tbuckley/cabot-search huggingface dataset:
Phase I trial of liposomal doxorubicin and ZD 1839 in patients with refractory gynecological malignancies or metastatic breast cancer
Authors: S. M. Campos, L. Parker, W. Chen, C. A. Bunnell, T. Atkinson, J. Lee, U. A. Matulonis, L. N. Harris, C. N. Krasner
Journal: Journal of Clinical Oncology (2006)

5085 Background: Liposomal Doxorubicin has activity in both breast and ovarian cancer. Preclinical data reported by several investigators have suggested that ZD1839 acts synergistically with chemotherapy in ovarian cancer cells expressing high levels of EGFR. Given the lack of cross resistance and the different targets for these agents a Phase I trial was initiated examining the safety and the efficacy of the combination of Liposomal Doxorubicin and ZD1839. Methods: Dose limiting toxicity was defined within the first two cycles of treatment. The dose escalation schema was described as such: Results: As of January 2006, 23 patients have been enrolled in this study (GYN = 6; Breast 17). Six patients were enrolled in dose level 1 and no DLTs were observed. Dose level 2 enrolled six patients. One DLT was observed (febrile neutropenia). As defined by protocol an additional 6 patients were accrued to dose level 2. Accrual to dose level 3 began on 11/2005. One patient has completed 2 cycles and no additional DLTs have been noted. MTD has not yet been reached. SAEs have included mental status changes, and two CNS bleeds (believed most likely to be unrelated to study drug combination). Toxicities noted in cycle 3 and above have been mild with the exception of 2 grade 3 and 2 grade 4 toxicities related to skin and GI toxicity. No cardiac toxicity was observed. Doxil dose modifications (cycle 3 +) occurred in 7 patients. Best response to therapy has included 2 PRs and 10 patients with SD. Eleven patients to date have had progressive disease. The trial continues to accrue. Correlative studies including EGFR expression and CECs and PKs (at MTD) are planned. Conclusion: Liposomal Doxorubicin in conjunction with ZD1839 is tolerable regimen in patients with advanced breast and ovarian cancer. To date MTD has not been reached. [Table: see text] [Table: see text]
Radiosensitivity of orthotopic ileal neobladders.
Authors: Leslie K. Ballas, Shelly X. Bian, Gus Miranda, Siamak Daneshmand
Journal: Journal of Clinical Oncology (2015)

350 Background: A prior report from our institution documented that Kock ileal reservoirs can tolerate doses of 45-50.4Gy. This study provides retrospective information on the radiosensitivity of orthotopic neobladders by reviewing the acute and late toxicity in patients who underwent post-operative radiotherapy following radical cystoprostatectomy with orthotopic ileal neobladder reconstruction. Methods: The USC bladder cancer database was queried for all patients who underwent cystoprostatectomy and neobladder reconstruction followed by adjuvant radiation therapy related to their bladder cancer. The original patient charts and radiation therapy records were reviewed to determine the dose of radiation received by the neobladder. The patient charts were also reviewed to determine acute and late toxicity related to radiation. Results: From 1980 to 2013, 1,742 patients underwent radical cystoprostatectomy with orthotopic neobladder reconstruction. Of those 1,742 patients, 10 patients met the criteria of the study. The median age of the patients who received post-operative radiotherapy was 66.9 years. Forty percent of the study population received a dose of 50.4Gy, 50% received a dose of 45-46.8Gy and one patient, while prescribed a dose of 61.2Gy, only received 39.6Gy secondary to progression of disease on treatment that required termination of RT. All patients received 1.7-1.8Gy per fraction. The most common indications for radiotherapy were close or positive surgical margins. Two patients were treated with IMRT while the rest of the patients received 4 field or AP-PA beam arrangements. Of the patients that completed radiation, 3 had grade 2 or less CTCAE v4.0 acute GI toxicity; no patients reported acute GU toxicity. Two patients reported chronic grade 1 GU toxicity, likely related to their neobladders, with no reports of chronic GI toxicity. No patients experienced neobladder perforation, leak, or fistula. Conclusions: The use of moderate doses of pelvic radiotherapy (45-50.4Gy) was well tolerated among the 10 patients who had radiotherapy following cystoprostatectomy with orthotopic neobladder creation. This data supports the use of post-operative radiotherapy to moderate doses in this patient population when clinically indicated.
Association of prior treatment with anti-EGFR monoclonal antibodies with downregulation of circulating TRAIL and upregulation of EGFR and VEGF family ligands in metastatic colorectal cancer.
Authors: Michael Sangmin Lee, Christopher Hanyoung Lieu, Michael J. Overman, Cathy Eng, Jeffrey Morris, Zhi-Qin Jiang, Maria Morelli, John Heymach, Hai T. Tran, Scott Kopetz
Journal: Journal of Clinical Oncology (2014)

452 Background: Inhibition of growth factor receptor signaling leads to unintended compensatory pathway activation in preclinical models, which may impact the success of subsequent therapies. We hypothesized that increased circulating levels of receptor ligands after anti-EGFR monoclonal antibody (mAb) therapy, including VEGF ligands or EGFR family ligands, may provide insights into clinically relevant feedback mechanisms. Methods: Plasma was obtained from 96 metastatic colorectal cancer (mCRC) patients: 48 previously treated with anti-EGFR mAbs and 48 mCRC patients previously treated without prior anti-EGFR therapy who were matched for total months of prior chemotherapy and interval since last chemotherapy treatment. Plasma levels of circulating cytokines with emphasis on EGFR and VEGF ligands were determined using suspension bead multiplex assay (BioRad). Comparisons were done by the two-sided nonparametric Wilcoxon signed rank test. Multivariate linear regression analysis was done with forward selection at p&lt;0.1. Results: By Wilcoxon signed rank test, prior anti-EGFR mAb treatment was associated with differences in EGF (3.5-fold increase, p=0.0001), epiregulin (1.6-fold increase, p=0.02), and TGF-alpha (1.4-fold increase, p=0.04). There was no significant association with amphiregulin, betacellulin, or HB-EGF. Prior anti-EGFR mAb treatment was also associated with differences in TRAIL (1.4-fold decrease, p=0.001) and with differences in VEGF-C (1.4-fold increase, p=0.01), and FGF-basic (1.8-fold increase, p=0.02). After multivariate analysis, prior anti-EGFR mAb treatment remained significantly associated with differences in EGF (p=0.003), TRAIL (p=0.045), VEGF-C (p=0.02), and FGF-basic (p=0.02). Conclusions: Prior treatment with anti-EGFR mAbs is associated with an apparent compensatory increase in EGFR ligands and pro-angiogenic factors, and lower levels of the pro-apoptotic cytokine TRAIL. These differences in circulating growth factor receptor ligands may provide insights on resistance mechanisms and optimal treatment sequencing.
Induction docetaxel and S-1 followed by concomitant radiotherapy with low-dose daily cisplatin in locally advanced head and neck carcinoma.
Authors: S. Hong, B. Cho, S. Shin, M. Jung, M. Hong, Y. Lee, J. Kim
Journal: Journal of Clinical Oncology (2010)

e16020 Background: To assess the efficacy and safety of induction chemotherapy with docetaxel (40 mg/m2 d1) and S-1 (40 mg/m2 bid d1-14) (DS), and radiotherapy with concurrent daily cisplatin (6 mg/m2) (PX) in locally advanced head and neck carcinoma (LAHNC). Methods: Twenty-five patients with LAHNC [stage III or IV (M0)] arising from the oral cavity, larynx, oropharynx, or hypopharynx received two cycles of induction chemotherapy with DS, followed by seven cycles of PX. Results: All patients had stage IV. The most common site of the primary tumor was the oropharynx (56%). Twenty- one (84%) of 25 eligible patients completed DS. The most frequent grade 3-4 hematologic toxicity was neutropenia (20%). The median relative dose intensity (RDI) of docetaxel and S-1 was 1.0 (range, 0.94-1.0) and 1.0 (range, 0.34≂f1.0), respectively. Twenty of 21 patients who completed DS started PX, all within 3 to 4 weeks after the start of the second cycle of DS. The most common grade 3 nonhematologic toxicity of PX was mucositis (35%). Nineteen of 20 patients received full doses of cisplatin (95% compliance). Best response to DS and following completion of PX was partial response in 84% and complete response in 80%, respectively. With a median follow-up of 15 months, 2-year progression- free survival and overall survival was 75.6% and 69.6%, respectively. Conclusions: Administration of DS before PX chemoradiotherapy resulted in high response rate with good tolerability, and did not compromise subsequent chemoradiotherapy. Sequential treatment approach using this induction regimen and PX chemoradiotherapy was feasible and efficacious. No significant financial relationships to disclose.
Antigenic Heterogeneity of Human Colorectal Cancer Cell Lines Analyzed by a Panel of Monoclonal Antibodies. I. Heterogeneous Expression of la-Like and HLA-Like Antigenic Determinants&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: G D MacLean, J Seehafer, A R Shaw, M W Kieran, B M Longenecker
Journal: JNCI Journal of the National Cancer Institute (1982)

The pattern of reactivity of 10 monoclonal antibodies (MCA) developed against human lymphoid leukemia cells and tested with human T-cells, B-cells, as well T-lymphoma and B-lymphoma cell lines suggested that six of them detect la-like determinants, three detect HLA-like determinants, and the remaining one detects a non-Ia B-cell antigen. With the use of three binding assays, the six MCA that appeared to detect Ia-like determinants reacted strongly with the human colorectal cancer cell (CCC) line LoVo, and none of the three MCA that reacted with HLA-like determinants reacted with this cell line. Immunoprecipitation and polyacrylamide gel electrophoresis analysis confirmed the apparent specificities of the MCA for Ia-like and HLA molecules, demonstrated the presence of Ia-like molecules in LoVo, and failed to detect HLA in these cells. The cellular enzyme-linked immunosorbent assay was used for the testing of our anti-Ia and anti-HLA MCA with 15 other CCC lines. Marked heterogeneity was found in the expression of different Ia-like and HLA determinants defined by different or overlapping subsets of MCA, which suggested that these determinants might be present on different molecules or that different conformations of the same molecules exist in various CCC lines. Analysis of the surface phenotype of subclones of LoVo cells revealed the presence of stable variant cell subpopulations, which lost reactivity with four out of six of the anti-Ia-like MCA but retained at least one Ia-like molecule recognized by two of our MCA. All of the subclones maintained the HLA-negative phenotype. The possible immunologic and diagnostic consequences of the presence or absence of Ia-like or HLA markers on nonlymphoid tumor cells are discussed.
Microarray gene expression analysis of cells isolated from malignant pleural effusions (MPE) from patients with non-small cell lung cancer (NSCLC)
Authors: B. J. Park, S. Bhattacharya, C. Azzoli, V. Rusch, M. Kris, R. Ghossein
Journal: Journal of Clinical Oncology (2004)

7369 Background: Many patients with advanced NSCLC are diagnosed via needle biopsy, providing little tissue for molecular profiling of their cancer. MPE may offer an easily accessible source of cancer cells in these patients. Methods: We collected pleural fluid from 14 patients with advanced NSCLC and MPE. Cells were isolated and treated as follows: 1) total RNA extraction (n=6); 2) positive selection of malignant cells using immunomagnetic beads coated with Ber-EP4 antibody followed by total RNA extraction (n=5); 3) both immunobead and non-immunobead methods (n=3). Cytologic examination was performed in all cases. RNA quality and quantity were assessed using the Agilent 2100 bioanalyzer system (Agilent Technologies, Palo Alto, CA). Cases with RNA suitable for gene expression analysis were assayed using oligonucleotide-based microarray (Affimetrix chips U133A and B). Results: All patients in the study had carcinoma cells by cytology, except one. The MPEs in 3 of 14 patients (21%) yielded RNA suitable for microarray analysis, including the patient whose MPE was cytologically negative for cancer. The presence of good quality RNA did not appear to correlate with specimen cellularity, the percentage of tumor cells versus other types of cells seen on cytologic examination, the time interval between collection and extraction, or whether or not immunobead separation was performed. Two cases that were cytologically positive for cancer had a much higher level of Mucin 5b (a specific tracheobronchial mucin) gene expression than the patient with cytologically negative MPE. Conclusion: RNA of sufficient quality for gene microarray expression analysis can be obtained from cells in MPE using a variety of techniques. More studies are required to determine whether the RNA signal obtained is cancer-specific. No significant financial relationships to disclose.
Intravenous Iron in Oncology
Authors: Michael Auerbach, Harold Ballard
Journal: Journal of the National Comprehensive Cancer Network (2008)

Intravenous iron (IV Fe) as an adjunct to therapy with erythropoiesis-stimulatory agents (ESAs) is standard care in dialysis-associated anemia, adding huge increments in hemoglobin and hematopoietic responses and decreased transfusions without significant toxicity. Cost savings, decreased exposure to ESAs, and decreased times to reach target hemoglobins are realized. Although similar benefits have been seen in all studies performed in patients with chemotherapy-induced anemia (CIA), experts are reluctant to incorporate routine use of IV Fe into treatment, largely because of misinterpretation and misunderstanding of the clinical nature of adverse events reportedly associated with its administration. IV Fe is therefore underused in oncology patients with anemia. Published experience with more than 1000 patients in clinical trials involving the use of IV Fe suggests minimal toxicity and substantial benefit are experienced when high molecular weight iron dextran is avoided. This article presents evidence recommending routine incorporation of IV Fe into treatment for CIA.
A novel histopathological evaluation method for predicting the outcome of non-small cell lung cancer treated by neoadjuvant therapy
Authors: Y. Yamane, G. Ishii, K. Goto, M. Kojima, M. Nakao, Y. Shimada, Y. Nishiwaki, K. Nagai, A. Ochiai
Journal: Journal of Clinical Oncology (2009)

e11574 Background: Chemotherapy, chemoradiotherapy, or radiotherapy is sometimes used to treat non-small cell lung cancer (NSCLC) before surgical resection (neoadjuvant therapy). However, no histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy has been fully assessed. The purpose of this study was to assess a novel histopathological evaluation method for predicting the outcome of NSCLC patients who received neoadjuvant therapy followed by surgical resection. Methods: We reviewed the histopathology of the tumors of 61 NSCLC patients who received neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy and identified the histological features produced by neoadjuvant therapy by comparing them with the histopathological features of the tumors in 138 NSCLC cases treated by surgery without neoadjuvant therapy. We also measured the area of residual tumor (ART) on the maximum cut surface of the tumors and analyzed the relationships between the histological features, ART, and the outcome. Results: The proportions of cases with the histological features “cholesterin clefts,” “foreign body reactive giant cells,” “stromal hyalinosis,” and “cancer cells more than 50% of which contained a bizarre nucleus” were significantly higher in the neoadjuvant therapy group than in the surgery alone group. However, the presence of none of these features except “stromal hyalinosis” had any significant effect on survival in the neoadjuvant therapy group. Although pathological T factor (ypT) and N factor (ypN) had no significant effect on overall survival, smaller ART (≤400 mm 2 ) and absence of pleural invasion (p(-)) were predictors of a outcome (p=0.004 and p=0.001, respectively). Conclusions: Smaller ART (≤400 mm 2 ) and p(-) predict a better outcome of NSCLC in patients who receive neoadjuvant therapy. We concluded that ART is a novel histopathological parameter for predicting the outcome of NSCLC patients who receive neoadjuvant therapy followed by surgical resection. No significant financial relationships to disclose.
Abstract #5486: Antigen displaying fluoromagnetic particles for drug assay in serum
Authors: Manuel Ruidiaz, Ana Sanchez, Thomas Kipps, Andrew Kummel, Bradley Messmer
Journal: Cancer Research (2009)

Background: Monoclonal antibodies are increasingly used in the treatment of cancer and other proliferative diseases. Currently, the dosage is calculated by body mass without taking into account the actual tumor load. It is proposed that antibody levels during treatment is indicative of tumor load. Therefore, in the case of high tumor load, insufficient dosage may be given resulting in reduced effectiveness of the drug and increased probability of the tumor becoming resistant to the treatment. Conversely, for low tumor load, an overdose of the drug may occur which could result in decreased patient health. An assay system has been developed to rapidly determine the concentration of antibody present in plasma specimens with high sensitivity. Two monoclonal antibodies, alemtuzumab (anti-CD52) and rituximab (anti-CD20), were used as a model. Both are currently used commonly in patients with chronic lymphocytic leukemia (CLL). Methods: Alemtuzumab and rituximab antigen peptides, as determined by phage display, were synthesized on TentaGel resin beads using conventional solid phase peptide synthesis techniques. Post-synthesized beads were modified in two ways. First, beads were integrated with magnetic nanoparticles to allow easier manipulation and washing of beads during the incubation process. Second, beads were integrated with fluorescence polystyrene nanoparticles to allow for multiplex measurements. Antigen displaying fluoromagnetic particles were incubated with serum samples of interest which allowed free antibody to bind to the bead. After washing, the beads were incubated with a fluorescently tagged secondary antibody for measurement by flow or image cytometry. Results: Multiplex measurements within a single sample were performed with control beads having known concentrations of antibody drug. Analysis of bead fluorescence data allows detection down to 0.5ug/ml of serum antibody drug concentration. Conclusion: The ability to accurately determine the concentration of antibody drug allows accurate dosing that is dependent on the intrinsic cancer load of the patient. This has the potential to increase the overall therapeutic efficacy of the drug while minimizing negative secondary effects that are associated with overdosage. The fluoromagnetic properties of the beads also allows for easier integration into automated measurement systems. Currently, an automated analysis system for multiplex analysis of antibody drug treatment is being developed.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5486.
Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial
Authors: Christina S. Polyak, Krista Yuhas, Benson Singa, Monica Khaemba, Judd Walson, Barbra A. Richardson, Grace John-Stewart
Journal: PLoS Medicine (2016)

Background Cotrimoxazole (CTX) prophylaxis is recommended by the World Health Organization (WHO) for HIV-1-infected individuals in settings with high infectious disease prevalence. The WHO 2006 guidelines were developed prior to the scale-up of antiretroviral therapy (ART). The threshold for CTX discontinuation following ART is undefined in resource-limited settings. Methods and Findings Between 1 February 2012 and 30 September 2013, we conducted an unblinded non-inferiority randomized controlled trial of CTX prophylaxis cessation versus continuation among HIV-1-infected adults on ART for ≥18 mo with CD4 count > 350 cells/mm3 in a malaria-endemic region in Kenya. Participants were randomized and followed up at 3-mo intervals for 12 mo. The primary endpoint was a composite of morbidity (malaria, pneumonia, and diarrhea) and mortality. Incidence rate ratios (IRRs) were estimated using Poisson regression. Among 538 ART-treated adults screened, 500 were enrolled and randomized, 250 per arm. Median age was 40 y, 361 (72%) were women, and 442 (88%) reported insecticide-treated bednet use. Combined morbidity/mortality was significantly higher in the CTX discontinuation arm (IRR = 2.27, 95% CI 1.52–3.38; p < 0.001), driven by malaria morbidity. There were 34 cases of malaria, with 33 in the CTX discontinuation arm (IRR = 33.02, 95% CI 4.52–241.02; p = 0.001). Diarrhea and pneumonia rates did not differ significantly between arms (IRR = 1.36, 95% CI 0.82–2.27, and IRR = 1.43, 95% CI 0.54–3.75, respectively). Study limitations include a lack of placebo and a lower incidence of morbidity events than expected. Conclusions CTX discontinuation among ART-treated, immune-reconstituted adults in a malaria-endemic region resulted in increased incidence of malaria but not pneumonia or diarrhea. Malaria endemicity may be the most relevant factor to consider in the decision to stop CTX after ART-induced immune reconstitution in regions with high infectious disease prevalence. These data support the 2014 WHO CTX guidelines. Trial registration ClinicalTrials.gov NCT01425073
Evaluation of the QuantiFERON-TB Gold in tube cut-off for diagnosing tuberculosis in HIV-infected and non-HIV infected individuals
Authors: Line Lindebo Holm, Martine G. Aabye, Pernille Ravn, Morten Ruhwald
Journal: European Respiratory Journal (2012)

Background

The QuantiFERON-TB Gold In tube (QFT) is used for diagnosing tuberculosis (TB) infection. But the test has compromised sensitivity in HIV infected patients. This study assesses if the diagnostic accuracy of the QFT test can be improved by adjustment of the cut-off for a positive test in HIV-positive individuals.

Materials and methods:

This case-control study pools data from three cohorts from Tanzania and Denmark. Cases were 72 HIV-positive and 94 HIV-negative Tanzanian patients with confirmed TB. The control-groups comprised 389 HIV-positive patients and 305 healthy Danish high-school students with no known risk factors for TB. Potential cut-offs were determined by ROC curve analysis.

Results

HIV infected TB patients had lower responses to M.tuberculosis antigens compared to non-HIV infected TB patients, median 0.9IU/ml (IQR 0.1-0.9) vs. 1.5IU/ml (IQR 0.6-1.5) (p<0.04). In the groups of HIV non-infected; ROC curve analysis suggested that by reducing the cut-off from 0.35 to 0.135 IU/ml sensitivity could be increased from 79.8% (CI: 70.3-87.4) to 87.2% (CI: 78.8-93.2) without a major loss of specificity (specificity= 98.0% (CI: 95.8-99.3)). We were not able to demonstrate a similar effect among the HIV-infected as the increase in sensitivity occurred at a high compromise in specificity (from 98.1 to 94.3%).

Conclusion

In line with previous studies the QFT had poor sensitivity in HIV-infected. The diagnostic sensitivity improved in both HIV-negative and -positive by lowering the cut-off, but specificity was significantly compromised in HIV-positive non-exposed Danish controls compromising the benefit of this approach to improve the QFT test.