tbuckley/cabot-search huggingface dataset:
Evaluation of dynamic tumor-tracking IMRT for patients with pancreatic cancer using gimbaled linac of vero system.
Authors: Akira Nakamura, Mitsuhiro Nakamura, Satoshi Itasaka, Takahiro Kishi, Yoshitomo Ishihara, Nobutaka Mukumoto, Mami Akimoto, Takashi Mizowaki, Masaki Kokubo, Masahiro Hiraoka
Journal: Journal of Clinical Oncology (2015)

481 Background: We have started dynamic tumor-tracking intensity-modulated radiotherapy (DT-IMRT) using the gimbaled linac of Vero4DRT from June 2013. This study reports the first clinical evaluation of DT-IMRT for patients with locally-advanced pancreatic cancer (LAPC). Methods: Five patients with histologically proven LAPC and written informed consent were enrolled. One Visicoil fiducial marker was percutaneously or endoscopically inserted inside the tumor. DT-IMRT was performed with the gimbaled X-ray head which can swing the intensity-modulated beam towards the moving tumor based on a correlation model of external-to-internal motion. During the beam delivery, the Visicoil was continually monitored with the kV and MV imagers mounted on the gantry of the Vero4DRT, and the correlation model was recalibrated when needed. An escalated dose of 45-51 Gy in 15 fractions was delivered to the planning target volume (PTV) with concurrent full-dose gemcitabine (1,000 mg/m 2 ). The following factors were evaluated: the differences in PTV volume and the absolute volume receiving 39Gy or 42Gy (V39 or V42) for stomach and duodenum between DT-IMRT and a conventional technique; positional errors between the predicted tumor and irradiated positions; in-room time for the daily treatment; and radiotherapy-induced toxicities. Results: The mean reduction in PTV volume was 15%. The planned V39/V42 to stomach and duodenum were reduced approximately by 92%/96% and 83%/91%, respectively, when compared with a conventional technique, while tumor doses were comparable. The 95th percentiles of positional errors were within 2.5, 2.8, and 3.2 mm in left-right, anterior-posterior, and cranio-caudal directions, respectively. The mean in-room time was 24.5 minutes. All patients completed the planned radiotherapy and concurrent full-dose gemcitabine. There were mild hematological toxicities, but no severe gastrointestinal toxicities directly attributable to the DT-IMRT. Conclusions: A safe dose-intensification was achieved applying DT-IMRT for patients with LAPC, based on the high accuracy for tumor-tracking and the reductions in PTV volume and high-dose volume in critical organs.
<sup>64</sup>Cu-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast cancer.
Authors: Kenji Tamura, Hiroaki Kurihara, Kan Yonemori, Kazuhiro Takahashi, Yasuhiro Wada, Koki Hasegawa, Fumiaki Koizumi, Hitoshi Tsuda, Makoto Kodaira, Mayu Yunokawa, Chikako Shimizu, Masashi Ando, Yasuyoshi Watanabe, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2012)

10519 Background: Targeting of HER2 with trastuzumab (T) is a well-established strategy in the metastatic and adjuvant setting in HER2 positive breast cancer (HER2-BC). Although HER2 status is routinely determined using immunohistochemistry or fluorescence in situ hybridization, technical problem can arise when lesions are poorly accessible. HER2 expression can vary during the course of the disease, and there can be discordance in HER2 expression across tumor lesion even in the same patients. Noninvasive HER2 imaging is crucial needed to solve these problems. Previous imaging using 111 In or 89 Zn- trastuzumab produced high radiation exposure to patients by their long half life (=67.9and 78.4h) and low resolution image. Half life of 64 Cu is 12.7h. We performed a feasibility study of the 64 Cu-1, 4, 7, 10- tetraazacylododecane-N,N',N",N"'-tetraacetic acid (DOTA)-T to perform PET imaging in patients with HER2-BC. Methods: Patients with HER2-BC received 150 MBq of 64 Cu-DOTA-T and underwent PET scan 1, 24 and 48h after the injection. Six patients were evaluated internal dosimetry by collecting radioactivity data of blood and normal tissue in each time point from PET study, and radiation exposure by collecting clothes, linen and urine to test feasibility for outpatients. Results: Fifteen patients who received T therapy were enrolled in the “first-in-human” trial. All patients had no severe toxicity. Radiation excretion evaluating clothes, linen were under background level. Radiation exposure of 64 Cu-DOTA-T was equivalent to that of conventional 18 F-FDG-PET. Distribution of liver, kidney, spleen, and blood vessel was 2-8 SUV, and uptake in other normal tissue was low. At visual examination, in two patients brain metastases were clearly visualized by 64 Cu-DOTA-T-PET, suggesting that there are disruptions of the blood-brain barrier at the site of the brain metastases. The sternum bone metastasis was well visualized and quantitatively monitored according to the response by T. Primary breast cancers, lymph node metastases and lung metastases could also be visualized at the lesion indentified by CT. Conclusions: 64 Cu-DOTA-T-PET was feasible test even for outpatient, and provides specific and high resolution image in HER2 positive lesion.
Potential Role of Cyclosporin a in Corneal Grafting
Authors: P A Hunter
Journal: Journal of the Royal Society of Medicine (1981)

The immunosuppressive drug cyclosporin A has been shown to be effective in preventing corneal allograft reactions in rabbits when administered by intramuscular injection. However, when used systemically in man, the drug may have potentially serious side effects and a series of experiments has therefore been performed in order to investigate the use of topically applied cyclosporin A in rabbit corneal transplants. Using a single set model of the corneal allograft reaction, two groups of rabbits treated with topically applied cyclosporin A for periods of four and thirteen weeks respectively showed significantly increased graft survival compared with untreated controls (P less than 0.001).
1-Year Results From A Prospective Randomized Trial Comparing Phlebotomy with Deferasirox for the Treatment of Iron Overload in Pediatric Patients with Thalassemia Major Following Curative Stem Cell Transplantation
Authors: Adlette Inati, Nada Sbeiti, Evelyne Khoriaty, M Domenica Cappellini, Suzanne Koussa, Therese Abi Nasr, Khaled M Musallam, Ali T Taher
Journal: Blood (2011)
Phase I study of PF-03446962 (anti-ALK-1 mAb) in hepatocellular carcinoma (HCC).
Authors: Matteo Simonelli, Paolo A. Zucali, Melanie B. Thomas, Alan Brisendine, Jordan Berlin, Cristina Noberasco, Crystal Shereen Denlinger, Tae-You Kim, Armando Santoro, Corrado Gallo-Stampino, Marina Carpentieri, Erjian Wang, James Andrew Williams, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2013)

4121 Background: PF-03446962, a fully human IgG2 mAb against ALK-1 (Activin-Receptor Like Kinase-1, a specific TGF-β receptor) with anti-angiogenesis activity, showed a favourable safety profile and early signs of efficacy in a dose escalation study in patients (pts) with solid tumors. While the interplay between ALK-1 and VEGF-A is not fully elucidated, the clinical benefit observed in VEGF-TKI pre-treated pts supports ALK-1 acting as an escape mechanism after failure of VEGF blockade. Herein we report preliminary efficacy, safety and PK results from an expansion cohort in HCC pts who progressed after receiving at minimum sorafenib. Methods: Child-Pugh A HCC pts progressed on/intolerant to sorafenib. Tumor specimens (diagnostic and pre-PF-03446962) collected for IHC assessment of CD31, TGF-β, ALK-1 and cMET. Pts treated with 7 mg/kg PF-03446962 on Day 1, 29 and then q2 wks. Efficacy endpoints: Objective Tumor Response (OR) by RECIST, Disease Control Rate (DCR) at 12 wks, and Time To Progression (TTP). Secondary objectives: safety, PK and PD. Results: 24 pts with advanced HCC pre-treated at minimum with sorafenib (12/24 with ≥ 2 prior therapies) have been enrolled; 19 males and 5 females (median age: 64 y). Pts’ characteristics were: ECOG PS = 0 in 10 and = 1 in 14 pts; Child-Pugh = A5 in 16 and = A6 in 8 pts. The PK profiles from the HCC cohort were consistent with those of the dose escalation cohorts. Safety profile was manageable and mainly characterized by Gr 1-2 events. Gr 3-4 events were represented by thrombocytopenia (12.5%) and lipase increase, AST increase and abdominal pain (4.2% each). Telangiectasia, an anti-ALK-1 mediated toxicity, was also observed (8.3%, Gr 1). There were 3 treatment-related serious AEs (one tumor necrosis and two abdominal pain). No CRs or PRs were reported; DCR was 29.2% and mTTP was 3.0 months. In 7 pts, PF-03446962 was associated with stable disease for ≥ 12 weeks, suggesting that anti-ALK-1 treatment may be an effective strategy in the post-VEGFi setting. Correlation data of target tumor protein expression with efficacy will be presented at the Conference. Conclusions: PF-03446962 is a first in class mAb anti ALK-1. Preliminary clinical activity observed in this HCC expansion cohort warrants further investigations. Clinical trial information: NCT00557856.
Reflex Lynch syndrome screening by example: A review of existing programs.
Authors: Corinne Daly, Carolyn Rotenberg, Marcia Facey, Natalie A. Baker, Nancy N. Baxter
Journal: Journal of Clinical Oncology (2015)

543 Background: Reflex screening for Lynch Syndrome (LS) has been recommended, however occurs in few jurisdictions worldwide. We aimed to explore program structure, pathology testing, implementation challenges and future directions of existing reflex LS screening programs in various jurisdictions to develop best practices for future programs. Methods: We identified existing reflex LS screening programs through a literature search and expert opinion. Information on program implementation, patient population, family care involvement, monitoring and improvements was collected through semi-structured interviews with program leaders, pathologists, technical staff, and family physicians. Pattern, thematic and content analysis were used to analyze and extract program features, sequence of pathological testing and best practices. Results: 26 participants across 7 programs completed interviews. There were 3 government-funded, population-based programs (Manitoba, Western Australia, and New South Wales), 2 private health management organization programs implemented across affiliated healthcare centers (Pennsylvania and Southern California); and 2 hospital-based programs (Ohio and Utah). Five programs screened all patients with CRC for LS while 2 programs designated an upper age limit for screening. The majority of programs tested tumor samples for LS using a combination of immunohistochemistry and BRAF mutation analysis. In jurisdictions relying on surgeons' referral to genetic counseling without navigation, uptake of genetic testing was lower than expected. Programs implementing early education of surgeons and pathologists in reflex screening procedures reported confidence in skills, collaboration and communication. Communication materials for family members of affected individuals were recommended to increase family engagement in genetic counselling. Conclusions: There are a variety of reflex LS screening programs with varying standards and protocols. Program design influences uptake of genetic testing; programs with an imbedded navigation plan for those who need genetic counseling enhance rates of adherence. This should be an important consideration when planning future reflex screening programs.
Identification of AEG-1 and BARD1 as predictors of erlotinib outcome in EGFR-mutant non-small cell lung cancer (NSCLC) by NanoString multiple target profiling.
Authors: M. Taron, S. Benlloch, R. Rosell, J. J. Sanchez, C. Costa, A. Gimenez Capitan, C. Mayo, J. Bertran-Alamillo, M. A. Molina, B. Massuti, C. Camps, M. Majem, D. Isla, M. Santarpia, S. Viteri, A. Gasco, T. Moran, E. Carcereny, C. Queralt, I. de Aguirre
Journal: Journal of Clinical Oncology (2011)

7589 Background: Low BRCA1 mRNA expression prolongs progression-free survival (PFS) to erlotinib in EGFR-mutant NSCLC patients (p). In order to explore other genes potentially involved in erlotinib resistance, we used NanoString, an integrated digital technology, to examine expression levels of 48 genes in a single reaction. Several genes involved in homologous recombination repair were included in the 48-gene assessment. BARD1 couples with BRCA1 and, together with the E3 ubiquitin ligases RNF8, RNF168 and RAP80, is essential for DNA repair. AEG-1 activates the NF-kB and PI3K/Akt pathways and causes chemoresistance. Methods: CodeSets (Reporter and Capture probe sets) for 48 genes were custom-designed by NanoString Technologies. 100ng of total RNA for each sample was mixed with the reagents and hybridized at 65º overnight. Samples were processed and analyzed with the nCounter Prep Station (NanoString Technologies). Data analysis was performed adjusting the expression values according to positive control values and normalizing the data according to housekeeping genes. Results: In 55 EGFR-mutant NSCLC p treated with erlotinib, response rate was 67.6%, PFS was 16 months (m), median survival (MS) was 29 m. AEG-1 expression levels were significantly associated with PFS: low, 22 m; high, 6 m (P=0.003). BARD1 levels were also significantly associated with PFS: low, 23 m; high, 6 m (P=0.03). We generated an AEG-1/BARD1 risk model: p with high levels of both genes were considered high-risk, p with low levels of both genes were low-risk, and p with high levels of one and low levels of the other gene were intermediate-risk. PFS was not reached in the low-risk group, while it was 16 m for the intermediate-risk group and 6 m for the high-risk group (P=0.004). MS was not reached in the low-risk group, while it was 21 m for the intermediate-risk group and 31 m for the high-risk group (P=0.14). Conclusions: NanoString is a feasible technique to detect the expression of multiple genes in a single reaction, making it suitable for clinical use. Together with BARD1, AEG-1 predicts PFS in erlotinib-treated EGFR-mutant NSCLC p and could have important implications for the optimal management of NSCLC.
Vaccination of renal cell cancer patients with TroVax (modified vaccinia Ankara delivering the tumor antigen 5T4) plus IFNα: A phase II trial
Authors: R. Harrop, C. Macdermott, A. Shablak, C. Hamer, F. Thistlethwaite, N. L. Drury, P. Chikoti, W. H. Shingler, S. Naylor, R. Hawkins Prof
Journal: Journal of Clinical Oncology (2008)

3053 Background: The attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to express the tumor antigen 5T4 (TroVax [T]). Approximately 90% of renal cell tumors overexpress 5T4. T has been evaluated in an open-label phase II trial in metastatic renal cell cancer (MRCC) patients in which the vaccine was administered in combination with interferon-alpha (IFNα). The safety and immunological and clinical efficacy of T in combination with IFNα was determined. Methods: T plus IFNα was administered to 11 patients with MRCC. 5T4-specific cellular and humoral responses were monitored and clinical responses assessed by measuring changes in tumor burden by CT scan (RECIST criteria). Subcutaneous interferon (9MU) was administered 3 times a week. Patients were recruited between August and November 2006 and the minimum follow up is 56 weeks. Results: All patients treated were receiving first-line systemic therapy with 10 having clear cell and one papillary histology. Their MSKCC prognostic scores were 0 (5 patients) or 1 (6 patients). Administration of T alongside IFN-α was safe and well tolerated with no serious adverse events attributed to T. Of 11 ITT patients, all mounted 5T4-specific antibody responses and 4 (36.4%) mounted cellular responses. No objective tumor responses were seen, but the overall time to progression was longer than expected for interferon alone, ranging from 9–42+ weeks (median TTP=41 weeks). For the 10 clear cell patients the TTP ranged from 17–42+ weeks (median TTP=47.5 weeks). The only patient with papillary carcinoma had evidence of progression at their first CT scan at 9 weeks. Conclusions: T was safe and well tolerated in all patients in combination with IFNα. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared to that expected for interferon alone is encouraging and warrants further investigation. Indeed, T is now being tested in a randomized, placebo-controlled phase III clinical trial in clear cell renal cancer patients, including a patient group receiving T plus IFNα. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Oxford BioMedica Oxford BioMedica
Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer
Authors: C.-M. Tsai, C.-H. Chiu, T.-Y. Chou, L.-H. Li, C.-Y. Hsiao, Y.-M. Chen, R.-P. Perng, S.-F. Tsai
Journal: Journal of Clinical Oncology (2005)

7086 Background: It has been reported that mutations in epidermal growth factor receptor (EGFR) play a critical role in predicting tumor response in patients receiving gefitinib for non-small cell lung cancer (NSCLC). We investigated the associations of EGFR mutations to tumor response and survival in gefitinib-treated NSCLC patients. Methods: We examined EGFR gene mutations in exons 18, 19 and 21 by DNA sequencing in paraffin-embedded tumor tissues of NSCLC patients who have received gefitinib. The results were correlated with the clinical parameters. Results: Mutations in the tyrosine kinase domain of EGFR were found in 29 of 54 cases (53.7%). Of them, twelve cases had a deletion in exon 19 and seventeen cases had a substitution in exon 18 and/or 21. Mutation was an independent predictor for disease control (P< 0.001) and tumor response (P= 0.020); the positive predictive values were 93% and 75% and negative predictive values were 60% and 65%, respectively. Compared with patients whose tumor bearing non-mutant EGFR, patients with EGFR mutations showed better progression-free survival (median 7.9 m vs. 1.8 m, P< 0.001) and overall survival (median 12 m vs. 4.7 m, P= 0.029). Moreover, in the gefitinib responders, patients with mutations had a longer response duration than patients without mutations (median 9.1 m vs. 2.9 m, P= 0.033). It was unlikely that patients with EGFR mutations in different exons have variable response or survival to gefitinib treatment. Conclusions: EGFR mutations can be used as a predictive and prognostic indicator in patients receiving gefitinib for NSCLC No significant financial relationships to disclose.
Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)
Authors: G. Garcia-Manero, A. S. Yang, V. Klimek, S. Luger, W. M. Newsome, N. Berman, T. Patterson, C. Maroun, Z. Li, R. Ward, R. Martell
Journal: Journal of Clinical Oncology (2007)

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m 2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea &amp; anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 &amp; 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic &amp; clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.
National multi-center study on chemotherapy safety practice
Authors: S. C. Lee, M. S. Lai, S. Chiang, M. K. Lai, H. Chang, J. C. Chen, K. Rav, C Chang, Y. Liao, C. Hwang
Journal: Journal of Clinical Oncology (2008)

17569 Background: Safety practice is an important quality indicator of cancer care. Given the potential toxicity of chemotherapy (CT), the safety practices of intravenous (IV) CT for cancer have received little attention. The purpose of this study was to characterize the safety practices of prescribing IV CT and examine their association with the adverse drug events (ADR) after CT in Taiwan. Methods: A total sample of 948 medical records of newly diagnosed breast (BC), lung (LC), colon-rectal (CRC) and oral cancer (OC) were drawn via proportional probability random sampling from 7 medical centers across the Taiwan. Using data from reviewing the medical records, the safety practices were measured as characteristics of prescribing IV CT, including record of protocol name, format of prescriptions, calculation of dosage and double checking. Near-miss prescription (NM) was determined as percentage of inconsistent, unrecognized recordings about the CT regiments throughout the CT course, or unreadable prescription. ADR was determined as percentage of re-utilizations of healthcare that were associated with the CT complications after administering the CT. Inter-rater agreement of 90% or above was achieved. Results: The sample were consisted of 31% BC (n=293), 28% LC (n=265), 27.3% CRC (n=259) and 13.8% OC (n=131), with mean age of 56 years old and stage III or IV at the half. No calculation of dosage was accounted for 52%. There was 8.3% (n=79) of near-miss IV CT prescription. The ADR included 10% (n=95) re-hospitalization and 32% of clinic visits associated with the CT complication. The NM was significant related with the cancer type of LC (OR=1.96), no record of protocol name and not pre-print CT prescription. The ARD related to the CT was significantly more likely to be those whose CT prescriptions were without double checking and not pre-print CT prescription. ADR was not related to the occurrence of NM. Conclusions: These results indicated that there is a gap remained in the prescribing safety practice. Misses of some safety practices was related to rate of the re-hospitalization or clinic visits that were related to the CT complication. No significant financial relationships to disclose.