tbuckley/cabot-search huggingface dataset:
A novel loading regimen for trastuzumab in MBC: Boost serum levels in early cycles
Authors: B. Leyland-Jones, J. Baselga, J. Latreille, A. Wardley, S. Lennon
Journal: Journal of Clinical Oncology (2005)

594 Background: The long half-life of trastuzumab (Herceptin; H) (approximately 4 wks) dictates that steady-state serum levels are reached after many weeks (24–30) of therapy, regardless of the regimen (qw or q3w) used. It is prudent to target these higher steady-state levels early in the course of therapy. To this end, a novel loading regimen has been designed using pharmacokinetic (PK) simulation: 6mg/kg on day (d) 1, 8 and 15, then 6mg/kg q3w from d22. Preliminary PK data are presented. Methods: Data from the first 6 patients evaluable for PK are included. H was given as monotherapy as described above, and a sparse sampling scheme employed. Exposure was estimated during the 2nd and 4th cycles, and compared with that derived at steady-state using population (PPK) methods (Washington et al. Clin Pharmacol Ther 2002). The observed PK profiles obtained using this novel loading regimen were compared with the predicted PK profile (mean; 90% CI), constructed using this PPK model. Results: Serum levels in the first 12 wks are in good agreement with those predicted, falling within the range described by the mean predicted profile and confidence limits. Mean (SD) trough levels after the first 3 doses were as follows: d8: 84 (60) μg/mL; d15: 92.3 (21) μg/mL; d22: 138.2 (31) μg/mL. Exposure in cycles 2 (wks 4–7) and 4 (wks 10–13) exceeds that estimated at steady-state by PPK methods (Table 1). The highest exposure is achieved in cycle 2, the result of the high initial dose density. The less frequent maintenance dosing is then reflected in a lower AUC during cycle 4. Conclusions: This simple and convenient loading regimen appears to provide higher than steady-state serum levels early in the course of therapy. At ASCO, additional analyses using population methods to assess time taken to reach steady-state will be presented, as well as the tolerability profile. This loading regimen not only holds the potential of improved efficacy, but is also especially desirable in terms of synergy with chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Genentech, Roche Genentech, Roche Roche
Identifying optimal cutpoints for quality of life function in patients with advanced cancer
Authors: J. F. Grutsch, C. G. Lis, J. Granick, R. D. Levin, S. Williams, T. Wodek, D. Gupta
Journal: Journal of Clinical Oncology (2005)

8139 Background: Substantial resources have been spent to develop validated quality of life (QoL) tools in cancer. However, few hospitals in the US routinely utilize QoL measures to develop treatment plans in patient care. Indeed, to our knowledge, our center is the only hospital-based oncology program in the US that routinely collects QoL data on patients not participating in clinical trials. We used survival analysis to determine if we could convert continuous scales of QoL data into categorical prognostic outcomes. Methods: Baseline QoL data were collected from 310 patients treated at our center between 04/01 and 10/03. 2 QoL tools were used: Ferrans and Powers Quality of Life Index (QLI), which has 4 functional domains, and EORTC QLQ-C30, which has 5 functional domains and 9 symptom items. Using the Wilcoxon test, differences in survival were measured in serial increments of 10 points for EORTC and 3 points for QLI (these levels are associated with significant improvement in QoL). Results from Wilcoxon test were plotted as a function of QoL cutoff points. Linear and polynomial solutions were fitted and Wald statistic identified the best fit. Results: Of 310 patients, 180 were females and 130 males, with a median age of 55 years (range 21 - 82). 64.2% had failed prior treatment. Most common cancers were breast (25%), colorectal (23.3%), and lung (17.7%). Statistical analysis indicated that Health and Function Domain (Wald Test P = 0.0194) had two cutpoints at values 10 and 20. We found a statistically significant difference in survival between patients with scores < 10, 10 to 20, and > 20, the median survival being 169, 349, and 692 days respectively (p < 0.0001). Similarly, EORTC fatigue item (Wald Test P = 0.022) has two cutpoints at values 35 and 80. The median survival of patients with scores < 35, 35 to 80, and > 80 were 450, 413, and 129 days respectively (p < 0.0001). Conclusions: The transformation of a QoL research tool into a clinical management tool is a challenge. As an initial step, we showed that we could produce categorical survival outcome categories from QoL data in 310 patients with advanced cancer. The next step is to refine this analysis to produce discrete outcome categories that will facilitate physician thinking on treatment planning. No significant financial relationships to disclose.
Molecular tumor profiling (MTP) in cancer of unknown primary site (CUP): A complement to standard pathologic diagnosis.
Authors: D. S. Thompson, J. D. Hainsworth, C. M. Lane, W. J. Lennington, D. R. Spigel, F. A. Greco
Journal: Journal of Clinical Oncology (2011)

10560 Background: MTP may predict the tissue of origin in CUP and thus improve therapy for some patients. The ability of MTP to improve diagnosis over standard pathology is undefined. We evaluated MTP on biopsies to assess accuracy and diagnostic ability. Methods: From March 2008–January 2010 clinicopathologic data from 171 CUP patients who had MTP performed (bioTheranostics) on paraffin embedded biopsies were collected. The MTP diagnoses were validated by correlation with: 1) latent primaries found months later; 2) initial diagnosis by immunohistochemistry (IHC); 3) additional IHC and/or clinical findings after MTP; 4) clinical features, and 5) outcome of colorectal MTP patients treated with site-specific chemotherapy. Results: MTP provided a diagnosis in 144 of 171 tumors (84%); 22 had insufficient tumor for MTP (13%) and 5 were unclassifiable (3%). Histopathologic diagnoses were adenocarcinoma 56%, poorly differentiated carcinoma 27%, and others 17%. MTP diagnosed 21 tumor types [colorectal (16%), lung (11%), breast (9%), liver (6%), pancreas (5%), ovary (5%), other (48%)]. 18 of 24 patients with latent primaries had a correct diagnosis by MTP (75%). A specific IHC diagnosis was made in 52 patients (30%) and in 40 (77%) MTP diagnosis agreed (100% concordance breast, 93% colorectal and 74% lung). An IHC diagnosis of 2 or 3 possible types was made in 97 patients (70%) and in 43 MTP diagnosis agreed with 1 IHC diagnosis (44%). In 54 patients MTP disagreed with any IHC diagnosis (56%). In 41 (75%) the clinical features were consistent with MTP diagnosis and in 18 of 25 (72%) additional IHC and/or clinical findings supported MTP diagnosis. Twenty-one patients with colorectal MTP diagnosis received colorectal chemotherapy (response rate 70%, median survival 21 months). Conclusions: MTP predicts a tumor type in most CUP patients and the accuracy was supported by a high level of agreement with: identified latent primaries (75%); specific IHC diagnoses (77%); additional directed IHC and/or clinical findings (72%); clinical features (75%); expected outcome in the colorectal subset treated with colorectal chemotherapy. MTP is a valuable test in CUP and complements standard diagnostic pathology.
How well are cancer centers addressing supportive oncology needs?
Authors: Christine B. Weldon, Jennifer Carrie Obel, Catherine Deamant, Rosa Berardi, Patricia A. Robinson, William Dale, Oana C. Danciu, James Gerhart, Paramjeet Khosla, Urjeet Patel, Colleen Savory, Julia Rachel Trosman
Journal: Journal of Clinical Oncology (2016)

96 Background: The IOM 2013 report recommends comprehensive supportive oncology care from diagnosis through survivorship to end of life. The Coleman Foundation supported a baseline assessment of supportive oncology care using key COC, ASCO-QOPI and NQF measures. Methods: Data extracted from medical records at 6 Chicago cancer centers in 2014 (n = 843 patients), including stage I-III (n = 391) and stage IV solid tumor or refractory hematologic malignancy (n = 452). Results: Fifty-four percent of patients had discussions on understanding of illness, 24% were informed of prognosis timeframe, and 5% had a documented healthcare power of attorney. Only 6% of stage IV patients received distress screening within 2 weeks of diagnosis and 15% of Stage IV patients had referrals to palliative care. Among patients with Stage I-III cancer, 38% had a supportive oncology screening, and 2% received treatment summaries and a SCPs. Conclusions: There are still large gaps in important supportive care processes based on IOM 2013 recommendations, COC, and ASCO QOPI measures. Future steps include implementing supportive care processes that address gaps across the 6 cancer centers. [Table: see text]
Sunitinib rechallenge in two advanced GIST patients after third-line anti-tyrosine kinase therapy.
Authors: E. Fumagalli, P. Coco, C. Morosi, R. Bertulli, P. G. Casali
Journal: Journal of Clinical Oncology (2010)

e20519 Background: Imatinib and sunitinib are standard treatment for metastatic/advanced GIST patients. Upon resistance, further treatments are experimental. Rechallenge with imatinib was anecdotally reported to be effective. Methods: We rechallenged with sunitinib two patients failing to previous standard and experimental therapies, including sunitinib. Both patients had a primary resistance to imatinib and were then treated with sunitinib, achieving a partial response, maintained for 14 and 36 months, respectively. On progression, they were treated with nilotinib. They were then rechallenged with sunitinib again, according to a continuous-dose regimen (37.5 mg daily) for the first patient and an intermittent dosing schedule (50 mg/day) for the other. The first patient had a WT GIST for known KIT and PDGFRA mutations, and the other had an unreported exon 17 KIT mutation. Results: One patient achieved a Choi tumor response, lasting for 7 months, while the other had a RECIST PR, lasting for 5 months. Overall survival from sunitinib rechallenge was 20 and 12 months, respectively, being 4 and 6 years from starting imatinib for advanced disease. Treatment was fairly well tolerated, with severe hand and foot skin toxicity in one. Conclusions: Rechallenge with tirosine kinase inhibitors can be defined as retreating a patient with the same agent to which he responded and then developed a secondary resistance. Re-expansion of sensitive tumor clones, after relaxing the selection pressure with the anti-tyrosine kinase agent, is the most obvious explanation. Rechallenge with sunitinib adds to rechallenge with imatinib as a therapeutic option in selected advanced GIST patients, after exploiting standard and experimental available therapeutic resources. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer Novartis, Pfizer Novartis, Pfizer Novartis
Reduced Osteoarthritis Severity in Aged Mice With Deletion of Macrophage Migration Inhibitory Factor
Authors: Meredith A. Rowe, Lindsey R. Harper, Margaret A. McNulty, Anthony G. Lau, Cathy S. Carlson, Lin Leng, Richard J. Bucala, Richard A. Miller, Richard F. Loeser
Journal: Arthritis & Rheumatology (2016)

Objective Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is elevated in the serum and synovial fluid of patients with osteoarthritis (OA). This study was undertaken to investigate the potential role of MIF in OA in human joint tissues and in vivo in mice with age‐related and surgically induced OA. Methods MIF in conditioned media from human chondrocytes and meniscal cells and from cartilage explants was measured by enzyme‐linked immunosorbent assay. The severity of OA was analyzed histologically in male wild‐type and MIF −/− mice at 12 and 22 months of age and following destabilization of the medial meniscus (DMM) surgery in 12‐week‐old MIF −/− mice as well as in wild‐type mice treated with a neutralizing MIF antibody. Synovial hyperplasia was graded in S100A8‐immunostained histologic sections. Bone morphometric parameters were measured by micro–computed tomography. Results Human OA chondrocytes secreted 3‐fold higher levels of MIF than normal chondrocytes, while normal and OA meniscal cells produced equivalent amounts. Compared to age‐ and strain‐matched controls, the cartilage, bone, and synovium in older adult mice with MIF deletion were protected against changes of naturally occurring age‐related OA. No protection against DMM‐induced OA was seen in young adult MIF −/− mice or in wild‐type mice treated with anti‐MIF. Increased bone density in 8‐week‐old mice with MIF deletion was not maintained at 12 months. Conclusion These results demonstrate a differential mechanism in the pathogenesis of naturally occurring age‐related OA compared to injury‐induced OA. The inhibition of MIF may represent a novel therapeutic target in the reduction of the severity of age‐related OA.
The Molecular Profile of Richter Syndrome Predicts Survival From Transformation: The Role of Clonal Relationship
Authors: Davide Rossi, Valeria Spina, Clara Deambrogi, Silvia Rasi, Luca Laurenti, Kostas Stamatopoulos, Luca Arcaini, Marco Lucioni, Gabrielle R. Rocque, Zijun Y. Xu-Monette, Carlo Visco, Julie Chang, Ekaterina Chigrinova, Francesco Forconi, Roberto Marasca, Caroline Besson, Theodora Papadaki, Marco Paulli, Luigi M. Larocca, Stefano A. Pileri, Valter Gattei, Francesco Bertoni, Robin Foà, Ken H. Young, Gianluca Gaidano
Journal: Blood (2010)
A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report.
Authors: D. C. Cho, E. I. Heath, J. M. Cleary, E. L. Kwak, L. Gandhi, D. P. Lawrence, C. Zack, F. Teofilovici, R. Bradley, M. D. Karol, G. Shapiro, P. LoRusso
Journal: Journal of Clinical Oncology (2011)

3051 Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. It has been well tolerated and shown promising antitumor activity in early trials in multiple cancers. Preclinical data indicate that different client proteins show disparate expression kinetics upon Hsp90 inhibition. Therefore, twice-weekly dosing may be needed in some tumor types. Methods: Patients (pts) with solid tumors who have exhausted standard treatment options received ganetespib as a 1 hr infusion twice weekly for 3 weeks (wks) of a 28 day cycle until disease progression. Serial PK and pharmacodynamic samples were obtained during cycle 1. Safety assessments included frequency and grade of AEs, laboratory parameters and ECG changes. Results: Data are presented for 49 pts (22 M, 27 F; median age 55 yrs, range 32-81; ECOG status range 0-2) treated at doses from 2-144 mg/m2. Pts received a median of 2 (range 1-12) cycles of ganetespib. AEs reported in ≥20% of pts treated at doses from 2-120 mg/m2 are fatigue, diarrhea, nausea, anemia, abdominal pain, constipation, anorexia, vomiting, and headache; the majority of events were mild to moderate in severity with absence of severe liver, ocular, cardiac and renal toxicity. Two DLTs (elevated transaminases) have been reported in the 10 and 144 mg/m2 cohorts; expansion of the latter cohort is ongoing. Ganetespib shows linear PK, rapid distribution, a mean terminal half-life of 10-14 hours, a volume of distribution greater than total body water and no accumulation in plasma. HSP70 plasma protein levels will be presented. A confirmed durable PR by RECIST has been seen in a pt with metastatic melanoma. Additionally, 2 NSCLC pts who received 6 months of treatment had durable SD, with tumor shrinkage. Conclusions: Ganetespib has been well tolerated at dose levels up to 120 mg/m2 administered twice weekly. Preliminary safety profile, activity signals and differences in client protein kinetics warrant continued evaluation of ganetespib using a twice-weekly dosing regimen. Dose escalation continues.
Prognostic utility of the cell cycle progression (CCP) score generated from needle biopsy in men treated with prostatectomy.
Authors: Jay T. Bishoff, Stephen J. Freedland, Leah Gerber, Pierre Tennstedt, William Welbourn, Julia E. Reid, Markus Graefen, Zaina Sangale, Eliso Tikishvili, Jimmy Park, Adib Younus, Alexander Gutin, Jerry S. Lanchbury, Guido Sauter, Michael K. Brawer, Steven Stone, Thorsten Schlomm
Journal: Journal of Clinical Oncology (2014)

17 Background: We developed a prognostic RNA signature that is strongly associated with prostate cancer outcomes. The cell cycle progression (CCP) score has proven to have prognostic utility in predicting disease progression in various clinical settings utilizing biopsy, transurethral resection of the prostate (TURP) and post-prostatectomy specimens. Previous studies evaluating post-surgical outcomes were conducted using CCP gene expression measured in the prostatectomy specimen. Here, we demonstrate the ability of the CCP score to predict cancer progression, as measured by both biochemical recurrence (BCR) and metastatic disease after radical prostatectomy, using needle biopsy tissue. Methods: We evaluated the CCP score in three patient cohorts. These included men from the Martini Clinic (MC, N=283), the Durham VA Medical Center (DVA, N=176), and Intermountain Healthcare (IHC, N=123). The CCP score was derived from a simulated biopsy (MC) or diagnostic biopsy (DVA and IHC), and evaluated for association with BCR and metastatic disease in univariable analysis and after adjusting for other clinical information. Results: In all three cohorts, the CCP score was associated with BCR and metastatic disease. The association with BCR remained significant after adjusting for other prognostic clinical variables. In a combined analysis of all three cohorts (N=582), the CCP score was a strong predictor of BCR in both univariable (HR per Interquartile Range [IQR] = 1.68 [95% CI: 1.41, 1.99), p value&lt;10−6]) and multivariable analyses (HR per IQR = 1.53 [95%CI: 1.28, 1.84], p value &lt; 10−4). CCP score was the strongest predictor of metastatic disease in both univariable analysis (HR per IQR = 6.32 [95% CI: 3.41, 11.71, p value&lt;10−7]), and after adjusting for clinical variables (HR per IQR = 4.83 [95% CI: 2.40, 9.74, p value&lt;10−5]). Conclusions: The CCP score derived from a needle biopsy sample was strongly associated with adverse outcome after surgery. It was the strongest predictor of eventual metastatic disease of the tested variables including Gleason and PSA. These results indicate that the CCP score can be used at disease diagnosis to better define patient prognosis and appropriate clinical care.
A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus
Authors: Dilip Kumar, Kia Joo Puan, Anand Kumar Andiappan, Bernett Lee, Geertje H. A. Westerlaken, Doreen Haase, Rossella Melchiotti, Zhuang Li, Nurhashikin Yusof, Josephine Lum, Geraldine Koh, Shihui Foo, Joe Yeong, Alexessander Couto Alves, Juha Pekkanen, Liang Dan Sun, Astrid Irwanto, Benjamin P. Fairfax, Vivek Naranbhai, John E. A. Common, Mark Tang, Chin Keh Chuang, Marjo-Riitta Jarvelin, Julian C. Knight, Xuejun Zhang, Fook Tim Chew, Shyam Prabhakar, Liu Jianjun, De Yun Wang, Francesca Zolezzi, Michael Poidinger, E. Birgitte Lane, Linde Meyaard, Olaf Rötzschke
Journal: Genome Medicine (2017)

Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10–6 for rs612529 for association to atopic dermatitis (AD). Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.