tbuckley/cabot-search huggingface dataset:
Longterm outcome of peptide receptor radionuclide therapy (PRRT) in 454 patients with progressive neuroendocrine tumors using yttrium-90 and lutetium-177 labelled somatostatin receptor targeting peptides
Authors: D. Hörsch, V. Prasad, R. P. Baum
Journal: Journal of Clinical Oncology (2008)

4517 Background: Peptide receptor radionuclide therapy (PRRT) is an important new treatment for patients with metastasized neuroendocrine tumors (NET) resistant to biotherapy or chemotherapy. Yttrium-90 (Y-90)- and/or lutetium-177 (Lu-177) DOTA-TATE (Lu-TATE) have been used alone or in combination over the last 6 years by us in patients with progressive neuroendocrine tumors. Lu-TATE was predominantly used for small metastases or in patients with impaired renal or hematological function. Methods: 454 pts (mean age 59.1 years, 248 m, 206f) received a total of 1,303 administrations (mean activity 4.2 GBq, max. 7.5 GBq per cycle, time between courses 3 to 6 months). For kidney protection, 1.5 L of an AA solution (arginine/lysine) were infused IV over 4 hrs. Staging was performed by CT/MRI and Ga- 68 DOTA-NOC PET-CT or FDG/fluoride PET/CT, blood chemistry and tumor markers (CgA, serotonin). Renal function was serially determined (Tc-99m MAG3 scan/clearance (TER) and Tc-99m DTPA/GFR measurements). Tumor dosimetry (MIRD/OLINDA) was performed after PRRT (serial scintigraphies). All data were entered in a structured ACCESS database (284 items/patient). Results: Significant hematological toxicity (mainly erythrocytopenia, rarely neutropenia, thrombocytopenia) occurred in less than 15% of all patients. End stage renal insuffiency was not observed in any of the patients with normal kidney function before PRRT. In most patients receiving Lu-TATE alone (n=417 cycles) serum creatinine and TER/GFR did not change. Tumor response in patients with NETs of non-pancreatic origin and pancreatic NET after a mean follow-up of 2 years: 73/76% stable disease (progressive disease before), 15/17% had partial and complete remissions and 12/7% PD. 36 patients with advanced disease died of PD. Objective tumor responses (including improvement of clinical symptoms) were seen in 88/93% of the patients. Conclusions: Fractionated, individualized PRRT with lower administered radioactivity given over a longer period of time results in good therapeutic responses in patients with progressive neuroendocrine tumors. No significant financial relationships to disclose.
A phase I clinical trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma.
Authors: J. Yi, H. Ahn, S. Lee, J. Uhm, J. Lee, S. Park, J. Park, Y. Park, H. Lim, W. Kang
Journal: Journal of Clinical Oncology (2010)

e14655 Background: This phase I dose-escalation study was conducted to determine the recommended dose of oral S-1 in combination with a fixed dose of sorafenib in patients with advanced HCC. Secondary objectives included evaluation of the pharmacokinatics (PK), safety profile and antitumor activity. Methods: Eligible patients had advanced HCC not amenable to local or regional therapy, Child-Pugh class A or B, and adequate organ functions. Traditional phase I methodology was employed in which patients were to be treated at the same dose level (DL) in groups of three. Patients were treated with a 3-week regimen of oral S-1 (25, 30, 35 or 40 mg/m2 twice daily, days 1 to 14) in combination with sorafenib (400 mg twice daily). Dose-limiting toxicities (DLT) and PK were evaluated during the first cycle, and the safety and activity were evaluated throughout treatment. Results: As of Dec 2009, a total of 7 eligible patients were registered. The median age was 49 years (range, 39- 74), and all had Child-Pugh class A. Hepatitis B viral serology was positive in 5 patients. Three patients were enrolled on 25 mg DL without DLT. On 30 mg DL, no DLT was developed in first 3 patients, but one patient withdrew consent during the first cycle because of grade 2 hand-foot skin reaction. The most frequently observed adverse events were skin reaction, diarrhea, and anorexia. Conclusions: In this phase I study, S-1 at doses up to 30 mg twice daily can be safely administered in combination with sorafenib. No significant financial relationships to disclose.
A phase 1 study of daily oral perifosine (P) and weekly gemcitabine (G)
Authors: S. Weiss, J. J. Nemunaitis, M. Diaz-Lacayo, R. Birch, B. Ebrahimi, D. H. Berdeaux, J. P. Allerton, L. R. Gardner, I. C. Henderson
Journal: Journal of Clinical Oncology (2006)

13084 Background: Miltefosine (M) has been shown to be synergistic with gemcitabine (G) in vitro (Georgieva Cancer Letters 182: 163–174, 2002). Perifosine (P) is a derivative of M with less GI toxicity. Methods: Twenty-two patients (pts) were enrolled on a phase 1 study to determine if G could be given at a dose of 1000 mg/m 2 on days 1 and 8 of a 21-day cycle with 50 mg of P given orally 1, 2 or 3 times a day on days 1–14. Three pts were entered at each dose and the cohort expanded to 6 if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Ten additional pts were entered at the highest dose achieved. Results: Disease sites: lung 6, pancreas 3, breast 3, renal 2, sarcoma 2, other 5. The median age was 61 (range 29–82); 11 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 3, range 1–4) &amp; 6 had received prior G. 10 pts had received prior radiotherapy. The grade 3/4 non hematologic toxicities for each cohort are given in the table below: One pt on cohort 3 died from pneumonia and sepsis unrelated to therapy after cycle 1. A median of 4 cycles (range 1 - 18) were delivered. At each dose 50% of pts had no G dose reductions. P doses were reduced in 7% of cycles (50 mg - 5%, 100 mg - 15%, 150 mg - 7%). Fifteen pts were evaluable &amp; 4 partial responses (lung, breast, pancreas and unknown primary) were seen; 6 pts had stable disease (renal (2), sarcoma (2), liver and head/neck) for a median of 6 (range 3 - 9) months. No responder had received prior G. Pharmacokinetic (PK) studies showed that the steady state level at 150 mg was 9.47 ± 4.56 μM compared to 10.14 ± 2.02 μM in an earlier study (Crul, Eur. J. Cancer 38: 1615–21, 2002) when this dose of perifosine was used alone. Conclusions: It is concluded that full dose G can be safely administered with perifosine doses up to 150 mg with manageable toxicity and without affecting the PK of P. Phase II studies are warranted to further define the activity of the combination and the contribution of P. [Table: see text] [Table: see text]
Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: a pharmacokinetic and clinical survey.
Authors: M Schneider, M C Etienne, G Milano, A Thyss, J Otto, O Dassonville, H Mobayen, L Saudes, T Guillot, F Demard
Journal: Journal of Clinical Oncology (1995)

PURPOSE To analyze clinical and pharmacokinetic data of cisplatin (CP)/fluorouracil (FU)/l folinic acid (l FA) chemotherapy administered as first-line treatment to locally advanced head and neck cancer patients. PATIENTS AND METHODS Thirty-nine patients (35 men and four women; median age, 60 years; six stage III and 33 stage IV) received CP on day 1 (100 mg/m2) followed by l FA (200 mg/m2/d x 5) plus FU (500 mg/m2/d x 5) administered by continuous venous infusion (three cycles planned). Mean plasma concentrations of FU, l FA, and 5-methyltetrahydrofolate (5MTHF) over the cycle were computed. RESULTS Clinical response was assessable for 33 patients. Response rates on the primary tumor site (n = 33) were 63.7% complete responses (CRs), 24.2% partial responses (PRs), and 12.1% treatment failures. Response rates on lymph nodes (n = 27) were 40.7% CRs, 37.1% PRs, and 22.2% treatment failures. The most frequent toxicity was mucositis (36.2% of cycles grade 3 to 4). Grade 3 to 4 nausea-vomiting, diarrhea, neutropenia, and thrombocytopenia occurred in 6.7%, 1.9%, 13.3%, and 1% of cycles, respectively. Pharmacokinetic analysis showed a wide interpatient variability for both FU (mean, 1.01 mumol/L; range, 0.16 to 2.09), l FA (mean, 1.89, mumol/L; range, 0.52 to 7.88) and 5MTHF plasma concentrations (mean, 3.85 mumol/L; range, 1.30 to 8.11). A significant correlation was demonstrated between FU concentration and hematologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade. Regarding tumor response, patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR. CONCLUSION This study highlights the efficacy of CP/FU/l FA in head and neck carcinoma and establishes the clinical importance of coupled FU/FA pharmacokinetics to predict pharmacodynamic variability.
Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013
Journal: Eurosurveillance (2015)

Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010–2013. People aged ≥ 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrolment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count &lt; 350/mm 3 or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm 3 (interquartile range (IQR) 193–555/mm 3 ), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p &lt; 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02–1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85–0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent.
ZD1839 (gefitinib) and hormone resistant (HR) prostate cancer - final results of a double blind randomized placebo-controlled phase II study
Authors: F. H. Schröder, M. F. Wildhagen
Journal: Journal of Clinical Oncology (2004)

4698 Background: The epidermal growth factor receptor (EGFR) is expressed in most prostate cancers. We investigated the effect of gefitinib (ZD1839), an orally active EGFR tyrosine kinase inhibitor, on the slope of changing prostate specific antigen (PSA) levels. Methods: We conducted a placebo-controlled, double blind, randomized Phase II study of gefitinib (500 mg/day) in patients with prostate cancer and hormone-independent PSA progression. To calculate sample size, the method of Schlesselman (J Chron Dis 1973; 26: 561–70) was applied; 24 patients per group were necessary to detect a change in slope of 0.25 (ie to zero slope) with 90% power using a two-sided significance level of alpha = 0.05. Asymptomatic patients with PSA progression after castration or under luteinizing hormone-releasing hormone treatment (excluding antiandrogens and recent radiotherapy) were eligible. Unblinding took place after 6 months or in the case of medical emergencies. Secondary endpoints included PSA response rate at 6 months, time to response, PSA progression, time to progression (TTP), overall survival (OS), and safety. The study was approved by regional and institutional ethical review boards. Results: All 58 patients randomized (28 to placebo and 30 to gefitinib) were evaluable for comparison of PSA slopes. Both slopes differed significantly from zero (placebo: p<0.0001; gefitinib: p<0.0023). The slopes amounted to 0.2569 for placebo and 0.2001 for gefitinib per month, translating into doubling times of 3.9 and 5.0 months (p=0.25), respectively. This study was not powered to compare changes in slope between treatment arms however, no relevant differences in progression rates, TTP, and OS were seen between arms in intention-to-treat and treatment-received analysis. Adverse events (AEs) were usually mild; CTC grade 3/4 AEs occurred in 2 patients receiving placebo and 5 receiving gefitinib (liver toxicity, diarrhea). Conclusions: Gefitinib showed modest activity in delaying PSA rise. Differences in clinical progression rates were not seen. Gefitinib was generally well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering AG Schering AG Schering AG AstraZeneca Uroconsultancy BV Uroconsultancy BV
A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML)
Authors: Eric Padron, Amy Dezern, Marcio Andrade-Campos, Kris Vaddi, Peggy Scherle, Qing Zhang, Yan Ma, Maria E. Balasis, Sara Tinsley, Hanadi Ramadan, Cassandra Zimmerman, David P. Steensma, Gail J. Roboz, Jeffrey E. Lancet, Alan F. List, Mikkael A. Sekeres, Rami S. Komrokji
Journal: Clinical Cancer Research (2016)

To conduct a phase I clinical trial exploring the safety and efficacy of ruxolitinib, a JAK1/2 inhibitor, for chronic myelomonocytic leukemia (CMML).Patients with CMML-1 were included without regard to previous therapy. Key exclusion criteria included an absolute neutrophil count (ANC) <0.25 × 10(3) cells/dL and a platelet count <35 × 10(3) cells/dL. Four cohorts were enrolled using a "rolling six" study design, with doses ranging from 5 to 20 mg twice daily of ruxolitinib in 5-mg dose escalations.Between March 2013 and January 2015, 20 patients were enrolled and treated with ruxolitinib. Seventy percent of patients had the proliferative subtype and 47% had higher risk disease by the Global MD Anderson Scoring System. Eight patients (42%) received a prior hypomethylating agent. No dose-limiting toxicities for ruxolitinib were identified. One subject had grade (G)3 thrombocytopenia with no other drug-associated G3 or G4 adverse events. The mean duration of therapy was 122 days (range, 28-409 days). Four had hematologic improvement and one patient had a partial response per 2006 International Working Group (IWG) criteria. Five of 9 patients with splenomegaly had a reduction in spleen size. Ten of 11 patients with reported disease-related symptoms had clinically meaningful or complete resolution. When combining IWG and spleen responses, a total response rate of 35% (n = 7) was identified. Correlative analysis demonstrated a reduction in inflammatory cytokines and GM-CSF-dependent STAT5 phosphorylation.The recommended phase II dose of ruxolitinib is 20 mg twice daily. We demonstrate that ruxolitinib has promising activity in CMML with particular benefit in those with disease-related B symptoms that warrants further study. Clin Cancer Res; 22(15); 3746-54. ©2016 AACRSee related commentary by Solary, p. 3707.
알코올 대사 효소들의 유전적 다형성이 알코올성 간경변증의 발생에 미치는 영향
Authors: 정숙향, 이한주, 윤정환, 이효석, 김정룡 ( Sook Hyang Jung), Han Chu Lee, Jung Hwan Yoon, Hyo Suk Lee, Chung Yong Kim
Journal: Clinical and Molecular Hepatology (1998)

Background/Aims  There is considerable variance in individual susceptibility to hepato- toxic effects of ethanol as evidenced by the finding that only about 10-20% of alcoholics develop alcoholic liver cirrhosis. The aims of this study were', 1) to get the data on the genetic polymorphisms of three major ethanol-metabolizing enzymes (ADH, CYP2E1, ALDH) in normal Korean adults, and to search for the specific genotypes influencing alcohol drinking behavior by the comparison of allele frequencies between healthy control group and heavy drinker group with or without liver disease, 2) to investigate the influence of the genetic polymorphisms of these enzymes on the susceptibility to alcoholic liver disease by the comparison of allele frequencies between heavy drinker group without liver disease and alcoholic liver cirrhosis group. Methods - Healthy control group included 53 healthy males in military service without evidence of liver disease or alcoholism. Heavy drinker group without liver cirrhosis included 29 males who had been drinking 80g or more of alcohol daily for more than ten years but did not have any clinical evidence of liver disease. Alcoholic cirrhosis group included 43 male patients who had drunk 80g or more of alcohol daily for more than ten years and had clinical evidences of overt cirrhosis. Subjects with hepatitis B surface antigen or anti-hepatitis C antibody were excluded. Genotypes of the three enzymes were determined by PCR (polymerase chain reaction) and restriction fragment length polymorphism (RFLP) with genomic DNAs extracted from peripheral leukocytes. Results' 1) In healthy Korean males, allele frequency of ADH22, ADH31, CYP2E1 c2 and ALDH22 was 81%, 94%, 30% and 14%, respectively. 2) The absence of ALDH22 or CYP2E1 c2 allele were significant risk factors for being a heavy drinker (odds ratio,' 0.09, 0.42, respectively). 3) Although it was not associated with the polymorphism of each ethanol-metabolizing enzymes, the susceptibility to  alcoholic liver cirrhosis was significantly associated with combined genotypes of ADH2(22) & ADH3(1+1)& CYP2E1 B or C. Conclusion- Genetic polymorphisms of ethanol-metabolizing enzyrnes are significantly associated with the suseptability to alcoholic liver disease as well as alcohol drinking behavior. (Korean J Hepatol 1998;8:1  11)
Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome.
Authors: W G Scheurlen, G C Schwabe, S Joos, J Mollenhauer, N Sörensen, J Kühl
Journal: Journal of Clinical Oncology (1998)

PURPOSE The diagnostic and prognostic significance of well-defined molecular markers was investigated in childhood primitive neuroectodermal tumors (PNET). MATERIALS AND METHODS Using microsatellite analysis, Southern blot analysis, and fluorescence in situ hybridization (FISH), 30 primary tumors and six CSF metastasis specimens were analyzed for loss of heterozygosity (LOH) of chromosomes 1q31, 6q, 9q22, 10q, 11, 16q22, and 17p13.1 and/or high-level amplification of the c-myc gene. Experimental data were compared with clinical stage and outcome. RESULTS LOH of chromosome 17p13.1 was found most frequently (14 of 30 tumors, six of six CSF metastasis specimens); LOH of chromosomes 10q, 16q22, 11, 6, 9q22, and 1q31 was observed in 20.6%, 20%, 14.3%, 12%, 10%, and 0%, respectively. Eight of 32 tumors and CSF specimens showed amplification of c-myc. All tumors with amplification of c-myc were resistant to therapy and had a fatal outcome (mean survival time, 9.3 months). Tumors that displayed LOH of chromosome 17p were associated with metastatic disease. The prognosis of these tumors was worse only when associated with amplification of c-myc. Three of three patients with LOH of 9q22 relapsed. CONCLUSION In our study, amplification of c-myc was a poor-prognosis marker in PNET. LOH of chromosome 17p was associated with metastatic disease. Molecular analysis of primary tumors using these markers may be useful for stratification of children with PNET in future prospective studies. The other aberrations investigated were not of significant prognostic value, but may provide an entry point for future large-scale molecular studies.
miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors
Authors: Marina Bacci, Elisa Giannoni, Antony Fearns, Ricardo Ribas, Qiong Gao, Maria Letizia Taddei, Gianfranco Pintus, Mitch Dowsett, Clare M. Isacke, Lesley-Ann Martin, Paola Chiarugi, Andrea Morandi
Journal: Cancer Research (2016)

Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy.
Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.
Authors: Thomas B Brunner, Serena Lunardi, Nigel B Jamieson, Su Yin Lim, Kristin L Griffiths, Manuela Maria Carvalho-Gaspar, Osama Al-Assar, Ross Carter, Colin J McKay, Gabriele Spoletini, Stefano D'Ugo, Michael A Silva, Owen J Samson, Klaus Peter Janssen, Ruth J Muschel
Journal: Journal of Clinical Oncology (2015)

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3 + effector T cells as well as CXCR3 + Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3 + Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.