tbuckley/cabot-search huggingface dataset:
Phase II trial of rituximab and short duration chemotherapy followed by <sup>90</sup>Y-ibritumomab tiuxetan as first-line treatment for patients with follicular lymphoma: A Minnie Pearl Cancer Research Network phase II trial
Authors: D. L. Shipley, D. R. Spigel, D. L. Carrell, C. Dannaher, F. A. Greco, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2004)

6519 Background: First-line treatment with combination chemotherapy + rituximab improves molecular complete remission (CR) rates and lengthens remission duration in patients (pts) with follicular NHL. In a previous phase II trial, we demonstrated a high CR rate with short course chemotherapy + rituximab (CHOP-R or CVP-R). In an attempt to further improve the CR rate, we added 90Y-ibritumomab tiuxetan (Zevalin) after CHOP-R. Methods: Previously untreated pts with follicular lymphoma (grades 1–3) and stages II-IV were eligible. Additional entry criteria: ECOG PS 0–2; adequate organ function; no CNS involvement; no HIV infection; informed consent. Pts with cardiac ejection fraction < 45% received CVP instead of CHOP. All pts first received 4-weeks of rituximab (375mg/m2 weekly x 4), then 3 courses of CHOP-R (standard doses). After complete restaging, responding pts with bone marrow involvement < 25% received 90Y-ibritumomab tiuxetan 5 weeks after the last dose of CHOP-R. Final restaging was performed 12 weeks after 90Y-ibritumomab tiuxetan. Results: 33 of 40 pts have been accrued, with median follow-up of 10 months. Pt characteristics: median age, 56 years; stage IV, 54%; M/F = 16/17. Prior to 90Y-ibritumomab tiuxetan, 27 of 28 pts (96%) had objective response (9 CR). All pts completing CHOP-R were eligible for 90Y-ibritumomab tiuxetan. 22 pts have completed therapy and been restaged: 19 pts (86%) are in CR, with 3 PR's. 10 pts with PR converted to CR after 90Y-ibritumomab tiuxetan. No unexpected toxicity was seen during CHOP-R therapy. Hematologic toxicity following 90Y-ibritumomab tiuxetan: gr 4 neutropenia 18%; gr 4 thrombocytopenia 0; RBC transfusion 5%; platelet transfusion 18%; neutropenia/fever 5%; GI bleed 5%. 90Y-ibritumomab tiuxetan caused no grade 3/4 nonhematologic toxicities. Conclusions: First-line CHOP-R followed by 90Y-ibritumomab tiuxetan is highly active and well tolerated in pts with follicular NHL. Further follow-up is necessary to determine progression-free and overall survival, and to monitor for late toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Brogen IDEC
Abstract 5315: Hydroxychloroquine inhibits proliferation and S6 phosphorylation in human renal carcinoma cells
Authors: Hyung-Ok Lee, Aladdin Mustafa, Gary R. Hudes, Warren D. Kruger
Journal: Cancer Research (2015)

Abstract mTOR inhibitors are used to treat metastatic renal cell cancer (RCC), but most patients eventually become resistant. One possible mechanism for resistance is upregulation of autophagy, a pathway which helps recycle intracellular proteins and promotes cell survival. Hydroxychloroquine (HCQ), a potent autophagy inhibitor used to treat malaria and autoimmune disorders, is currently being studied in the context of cancer treatment. Here, we have investigated the effects of HCQ on three different renal carcinoma derived cell lines. We found that HCQ treatment inhibits RCC cell growth, promotes apoptosis, inhibits mitochondrial oxygen consumption, and increases glycolysis rates. To understand the molecular mechanism behind these effects, we examined various nodes in the mTOR pathway and compared the effects of HCQ with the effects of the mTOR inhibitor RAD001. A key downstream readout of the pathway, phospho-S6 protein, was inhibited by both HCQ and RAD001. However, the upstream kinase, P70S6K, was only inhibited by RAD001 and not HCQ, suggesting that the block by HCQ was downstream of the p70S6K. Treatment with the proteasome inhibitor bortezomib, restored phospho-S6 levels, suggesting that the reduction of phospho S6 is caused by increased degradation of phospho, but not total S6. Surprisingly, depletion of the key autophagy regulator Atg7 did not mimic the effects of HCQ, indicating that HCQ regulates S6 phosphorylation by ATG7-independent mechanism. Our finding suggests that HCQ may be useful in the treatment of renal cell carcinoma. Citation Format: Hyung-Ok Lee, Aladdin Mustafa, Gary R. Hudes, Warren D. Kruger. Hydroxychloroquine inhibits proliferation and S6 phosphorylation in human renal carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5315. doi:10.1158/1538-7445.AM2015-5315
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer
Authors: K. Flaherty, I. Puzanov, J. Sosman, K. Kim, A. Ribas, G. McArthur, R. J. Lee, J. F. Grippo, K. Nolop, P. Chapman
Journal: Journal of Clinical Oncology (2009)

9000 Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase with preclinical activity. V600E BRAF is the most common kinase mutation in melanoma (60%), also found in colorectal carcinomas (10%), most anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas. Methods: Phase I, dose-escalation study designed to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic (PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and 15. Results: 54 pts have been enrolled: metastatic melanoma (n=49), thyroid (n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with associated exposures below target plasma levels. 28 pts received an optimized formulation with increased bioavailability, predicted to have 10-fold greater bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-proportional and above target levels at 240 mg BID and higher. There was 1 DLT at 720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at doses of 240 mg BID or higher of the increased bioavailability formulation have a minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at ≥ 240 mg BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1 unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to 14 months. 3 thyroid cancer pts with V600E mutations have tumor regression (range 9–16%) and are progression-free (4–7 months). Conclusions: Dose escalation of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960 mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic target in human cancer. [Table: see text]
Incidence of secondary leukemia/myelodysplasia (AML/MDS) in Hodgkin’s disease (HD) with three generations of therapy at Stanford University
Authors: R. H. Advani, R. T. Hoppe, S. A. Rosenberg, S. J. Horning
Journal: Journal of Clinical Oncology (2006)

7516 Background: Long term HD survivors have an increased risk of therapy-related AML/MDS that peaks about 5 years (yr) after alkylating agent (AA)-based chemotherapy (CT). Successive generations of Stanford studies limited AA exposure to address this risk. Methods: Patients (pt) treated with CT from 1974–2003 (RT only excluded) were retrospectively analyzed. S study pt received AA-based CT (MOPP or PAVE) alone (6%), with involved (IF) (21%) or extended field (EF) radiotherapy (RT) (73%); C pt received AA-based CT alone (26%) or with RT (37%) or non-AA-based CT (VBM or ABVD) + IFRT (37%); G pt received VBM + IFRT (12%) or the Stanford V + RT regimen (88%). Results: 21 (3.3%) of 639 pt developed AML/MDS: 13 after primary and 8 after secondary CT. AML/MDS incidence was significantly less in G pt (0.3%) compared to S (6.7%) and C pt (4.5%), p &lt; 0.0001 and remained significant when pt followed &lt;5 yr (18%) were excluded, p = 0.001. Secondary therapy was required more often for S (29%) and C (28%) pt than G (11%) pt. Number and Percent of AML/MDS in Three Eras Conclusion: AML/MDS was rare in the current Stanford V regimen era, indicating that limiting the cumulative dose of AA CT in combination with lesser RT volumes have significantly reduced the incidence of leukemia and the need for secondary CT. Longer follow-up is required to assess the impact of the Stanford V regimen on solid tumor and cardio-vascular risks. [Table: see text] No significant financial relationships to disclose.
Serum carcinoembryonic antigen (CEA) in the management of advanced colorectal cancer (ACRC) treated with CAPIRI plus bevacizumab.
Authors: J. Vieitez, P. J Fonseca, A. Llaneza, N. Avello, M. Fernandez de Sanmamed, E. Gutierrez Restrepo, C. Muriel, F. S. Sotomayor, A. J. Lacave
Journal: Journal of Clinical Oncology (2010)

e14049 Background: Although in use for almost 30 years, the clinical value of CEA as the marker of choice for monitoring the response of advanced colorectal cancer (ACRC) to systemic therapy is not clearly established and no study has investigated the usefulness of CEA in patients (pts) treated with new drugs as angiogenesis inhibitors. The aim of this study was to prospectively evaluate the relationship between serum CEA, and computed tomography (CT) scan, gold standar test, in patients with ACRC by calculating sensitivity (S), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). Methods: 150pts with previously untreated histopatologically confirmed ACRC, age > 18 years and Karnosky (PSK) ≥ 60% were treated with capecitabine, irinotecan and bevacizumab, in a 3-week cycle. Response was evaluated every 2-3 month by CT scan, CEA was checked on day 1 of every cycle. Response by tumour marker was defined as a reduction of 50%, and progression as an increase of 30%. Results: From March 2005 to July 2009, 150 pts entered in the study. 111 pts have progressed to first line treatment and 71 have died. CEA was 2x upper normal limit (UNL) in 109 (72%), 5x UNL in 88 (58%), inferior a 2x ULN in 41 (28%), and normal (< 5 ng/mL) in 28 (18%) pts. 17 pts with normal baseline CEA have progressed, and CEA increased in 14 (82%) during progressive disease. For response, there were 57 pts truly positive (TP), 45 truly negative (TN), 31 false-positive (FP), and one false-negative (FN) pts (Chi-square 48.2, p < 0.0001) so response resulted in S of 98% (CI 95%, 0.90-0.99), Sp of 59%, (CI 95%, 0.47-0.70) PPV of 64.7%, and NPV of 97%. For progression, there were 101 TP, 84 TN, 44 FN, and no FP pts (Chi- square 158.5, p < 0.0001) so progression resulted in S of 90.9% (CI 95%, 0.84-0.95), Sp of 100% (CI 95%, 0.95-1), PPV of 100%, and NPV of 65.6%. CEA indicated progression with a median of 6 weeks prior to the CT scan and response with a median of 3 weeks prior to CT scan. Conclusions: CEA is an accurate, simple, accessibility, low cost and robust method and these results suggest that CEA analysis could help in the decision of accelerate or delay CT scan in order to avoid un-useful treatments/CT scan. No significant financial relationships to disclose.
Noninvasive ventilation in emergency: Predictors of success or failure in cases of acute pulmonary edema and the exacerbation COPD
Authors: Ivete Alonso Bredda Saad, Juliana Nalin de Souza Passarini, Carolina Kosour, Andre Morcillo, Lair Zambon
Journal: European Respiratory Journal (2012)

BACKGROUND AND OBJECTIVES: The noninvasive ventilation (NIV) has been the technique chosen for cases of acute respiratory failure due to acute pulmonary edema (APE) and exacerbation of Chronic Obstructive Pulmonary Disease (COPD). The objective was to evaluate predictors of success or failure of NIV in an emergency department from Brazil. METHODS: The NIV was used in patients with COPD exacerbation or APE. If no improvement in 2 hours or there is any contraindication to continue with NIV, endotracheal intubation (EI) is performed and considered the endpoint. RESULTS: The study included 152 patients. On average, the use of NIV was 10 hours for patients with COPD (n = 60) and 7.5 hours for patients with APE (n = 92). It was observed that 75.7% successfully evolved and 24.3% were intubated, and those who progressed unfavorably presented lower oxygen saturation 78.3% compared with those who achieved successfully after NIV, with mean oxygen saturation 84.2%. The findings showed there was a statistically significant difference when researching the APACHE II score and respiratory frequency above 25 in the patients who developed IE. Among patients diagnosed APE, a chance of evolution EI was 63% lower (adjusted OR = 0.37 95% CI :0,14-0, 96). Similarly, higher values of the Glasgow Coma Score (GCS) and oxygen saturation reduce the chance of adverse developments. CONCLUSIONS: The NIV should be used in emergency services in this cases. Variables like oxygen saturation below 80%, respiratory frequency above 25, higher value of APACHE II and among those who received Bilevel may indicate progression to EI.
Stromal elements and engraftment (ENG) in autologous hematopoietic progenitor cell transplant (autoHCT) for myeloma.
Authors: M. Veeraputhiran, Z. Singh, B. Barlogie, M. Cottler-Fox
Journal: Journal of Clinical Oncology (2010)

8149 Background: ENG after autoHCT involves stromal elements of the stem cell niche. We present a retrospective analysis of marrow biopsies (BM) from patients with myeloma prior to autoHCT and correlate stromal variables with ENG. Methods: BM done just prior to autoHCT from 26 patients (pts) with good engraftment and those from 12 pts with delayed engraftment, were compared. Hematoxylin/eosin stained sections were examined for: stromal components (fat, regenerating adipocytes, fat necrosis, stromal edema, granular degeneration, vascular sinusoids and hemorrhage); bone remodeling (osteoblasts vs osteoclasts); hematopoeisis (endosteal vs peri-sinusoidal hematopoesis); cellularity; and reticulin fibrosis. Reticulin fibrosis was graded using Gomori's silver and Trichrome stains. Duration of disease before autoHCT; total viable CD34 stem cells infused; time to WBC ENG (ANC>500) and platelet ENG (20,000/mm3 and 50,000/mm3) were determined. Univariate and multivariate regression were applied to determine, the correlation of significant stromal parameters with ENG between groups and for the two groups combined Results: Median time to WBC ENG among good and poor engrafters was 12 and 14.5 days respectively. Median time to platelet count of 20,000/cmm and 50,000/cmm for good engrafters was 12.5 and 16 days respectively and for poor engrafters it was 45.5 and 57 days respectively. Endosteal hematopoesis was significantly correlated with WBC and platelet ENG (p < 0.01 and Hazards ratio of > 2.7). Stromal vascularity was significantly associated with platelet ENG but not WBC ENG (p < 0.05 and p > 0.1 respectively). Osteoblastic activity showed significant correlation with WBC ENG (p = 0.003) and platelet ENG to 20,000 (p = 0.016). In univariate analysis between the groups, osteoblastic activity had marginal significance in good engrafters (OR 8.3 with p = 0.05) as did stromal vascularity (OR 8.1 and p = 0.06). No other variables were statistically significant. Conclusions: Pretransplant BM evaluation for stromal elements such as endosteal hematopoesis, stromal vascularity and osteoblastic activity may be useful to predict good WBC and platelet ENG. No significant financial relationships to disclose.
Identification of prognostic factors predictive of CNS metastasis in patients (pts) with advanced unresectable metastatic melanoma (MM)
Authors: A. Y. Bedikian, C. Wei, M. Detry, K. Kim, N. Papadopoulos, W. Hwu, S. McIntyre, T. Smith, X. Gumpel, P. Hwu
Journal: Journal of Clinical Oncology (2006)

8060 Background: Diagnosis (Dx) ofCNS metastasis (met) in MM is associated with poor prognosis. The objective of this study was to find prognostic factors that may predict CNS met. Methods: 743 chemotherapy (CRx) naïve MM pts were treated on 12 clinical trials during the past 15 years at MDACC. Demographics, tumor stage, and Rx outcomes were collected. Seven prognostic factors likely to predispose pts to CNS met were assessed: presence of liver met, elevated serum LDH, low serum albumin, site of primary, Clark level ≥ IV / Breslow thickness (BT) &gt; 3.5 mm, M1 stage, and number of visceral met sites. Time to event analyses considered the time from unresectable stage III/ IV disease to Dx of CNS met, or last follow-up if noCNS met. Prognostic factors were examined separately using a Cox proportional hazards model, with time from Dx of primary melanoma to Dx of unresectable stage III/ IV disease also included as a covariate. Estimates of CNS met-free curves were calculated using the Kaplan-Meier product-limit method. The incidence of CNS met between CRx-sensitive and CRx-resistant groups was assessed by Chi-square test. Results: CNS met (n=333) and CNS met-free (n=410) pt groups were similar in median age, gender distribution and primary M sites. Compared to CNS met-free pts, CNS met pts were more likely to have M1b + M1c advanced disease stage (M1b+c 291/333 (87%) vs. 286/410 (70%); p&lt;0.0001) and ≥ 2 visceral met sites (138/333 (41%) vs. 126/410 (30%), p=0.003), as well as greater BT (median 2.3 vs. 1.5 mm). Pts with elevated serum LDH had significantly shorter CNS met-free interval those with normal serum LDH (p=0.0009). CNS met-free interval was also significantly shorter for M1b (p=0.028) and M1c pts (p=0.05), but not M1a (p=0.8) pts, compared to unresectable stage III pts. Compared to pts with soft tissue/l. node disease, CNS met-free interval was significantly shorter for pts with 1–3 met sites (p&lt;0.0001), but not for pts with ≥ 4 sites (p=0.03). The incidence of CNS met was not significantly different between CRx-sensitive and CRx-resistant pts (p=0.2821). Conclusion: Prognostic factors predictive of high risk CNS met were identified that could be used to individualize Rx for MM pts. Supported in part by Chiron Corporation and Carol Courtney Memorial Fund. No significant financial relationships to disclose.
The value of early decrease in CA125 levels as a prognostic or surrogate marker for disease progression in patients with recurrent ovarian cancer: Results from the CALYPSO study.
Authors: R. J. Simes, C. K. Lee, M. R. Mirza, P. Sauthier, A. Georgopoulos, I. B. Vergote, G. Ferrandina, N. Donadello, B. Schmalfeldt, R. Delva
Journal: Journal of Clinical Oncology (2010)

5080 Background: In the CALYPSO trial, carboplatin (C)- pegylated liposomal doxorubicin (PLD) demonstrated superior therapeutic index versus C-paclitaxel (P) in recurrent ovarian cancer (ROC): ≥ 6 months after first- or second-line platinum-based therapy. CA125 is routinely used as a surrogate marker to monitor the efficacy of chemotherapy and guide treatment decisions. Its value alone as a predictor of progression-free survival (PFS) in ROC is not well-established. We evaluated early decrease (ED) in CA125 as a prognostic factor for PFS and as a potential surrogate for the benefit of longer PFS from CPLD over CP. Methods: 886 from 976 randomized patients (pts) who were alive at 100 days with no disease progression and at least two CA125 values were eligible. Using a landmark analysis at 100 days post- randomization, ED in CA125 and early response (ER) measured by RECIST were evaluated as prognostic factors. ED was defined as rate of decrease in CA125 of ≥ 50% per month during the first 100 days of treatment. ER was defined as a status of complete or partial response at 100 days. Results: For the overall population, ED and ER were associated with longer PFS after 100 days. Pts with ED CA125 had a median PFS of 8.6 mo versus 8.2 for pts without an ED (HR 0.86, p=0.07). Pts with ER had a median PFS of 10.2 mo versus 8.0 for pts without ER (HR 0.59 p<0.001). In comparing treatment groups, CPLD was associated with a higher PFS than CP after 100 days (p=0.02). But contrary to expectations, ED (p<0.01) and ER (p=NS) were lower in CPLD that in CP arm (Table). Conclusions: ED in CA125 is prognostic in ROC for longer progression-free survival. However it is a poor surrogate marker for the chemotherapy benefit in PLD-containing arm. We hypothesize that the benefit in CPLD arm may require longer treatment time in order to manifest a better outcome for these patients. CPLD(n=431) CP(n=455) Odds ratio (OR) or hazard ratio (HR)* 95% CI ED in CA125 37% 51% OR=1.76 1.35-2.30 ER 32% 36% OR=1.23 0.94-1.62 Median PFS (after 100 days) 8.8 7.7 HR=0.82 0.69-0.96 * Ratio < 1 favors CPLD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Adjuvant bisphosphonates in early breast cancer: consensus guidance for clinical practice from a European Panel
Authors: P. Hadji, R.E. Coleman, C. Wilson, T.J. Powles, P. Clézardin, M. Aapro, L. Costa, J.-J. Body, C. Markopoulos, D. Santini, I. Diel, A. Di Leo, D. Cameron, D. Dodwell, I. Smith, M. Gnant, R. Gray, N. Harbeck, B. Thurlimann, M. Untch, J. Cortes, M. Martin, U.-S. Albert, P.-F. Conte, B. Ejlertsen, J. Bergh, M. Kaufmann, I. Holen
Journal: Annals of Oncology (2015)
Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT
Authors: Bin Liu, Hsiang-Ting Ho, Lucia Brunello, Sathya D. Unudurthi, Qing Lou, Andriy E. Belevych, Lan Qian, Do Han Kim, Chunghee Cho, Paul M. L. Janssen, Thomas J. Hund, Bjorn C. Knollmann, Evangelia G. Kranias, Sándor Györke
Journal: Cardiovascular Research (2015)

Cardiac calsequestrin (CASQ2) and histidine-rich Ca-binding protein (HRC) are sarcoplasmic reticulum (SR) Ca-binding proteins that regulate SR Ca release in mammalian heart. Deletion of either CASQ2 or HRC results in relatively mild phenotypes characterized by preserved cardiac structure and function, although CASQ2 knockout (KO), or Cnull, shows increased arrhythmia burden under conditions of catecholaminergic stress. We hypothesized that given the apparent overlap of functions of CASQ2 and HRC, simultaneous ablation of both would deteriorate the cardiac phenotype compared with the single knockouts. In contrast to this expectation, double knockout (DKO) mice lacking both CASQ2 and HRC exhibited normal cardiac ejection fraction and ultrastructure. Moreover, the predisposition to catecholamine-dependent arrhythmia that characterizes the Cnull phenotype was alleviated in the DKO mice. At the myocyte level, DKO mice displayed Ca transients of normal amplitude; additionally, the frequency of spontaneous Ca waves and sparks in the presence of isoproterenol were decreased markedly compared with Cnull. Furthermore, restitution of SR Ca release was slowed in DKO myocytes compared with Cnull cells. Our results suggest that rather than being functionally redundant, CASQ2 and HRC modulate cardiac ryanodine receptor-mediated (RyR2) Ca release in an opposing manner. In particular, while CASQ2 stabilizes RyR2 rendering it refractory in the diastolic phase, HRC enhances RyR2 activity facilitating RyR2 recovery from refractoriness.