tbuckley/cabot-search huggingface dataset:
Metabolic communication in tumors: a new layer of immunoregulation for immune evasion
Authors: Ping-Chih Ho, Pu-Ste Liu
Journal: Journal for ImmunoTherapy of Cancer (2016)

The success of cancer immunotherapy reveals the power of host immunity on killing cancer cells and the feasibility to unleash restraints of anti-tumor immunity. However, the immunosuppressive tumor microenvironment and low immunogenicity of cancer cells restrict the therapeutic efficacy of cancer immunotherapies in a small fraction of patients. Therefore deciphering the underlying mechanisms promoting the generation of an immunosuppressive tumor microenvironment is direly needed to better harness host anti-tumor immunity. Early works revealed that deregulated metabolic activities in cancer cells support unrestricted proliferation and survival by producing macromolecules. Intriguingly, recent studies uncovered that metabolic switch in immune and endothelial cells modulate cellular activities and contribute to the progression of several diseases, including cancers. Herein, we review the progress on immunometabolic regulations on fine-tuning activities of immune cells and discuss how metabolic communication between cancer and infiltrating immune cells contributes to cancer immune evasion. Moreover, we would like to discuss how we might exploit this knowledge to improve current immunotherapies and the unresolved issues in this field.
Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C)
Authors: M. J. Mauro, M. Baccarani, F. Cervantes, J. H. Lipton, Y. Matloub, R. Sinha, R. M. Stone
Journal: Journal of Clinical Oncology (2008)

7009 Background: Dasatinib is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against BCR-ABL in vitro. Extended 2-year follow-up data are available for the START-C study, an international, 75-center, phase II study in patients (pts) with CML-CP resistant or intolerant to imatinib. Methods: Pts were required to be either imatinib-resistant or -intolerant. The starting dose was dasatinib 70 mg BID, with dose escalations (90 mg BID) or reductions (50 or 40 mg BID) allowed for lack of response or toxicity. The primary endpoint was major cytogenetic response rate (MCyR). Results: Median time from CML diagnosis at baseline was 61 mos (range 3- 251). Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, complete cytogenetic response (CCyR) in 19%, and MCyR in 37% of pts. After a minimum follow up of 24 mos (LPFV to database closure; n=387, 288 imatinib-resistant, 99 imatinib-intolerant), CHR was noted in 91% (95% CI 88–94%), MCyR in 62% (95% CI 57–67%), CCyR in 53% and major molecular response (MMR) in 47% of pts. Rates of MCyR were 55% for imatinib-resistant pts, and 63% for pts with baseline BCR-ABL mutations; responses were seen across all mutations except T315I. In imatinib-intolerant pts, the CCyR (n=99) rate and MMR (n=94 evaluable) rate were both 78%. MCyRs were durable, with 88% of pts maintaining response at 24 mos. Progression-free survival (PFS) at 24 mos was 80% (75% in imatinib-resistant and 94% in imatinib-intolerant pts). Overall survival at 24 mos was 94% (92% in imatinib -resistant and 100% in imatinib-intolerant pts). Grade 3–4 toxicities included thrombocytopenia (49%) and neutropenia (50%), pleural effusion (9%), dyspnea (6%), bleeding (4%), diarrhea (3%), and fatigue (3%). 3% of imatinib-intolerant pts developed similar grade 3–4 toxicities; all were able to continue treatment after dose reduction, demonstrating lack of cross intolerance. The appearance of new higher grade toxicity between 12 and 24 months was uncommon. Conclusions: Dasatinib is well-tolerated in pts with CML-CP and induces cytogenetic responses that are highly durable and result in a PFS of 80% at 24-mos. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb
Prevalence and presentation of depressive illness in a primary health care setting in Kenya
Authors: M Dhadphale, G Cooper, L Cartwright-Taylor
Journal: American Journal of Psychiatry (1989)

Using a two-stage screening procedure, ICD-9 diagnostic criteria, and the Hamilton Rating Scale for Depression, the authors diagnosed depressive disorders in 81 (9.2%) of 881 patients in a primary care setting in Kenya. All depressed patients had somatic symptoms, and all of the 27 depressed patients assessed with the Hamilton scale scored higher than 2 on the work and activities item. These findings contradict the earlier reports that Africans do not admit to being depressed. Nearly one-third of the depressed patients were moderately or severely ill and would have benefited from psychiatric assessment and treatment.
Morbidity associated with oral corticosteroids in patients with severe asthma
Authors: Xue Ning Choo, Ian D Pavord
Journal: Thorax (2016)

Cross-sectional primary care record studies show that 0.9% of the adult population receive regular oral corticosteroids (OCS). Prescriptions have increased steadily over the past 20 years, presumably reflecting an increasingly elderly and infirm population.1 Respiratory conditions (mainly airway diseases) are responsible for 25–40% of these OCS prescriptions,1 ,2 by some way the largest proportion of any specialty. Against this background, it is surprising and disappointing that little is known about morbidity due to OCS usage in patients with airway disease and we remain in the unsatisfactory position of having to extrapolate from studies carried out in non-respiratory conditions. Better information in an airway disease population is important as we are approaching the biological treatment era and have within our sights treatments that offer a realistic potential to be alternatives to OCS and to allow patients already taking them to withdraw therapy safely.3–9 High quality data will be key to inform cost-effectiveness analyses for these new asthma therapies.

The paper by Sweeney et al 10 in this issue of the journal is therefore timely. The authors present data from two large severe asthma populations derived from the Optimum Patient Care Research Database (OPCRD) and British Thoracic Society (BTS) Difficult Asthma Registry on the occurrence of corticosteroid associated comorbidities. OPCRD is a respiratory database that contains anonymous longitudinal medical records supplemented by information from patient-completed questionnaires from over 525 general practices across UK. This data set was used to examine potentially OCS-related morbidity in a severe asthma cohort requiring regular OCS and two age and gender-matched control cohorts: one with mild/moderate asthma requiring minimal OCS use and the other without asthma. The BTS Difficult Asthma Registry consists of anonymised data collected from Specialist UK Difficult Asthma Services. Potentially OCS-related morbidity was compared in patients with severe asthma requiring daily …
Analysis of prognostic factors in patients with advanced non-small cell lung cancer (NSCLC) who are candidates to receive a second-line treatment.
Authors: M. Provencio, M. Cobo, S. Vazquez-Estevez, J. Firvida, S. Maciá, I. Barneto, J. Oramas, A. Sanchez-Hernandez, N. Ferrer, A. Paredes
Journal: Journal of Clinical Oncology (2010)

e18109 Background: The availability of new drugs for the treatment of advanced NSCLC and the need for a better selection of patients (P) deserve a new analysis of prognostic factors in p receiving more than one line treatment in order to improve outcomes. Methods: An epidemiological, prospective study to evaluate prognostic factors associated with the evolution of progressive advanced NSCLC in p candidate to receive further treatment has been carried out in 65 Spanish institutions. Primary objective: to identify prognostic factors associated with overall survival in p receiving second-line treatment. Secondary objective: to define subgroups with similar survival. 25 proposed prognostic factors were evaluated by Cox regression analysis. Results: 293 evaluable patients were analyzed. 78.2% male; median age: 63.2 yrs.: 81.6% ex/current smokers; 50.2% adenocarcinoma; 85.5% stage IV. 28,3%; ECPG PS ≥ 2: 79.8%/ received erlotinib as 2nd-line. Overall survival (OS): 7.5 months (95% CI: 6.7-8.4). OS for p treated with E/other: 7.9/6.7 months (p=0.16). In the multivariate analysis, ECOG PS>1, squamous histology negative prognostic factors for OS (Table). Interestingly, prognosis was not conditioned by stage and gender in our model. Progression-free survival (PFS) for the 2nd line treatment: 2.8 months (95% CI: 2.4-3.1). SLP for p treated with E/other: 3.1/2.1 (p<0.001). Regarding PFS, higher levels of hemoglobin (HR: 0.9 [0.8-0.9]; p<0.05), albumin (HR: 0.8 [0.7-1.0]; p=0.05), and the treatment with erlotinib (vs. other; HR: 0.5 [0.3-0.8]; p<0.01) were associated with better prognosis. Conclusions: PS and histology are prognostic factors for the OS of patients with advanced NSCLC receiving a 2nd-line treatment. A better understanding of prognostic factors is crucial for the better selection of p receiving several lines of treatment. HR 95% IC p ECOG PS (PS 0: reference group) 1 2.37 0.97-5.77 0.058 2 3.18 1.23-8.22 <0.05 Histology (adeno: reference group) Large cell carcinoma 1.44 0.72-2.88 0.30 Squamous 2.14 1.33-3.45 <0.01 Differentiation (poor differentiation: reference group) Moderate 0.43 0.20-0.89 0.05 Well differentiated 0.55 0.22-1.37 0.200 Unknown 1.34 0.79-2.28 0.1 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche
Management of Anticoagulants in the Periprocedural Period for Patients With Cancer
Authors: Anita Pudusseri, Alex C Spyropoulos
Journal: Journal of the National Comprehensive Cancer Network (2014)

Patients with cancer undergo surgeries and procedures for various purposes, including prophylaxis, diagnosis, staging, cure, debulking, palliation, and reconstruction. The diagnosis of cancer itself, along with the well-established complication of venous thromboembolism (VTE), places these patients at risk for perioperative thromboembolism. It is also well-established that continuing patients on oral anticoagulation therapy during the periprocedural period is associated with an increased risk of bleeding. Rates of periprocedural VTE and major bleeding are significantly higher in patients with cancer, presenting a complex problem for clinicians in terms of periprocedural anticoagulation management. This article reviews the current recommendations regarding periprocedural anticoagulation management in patients with cancer.
Overexpression of the osteopontin correlates with the aggressiveness of endometrial cancer
Authors: C. Cho, S. Kwon, S. Ramachandran, S. Kwon, K. Kwon, S. Cha, Y. Do
Journal: Journal of Clinical Oncology (2006)

5038 Background: To test the hypothesis that expression of osteopontin (OPN), an integrin-binding glycoprotein, can independently predict the potential aggressiveness of endometrial cancer. We studied OPN expression in endometrial cell carcinomas and correlated OPN expression levels with clinicopathologic tumor features. Methods: The status of OPN expression in benign and malignant endometrial cancer cell lines and tissues was analyzed by Western blot and immunohistochemistry. Nonparametric Spearman’s correlation coefficient method was used to assess the statistical significance of the correlation between clinicopathologic characteristics of tumor and OPN expression. Results: An increased expression of OPN was observed in the endometrial cancer compared to normal endometrial tissue samples. When the level of OPN in normal tissue was set at 1, its level in benign endometrial hyperplasia was slightly increased at 1.2, whereas the OPN level in the highly malignant endometrial carcinoma tissue was greatly increased by nearly 3- 5 folds. Amongst the 70 cases examined immunocytochemically, of the 23 grade 1 endometrial carcinomas, 6 were unstained and 12 stained weakly positive (+). For the 20 grade 3 or serous type endometrial carcinomas analyzed, 8 (40%) stained strongly positive (+++), 8 (40%) stained moderately positive (++) and 1 stained weakly positive (+). These results showed that the level of OPN expressed between grade 1 and grde 3 or more was significantly different (Spearman’s correlation coefficient method, p = 0.001). Kaplan-Meier survival analysis showed that the increased level of OPN expression was significantly associated with reduced survival time of the patients. Conclusions: The results suggest that the increased OPN level may be involved in the malignant transformation of endometrial adenocarcinoma cells and OPN expression level is an important determinant for patient survival. No significant financial relationships to disclose.
Evaluation of a novel MUC1 biomarker/target antigen for pancreatic cancer
Authors: D. V. Gold, D. E. Modrak, G. Newsome, H. Karacay, R. M. Sharkey, D. M. Goldenberg
Journal: Journal of Clinical Oncology (2006)

4096 Background: Pancreatic cancer provides a major challenge in terms of diagnosis and treatment. We have developed an anti-MUC1 MAb, PAM4, which identifies an epitope that is more restricted to MUC1-expressed by pancreatic cancer than MUC1 from other forms of cancer. PAM4 has been studied for in vitro and in vivo detection and therapy of pancreatic cancer. Methods: The in vitro immunoassay consists of PAM4 as the capture reagent and an IgG fraction derived from a polyclonal, anti-MUC1 antiserum as the probe. For in vivo detection and therapy, PAM4 is either directly radiolabeled or used in a 2-step pretargeting protocol. Results: The PAM4-based immunoassay provided high sensitivity (77%) and specificity (95%), with a value ≥ 10.2 units/ml indicating a high likelihood of pancreatic cancer, as compared to normal and benign disease groups and non-pancreatic cancers. A direct pairwise comparison of the PAM4 and CA19–9 immunoassays for discrimination of pancreatic cancer and pancreatitis demonstrated a superior performance of the PAM4-immunoassay (P&lt;0.003). Initial clinical studies with directly labeled 131 I-PAM4 provided positive imaging in 8/10 patients, with one negative patient having only pancreatitis, and the other negative patient having a tumor that was MUC1-negative. A Phase I, dose-escalation study of 90 Y-humanized PAM4 administered as a single dose to patients with advanced pancreatic cancer is in progress (Immunomedics, Inc), and has already achieved doses of 20 mCi/m 2 . Finally, pretargeting involving a bispecific MAb with one arm being PAM4 targeting MUC1 and the other arm capturing a hapten peptide carrying a radionuclide is under preclinical evaluation. This second generation targeting system has shown higher tumor/nontumor ratios and improved imaging ( 111 In) as compared to directly radiolabeled PAM4. Conclusions: These results suggest that the PAM4-reactive MUC1 epitope may prove useful as a selective biomarker/target antigen for diagnosis, detection, imaging, and therapy of pancreatic cancer. (Supported in part by grants CA96924and CA98488 from the NIH). [Table: see text]
Abstract 19049: MiR-126 Containing Exosomes From Human CD34+ Stem Cells Activate Endothelial Cells to Initiate Angiogenesis and Ischemic Tissue Repair
Authors: Susmita Sahoo, Sol Misener, David Kim, Tina Thorne, Douglas E Vaughan, Douglas W Losordo
Journal: Circulation (2013)

Introduction: Locally transplanted human CD34+ stem cells have been shown to improve exercise tolerance in patients with myocardial ischemia and promote angiogenesis in animal models. Recently we have demonstrated that CD34+ cells secrete membrane bound nano-vesicles called exosomes as a major component of their pro-angiogenic paracrine secretion. We hypothesize that cell-free exosomes from CD34+ cells (CD34 Exo) mimic the beneficial effects of the cells and promote angiogenesis and ischemic tissue repair via transfer of pro-angiogenic microRNAs, possibly to endothelial cells. Methods and Results: Therapeutic potential of CD34 Exo isolated from equal number of adult human peripheral blood-derived CD34+ cells was evaluated in an immunodeficient murine model of hind limb ischemia. Similar to cells, treatment with CD34 Exo resulted in significant improvement in ischemia compared to treatment with PBS (perfusion ratio: 1.01±0.04 v 0.57±0.1; capillary density: 1.8±0.3 v 0.9±0.1/HPF; limb amputation: 16% v 100%; p&lt;0.05; n=10-21). MicroRNA expression profiling and confirmatory tests indicated that CD34 Exo are significantly enriched with pro-angiogenic miRNAs such as miR126. Treatment with CD34 Exo in mouse hind limb ischemic tissue increased mature miR126 expression, but not endogenous mouse pri-miR126, and activated pro-angiogenic miR126 target-gene expression. Treatment of CD34 Exo lacking miR126 abolished this increase and diminished the pro-angiogenic function of CD34 Exo-treated endothelial cells. This data suggests that miR126 is important for CD34 Exo function. Interestingly, confocal imaging and flow cytometry analyses revealed that CD34 Exo were selectively internalized by endothelial cells when injected to the ischemic tissue. Live imaging using fluorescent miR126 confirmed that CD34 Exo directly transfers miR126 and possibly other yet to be identified moieties from its repertoire specifically to endothelial cells in the ischemic tissue. Conclusion: CD34+ exosomes transfer miR126 to endothelial cells to induce angiogenesis and ischemic tissue repair. The functional benefits associated with CD34+ cell therapy may be mediated by exosomes-mediated targeted transfer of angiogenic microRNAs to endothelial cells.
Targeting ALK: The Ten Lives of a Tumor
Authors: Rogier Versteeg, Rani E. George
Journal: Cancer Discovery (2016)

Abstract Summary: In this issue, Infarinato and colleagues report the results of preclinical testing of a novel ALK/ROS1 inhibitor, PF-06463922, in neuroblastoma. This small-molecule inhibitor was shown to efficiently inhibit the growth of patient-derived and established neuroblastoma xenograft models expressing mutated ALK. Although the in vivo data are impressive and the authors suggest that clinical trials are warranted, the presented data also suggest that it is as yet too early to welcome the new drug as a magic bullet. Cancer Discov; 6(1); 20–1. ©2016 AACR. See related article by Infarinato et al., p. 96.
<sup>11</sup>C-acetate PET/CT imaging of prostate cancer: Detection of recurrent disease in patients with PSA relapse following radical prostatectomy.
Authors: P. Albers, M. Fahlbusch, H. Hautzel, V. Mueller-Mattheis
Journal: Journal of Clinical Oncology (2010)

e15080 Background: Patients with rising PSA after definitive local therapy of prostate carcinoma (PC) often present a diagnostic dilemma. A local recurrence or metastatic lymphnode lesions would be amenable to additional local therapy, whereas distant metastases usually require androgen deprivation. In this prospective study the effectiveness of 11C-acetate PET (AC-PET) matched with corresponding CT scans in pats. with PSA relapse following radical prostatectomy (RP) was evaluated. Methods: 45 pats. with histologically confirmed PC were enrolled in this study because of rising PSA following RP (n = 39) or radiotherapy (RTx) (n=6). Whole-body PET images were obtained after iv - administration of 1,000 MBq of 11C-acetate, CT from the neck to the pelvic floor was performed additionally. An image overlay of corresponding CT and PET scans was done using a specific image software (developed in Max Planck Institute, Cologne, Germany). Results: Out of 45 pats. n=17 were AC-PET pos. PSA in 8 of this subset was between 0.9 and 1.45 ng/mL, in 7 pats. between 2.7 and 7.3 ng/mL, and 2 pats. had a PSA of 19.2 and 23.1 ng/mL, respectively. Analysing the AC-PET pos. patients, in 6/17 AC-PET demonstrated lymphnode metastases, in 3/6 metastatic lesions were histopathologically confirmed, in the remaining 3 unspecific inflammatory tissue alterations were identified. In 4 pats. with corresponding AC-PET and CT scans RTx of proven lymphnode metastases was performed followed by decreasing PSA . After diagnostic work-up with PET and CT, 7/17 pats. were treated with hormone manipulation (6/7) or chemotherapy (1/7), in this AC-PET pos. subgroup CT had revealed tumour lesions in only 3 of them. Combining the pats. having undergone surgery and RTx (n=10) there were 7/10 true pos. in terms of AC-PET. In 5 / 10 PSA was < 2.0 ng/mL, in the remaining 5 PSA distribution was from 5.4 to 23.1 ng/mL. PPV (AC-PET pos): 0.824. Updated results will be presented. Conclusions: Although AC-PET seems to be a promising tool in the detection of recurrent PC even with PSA <2 ng/mL, false pos. pats. with a different metabolism marked by 11C-acetate decrease the specifity of the approach. Thus there is still more specific tracer requirement. No significant financial relationships to disclose.
A Micro/Nano Composite for Combination Treatment of Melanoma Lung Metastasis
Authors: Yu Mi, Chaofeng Mu, Joy Wolfram, Zaian Deng, Tony Ye Hu, Xuewu Liu, Elvin Blanco, Haifa Shen, Mauro Ferrari
Journal: Advanced Healthcare Materials (2016)

The successful treatment of malignant disease generally requires the use of multiple therapeutic agents that are coordinated in a spatiotemporal manner to enable synergy. Here, a porous silicon‐based micro/nano composite (MNC) that is capable of simultaneously delivering chemotherapeutic agents and small interfering RNA (siRNA) to the lungs following intravenous injection is designed. The pores of the silicon microparticles are loaded with B‐Raf proto‐oncogene serine/threonine kinase (BRAF) siRNA‐containing liposomes, while the surface is conjugated with docetaxel‐encapsulated polymeric nanoparticles. The synergistic antitumor effect of the MNC is demonstrated in vitro in melanoma cells and in vivo using a mouse model for melanoma lung metastasis. The MNC displays superior therapeutic efficacy and increased accumulation in metastatic melanoma lesions in the lungs in comparison to combination therapy with liposomes and polymers. The results indicate that the MNC can be used as an effective delivery vehicle for simultaneous enrichment of multiple therapeutic agents in the lungs.
One-Third of Patients in a National Cohort Initiating Hemodialysis With a Catheter Despite 6 Months of Nephrology Care
Authors: Devin S. Zarkowsky, Caitlin W. Hicks, Mahmoud B. Malas
Journal: JAMA Surgery (2016)

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