tbuckley/cabot-search huggingface dataset:
A phase I study of busulfan consolidation/intensification therapy for patients with high risk acute myeloid leukemia (AML)
Authors: M. M. Gharibo, D. Schaar, A. Rubin, S. Grospe, L. Dudek, R. Strair
Journal: Journal of Clinical Oncology (2006)

6580 Background: Elderly AML patients have a poor prognosis. More effective well-tolerated treatments are needed to improve outcomes. Busulfan is an effective anti-leukemia drug commonly used in transplant regimens. We designed a phase I dose escalation study of single dose busulfan as consolidation/intensification therapy for elderly patients with AML. Methods: Patients in CR1 not candidates for transplantation or anticipated to benefit from high-dose cytarabine were enrolled. Cohorts were studied at 100mg/m 2 -120mg/m 2 , as a single oral dose of busulfan. The starting dose was based on a previous report (Ranson et al. Br J Haematol 79:162.1991). GM-CSF was started after busulfan until ANC&gt; 2000/mm 3 . Dilantin was used for seizure prophylaxis. Results: 15 patients median age 71 (range 64–82) received treatment and are evaluable for toxicity, 14 are evaluable for response. No DLT was observed. Ongoing remission was seen in 3 patients (range 3 +- 7 + years). One patient (AML/MDS) was in remission for 52 months and died from small cell lung cancer and 1 patient was in remission for 15 months and died from cervical cancer. Two additional patients had prolonged remissions (32 and 55 months) prior to relapse. Seven patients relapsed between 4 weeks and 6 months. Treatment was well tolerated with no prolonged neutropenia. In patients who recovered without evidence of leukemia transient grade 3/4 thrombocytopenia occurred with average duration of 16 days (10–23 days) requiring 0–5 transfusions (average 2). Only 2 patients required RBC transfusion. No infectious complications or hospitalizations occurred in the absence of recurrent AML. Three patients experienced side effects from GM-CSF and received G-CSF in it’s place. Two patients experienced grade 2 fatigue and dyspnea. Conclusions: Single dose oral busulfan is an effective and well-tolerated outpatient consolidation/intensification therapy for patients with high-risk, AML. Prolonged remissions have been seen in 6 of 14 evaluable patients treated to date. Only transient bone marrow suppression requiring minimal transfusion support was seen. There were no hospitalizations or infections noted in patients without recurrent AML. The dose escalation will continue until MTD reached. No significant financial relationships to disclose.
Phase I study of everolimus (RAD001) with irinotecan (Iri) and cetuximab (C) in second-line metastatic colorectal cancer (mCRC): Hoosier Oncology Group GI05-102—Final report.
Authors: S. Shahda, M. Yu, J. Picus, J. A. Bufill, W. A. Harb, M. Burns, A. J. Spittler, J. Flynn, Y. Zeng, G. H. Vance, J. Wu, C. R. Currie, P. J. Loehrer, E. G. Chiorean
Journal: Journal of Clinical Oncology (2011)

3587 Background: Preclinically, mTOR and EGFR inhibitors are synergistic. We hypothesize that the mTOR inhibitor RAD001 would enhance clinical efficacy when added to C. The main purpose of this study was to determine the safety, and maximum tolerated dose (MTD) of daily RAD001 combined with Iri and C in mCRC. Methods: Pts were treated with Iri 125 mg/m2 weekly (qw) x 2 every 3 wks, C 400 mg/m2 loading, then 250 mg/m2 qw, and escalating doses of RAD001 orally: 5 mg qod, 5 mg qd and 10 mg qd during 21-day cycles, with a “3+3” design. Eligibility allowed KRAS mutated (MUT) mCRC. The study was amended after the first 9 pts*, to include stopping rules for excessive toxicity beyond expected rates for diarrhea, nausea/vomiting and febrile neutropenia due to Iri, and skin rash due to C. PK (Cmin) for RAD001 was done on C2D1, and archival tumors were analyzed for pharmacodynamic (PD) markers of EGFR and mTOR pathway activation. Results: 30 pts were enrolled (KRAS WT 12; MUT 15; unknown 3), median age 60.5 y (25-77), 16 male, ECOG PS 0/1 (20/10). Reasons for treatment discontinuation were: PD (13), adverse events (AEs) (8), pt withdrawal (2), symptomatic deterioration and non-compliance (1 each). Prior to study’s amendment*, 3 pts were not evaluable for DLT due to: gr 3 Iri and C infusion reactions with 1st infusion (1 each), non-compliance (1). DLTs and number of cycles are listed in Table. The most common gr 3/4 AEs were diarrhea (9), rash (6), mucositis, ANC, fatigue (4 each), nausea (3), vomiting, anorexia, febrile neutropenia (2 each). RAD001 mean Cmin at MTD was 8.5 ng/mL, similar to that seen with RAD001 alone. Among pts evaluable for response (n=24), there were 1 CR, 4 PR (21%, including 1PR in KRAS MUT pt for 26 mos), 9 SD (37%). Median PFS and OS were 6 and 28 mos for KRAS WT, and 3.3 and 12 mos for KRAS MUT pts, respectively. PD markers will be presented. Conclusions: The MTD of RAD001 of 5 mg QD with Iri/C qw is safe and clinically active. A phase II study is ongoing. Cohort (# pts) RAD001 # DLT DLT # Cycles median (range) 1* (9) 5 mg QOD 2 Gr 3 diarrhea Gr 3 febrile neutropenia 2 (1-34) 1 (3) 5 mg QOD 0 6 (2-10) 2 (MTD) (4) 5 mg QD 0 5 (1-13) 3 (4) 10 mg QD 2 Gr 3 mucositis 2 (2-6) 2 expansion (10) 5 mg QD 1 Gr 3 diarrhea 2 (1-9+)
Gemcitabine (G) vs gemcitabine-carboplatin (GCB) for patients with advanced non-small cell lung cancer (NSCLC) and PS:2. A prospective randomized phase II study of the Hellenic Co-Operative Oncology Group
Authors: P. A. Kosmidis, M. A. Dimopoulos, C. Syrigos, C. Nicolaides, G. Aravantinos, I. Boukovinas, D. Pectasides, D. Bafaloukos, M. Karina, H. P. Kalofonos
Journal: Journal of Clinical Oncology (2004)

7058 Background: PS:2 is an independent negative prognostic factor for patients(pts) with NSCLC. Most of the information about prognosis, response, survival and treatment options was obtained from subset analysis of large trials. Single agent chemotherapy has been proven superior to best supportive care on survival or quality of life. Purpose was to evaluate prospectively if the combination chemotherapy GCb has superior efficacy compared to single agent G in pts with advanced NSCLC PS:2. Primary end-point was clinical benefit. Methods: Pts received either G: 1250 mg/m2 every 14 days (Arm A) or G: 1250 mg/m2 and Cb: 3AUC every 14 days (Arm B). Both treatments were given in cycles of 28 days. Four were the maximum number of cycles. 102 pts were enrolled. Ten pts were non -eligible. Baseline demographics were comparable for both groups. Median age was 73 and 70.5 for group A and B, male 83% and 72%, stage IV 64% and 72%, two disease sites 36% and 40.5% respectively. Relative dose intensity for G was 76% and 71% for arm A and B. For the clinical benefit, the following factors were evaluated: pain, cough, dyspnea, weight loss, appetite, weakness, nausea, vomiting and overall general feeling. Results: are summarized below. Conclusions: The combination GCb is not superior to G alone in terms of clinical benefit, TTP, m. survival and 1 -year survival. The combination causes more toxicity particularly neutropenia. No significant financial relationships to disclose.
Use of MDR1/ABCB1 single nucleotide polymorphism (SNP) as a prognostic factor for breast cancer patients receiving docetaxel + doxorubicin neoadjuvant chemotherapy
Authors: H. J. Kim, B. Keam, S. Im, H. S. Ham, D. Oh, J. Kim, W. S. Han, T. Kim, I. A. Park, Y. J. Bang
Journal: Journal of Clinical Oncology (2008)

569 Background: Expression of the ABC transporter P-glycoprotein (P-gp or ABCB1) is associated with resistance to chemotherapy in cancer. C3435T and G2677T polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a chemotherapeutic drug including docetaxel and doxorubicin from the cells. The aim of this study was to investigate the clinical significance of SNPs (C1236T, G2677T, C3435T) in MDR1/ABCB1 genes in breast cancer treated with neoadjuvant chemotherapy (CTx). Methods: One hundred thirty-two stage II or III patients (pts.) (median age 45; range 25–69) were treated with 3 cycles of neoadjuvant CTx consisted of docetaxel 75 mg/m2 iv and doxorubicin 50 mg/m2 iv D1 every 3 weeks before curative surgery. The objective tumor response was evaluated by RECIST criteria. Pathologic CR (pCR) was defined as complete disappearance of invasive carcinoma in both breast and axillary lymph nodes after 3 cycles of CTx. Whole blood samples were obtained before CTx. DNA was extracted from the PB MNCs and C1236T, G2677T/A, C3435T polymorphisms of the MDR1 gene were genotyped by PCR-restriction fragment length polymorphism (RFLP). We evaluated the correlation between the clinico-pathologic prognostic factors, polymorphisms and clinical outcomes. Results: Out of 132 pts, blood samples were available from 115 pts (ER- and PR- : 41.2 %, HER2+: 24.0%). The overall radiologic response rate (RR) was 71.3 % (CR 6.1%, PR 65.2%) and 8 patients (7.0%) achieved a pCR. Although statistically insignificant, clinical RR is higher in CT or TT allele than wild type CC allele on C1236T site (60.8% vs. 73.9%, p=0.16). Genetic linkage was observed between C1236T and C3435T. No polymorphism predicted severe chemotherapy related toxicities. Two-year relapse free survival rate (RFS) was higher in CT or TT group compared with CC wild type (90% vs 49%, p=0.01) in C1236T polymorphism. Conclusions: The MDR1 C1236T polymorphism correlated with the prolongation of RFS in this study. More research is warranted to identify the molecular biological characteristics of C1236T that lead to altered P-gp function. No significant financial relationships to disclose.
Sylvia Madeleine Watkins
Authors: John Watkins
Journal: BMJ (2015)

Sylvia Madeleine Watkins had a reputation as an exceptionally kind and caring physician, qualities much valued by her patients. In her retirement, she committed her energies to postgraduate development in several African medical schools. She was also an accomplished violinist, involved with chamber and orchestral music throughout her life.

Sylvia was born into a family of doctors—the 12th in six generations, ranging from Timothy Watkins, surgeon apothecary in the 18th century, to her father, Kenneth Harold Watkins (1903-38), a urological surgeon at the Manchester Royal Infirmary, and her brother,. Peter Watkins (FRCP). She always excelled academically, was determined to be a doctor, and gained a place at Lady Margaret Hall in Oxford, followed by clinical studies at St Bartholomew’s Hospital in London. She undertook junior posts at St Bartholomew’s Hospital and in Leicester, passed the MRCP just three years later (1964), and was elected FRCP in 1980. She was at this stage determined to pursue a career in neurology. To this end, and using her linguistic skills (fluent in German and French), she worked as a registrar at the University Nervenklinik in Heidelberg, before returning to England. Subsequently she persevered with general internal medicine as senior registrar at the Royal Free Hospital in …
A survey of currently active late-phase oncology studies for cellular, gene therapy and antigenic products regulated by the US Food &amp; Drug Administration, Center for Biologics Evaluation and Research (CBER)
Authors: K. Liu, R. P. Fiorentino, S. Hirschfeld
Journal: Journal of Clinical Oncology (2005)

6063 Background: Federal regulations require adequate and well-controlled investigations that demonstrate safety and efficacy as basis for licensure of biologic products. We surveyed currently active late phase studies for cellular, gene therapy and antigenic products intended to treat malignancies with the intent to provide background data for sponsors and investigators contemplating clinical studies. Methods: From CBER documents, we analyzed 17 late-phase oncology clinical studies selected from 12 currently active INDs in the year 2004. Data collected included design, type of comparator arm (placebo vs. active control), primary and secondary endpoints. Endpoints were categorized as response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival, and patient reported outcomes (PRO). Products were classified as gene therapy, cellular therapy or vaccine. Results: Study design characteristics varied widely among each product type. All 17 studies had concurrent control arms (47% placebo, 53% active control). PFS or TTP was the most frequently used primary endpoint (59%), followed by survival (35%) and response rate (6%). Secondary endpoints included PROs (42%), PFS or TTP (35%), survival (29%), response rate (29%). Conclusions: All late phase studies surveyed were designed with concurrent controls consistent with the intent of the regulations. Primary endpoints focused on disease specific parameters of delaying progression or prolonging survival. Secondary endpoints included PROs as well as disease-specific parameters. These findings suggest that a variety of clinical study designs may be used for late phase oncology studies for cellular, gene therapy and antigenic products. No significant financial relationships to disclose.
Role of systemic and muscle oxidative stress and cytokines in patients with lung cancer cachexia
Authors: Esther Barreiro, Pilar Ausin, Francisco Sanchez, Ester Puig-Vilanova, Juana Martinez-Llorens, Victor Curull, Joan Broquetas, Joaquim Gea
Journal: European Respiratory Journal (2011)

Oxidative stress and proinflammatory cytokines are involved in muscle mass loss in several conditions such as COPD and cancer cachexia.

Objectives: To explore redox balance, inflammation, proteolysis, signaling pathways and muscle structure in the vastus lateralis of patients with lung cancer cachexia.

Methods: Molecular markers of oxidative stress and proteolysis, proinflammatory cytokines, signaling pathways, and muscle fiber types, size, and damage were assessed in the vastus lateralis and blood of patients with lung cancer with and without cachexia, patients with COPD and cachexia, and healthy volunteers (controls). All patients and control subjects were clinically evaluated (body composition and exercise capacity).

Results: Compared to controls, COPD patients and patients with lung cancer exhibited exercise limitation and muscle dysfunction, increased muscle oxidative stress and activation of proteolytic pathways. Cachexia in both COPD and lung cancer patients, compared to healthy controls, also induced greater levels of muscle oxidative stress, proteolysis, damage and atrophy, along with increased systemic oxidative stress, and worsened peripheral muscle dysfunction and exercise tolerance.

Conclusions: Within peripheral muscles, lung cancer induced functional, structural, and molecular alterations, which were significantly worsened when cachexia developed. These results may offer potential therapeutic targets for the management of COPD and cancer associated cachexia.

Funded by: SEPAR 2007, MTV3-07-1010, 2009-SGR-393, FIS 05/2458 & CIBERES.
High-dose methotrexate and HELP [Holoxan (ifosfamide), Eldesine (vindesine), platinum] - doxorubicin in non-metastatic osteosarcoma of the extremity: A French multicentre pilot study
Authors: T Philip, C Iliescu, M C Demaille, H Pacquement, J C Gentet, I Krakowski, P Soler-Michel, P Thiesse, F Chauvin, J Y Blay, M Brunat-Mentigny
Journal: Annals of Oncology (1999)

This study evaluates histological response, long-term outcome, and toxicity in an intensive chemotherapy program given before surgery.Sixty-two patients (39 males, 23 females: median age 14) with biopsy, chest computerised-tomography, technetium bone-scan and magnetic resonance imaging, were enrolled. Primary localisations were femur (44%) and tibia (26%). Induction chemotherapy involved seven courses of high-dose methotrexate and two courses of HELP (ifosfamide, eldesine (vindesine), cisplatin (platinum)-doxorubicin. After surgery, patients received six courses of high-dose methotrexate and two courses of HELP-doxorubicin.Pre- and postoperative toxicities were similar. Fifty-nine patients underwent surgery; histological response was good in thirty-eight patients (64%) and poor in twenty-one (36%). Median follow-up is 57 months (range 30-80), with 77% overall survival and 59% progression-free survival. In a multivariate analysis, age under 10 years is the only prognostic factor that significantly correlates with outcome.This regimen appears to increase histological necrosis, but associates with severe toxicity. Results for patients with less necrosis at surgery are encouraging. Future trials should determine the minimum effective doses to reduce toxicity. New drugs should be added.
Accelerating achievement of the sustainable development goals
Authors: Ashish Jha, Ilona Kickbusch, Peter Taylor, Kamran Abbasi
Journal: BMJ (2016)

A game changer in global health

In September 2015, nearly 200 nations adopted the 17 sustainable development goals (SDGs) as a transformative, universal framework to address three interwoven dimensions of our global existence—people, planet, and prosperity.1 They are predicated on the notion that sustainability is not just an aspiration but a necessity. However, by substantially expanding on the scope and targets of their predecessors (the millennium development goals), the SDGs have set a high bar. To achieve them, we will need collective action to create new knowledge, share and broker knowledge, and implement insights through working with many sectors and diverse global health policy stakeholders. With this in mind, 60 global health policy think tanks from around the world met in Geneva in November 2015 to explore the role that think tanks and academic institutions have in implementing the SDGs.

Although only SDG3 focuses primarily on health, many other development goals, including those that relate to the environment, nutrition, hunger, sustainable production and consumption, agriculture, and education, also have a big effect on health. To achieve progress on human health, countries will therefore need to commit to a broad agenda of sustainable development that acknowledges and exploits the links between different goals and targets. This provides an opportunity for systems thinking: applying an ecological perspective and implementing an …
Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma
Authors: Suhendan Ekmekcioglu, Michael A. Davies, Keiji Tanese, Jason Roszik, Myung Shin-Sim, Roland L. Bassett, Denái R. Milton, Scott E. Woodman, Victor G. Prieto, Jeffrey E. Gershenwald, Donald L. Morton, Dave S. Hoon, Elizabeth A. Grimm
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. Experimental Design: Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan–Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. Results: Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set. Conclusions: Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016–24. ©2016 AACR.
Persistency with oral bisphosphonates in cancer patients
Authors: D. Göl, A. Höer, G. Schiffhorst, J. Brandman, B. Häussler
Journal: Journal of Clinical Oncology (2005)

8221 Background: Cancer patients often experience treatment and disease related bone complications. Bisphosphonates can significantly reduce occurrence of these complications. However, patients must remain on therapy to ensure optimum clinical benefit. Clinical studies have reported high percentage of patient discontinuation with oral bisphosphonates. However, the persistency rates and the drivers of persistency have not been quantified in a naturalistic setting. Methods: We used data from a German sickness fund (01/00 to 12/03) to examine the persistency rate of oral bisphosphonates. All patients had 1) ICD-10 diagnoses for selected cancer types: breast, colon, kidney, lung, lymphoma, prostate or thyroid gland; 2) were receiving oral bisphosphonates; and 3)were alive at least 7 months post their index date. Persistency was defined as the duration of continuous prescription refill without an interruption of longer than 30 days. Cox-regression models were used to analyze persistency periods controlling for age, sex and bone metastasis. Results: We identified 497 patients who met our inclusion criteria. The majority of these patients had breast cancer (47%) and were receiving alendronate (39%), clodronate (32,6%), risedronate (15,5%), etidronate and calcium (12,9%) or etidronate (3,0%). By the end of 6 months, only 35% of these patients remained on their oral bisphosphonate therapy. The median duration of therapy was 112 days. Patients with bone metastasis diagnosis had a higher risk (RR=1.31; p=0.016; CI: (1.05–1.65)) of being not persistent with the therapy compared to patients without such diagnosis. Age and sex had no effect on the duration of therapy. Conclusion: Persistency rates with oral bisphosphonates are very low, with 50% of patients stopping treatment by 3–4 months. Given the importance of preventing skeletal complications, patient persistency must be considered when selecting the optimum treatment choice for this patient population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis