5y (75.2–86), CB 32/78.7y (75.2–84.9), CBM 30/80.2y (75.2–83.4). Baseline characteristics were well balanced. 88% commenced C dose of 2000mg/m 2 /day, d1–14, q21 (61% for &lt;75y). ECOG 0–1 for 88%. Comorbidities were: (%) Ex/smoker 13/2, diabetes 15, HT 56, IHD 15, CVA/TIA 10. These are similar to reported rates ( http://www.aihw.gov.au/cdarf/data_pages/incidence_prevalence/index.cfm ) in this population. Proportion receiving all three chemotherapy drugs at some time (5FU/oxaliplatin/irinotecan) was 10% &gt;75y v 20% &lt;75y. RR, median PFS &amp; OS reported in Table. Interaction test for OS, RR and PFS revealed no impact of age. Gd 3-4 tox for &gt;75y C/CB/CBM respectively was (%); vomiting 5/13/3, diarrhea 19/22/20, stomatitis 3/0/3, HT 0/3/3, thrombosis/thrombus/embolism 5/6/13, cardiac 0/6 (3 Gd5)/3. There was one perforation (Gd5) in C. Grade 2/3 HFS (%) was 38/59/53. One Gd 3-4 neutropenia episode in CB, no Gd 3-4 thrombocytopenia. Overall, toxicity rate similar to &lt;75 y. Conclusions: Significant improvement in PFS with addition of B to C was seen in this geriatric population, similar to results of ITT group and those &lt;75yrs. Treatment was well tolerated with no signal of increased toxicity when compared to those &lt;75yrs, including VTE/ATE. [Table: see text] [Table: see text]
HLA-Haploidentical Bone Marrow Transplantation (BMT) for High Risk Hematologic Malignancies Using Myeloablative Conditioning and High-Dose, Posttransplantation Cyclophosphamide
Authors: Heather Symons, Allen R. Chen, M. Sue Leffell, Marianna Zahurak, Kathy Schultz, Heather Karaszkiewicz, Leo Luznik, Javier Bolanos Meade, Yvette L. Kasamon, Lode J. Swinnen, Douglas Edward Gladstone, Richard J. Jones, Ephraim Fuchs
Journal: Blood (2010)
Racial/ethnic variation in a common genetic alteration in prostate cancer.
Authors: Isabell Sesterhenn, Denise Young, Yongmei Chen, Gyorgy Petrovics, Jennifer Cullen, Jacob Kagan, Sudhir Srivastava, Inger L. Rosner, David G. McLeod, Albert Dobi, Shiv Srivastava
Journal: Journal of Clinical Oncology (2015)

14 Background: The molecular basis of racial/ethnic differences in the detection and outcomes of the carcinoma of the prostate (CaP) needs to be better defined to improve biomarkers and identify appropriate therapeutic targets. ETS-related gene fusions in proto-oncogenes (ERG, ETV1) are among the most common early oncogenic alterations described in CaP. Studies have highlighted the racial/ethnic variation in ERG fusion and ERG oncoprotein expression frequencies showing: the highest frequencies in Caucasian (CA) men, the lowest frequencies in Asian men, and intermediate frequencies in African American (AA) men. These differences persisted when patients were carefully matched for age and clinico-pathologic features. Building on previous work, the current study was conducted to evaluate ERG expression frequencies in a large cohort of AA and CA CaP patients. Methods: Patients enrolled at the Walter Reed National Military Medical Center who consented to provide radical prostatectomy (RP) specimens to the CPDR Tissue Bank and Clinical Database were evaluated. The current study included 443 AA and 696 CA patients. ERG oncoprotein expression was detected by immunohistochemistry using the 9FY mouse monoclonal anti-ERG antibody and was correlated with clinico-pathologic features and CaP outcomes. Results: Lower frequencies of ERG in the index tumors of AA men as compared to CA men (28.4% vs. 51.5%, p &lt; 0.0001) were observed. Furthermore, AA men with higher grade CaP (Gleason 8-10) had even lower ERG frequency (16%), suggesting distinct molecular biologic features in aggressive CaP for AA men. A trend with age was observed for both racial groups, with younger CA showing higher ERG frequencies. At least one focus of ERG positive PIN was present in prostates with ERG positive tumors. In both CA and AA patients, a very low frequency (8%) of ERG expression was noted in anterior index tumors compared to posterior tumors. Conclusions: This study lends increasing support to differences of the most common early genomic alteration (ERG) between AA and CA CaP patients. The study also underscores the importance of identifying new or improving existing biomarkers with consideration of patient race/ethnicity.
An updated overall survival analysis with correction for protocol-planned crossover of the international, phase III, randomized, placebo-controlled trial of regorafenib in advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID).
Authors: George D. Demetri, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Heikki Joensuu, Klaus Bernd Schaefer, Iris Kuss, Christian Kappeler, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2015)

110 Background: The GRID study showed that regorafenib improves progression-free survival compared with placebo in patients with advanced GIST after failure of at least imatinib and sunitinib (HR 0.27; 1-sided p&lt;0.0001; Demetri 2013). At the time of the primary analysis, no significant difference in the secondary endpoint of overall survival (OS) was observed (HR 0.77; p=0.199), but this result may have been confounded by the high rate of crossover to regorafenib (85%) of placebo patients at progression. We conducted exploratory analyses of updated OS data to assess the effect of correcting for this protocol-planned crossover. Methods: The data cut-off for this updated OS analysis was 31 January 2014 (2 years after the primary analysis). OS was corrected using two randomization-based methods: rank preserving structural failure time (RPSFT) and iterative parameter estimation (IPE); both methods are considered as best choice among all correction analytics. Hazard ratios and 95% CI were derived using the Cox model. Results: A total of 139 deaths had occurred at the time of data cut-off: 91 events (68.4% of patients) in the regorafenib group and 48 (72.7%) in the placebo group. A total of 22 patients remained on regorafenib treatment (median duration 2.1 years, range 0.9–2.4). The updated hazard ratio for OS favored regorafenib (0.85, 95% CI: 0.60 - 1.21; p=0.18). Median OS was estimated as 17.4 months in both groups, with crossover from placebo. The corrected HRs for OS are less than the uncorrected HR (Table). Conclusions: The updated analysis of OS in the GRID trial is consistent with the primary analysis. An exploratory analysis correcting for the impact of cross-over on OS suggests a survival benefit for regorafenib in GIST. Clinical trial information: NCT01271712. [Table: see text]
Sentinel lymph node detection using laser-assisted indocyanine green dye lymphangiography in melanoma and breast cancer patients.
Authors: B. Phillips, V. Jain, N. Conkling, C. R. Pameijer
Journal: Journal of Clinical Oncology (2011)

8587 Background: Sentinel lymph node (SLN) biopsy is a vital component of staging and management of multiple cancers. The current gold standard utilizes technetium 99 and methylene blue (MB) to detect regional nodes. These two methods can be inconclusive or inconvenient for both patient and surgeon. We evaluated a new technique using laser-assisted ICG dye lymphangiography to identify SLN. Methods: In this retrospective analysis, we identified patients with melanoma or breast cancer who required SLN biopsy. Patients received an injection of technetium 99 the day prior to surgery, then 1-2 mL of MB and 0.9 mL of ICG (2.25mg) in the operating room. After 10 minutes the ICG device (Novadaq SPY) was used to detect real time lymphatic flow towards the SLN bed. Any nodes that were denoted as hot by gamma probe, blue by direct visualization, intense for ICG, or any combination of the three, were removed and evaluated as SLNs. Results: A total of 16 patients were evaluated, with 9 females and 7 males having a median age of 61 (40-87). One patient had breast cancer, the remaining 15 melanoma. The number of SLNs ranged from one to six per patient. In total, 42 SLNs were removed, with final staging between stage IB to IIIB. An equivalent amount 90% (38/42) SLNs were identified using either ICG or a combination of tech 99 and MB. When analyzed individually, tech 99 found 74% (31/42) of the nodes, MB 45% (19/42) and ICG 90% (38/42). Four patients were found to have metastatic disease on final pathology. 100% of these 4 nodes were identified using ICG, while only 75% (3/4) were positive for tech 99 and/or MB. Furthermore, none of the nodes missed by ICG (4/42) had malignant cells. Conclusions: ICG dye lymphangiography is a reasonable alternative for locating SLNs in patients with melanoma and breast cancer. This technique could potentially eliminate MB, technetium 99 or both and result in reduced hospital trips, removal of radioactive material and decreased tissue staining. Prospective studies are needed to better ascertain the full functionality of this technique.
Development of a virtual multidisciplinary lung cancer tumor board in a community setting.
Authors: Marvaretta Miesha Stevenson, Tonia Irwin, Terry Lowry, Maleka Zafreen Ahmed, Thomas L. Walden, Linda Sutton
Journal: Journal of Clinical Oncology (2012)

325 Background: Creating an effective platform for multidisciplinary tumor conferences can be challenging in the rural community setting. The Duke Oncology Network, which is affiliated with hospitals in rural locations throughout North Carolina, created an internet-based platform for a multidisciplinary conference to enhance the care of lung cancer patients in the community. This conference incorporates providers from different physical locations within the community and affiliated providers from a university-based cancer center two hours away. An electronic approach connects providers through space and time vocally and visually. Methods: Development of the virtual conference began in February 2009. Biweekly conferences were set up using the Adobe Connect web conferencing platform. This provides a secure website and phone line to ensure patient confidentiality. Case information is de-identified and incorporated into a slideshow uploaded to the platform. Multiple disciplines are invited to participate, including radiology, radiation oncology, thoracic surgery, pathology, pulmonology, and medical oncology. Participants only need telephone access and internet connection to participate. Results: The first virtual tumor board occurred December 14, 2009. Patient histories and physicals are presented, and the web conferencing platform allows radiologic and histologic images to be reviewed. Treatment plans for patients are discussed, allowing providers to coordinate care among the different subspecialties. Patients are identified that need referral to the affiliated university-based cancer center for specialized services. Pertinent treatment guidelines and journal articles are reviewed. In 2011, there were 9-10 participants per session, with 2-3 cases presented, on average. Conclusions: The use of a web conferencing platform allows subspecialty providers throughout the community and hours away to participate in discussing lung cancer patient cases. This platform increases convenience for providers, eliminating travel time to a central location. Coordination of care for patients requiring multidisciplinary care is facilitated, shortening evaluation time prior to definitive treatment plan.