tbuckley/cabot-search huggingface dataset:
AUY922, a novel HSP90 inhibitor: Final results of a first-in-human study in patients with advanced solid malignancies.
Authors: T. A. Samuel, C. Sessa, C. Britten, K. S. Milligan, M. M. Mita, U. Banerji, T. J. Pluard, P. Stiegler, C. Quadt, G. Shapiro
Journal: Journal of Clinical Oncology (2010)

2528 Background: AUY922, a novel isoxazole-based HSP90 inhibitor, causes the degradation of multiple oncogenic cellular proteins and preclinical data suggest broad antitumor activity. Methods: Single agent AUY922 was administered as IV infusion over 1h, once weekly, to patients (pts) with advanced solid tumors to determine the maximum tolerated dose (MTD) in a phase I study. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Endpoints included safety, tolerability, preliminary activity, PK, and PD. Results: 96 pts received AUY922 at doses of 2–70 mg/m2 (23 pts at 70 mg/m2). Pt characteristics: median age 57 yrs, 96% WHO performance status 0 or 1, 41% male, and 82% Caucasian. The most frequently reported adverse events possibly related to AUY922 were diarrhea in 53 pts (55%), nausea in 34 pts (35%), fatigue in 31 pts (32%), night blindness in 19 pts (20%), and vomiting in 18 pts (19%). Visual symptoms (mainly grade 1–2 and mostly reversible) including blurred vision, flashing, and delayed dark/light accommodation were reported starting at 40 mg/m2, and increased in frequency or severity with dose. Dose limiting toxicities, all grade 3, included atrial flutter (22 mg/m2), anorexia, fatigue, and diarrhea (40 mg/m2), asthenia and diarrhea (54 mg/m2) and diarrhea and darkening of vision (70 mg/m2). The MTD was 70 mg/m2. Median duration of exposure was 7.0 weeks (range; 1, 80). Disease stabilization was reported in 16 pts and 9 pts reported partial metabolic response in FDG-PET scans. AUY922 blood concentration followed a bi-exponential decline with a fast a phase (t1/2 <10 min) and a slow β phase (t1/2 ∼60h). Dose-related induction of HSP70, indicating inhibition of HSP90, was seen. A phase II expansion study in pts with advanced breast cancer (HER2+ and ER+) has begun. Conclusions: Weekly IV infusion of single agent AUY922 was well tolerated at the MTD of 70 mg/m2. Disease stabilization was seen in a subset of pts receiving AUY922. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, The Institute of Cancer Research Novartis GlaxoSmithKline, Novartis, sanofi-aventis Novartis, Exelesis, Infinity Pharmaceuticals, Pfizer, Wyeth
ZIO-101 (S-dimethylarsino-glutathione): Phase I/II trials in advanced/progressive multiple myeloma
Authors: J. R. Berenson, S. Jaganath, D. Reece, R. Boccia, R. Soebel, A. Belch, B. Schwartz, R. P. Gale, M. Hussein
Journal: Journal of Clinical Oncology (2007)

8109 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD &gt; 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues. No significant financial relationships to disclose.
Response to Letter Regarding Article, “Surgical Ineligibility and Mortality Among Patients With Unprotected Left Main or Multivessel Coronary Artery Disease Undergoing Percutaneous Coronary Intervention”
Authors: Stephen W. Waldo, Eric A. Secemsky, Cashel O’Brien, Kevin F. Kennedy, Eugene Pomerantsev, Thoralf M. Sundt, Edward J. McNulty, Benjamin M. Scirica, Robert W. Yeh
Journal: Circulation (2015)
Long-term effects of a program of bladder preservation using chemotherapy plus radiotherapy in muscle invasive bladder cancer (BC). Analysis of biologic predictive factors and health-related quality of life (QOL)
Authors: R. Passalacqua, M. Brighenti, N. Naldi, D. Potenzoni, B. Monica, M. Fumagalli, S. Lazzarelli, C. Caminiti
Journal: Journal of Clinical Oncology (2009)

e16014 Background: Long-term effects of a combined approach of transurethral resection (TUR) plus chemotherapy (CT) and pelvic radiotherapy (RT) in terms of bladder preservation, survival, QOL are largely unknown. Moreover we investigated whether p53, Ki67, bcl-2, c-erbB-2 protein expression predict the achievement of a complete response (CR). Methods: From March 1994 to June 2000, 75 pts with muscle invasive BC were treated with a bladder sparing approach including an initial TUR, 3 cycles of CT (cisplatin + 5- FU) alternating with pelvic RT (40 Gy). At the response evaluation, pts with biopsy proven residual disease were considered incomplete responders (IR) and underwent immediate cystectomy. Pts with CR were treated with two additional CT cycles plus a bladder RT boost (20- 24 Gy). Paraffin embedded blocks of the primary tumors were collected and Ki67, p53, bcl-2 and c-erbB-2 protein expression were evaluated in a blind fashion. The Expanded Prostate Cancer Index Composite (EPIC) scores for urinary function, (especially storage, voiding symptoms and bowel function) was used to explore QOL in bladder preserved and compared with a group of matched patients treated by radical cystectomy only. Results: Median age was 67 yrs (range 42–80); T 2a -T 2b : 42%; T 3a -T 3b : 47%; T 4a : 11%; G 3 : 88%; hydronephrosis: 32%. Overall, 56 (74.7%) pts achieved a CR and the achievement of a CR was significantly related to lower T stage (p= 0.002), high Ki67 (p=0.001), absence of hydronephrosis (p= 0.007) and high p53 overexpression (p=0.007). Multivariate analysis showed that only a low T stage (p=0.002) and high p53 expression (p=0.043) predict the obtaining of a CR. At 5 years of follow-up, 44 (59%) were alive and in 33 of them (75%) bladder was preserved; after 10-years 28 (37.3%) were alive and in 23 of them (82%) bladder was preserved. Analysis of QOL scores is ongoing. Conclusions: This approach induces a long term survival similar to radical cystectomy with a high rate of bladder preservation and represents a valid treatment for muscle invasive BC. Overexpression of p53 is a predictive marker for the obtaining of CR and for bladder preservation. No significant financial relationships to disclose.
Phase I/II study of docetaxel and <sup>153</sup>Sm for castrate metastatic prostate cancer (CMPC): Summary of dose-escalation cohorts and first report on the expansion cohort
Authors: M. J. Morris, N. Pandit-Taskar, R. D. Stephenson, C. Hong, S. F. Slovin, D. Rathkopf, D. Solit, J. Carrasquillo, S. Larson, H. I. Scher
Journal: Journal of Clinical Oncology (2009)

5057 Background: We previously reported (ASCO 2008) that full doses of docetaxel (Tax) and Sm can be repetitively delivered safely using a schedule of q 3 week (wk) Tax and q 6–9 wk Sm. Here we summarize the dose-escalation cohorts and safety/efficacy data from the expansion cohort of 24 pts. Methods: Cohorts of 3–6 pts with CPMC were defined by: 65, 70, 75, 75, 75 mg/m 2 of Tax and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle was 6 wks. The expansion cohort used 75 mg/m 2 Tax (q 3 wk) and 1 mCi/kg Sm (q 9 wk). Pts with an ANC of grade 0–1 and platelet count of &gt; 100,000/mm 3 at the end of cycle 1 received additional cycles until progression or toxicity. Results: 52 pts have been treated. 28 pts were taxane naïve, 11 received previous taxanes but were not refractory, and 13 were taxane refractory. As anticipated, side effects were primarily hematologic. However, the leading cause for treatment termination was disease progression, involving 16/52 (31%) pts, rather than toxicity. 12/52 (23%) pts came off for thrombocytopenia, and 2/52 (4%) pts experienced neutropenic fever. Cohort 3 tolerated the highest cumulative dose and total number of doses of docetaxel (mean of 8 doses, range 4–12; mean total dose 600 mg/m 2 , range 300–900 mg/m 2 ). Cohort 5 tolerated the highest exposure to Sm (mean of 3 doses, range 1–5). 50 pts are evaluable for response; 22 (44%) achieved a ≥ 50% decline in PSA. 50% of the taxane naïve patients achieved a significant PSA decline, as did 55% of the taxane exposed, and 23% of the taxane refractory pts. Mean time to progression in the taxane naïve, treated, and refractory groups were: 7.5 (range 1.4–22.6), 5.8 (range 0.7–13.7), and 4.3 (range 0.7–11.2) months. Conclusions: This regimen is safe and appears to be active both in taxane naïve and taxane refractory patients, as reflected by favorable toxicity profiles, and rates of significant PSA declines and times to progression. The optimal phase II dose may differ by the population treated. For studies involving taxane naïve patients, the regimen of cohort 3 maximizes docetaxel exposure; for studies of taxane refractory patients, cohort 5 maximizes Sm exposure. Support: EUSA, NIH CA102544. [Table: see text]
Concordance of ColoPrint and MSI-print classification in paired endoscopic-surgical specimens of stage I-III colorectal cancer (CRC).
Authors: Rocio Garcia-Carbonero, Inmaculada Sanchez-Simon, Juan M. Bozada, Angela Araujo Miguez, Fernando De la Portilla, Frank Nieboer, Lisette Stork, Iris M. Simon
Journal: Journal of Clinical Oncology (2014)

501 Background: ColoPrint is a gene expression classifier that has demonstrated improved prognostic accuracy over conventional clinical and pathological factors in patients with stage II-III CRC (Salazar et al, JCO 2011). MSI-Print is a gene classifier that identifies patients with deficient mismatch repair system and MSI-H status (Tian et al. J Pathol 2012). The gene signatures have been validated in several independent patient cohorts. The aim of this study was to assess the performance of ColoPrint and MSI-Print in fresh-frozen endoscopic samples obtained by colonoscopy. Methods: A pilot study was initiated to address the concordance of gene signatures in paired endoscopic-surgical fresh-frozen samples from patients with stage I-III CRC. RNA was isolated from samples with &gt; 30% tumor cells. Nineteen paired samples passed quality control and were hybridized to the diagnostic microarrays. Results: Patient characteristics–median age: 74 years (range:49-84); male/ female: 58/42(%); ECOG 0-1/2-3: 84/16(%); stage I/II/III: 21/47/32(%). ColoPrint risk classification was highly concordant between paired endoscopic and surgical specimens from the same patient. 14 cases were equally classified as low risk; 3 cases were equally classified as high risk; 2 cases were not concordant but the risk score was close to the cut-off value between low and high risk for both matched pairs (borderline samples). A similar high concordance was observed for the MSI signature in paired endoscopic-surgical samples (13 cases were equally classified as MSS, 5 equally classified as MSI, and 1 case had borderline results (both samples close to the cut-off between MSS/MSI). Conclusions: These encouraging preliminary results suggest endoscopic procedures may be valuable, non-invasive and widely available tools to obtain adequate tumor tissue for molecular assays, and can allow for easy implementation of genomic signatures in patients not amenable to surgical resection (i.e., advanced disease) and/or in less complex community sites for routine clinical practice.
Treatment of leptomeningeal carcinomatosis from breast cancer with systemically administered chemotherapy
Authors: J. E. Trey, J. E. Simon, A. Khiyami
Journal: Journal of Clinical Oncology (2004)

764 Background: Leptomeningeal carcinomatosis is a rare complication of breast cancer. Standard treatment includes intrathecal methotrexate and radiation. The results of therapy are unsatisfactory and the prognosis is poor. Methods: We report two patients with breast cancer and meningeal involvement who responded to systemic chemotherapy with carboplatinum (AUC6) and docetaxel (75mg/M2. This regimen was chosen because of the preclinical synergy of these agents, proven efficacy in metastatic breast cancer, and the ability of carboplatinum to treat brain tumors. Results: Patient #1 developed isolated leptomeningeal disease 18 months after responding to neoadjuvant therapy with cyclophosphamide and doxorubicin for locally advanced breast cancer. She was originally treated with intrathecal methotrexate without response, followed by craniospinal irradiation with clinical stabilization. Eighteen months after radiation she again developed symptomatic meningeal disease along with early metastases in lung and liver. Treatment with carboplatinum and docetaxel was begun. Clinical response was prompt and MRI demonstrated improvement. Repeat CSF cytology showed only degenerating cells. She remained neurologically stable for more than 12 months. Patient #2 had previously undergone resection and cranial irradiation of cerebellar metastases from breast cancer and subsequent chemotherapy for metastatic disease with paclitaxel and trastuzumab when she developed symptomatic leptomeningeal disease. Based on the response in our previous patient, she was treated with carboplatinum and docetaxel. Trastuzumab was continued as her brain tumor overexpressed HER2/neu. Her symptoms improved, and repeat MRI and CSF exams documented response. She remains stable after 11 months of treatment. Conclusions: Systemic chemotherapy with carboplatinum and docetaxel (+trastuzumab)can be effective in the treatment of meningeal carcinomatosis from breast cancer. This regimen deserves formal study and comparison to standard treatments No significant financial relationships to disclose.
Abstract 10714: Elevated Systolic Blood Pressure Reactivity Before Exercise Stress Testing is Associated With the Risk of Hypertension in Healthy Men
Authors: Sae Young Jae, S Kurl, JA Laukkanen, Kevin Heffernan, Yoon-Ho Choi, Bo Fernhall
Journal: Circulation (2012)

Heightened cardiovascular reactivity has been associated with incident hypertension, but whether systolic blood pressure (SBP) reactivity prior to exercise stress testing is associated with incidence of hypertension in healthy men is not known. We tested the hypothesis that SBP reactivity prior to exercise stress testing is inversely associated with the incidence of hypertension in middle aged healthy men. Subjects were 3814 men (mean age 48±6 yrs) who participated in two health examinations during 1998-2009. All subjects were free of cardiovascular diseases and hypertension at baseline. Seated resting blood pressure in a quiet room and blood pressure at the beginning of treadmill exercise stress testing were measured. The reactivity in blood pressure was calculated as the difference between resting SBP and SBP immediately before exercise stress testing. Hypertension was defined as systolic and diastolic blood pressure ≥140/90mmHg. During an average follow-up of 5 years, 371 (9.7%) subjects developed hype...
Pharmacokinetics (PK) of gemcitabine (Gem), capecitabine (Cap), and erlotinib (Erlo) given in combination in patients with pancreatic carcinoma.
Authors: M. Etienne-Grimaldi, E. Francois, N. Renée, J. Bennouna, C. Bobin-Dubigeon, P. Follana, V. Mari, E. Chamorey, L. Evesque, G. A. Milano
Journal: Journal of Clinical Oncology (2010)

e13116 Background: The aim was to describe the PK of Erlo, Cap, and Gem, given in combination in the phase I CAPERGEM trial, performed in advanced pancreatic cancer patients. Methods: This study was conducted on 18 patients. Gem (1000 mg/m2, iv infusion) was given on day 1, day 8, and day 15 of a 28-day cycle. Cap (1660 mg/m2/d per os) was given from day 1 to day 14. Erlo, given per os from day 1 to day 28, was administered at 50, 75, 100, and 125 mg/d in 3, 3, 9, and 3 patients, respectively. PK was performed at first cycle on day 1 and day 15, over 5 hours. Plasma concentrations of Cap and metabolites 5′DFCR, 5′DFUR, FU, as well as those of Gem and Erlo were measured by HPLC. AUC0-5h were computed from 6 points for Cap and Erlo and 7 points for Gem. Results: PK was performed in all patients on day 1 and in 13 patients on day 15. On day 1, PK of Gem showed an 8-fold interpatient variability with AUC varying from 15 to 122 μM.h (median 30); AUC of the sum of Cap and metabolites showed a 29-fold interpatient variability (median 18,300, range 1,220-35,390 ng/ml.h) whereas AUC of FU alone exhibited a 5.5-fold interpatient variability (median 300, range 117-638 ng/ml). No significant correlation was observed between Erlo AUC and doses (median AUC 1,164, 2,585, 1,286, and 2,513 ng/ml.h at 50, 75, 100, and 125 mg/d, respectively). On day 15, AUC were not significantly different from those measured on day 1 for Gem and Cap; a significant increase (p=0.007) was observed for Erlo (median intrapatient increase = 120%, from -46 % to 2070%). Maximal toxicity grade at first cycle was 3 in 7 patients and 4 in 2 patients. Pretreatment lymphocytic DPD activity (median 280, range 84-435 pmol/mn/mg) was inversely correlated to 5'DFUR AUC measured on day 15 (p = 0.001, r2 = 67%). DPD activity was not related to toxicity grade. Mucositis grade was positively correlated to FU (p=0.035) and 5'DFCR (p=0.028) day 1 AUC, whereas those of anemia and leucopenia were associated with 5'DFCR (p = 0.020) and 5'DFUR (p = 0.029) day 1 AUC, respectively. Conclusions: Present data confirm the wide interpatient variability of Gem, Erlo, and Cap PK. However, toxicities were only associated with fluoropyrimidine PK. No significant financial relationships to disclose.
A prospective study of XELOX plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer (KSCC0902).
Authors: Masaaki Takeuchi, Yutaka Ogata, Takaho Tanaka, Atsushi Kaibara, Yasunori Emi, Hiroshi Saeki, Eiji Oki, Noriaki Sadanaga, Tetsuya Kusumoto, Tetsuo Touyama, Hiroo Matsushita, Mototugu Shimokawa, Hideo Baba, Kazuo Shirouzu, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2013)

583 Background: XELOX plus bevacizumab (Bev) is one of the standard therapies for metastatic colorectal cancer (mCRC). However there was no clinical practice date in Japan. This study was designed to evaluate the efficacy and safety of XELOX plus Bev in the clinical practice in Japanese mCRC patients (pts) including the elderly. Methods: The study design was multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated mCRC; presence of measurable lesions; age 20 years; ECOG performance status (PS) 0–2; and adequate organ function. Pts received Bev 7.5 mg/kg d1 and XELOX (oxaliplatin 130 mg/m 2 d1 plus capecitabine 1,000 mg/m 2 bid d1-14) q3w. This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint was RECIST-confirmed objective response rate (ORR). A sample size of 41 was planned for a threshold ORR of 30% and expected value of 50%, with one-sided alpha of 0.05 and beta of approximately 0.2. Results: Of the 47 pts (male/female, 29/18; median age, 66 years (range 38-81); PS 0/1/2, 40/5/2) enrolled from May 2010 to Mar 2011. One patient did not fulfill the eligibility criteria. 46 pts were assessed for response; CR 1 pts, PR 23 pts, SD 15 pts, PD 2 pts, and NE 5 pts. The confirmed ORR was 52.2% (90% CI, 39.2-65.0%). The response rate across all time points without confirmation was 67.4% (95% CI, 52.0-80.5%). Median PFS and OS have not yet been reached. The most common grade 3/4 adverse events were anorexia 12.8%, neutropenia 10.6%, fatigue 8.5%, hypertension 4.3%, thrombocytopenia 4.3%, hand-foot syndrome 2.1% and bleeding 2.1%. Grade 3/4 peripheral neuropathy did not occur. Conclusions: First-line treatment of XELOX + Bev showed a promising response rate and an acceptable tolerability profile in the clinical practice in Japanese mCRC pts including the elderly. Clinical trial information: UMIN000003915.
Survival rates after resection for localized kidney cancer: 1989 - 2004
Authors: T. L. Jang, J. A. Pettus, W. C. Huang, S. E. Eggener, M. F. O’Brien, M. E. Karellas, M. A. Kagiwada, P. Russo
Journal: Journal of Clinical Oncology (2008)

5115 Background: Kidney cancer mortality rates have continued to rise despite the increased detection of smaller renal tumors and rates of renal surgery. To explore potential explanatory factors, we evaluated how changes in tumor size have affected disease progression in patients after nephrectomy for localized kidney cancer. Also, we identified factors associated with disease progression and overall survival (OS) following surgery. Methods: 1,618 patients with localized kidney cancer treated by nephrectomy at Memorial Sloan- Kettering Cancer Center from 1989 to 2004 were identified and categorized by year of operation: 1989–1992, 1993–1996, 1997–2000, and 2001- 2004. Tumor size was classified as follows: <2, 2–4, 4–7, and >7 cm. Progression was defined as the development of local recurrence (LR) or distant metastases (DM). 5-year progression-free survival (PFS) was calculated for patients in each tumor size strata, according to year of operation, using the Kaplan-Meier method. Characteristics associated with PFS and OS were explored using univariable analysis. All significant variables were retained in a multivariable Cox regression analysis. Results: Overall, the number of nephrectomies increased for all tumor size categories from 1989 to 2004. The proportion of patients with tumors <2 and 2–4 cm increased while those with tumors >7 cm decreased. 179 patients (11%) developed disease progression. LR occurred in 16 (1%) and DM in 163 (10%). When 5-year PFS was calculated for each tumor size strata according to 4-year cohorts, trends in PFS did not improve nor differ significantly over time. Compared to historical cohorts, patients in more contemporary cohorts were more likely to undergo partial, versus radical, nephrectomy and less likely to have a concomitant lymphadenectomy and adrenalectomy. Multivariable analysis showed that pathologic stage and tumor grade were associated with disease progression. Patient age and tumor stage were associated with OS. Conclusions: Despite increasing numbers of nephrectomies and a favorable size migration, trends in 5-year PFS and OS did not improve nor differ significantly over time. Pathologic stage and tumor grade can be used to identify patients at risk for disease progression following resection for localized kidney cancer. No significant financial relationships to disclose.