tbuckley/cabot-search huggingface dataset:
Comparison of hospital costs versus DRG reimbursement for treatment of febrile neutropenia during adjuvant CTX for primary breast cancer.
Authors: S. C. Mayer, A. Ihbe-Heffinger, B. Paessens, U. R. Schwarz-Boeger, J. Ettl, S. Paepke, R. Bernard, N. Harbeck, M. Kiechle, V. R. Jacobs
Journal: Journal of Clinical Oncology (2010)

6150 Background: Febrile neutropenia (FN) is an undesired effect of chemotherapy (CTX). Under flat rate DRG reimbursement, a hospitals' own costs should not exceed the actual reimbursement which equals the target costs. In a study actual costs and reimbursement of FN were therefore compared. Methods: Prospective, observational study in primary BC patients with adjuvant anthracycline (A)-based CTX, enrolled over 1 year consecutively in a university clinic. FN was defined as fever > 38°C and ANC < 1x109/L. Resource use data and DRG reimbursement were analyzed from medical charts. Costs for therapy of FN were compared to DRG reimbursement and results are presented from provider's perspective. Results: Of all pat. approached (n = 61), n = 54 signed informed consent (88.5%), n = 2 withdrew (3.3%) and n = 2 were excluded because of non-A-based CTX. Pat. were on average 57.4 (32-74) years and otherwise healthy ECOG 1 (n = 50; 100%). Tumor classification was T1 n = 25, T2 n = 19, ≥ T3 n = 5 and pTx n = 1. Chemotherapy regimens were either A-based n = 29 (58.0%) or A+taxane-based n = 21 (42.0%). 12 episodes of FN occurred (24.0%) in 11 pat., one had 2 FN episodes; n = 11 were treated as inpatients, n = 1 as outpatient. Hospital stay for inpatients was 5.4 days (4-8), 0.7 days below average according to DRG catalog. Mean cost per inpatient FN episode was 1.827€, SD ±795€ (95%CI: 1293, 2361). Basic hospital costs were 83%, drug treatment 9% and diagnostics 8% of total direct costs. In principle, DRG reimbursement for inpatient FN was 2.145€ per episode, thus cost-covering for the provider. However, the average reimbursement rate/day was 417€ (253- 665€). Moreover, inadequate DRG coding (n = 4) resulted in reduced reimbursement of avg. 1.464€ instead of 2.533€, a loss of 1.069€/case (−42.2%). Conclusions: Costs for FN treatment vary and does not necessarily reflect providers' reimbursement. Main cost drivers are hospitalization, length of stay, diagnostics, and antibiotics. Surprisingly, inpatient treatment of FN is cost covering if adequately DRG coded. This evaluation and calculation of provider's costs and DRG reimbursement supports understanding of allocation of appropriate resources for cost-covering therapy. No significant financial relationships to disclose.
Maintenance treatment with bevacizumab after chemotherapy (CT) plus B in metastatic colorectal cancer: An Italian multicenter retrospective analysis.
Authors: L. Moscetti, E. Cortesi, T. Gamucci, I. Sperduti, I. Pavese, D. Franco, D. Alesini, A. Fabbri, R. Grande, D. Gemma, C. Signorelli, E. Ruggeri
Journal: Journal of Clinical Oncology (2011)

e14043 Background: Maintenance treatment with B is considered an option for mCRC pts in responding pts after a first line CT + B, but few data are available on its real benefit on progression-free survival (PFS). Methods: Two-hundred-twenty mCRC pts treated with first line CT + B achieving a response [partial (PR) or complete (CR)] or a stable disease (SD) were considered eligible. 118 pts had received B maintenance (BM) whereas 102 did not (noBM). The two groups were homogeneous for main characteristics. First-line therapy in the BM vs noBM group included FOLFIRI regimen (96 vs 73 pts), FOLFOX (18 vs 28 pts) and FUFA (4 vs 1 pts). K-ras status was analyzed in 115 pts with an higher percentage of wild-type (wt) in the BM group (65 vs 50 pts, p= 0.04). A CR or PR have been achieved in 56% of pts in the BM group and 49% of noBM group, while a SD was observed in 34% and 31% of pts respectively for the BM and noBM group. The median number of BM cycles administered was 7 (range 3-25). PFS analysis of was conducted on the entire population comparing BM and noBM and by response to prior CT+B (PR and CR versus SD). Results: At a median follow-up of 18 months (1-109), the median PFS was 13 months (C.I.95%: 11-15) vs 8 months (C.I.95%: 7-10) p<0.0001, and the 1-year PFS 53.% vs 28% for BM and noBM respectively. According to the response, pts with CR/PR had a mPFS of 15 months (CI 95% 12-19) vs 10 months (CI 95% 10-12) p=0.004, and a 1-year PFS of 62.6% and 33.7% for the BM vs noBM group respectively. No difference in PFS was found in pts showing SD after first-line CT + B. Furthermore, no difference was observed in PFS comparing, in the BM group alone, CR/PR vs SD nor when the k-ras status was considered. Conclusions: Our retrospective analysis, shows that the maintenance therapy with B is correlated with a longer PFS in pts responding to the first line CT + B. Results from ongoing randomized phase III studies addressed to explore the issue of maintenance treatment are needed.
Therapeutic response to HMGB1-R3V6-conjugated Ym1/Ym2 siRNA complex in ovalbumin-induced murine asthma
Authors: Jahyun Gu, Moonhwan Choi, Taehyun Ban, Sol Kim, Youngjin Kim, Minhyung Lee, Taiyoun Rhim
Journal: Journal of Controlled Release (2015)
Pathophysiology of pruritus in primary localized cutaneous amyloidosis
Authors: H.L. Tey, T. Cao, L.A. Nattkemper, V.W.D. Tan, Z.A.D. Pramono, G. Yosipovitch
Journal: British Journal of Dermatology (2016)

Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatosis prevalent among Southern Chinese and South American populations. Pruritus is frequently present and can be debilitating; its pathophysiology is largely unknown.To investigate if small-fibre neuropathy (SFN), which results in a reduction of intraepidermal nerve fibres (IENF) and abnormalities in quantitative thermal sensory testing (QST), is present in PLCA.Twenty Chinese patients (10 men) and 20 ethnicity-, sex- and age-matched controls underwent QST assessments. The patients' warm detection threshold (WDT) and heat pain threshold at the typical lesional sites were determined. Serum interleukin (IL)-31 levels were measured. Lesional biopsies were stained for IENF, IL-31 and its receptor's subunits [IL-31RA and oncostatin M receptor-β (OSMRβ)], and nerve growth factor (NGF) and its receptor [tropomyosin receptor kinase A (TrkA)], and were compared with normal skin obtained from archival paraffin-embedded specimens.WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0·59; P < 0·01). Patient biopsies revealed lower IENF counts (P < 0·01 using protein gene product 9.5, β3-tubulin and Neurofilament 200 stains) and increased epidermal expression of OSMRβ (P < 0·01) and IL-31RA (P < 0·01). Cutaneous IL-31, NGF and TrkA stains were not significantly increased in patients. Serum IL-31 was not significantly higher in patients.SFN is present in PLCA. Pruritus in PLCA is likely associated with hypersensitivity of cutaneous nerve fibres, which may be related to an increased expression of epidermal IL-31 receptors. Targeting IL-31 receptors is therefore a potential therapeutic approach.
Primary prevention of venous thromboembolic events (VTE) in cancer patients: An American survey study
Authors: S. R. Deitcher
Journal: Journal of Clinical Oncology (2004)

8086 Background: Optimal care of and research involving cancer patients at risk for and with documented VTE require insight into thrombosis risk factors plus risks and benefits of anticoagulation (AC). Formal quantification of oncologist attitudes towards VTE has been lacking. Methods: We performed a two-phase, web- and fax-based survey study of American oncologists, including 28 questions that asked respondents to quantify the "necessity" and "appropriateness" of VTE prophylaxis or treatment in several clinical scenarios. Mean responses provided assessment of group opinion. Results: In Phase I (n=507), 61% and 63% indicated regular prescription of inpatient and central line VTE prophylaxis, respectively; 39% believed that LMWHs can prolong cancer patient survival. Phase II (n=112 from 33 states) demographics: 63% private practice, 84% solid tumor focus, 79% Oncology board certified, 88% ASCO members. Respondents under-recognized known VTE risk factors (e.g. brain mets, antiangiogenesis drugs, and EPO) and high risk histologies (e.g. primary brain, lung, lymphoma, and ovary). Consensus on the necessity/appropriateness of VTE prophylaxis in cancer inpatients, outpatients, febrile neutropenia, advanced stage, and central lines was lacking. Prophylactic and treatment AC were deemed inappropriate in cancer patients without active bleeding and platelet counts < 50,000/μL. LMWHs were the preferred agents for active VTE prophylaxis in cancer inpatients and during febrile neutropenia; warfarin was preferred in those with advanced stage disease and central lines. 44% and 76% agreed that cancer patients require higher doses of thromboprophylaxis and are at higher risk for bleeding during thromboprophylaxis than non-cancer patients, respectively. Conclusions: Under-recognition of prevalent risk factors and high risk histologies and fear of bleeding especially in thrombocytopenic patients may explain the underutilization of VTE prophylaxis by American oncologists. Formal investigation of the risks and benefits of anticoagulation in several oncology settings seems indicated in order to guide clinical practice and consensus building. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Abstract #4419: HER receptors and fatty acid synthase in ovarian cancer: Molecular rationales for co-targeting approaches
Authors: Thomas Grunt, Renate Wagner, Michael Grusch, Walter Berger, Christian Singer, Brigitte Marian, Christoph Zielinski, Ruth Lupu
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Treatment of ovarian cancer is still unsatisfactory urging further search for improved therapies. In normal tissue, the lipogenic enzyme fatty acid synthase (FASN) converts dietary carbohydrates to triglycerides, whereas in cancer, FASN represents a metabolic oncogene and produces phospholipids for membrane microdomains (lipid rafts) that accommodate clusters of receptor tyrosine kinases including Epidermal Growth Factor Receptor (EGFR, HER1) and HER2/neu (ErbB2) thus providing the platform for signal initiation. Importantly, both FASN and HERs are overexpressed in ovarian cancer and represent druggable targets, which might be linked via molecular networks with each other. Therefore, we examined the effect of FASN and HER inhibition on A2780 and SKOV3 ovarian cancer cells. Interestingly, a FASN inhibitor (C75), given concurrently with a HER inhibitory agent such as pelitinib (EKB-569), canertinib (CI-1033), erlotinib, cetuximab, matuzumab or trastuzumab, sensitizes the cells against each of the HER-targeting agents (p<0.01) suggesting cooperation between FASN and HER pathways in ovarian cancer. qRT-PCR and Western blotting revealed that C75 represses FASN mRNA and protein, and impairs EGFR, HER2 and AKT expression and activity, which is consistent with the notion that FASN-induced lipid rafts accomodate and stabilize HERs and facilitate recruitment and activation of AKT. Activated AKT negatively crosstalks with ERK and stimulates EGFR and FASN, respectively, thus feeding an autostimulatory loop, which further boosts FASN and EGFR transcription. On the other hand, pharmacologic (pelitinib, canertinib, erlotinib) or gene-specific (siRNA) targeting of EGFR and/or HER2 represses FASN expression. Interestingly, cotransfection of both EGFR- and HER2-specific siRNAs inhibits FASN expression more efficiently than either siRNA alone indicating that both pathways have to be silenced in order to get maximal FASN downregulation. HER-dependent modulation of FASN is the result of PI3K/AKT/mTOR-mediated regulation of FASN mRNA transcription and protein synthesis. Our data indicate that HER and FASN pathways mutually interact with each other in ovarian cancer. Thus, interference with the FASN and the HER systems effectively abrogates their oncogenic activities and should be exploited for ovarian cancer treatment. Supp. by \#8216;Medizinisch-Wissenschaftlicher Fonds des Burgermeisters der Bundeshauptstadt Wien\#8217; (#08037) and by \#8216;Initiative Krebsforschung\#8217; (Medical University Vienna).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4419.
Proteasome inhibition with bortezomib (BORT) in combination with topotecan : A phase I solid tumor trial
Authors: G. Q. Chen, B. Vikstrom, L. Beckett, S. Scudder, P. N. Lara, D. Lau, D. Gandara, A. Davies
Journal: Journal of Clinical Oncology (2007)

14047 Background: Topoisomerase-I (Topo-I) down-regulation via the ubiquitin/26S proteasome pathway has been associated with drug resistance. We hypothesize that proteasome inhibition by BORT would enhance topotecan sensitivity by preventing down-regulation of topo-I. This phase I trial examined the safety and feasibility of combining weekly BORT with topotecan in patients (pts) with advanced solid tumors. Methods: Pts on 1 of 4 dose levels were treated with topotecan (3–4 mg/m 2 ) IV and BORT (1–1.6 mg/m 2 ) IV on days 1, 8, and 15. BORT was given 3 hours after topotecan based on preclinical studies (Flannery, 2003). Cycles were repeated q28 days. After 6 cycles, pts without progression could remain on BORT alone. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets (plts) (&lt;25K), Gr3 plts (&lt;50K) with bleeding, febrile neutropenia, neutropenia with infection, Gr3 neuropathy, or any=Gr3 non-heme toxicity. Results: 15 pts were accrued. Pt characteristics: Median age 58 years (range 25–73); Male sex:7; Performance status =80%:13. Two DLTs were seen at dose level 4 (Topotecan 4 mg/m 2 and BORT 1.6mg/m2): Gr 4 plts (1) and Gr 3 neutropenia with infection (1). Few other toxicities &gt; Gr3 were seen past cycle 1. Of 11 evaluable pts, 1 had a partial response (small cell bladder). 4 had stable disease (lung, brain, adenoid cystic and prostate). Conclusions: Weekly BORT and topotecan is feasible and well tolerated. The recommended phase II dose is topotecan 3mg/m 2 and BORT 1.6mg/m 2 IV weekly (3 of 4). An expanded cohort at this dose will examine efficacy of this combination in pts with small cell cancers. Correlative studies evaluating serum markers for proteasome inhibition and topo-1 activity are ongoing. No significant financial relationships to disclose.
Investigating androgen receptor antagonism by structural analyses, molecular dynamics simulations and support vector machines
Authors: Jian Hui Wu, Bing Liu
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4426 

To date, it is well established that androgen receptor (AR) is over-expressed in vast majority of the hormone-refractory prostate cancer and remains active through mechanisms that are refractory to androgen deprivation therapy. It has been found that AR must bind its ligand to confer hormone-refractory growth, indicating that AR remains to be a key therapeutic target for advanced prostate cancer. Accumulating biochemical data indicate antagonist profiles of antiandrogens could be changed by point mutations in AR ligand-binding domain (AR-LBD). For example, hydroxyflutamide is an antagonist for wild type AR, but an agonist for the T877A mutant. Despite crystal structures of a series of agonist-like AR-LBD are available, detailed structural mechanism by which T877A mutation results in antagonist-agonist conversion of hydroxyflutamide is unknown. Fortunately, given the structural and functional conservation among nuclear receptors, structural studies of the other family members could shed light on the AR antagonism. In this work, we have investigated AR antagonism by combining structural analyses, molecular dynamics (MD) simulations and support vector machines (SVM) method. First, we performed comparative structural analyses of ERα-LBD/agonist and ERα-LBD/antagonist structures. Our analyses indicated that residues D351 and L354 are critical for the antagonistic activity of ERα ligand, which were termed ‘switch residues’; Second, based on crystal structures of AR-LBD in complex with agonists containing various chemical scaffolds, we have detected a ‘soft spot’ inside the wall of AR hormone-binding pocket, which could be exploited to design novel AR antagonists with enhanced specificity and affinity; Third, by MD simulations, we showed T877A mutation result in significant change in distance between E709 and L712, which are the corresponding AR residues of ERα D351 and L354, respectively. This suggests a possible structural mechanism by which the T877A mutation results in the antagonist-agonist conversion of hydroxyflutamide; Next, to gain insights about the correlation between ligand binding modes and the helix-12 positioning, we have trained the SVM model by a dataset composed of ER/agonist, ER/antagonist and AR/agonist structures. Molecular descriptors used in the SVM include electrostatic complementarity, shape complementarity, hydrophilic interactions, surface fit rate as well as interaction between ligand and switch residues. The SVM model was subsequently used to classify a test dataset into antagonist-like or agonist-like structures solely based on the molecular descriptors. The area under the receiver operating characteristic curve of our SVM model is 0.898. These studies allow us to propose a pharmacophore model for AR antagonists, shedding light on further development of novel antiandrogens.
A multicenter, double-blind randomized phase II trial of neoadjuvant treatment with single-agent bevacizumab or placebo, followed by docetaxel, doxorubicin, and cyclophosphamide (TAC), with or without bevacizumab, in patients with stage II or stage III breast cancer
Authors: S. A. Hurvitz, L. D. Bosserman, B. Leland-Jones, M. Thirwell, M. K. Allison, J. Barstis, D. Molthrop, E. Quan, G. Upadhyaya, D. Slamon
Journal: Journal of Clinical Oncology (2008)

562 Background: One of the greatest potentials of antiangiogenic agents may be realized in the treatment (Tx) of nonmetastatic BC. This trial evaluates the safety, clinical, and molecular effects of neoadjuvant TAC + Bev for locally advanced BC. Methods: This is a placebo-controlled, blinded, phase II study in which 90 pts are randomized (2:1:2:1) to 1 of 4 arms: Arm A: TAC + low-dose Bev (Lo-Bev) (7.5 mg/kg); Arm B: TAC + low-dose placebo (Lo-P); Arm C: TAC + standard dose Bev (Std-Bev) (15 mg/kg); Arm D: TAC + Std-P. A run-in cycle of Bev or P is followed by 6 cycles of q3-weekly TAC (T: 75 mg/m2, A: 50 mg/m2, C: 500 mg/m2) plus P or Bev. Serial biopsies are taken. Pts are unblinded post surgery (Sx): Arms A/C receive maintenance (maint) Bev to complete 52 wks, Arms B/D receive no further P. Females over the age of 18 were eligible if they had stage II-III, >3 cm, noninflammatory, HER2(-) BC. Safety evaluation was a primary endpoint and clinical efficacy a secondary endpoint. Results: As of October 2007, 57 pts have started Tx. 37 pts received all neoadjuvant Tx and underwent Sx. Of these, 22 pts completed all Tx, 10 are on maint Bev and 5 are off study (4 toxicity, 1 withdrew). 20 pts have not yet had Sx. Of the 37 post-Sx pts, the objective response rate was 95% (35/37), including 59% clinical CR (5/12 Arm A; 7/11 Plac- Arms B/D; 10/14 Arm C) and 35% clinical PR (7/12 Arm A; 3/11 Arms B/D; 3/14 Arm C). The breast-conserving surgery rate is 41% (15/37) (5/12 Arm A; 2/5 Arm B; 6/14 Arm C; 2/6 Arm D). Of the 37 post-Sx pts, 3 had grade 3 CHF and 4 had a decline in EF >15% from baseline (2/12 in Arm A; 2/11 Arms B/D; 1/14 Arm C). Conclusions: The preliminary clinical response to neoadjuvant TAC ± Bev is promising. Pathologic response rates, wound healing data, and updated toxicity will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech GlaxoSmithKline, sanofi-aventis, Genentech
A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib
Authors: A. R. Craig, H. M. Kantarjian, J. E. Cortes, D. Jones, A. Hochhaus, S. O'Brien, M. Rios, C. Zander, L. Gleich, E. P. Carroll, O. G. Ottmann
Journal: Journal of Clinical Oncology (2007)

7046 Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines. Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase. Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18–74); 7 male, 7 female; median CML duration: 53 mo. (range 14–266); and median time on imatinib 45 months (range 12–129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg (2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients who have completed &gt;1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 mo. before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30–60 mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy. Conclusions: INNO-406 is well tolerated in patients at a dose of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose escalation continues. No significant financial relationships to disclose.