tbuckley/cabot-search huggingface dataset:
Intensification of Adjuvant Chemotherapy: 5-Year Results of a Randomized Trial Comparing Conventional Doxorubicin and Cyclophosphamide With High-Dose Mitoxantrone and Cyclophosphamide With Filgrastim in Operable Breast Cancer With 10 or More Involved Axillary Nodes
Authors: Pierre Fumoleau, Franck Chauvin, Moïse Namer, Roland Bugat, Michèle Tubiana-Hulin, Jean Paul Guastalla, Thierry Delozier, Pierre Kerbrat, Yves Devaux, Jacques Bonneterre, Annie Filleul, Michel Clavel
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m 2 plus cyclophosphamide 600 mg/m 2 , with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P = .44), DDFS (P = .67), or OS (P = .99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P = .01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P &lt; .001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m 2 with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.
Effect of Aminoacetonitrile on the Fine Structure and Cytochemistry of Hepatic Cells in Rats Fed Two Carcinogenic N-Nitrosodialkylamines2
Authors: D. Hadjiolov, D. Markov
Journal: JNCI Journal of the National Cancer Institute (1973)

We studied the ultrastructural and histochemical changes induced in rat liver cells by dimethylnitrosamine (DMNA) and diethylnitrosamine (DENA). Both dialkylnitrosamines produced progressive disorganization of the granular endoplasmic reticulum and hypertrophy of the agranular reticulum, accompanied by the disappearance of glycogen. DMNA and DENA also caused a loss of centrolobular glucose-6-phosphatase activity and markedly decreased DPNH- and TPNH-tetrazolium reductase activities. The incidence of these morphologic alterations was reduced by the subsequent administration of aminoacetonitrile. Persistent cytoplasmic abnormalities were a slight dilation of the membranous profiles of the granular endoplasmic reticulum and a moderate hypertrophy of the agranular reticulum. The glycogen content was almost normal. Centrolobular glucose-6-phosphatase activity also slightly decreased. These findings suggested that aminoacetonitrile has a direct stabilizing effect on cytoplasmic membrane systems and ribosomes in the early stage of nonspecific liver damage caused by 2 dialkylnitrosamines.
miRNA Deregulation in Cancer Cells and the Tumor Microenvironment
Authors: Rajesha Rupaimoole, George A. Calin, Gabriel Lopez-Berestein, Anil K. Sood
Journal: Cancer Discovery (2016)

Abstract miRNAs are a key component of the noncoding RNA family. The underlying mechanisms involved in the interplay between the tumor microenvironment and cancer cells involve highly dynamic factors such as hypoxia and cell types such as cancer-associated fibroblasts and macrophages. Although miRNA levels are known to be altered in cancer cells, recent evidence suggests a critical role for the tumor microenvironment in regulating miRNA biogenesis, methylation, and transcriptional changes. Here, we discuss the complex protumorigenic symbiotic role between tumor cells, the tumor microenvironment, and miRNA deregulation. Significance: miRNAs play a central role in cell signaling and homeostasis. In this article, we provide insights into the regulatory mechanisms involved in the deregulation of miRNAs in cancer cells and the tumor microenvironment and discuss therapeutic intervention strategies to overcome this deregulation. Cancer Discov; 6(3); 235–46. ©2016 AACR.
High glucose inhibits nitric oxide production in cultured rat mesangial cells.
Authors: H Trachtman, S Futterweit, D L Crimmins
Journal: Journal of the American Society of Nephrology (1997)

Hyperglycemia directly contributes to the development of diabetic nephropathy. A high-serum glucose concentration alters intraglomerular hemodynamics and promotes deposition of extracellular matrix in the kidney. Nitric oxide (NO) is a short-lived messenger molecule that participates in the regulation of renal blood flow, GFR, and mesangial matrix accumulation. Therefore, in this study it was tested whether high glucose directly modulates NO synthesis by rat mesangial cells in vitro by measuring the accumulation of nitrite, the stable metabolite of NO, in the incubation media. Raising the external glucose concentration to 33.3 mM for 24 to 72 h reduced nitrite levels in cell supernatants in a time-dependent manner to a nadir of 14 +/- 3% of the amount in normal glucose media (5.6 mM) (P < 0.01). The decline in NO synthesis in high glucose media was paralleled by decreased cyclic guanosine monophosphate generation; however, there was no alteration in rat mesangial cell expression of inducible NO synthase protein. The suppressive effect of high glucose on NO production by mesangial cells was not modified by inhibition of protein kinase C (H-7), the addition of antioxidants (vitamin E or superoxide dismutase), or a pan-specific anti-transforming growth factor-beta antibody. An elevated ambient glucose caused a time-dependent reduction in mesangial cell L-arginine content. Addition of L-arginine (10 to 20 mM) to external media partially reversed the inhibitory effect of high glucose on mesangial cell NO production in a dose-dependent manner. The highest dose of L-arginine (20 mM) increased mesangial cell L-arginine content to comparable levels in normal and high glucose media. These results indicate that high glucose causes depletion of L-arginine in mesangial cells and compromises NO synthesis. Limitation in the metabolic precursor and other, as yet unidentified, factors act to reduce NO production by mesangial cells in the presence of an elevated ambient glucose level, a change that may play a role in the development of diabetic glomerulosclerosis.
Utility of post-treatment FDG-PET in predicting outcomes in anal cancer managed with chemoradiotherapy.
Authors: A. G. Heriot, F. L. Day, E. Link, T. Leong, A. C. Lynch, M. Michael, R. Hicks, A. Hogg, S. Ngan
Journal: Journal of Clinical Oncology (2010)

4105 Background: 18-fluorodeoxyglucose positron emission tomography (FDG-PET) improves the accuracy of staging and radiotherapy planning in anal cancer, and in other malignancies has prognostic value. The aim was to investigate the correlation between FDG-PET metabolic response to chemoradiotherapy and clinical outcomes in anal cancer. Methods: Seventy-four consecutive patients with anal cancer referred to a single tertiary oncology centre between 1997 and 2006 were staged with whole body FDG PET or PET-CT scans. 48 patients underwent FDG-PET scans post-chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin), and were representative of the entire cohort in age, gender and N stage, but were higher T stage (p = 0.02). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response (complete, partial or no response). Results: Post-treatment FDG-PET scan was performed median 69 days (range 20-255) from final radiotherapy fraction. 79% patients (n = 38) had a complete metabolic response (CMR) at all sites of disease, 15% (n = 7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial response, PMR), and 6% (n = 3) had progressive distant disease despite CMR locoregionally (overall no response, NR). Median patient follow-up was 4.8 years (range 1.7-9.1). The 5-year progression-free survival (PFS) was 82% for patients with a CMR, 71% for PMR, 0% for NR, p < 0.0001. The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR, p < 0.0001. Cox proportional hazards regression analyses for PFS found significant associations for T stage (HR 1.9, 95% CI 1.0-3.4, p = 0.04) and incomplete (PMR + NR) FDG-PET response to treatment (HR 5.2, 95% CI 1.6-17.3, p = 0.01), but not N stage. Adjusted for T stage, incomplete FDG-PET response showed HR 6.0 (95% CI 1.7-20.9, p = 0.008) for disease progression. Incomplete FDG-PET response was the only significant association with OS, HR 6.7 (95% CI 2.1-21.6, p = 0.002). Conclusions: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with progression-free and overall survival, and a stronger predictor of PFS and OS than T or N stage. No significant financial relationships to disclose.
Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting.
Authors: S M Grunberg, L L Stevenson, C A Russell, J E McDermed
Journal: Journal of Clinical Oncology (1989)

GR38032F is a specific 5-HT3 (serotonin) receptor antagonist with antiemetic activity in animal and early human studies. We performed a dose-ranging phase I study of GR38032F in 43 evaluable patients receiving cisplatin 60 120 mg/m2 for the first time (38 of these patients were chemotherapy-naive). Intravenous GR38032F was administered over a dose range from 0.01 to 0.48 mg/kg given three times at four-hour intervals beginning one half hour before cisplatin, and patients were observed for 24 hours. An additional five patients were treated with 0.18 mg/kg given three times at six-hour intervals. Excellent antiemetic efficacy was noted, with 44% of patients experiencing no vomiting and 26% no nausea. Major protection from vomiting (less than or equal to 2 episodes) and from nausea (less than or equal to 2 hours) was experienced by 81% and 44%, respectively. Mild to moderate headache (40%), lightheadedness (21%), and elevated transaminase (19%) were the most common adverse events reported. One patient experienced an apparent hypersensitivity reaction that responded to conventional medications. No extrapyramidal reactions or akathisia were seen. GR38032F was effective through most of the dose range. However, efficacy decreased at the 0.01 mg/kg level and number and intensity of adverse events increased at the 0.48 mg/kg level. Analysis of those patients receiving high-dose cisplatin (100 to 120 mg/m2) revealed a positive association of GR38032F dose and antiemetic activity (Fisher's exact test, two-sided; P less than .05). The 5-HT3 receptor antagonists may provide antiemetic efficacy similar to high-dose metoclopramide without antidopaminergic toxicity. The maximum recommended dose on this schedule of GR38032F is 0.36 mg/kg.
Role of erythropoietin receptor expression in malignant melanoma
Authors: U. R. Hengge, A. Mirmohammadsadegh, S. Nambiar, D. Delia, A. Gustrau
Journal: Journal of Clinical Oncology (2008)

9070 Background: Erythropoietin (Epo) is known to promote proliferation and differentiation of erythroid precursors and to prevent apoptosis. Epo receptor (EpoR) belongs to the cytokine receptor superfamily and exerts its effects via receptor homodimerization, subsequent phosphorylation of Janus kinase 2 (Jak2) and activation of signal transducers and activators of transcription (STAT)-3 and -5. Epo is also able to induce the activation of the Ras-Raf-MEK-ERK pathway in different types of cells. Recombinant human erythropoietin (rHuEpo) can prevent anemia in tumor patients; recent evidence has suggested that rHuEpo may adversely affect the survival of selected cancer patients by promoting tumor growth. Methods and Results: In this study, we have investigated the expression of EpoR in malignant melanoma specimens and analyzed the effect of rHuEpo on proliferation and apoptosis of melanoma cells in vitro. We observed a transcriptional upregulation of EpoR in 50% of malignant melanoma metastases in comparison to benign nevi and primary melanoma using quantitative real- time RT-PCR. EpoR expression was weak in normal human melanocytes (NHM) and different melanoma cell lines (e.g. A375 and BLM cells), but was high in MV3 cells and melanoma metastasis specimens as assessed by Western blot analysis. Furthermore, rHuEpo treatment also induced the phosphorylation of JAK-2, STAT-3 and activated the Ras-Raf-ERK pathway as shown by Western blot experiments. In addition, rHuEpo seemed to prevent the cisplatin-induced apoptosis in certain melanoma cell lines. Conclusions: In summary, we demonstrate functional EpoR expression in stage IV melanoma specimens, thus cautioning the use of rHuEpo for the treatment of anemia in these patients. No significant financial relationships to disclose.
Phase I trial of intravenous 17-allylaminogeldanamycin (A) and oral sorafenib (B) in pretreated advanced malignancy: Plasma Hsp90α induction correlates with clinical benefit
Authors: U. N. Vaishampayan, E. A. Sausville, M. N. Horiba, M. Quinn, L. K. Heilbrun, A. Burger, P. Ivy, J. Li, P. Lorusso
Journal: Journal of Clinical Oncology (2007)

3531 Background: The combination of B with A was evaluated to recommend a phase II dose for using A in combination with B, since raf-kinase and VEGF inhibition by distinct pathways could result in synergy and prevent resistance to B. Patients and Methods: Eligibility included histologically confirmed advanced malignancy, at least 4 weeks since prior systemic cancer therapy and/or radiation, adequate organ function and performance status of 0–2. B was administered orally at fixed dose of 400 mg twice daily starting 2 weeks prior to A, which was added in escalating dose cohorts starting at 300mg/m 2 intravenously over 3 hours on days 1, 8 and 15 in a 28 day cycle. Toxicity was assessed weekly and clinical response evaluated every 2 cycles. Results: 19 patients have been registered (6 clear cell renal, 1 papillary renal, 4 colorectal, 1 each with cervix, adrenal, oral, thyroid, pancreas cancer and 3 with melanoma). 16 have been treated for at least the first two cycles at 4 dose levels on this ongoing study. Dose limiting toxicity has not yet been reached at 400mg/m 2 of A. Major toxicities were grade 3 fatigue in 1 patient and grade 2 nausea and diarrhea in 3 and 2 patients respectively. Grade 3 hand foot syndrome related to B was noted in 3 patients. Of 14 response evaluable patients, 1 demonstrated partial response (thyroid cancer) and 6 had stable disease;3 clear cell renal,1 each with papillary renal and cervix cancers, and 1 melanoma. Latter patient had stable disease for 10 cycles and was resected to render disease free. PK analysis reveals that steady-state was achieved after 1 week of B; addition of A did not alter PK of B. PK levels of A will be performed. Studies of Hsp90a in the plasma have been performed on 10 patients. Of the 10 patients evaluated for plasma Hsp90a (baseline values pre-A and at 4 and 18 days after A), 5 of the 6 clinically stable patients had 1.8 to 6.8- fold increase; 3 patients with clinical progression and 1 clinically inevaluable patient had induction of 0.8 to 1.7-fold. Conclusion: The combination of A and B is well tolerated and clinical benefit may correlate with induction of plasma Hsp90a. Supported by NIH# 5UO1CA062487- 14, 2MO1RR016500–006 and NCI CTEP. No significant financial relationships to disclose.
<scp>IL</scp>‐33 mediates reactive eosinophilopoiesis in response to airborne allergen exposure
Authors: E. L. Anderson, T. Kobayashi, K. Iijima, K. R. Bartemes, C.‐C. Chen, H. Kita
Journal: Allergy (2016)

Abstract Background Exposure to aeroallergens induces eosinophilic airway inflammation in patients with asthma and allergic airway diseases. The circulating number of eosinophils in peripheral blood is relatively small, leading us to hypothesize that bone marrow needs to be engaged quickly to meet the demands of the tissues. Methods To investigate the communication between the lungs and bone marrow, we used acute allergen exposure and airway inflammation models in mice. Gene‐deficient mice and cytokine reporter mice as well as in vitro cell culture models were used to dissect the mechanisms. Results Naïve BALB /c mice produced increased numbers of eosinophil precursors and mature eosinophils in the bone marrow when their airways were exposed to a common fungal allergen, Alternaria alternata . Expression of IL ‐5 and IL ‐33 increased rapidly in the lungs, but not in the bone marrow. Sera from allergen‐exposed mice promoted eosinophilopoiesis in bone marrow cells from naïve mice, which was blocked by anti‐ IL ‐5 antibody. Mice deficient in the IL ‐33 receptor ST 2 (i.e., Il1rl1 −/− mice) were unable to increase their serum levels of IL ‐5 and allergen‐induced eosinophilopoiesis in the bone marrow after allergen exposure. Finally, group 2 innate lymphoid cells ( ILC 2s) in the lungs showed robust expression of IL ‐5 after Alternaria exposure. Conclusions These finding suggests that lung IL ‐33, through innate activation of ILC 2s and their production of IL ‐5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions.
First-line therapy with metronomic capecitabine (mC) plus docetaxel (D) followed by mC as maintenance for patients with HER2-negative metastatic breast cancer (MBC): Preliminary analysis of a monocentric phase II trial.
Authors: G. Aurilio, A. Sciandivasci, E. Munzone, D. F. Riva, D. Radice, F. Bertolini, I. Minchella, D. Cullura, G. Curigliano, M. G. Zampino, A. Goldhirsch, F. Nole
Journal: Journal of Clinical Oncology (2011)

e11547 Background: In MBC patients (pts) capecitabine and D are effective, although the optimal schedule still needs to be defined. We assessed efficacy and safety of mC plus D as first-line treatment for MBC pts. Correlation between disease response and circulating endothelial cells (CEC), precursors (CEP) and other potential angiogenic biomarkers was also explored. Methods: From December 2009 to November 2010, 15 HER-2 negative MBC pts received mC 1500 mg daily plus D 75 mg/m(2) on day 1 of a 4-week cycle up to 6 cycles, followed by mC as maintenance, in case of response or stable disease. Results: Twelve pts (80%) were assessable for response, all pts were evaluable for toxicity, 3 pts are currently treated with mC as maintenance. Median number of delivered cycles was 6 (range, 1-10 cycles). According to RECIST 1.1 criteria, objective response rate was 41.7% (95% CI, 15.2-72.3%), 1 pt (8.3%) had complete response (CR), 4 pts (33.4%) had partial response (PR), 6 pts (50%) had stable disease (SD) with a clinical benefit of 66.7% (95% CI, 34.9-90.1%), only one pt (8.3%) had progressive disease (PD). Median disease-free interval was 42.2 months (95% CI, 21.5-90.3), median time to progression was 8.4 months (95% CI, 2.5-9.1). CEC, CEP, apoptotic cells, CEC viable, CD31, CD109 and CD140b were analyzed at different time point. CEC and CEP were significantly correlated with CR/PR/SD vs PD after 8 weeks (P = .023) and after 4 weeks (P = .043) from beginning of therapy, respectively. Main toxicity was haematological, 5 pts (33.4%) with grade 3-4 neutropenia, 3 (20%) of whom had febrile neutropenia. Grade 3 hand-foot syndrome occurred in 2 pts (13.4%), grade 3 transaminitis in only one (6.7%). All toxicities occurred during D plus mC combination. Conclusions: Although the sample considered is small, as the study is still ongoing, these preliminary data suggest D plus mC as an innovative combination and an additional useful option for MBC pts, with encouraging activity and acceptable toxicity profile. The biomarkers investigated seem promising for predicting response.
Paracetamol exposure prenatally and in infancy is linked to asthma, study shows
Authors: Susan Mayor
Journal: BMJ (2016)

Prenatal exposure to paracetamol and exposure during infancy are both independently associated with a raised risk of asthma, a follow-up study of children in Norway has shown.1

Paracetamol has previously been linked to a higher risk of asthma, but the relative importance of exposure before birth and in infancy has been unclear.

Researchers investigated this using data from the Norwegian Mother and Child Cohort Study, which recruited and studied pregnant women from 1999 to 2008 and then followed up their children.

The team evaluated prenatal paracetamol exposure and the …
A randomized controlled phase III trial to evaluate the effect of preoperative enteral immunonutrition on the surgical site infection after total gastrectomy (OGSG0507).
Authors: Y. Kimura, T. Tsujinaka, K. Fujitani, J. Fujita, I. Miyashiro, H. Imamura, K. Kobayashi, Y. Kurokawa, T. Shimokawa, H. Furukawa
Journal: Journal of Clinical Oncology (2011)

74 Background: To investigate the effect of preoperative enteral immunonutrion on the incidence of surgical site infection (SSI) after total gastrectomy for gastric cancer, we conducted a prospective randomized controlled trial. Methods: Eligibility criteria included: (1) histologically proven adenocarcinoma of stomach, (2) scheduled total gastrectomy, (3) aged less than 80 years, (4) not malnourished, (5) possible to ingest liquid diet, (6) written informed consent. Eligible patients (pts) wereassigned to the immunonutrition (I) group or the control (C) group. In the C group pts freely accessed to regular diet until surgery. In the I group, pts were supplemented with 1,000 ml/day of immunonutrient enriched with arginine, omega-3 fatty acids and RNA (Impact) in addition to the regular diet for 5 days before surgery. The primary endpoint was the incidence of SSI and the secondary endpoints were other infectious complications and serum CRP level on POD 3 or 4. Results: From 02/2004 to 12/2009, 240 gastric cancer patients (pts) who underwent gastric surgery were enrolled. 125 pts assigned to the I group and 115 pts assigned to the C group. Age, sex, body weight, serum albumin and general nutritional status were well balanced between the two groups. 223 pts underwent total gastrectomy, 6 pts proximal gastrectomy, 4 pts distal gastrectomy, and 7 pts simple laparotomy. In terms of tumor status, there were no significant difference between the groups in histological type, T stage, and lymph node metastasis. 104 of 125 pts assigned to the I group tolerated a daily intake 1,000 ml of Impact for 5 days. The incidence of SSI was 26 (20.8%) in the I group and 24 (20.9%) in the C group (R.R: 1.00, 95% C.I: 0.61-1.63). Postoperative morbidity was 36 (28.8%) in the I group and 30 (26.1%) in the C group. There was no difference in days of hospital stay after surgery between the groups. Conclusions: The oral administration of immunonutrient for 5 days before surgery did not contributed to the reduction of infectious complications after total gastrectomy in gastric cancer pts. No significant financial relationships to disclose.