tbuckley/cabot-search huggingface dataset:
A prospective blinded study of microsatellite instability (MSI) as a marker of overall survival (OS) in the adjuvant treatment of colorectal cancer (CRC) patients
Authors: S. Popat, H. Pan, Y. Shao, D. Zhao, Z. Chen, R. S. Houlston
Journal: Journal of Clinical Oncology (2005)

9544 Background: A number of studies have investigated the relationship between MSI and CRC OS. However, results have been inconsistent. This may have been influenced by design issues; specifically, underpowered datasets, retrospective analyses, potential patient selection, and non-blinded investigators. We investigated MSI as a marker of OS in the context of a multi-center randomized phase III trial of 10,000 CRC patients randomized to receive adjuvant portal fluorouracil infusion. Results were pooled with published work from adjuvant clinical trials. Methods: A random subset of 1,000 tissue blocks were centrally collected and anonymized. Tissue was microdissected and MSI status determined by genotyping BAT26 prospective to patient follow-up. Laboratory analyses were performed blinded to all clinical data. OS data was pooled with that from studies investigating MSI status in adjuvant clinical trials by standard meta-analysis techniques. Results: Efficacy data from the clinical trial has yet to report. 543 samples have been genotyped to date. 15% of tumors are MSI+. Median follow-up was 55 months. CRCs with MSI tended to have a better OS (HR=0.77, 95% CI:0.48–1.24). This was more pronounced for colonic tumors (HR=0.60, 95% CI:0.30–1.19; rectal tumors HR=1.12, 95% CI:0.58–2.13). Pooling our results with OS data from 3 adjuvant trials (n=1,684, MSI= 326) confirmed a significant survival advantage for MSI+ tumors (HR=0.76, 95% CI:0.61–0.94, phet=0.84, I2=0%). Conclusions: MSI is a marker for improved OS in stage II/III CRC. Additional prospective studies are required to define the role of adjuvant chemotherapy in these tumors. No significant financial relationships to disclose.
A longitudinal study of exhaled nitric oxide in children – What explains intersubject variability of measurements?
Authors: Rebecca Cutts, Steve Turner
Journal: European Respiratory Journal (2011)

Introduction: Exhaled nitric oxide (FENO) may be a biomarker for asthma but clinical trials where FENO is used to guide asthma treatment have been disappointing. Exhaled NO measurements may not be suited to individuals with increased variability of values. We hypothesised that the variability of FENO measurements is heterogeneous within a population and sought to describe factors associated with increased variability for repeated measurements of FENO.

Methods: Children with and without asthma were recruited from the community and completed respiratory questionnaires. A subset of the cohort attended an initial phenotyping assessment which included spirometry, bronchodilator response and skin prick reactivity. Exhaled NO was measured every two months over a 12 month period. The coefficient of variation (CV) for FENO measurements was calculated for each individual.

Results: One hundred and eighty children were recruited including 49 with asthma and 893 FENO measurements were made (median 5 measurements per child). Eighty two children attended the clinical assessment. The following were not associated with altered CV: asthma, eczema or hayfever; male gender; body mass index; skin prick reactivity; spirometry; bronchodilator response; exposure to pets, smokers or damp at home. There was an inverse relationship between age and FENO CV (rho= -0.16, p=0.038). Among the asthmatic children, there was no correlation between FENO CV and treatment step or dose of inhaled steroid.

Conclusions: Measurements of FENO are variable between individuals. Younger age, but not atopy, asthma status or treatment, is associated with increased variability in FENO over 12 months.
Three, two, or one drug chemotherapy for frail or elderly patients with advanced gastroesophageal cancer (321GO): A feasibility study.
Authors: Peter S. Hall, Simon Lord, Michelle Collinson, Helen Marshall, Marc Jones, Catherine Olivier, Helen Howard, Jenny Seligman, Daniel Swinson, Rajarshi Roy, Jo Dent, Sue Cheeseman, Kim William Last, Matthew T. Seymour
Journal: Journal of Clinical Oncology (2012)

97 Background: The median age of death from gastroesophageal (GO) cancer is 77 years. Palliative chemotherapy can improve survival and quality of life. Current standard combination regimens have been developed in trials involving patients of median age under 65 years with predominantly good performance status (PS). In light of audit and survey evidence of widespread use of arbitrarily modified chemotherapy schedules in frail and elderly patients, better evidence is needed to guide treatment. Based on our experience with the MRC FOCUS trial in colorectal cancer, 321GO aimed to test the feasibility of a randomised trial comparing chemotherapy in frail and elderly patients with advanced GO cancer. Methods: Patients with advanced GO cancer considered unfit for full-dose 3-drug chemotherapy, were randomly allocated (1:1:1) to 3, 2 or 1 drug chemotherapy at 80% dose of standard regimens with EOX: epirubicin 40mg/m 2 d1, oxaliplatin 104mg/m 2 d1, capecitabine 500mg/m 2 bd x21d, OX: oxaliplatin 104mg/m 2 d1, capecitabine 500mg/m 2 bd x21d or X: capecitabine 1000mg/m 2 bd d1-14, then 7 day rest. The primary endpoint for feasibility required 45 patients to be recruited over 18 months. Secondary endpoints included tolerability, treatment benefit and compliance with detailed health and quality of life (QoL) assessment. Results: 55 patients were recruited over an average of 18 months for each of the six recruiting centres; 17 to EOX, 19 to OX and 18 to X. The median age was 75. 37 (66%) patients were of WHO PS 0 or 1 and 18 (33%) were of PS 2. After 6-weeks, 12 (71%), 9 (47%) and 9 (50%) patients in the EOX, OX and X arms had experienced a treatment delay, dose reduction, grade 3 toxicity or stopped treatment. Treatment benefit (no radiological progression or clinical deterioration) at 12 weeks was seen in 8 (47%), 11 (58%) and 3 (16%) patients for EOX, OX and X respectively. Compliance with baseline health and QoL assessment was 98% at baseline and 69% at 12 weeks. Conclusions: A phase III trial randomising frail or elderly patients with advanced GO cancer to alternative chemotherapy regimens is feasible. EOX was associated with greater toxicity compared with OX; X offered no improvement in tolerability over OX.
The prognostic significance of p53, p27kip, p21waf1, Her-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study
Authors: M. S. Al-Moundhri, B. Al-Bahrani, V. Nirmala, I. Al-Hadabi, K. Al-Mawaly, I. Burney, M. Al-Nabhani, V. Thomas, S. S. Ganguly, C. Grant
Journal: Journal of Clinical Oncology (2005)

4052 Background: The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge this is the first study from an Arab population reporting on the relationship of p53, p27kip, p21waf1, Her-2/neu, and Ki67 expression and clinicopathological parameters and their prognostic significance. Methods: Formalin fixed paraffin embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27kip, p21waf1, Her-2/neu, and Ki67. The results were correlated with clinicopathological parameters and survival. Results: M: F 80:41; median age 60 years; stage III and IV =71%; and median follow up 34.4 months. Positive expression rates of p53 (nuclear staining (NS)>10%), p27kip (NS>10%), p21waf1 (NS>10%), Ki67 (NS >25%)and Her-2/neu (membranous staining +3) were 54%, 40%, 8.3%, 70%, and 12% respectively. Using Chi square test, p53 expression correlated with age <60 years (p=0.03), tumor size >5cm (p=0.02), p27kip and Ki67 expression (p=0.001), and Her-2/neu (p=0.04). P21waf-1 correlated inversely with T stage (p=0.03). Univariate analysis (long rank test) showed that p53 overexpression (p=0.01), fungating and infiltrative macroscopic appearance (p=0.02), size >5 cm (p=0.0001), lymph node metastasis (p=0.0001), p T3 and T4 disease (p=0.01), overall stage III and IV (p=0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (-)/p27 (-)(p=0.08), p53 (+)/p27 (-)(p=0.03), and p53 (+)/p27 (+) (p=0.007) profiles. On multivariate analysis by Cox regression model, the expression of p53 (p = 0.03) and lymph node involvement (p = 0.01) were significant adverse prognostic factors for overall survival. Conclusion: The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 is of added prognostic value. No significant financial relationships to disclose.
Short-course hormonal therapy and the risk of death from prostate cancer in men with intermediate-risk prostate cancer undergoing high-dose radiation therapy.
Authors: Florence K. Keane, Ming-Hui Chen, Danjie Zhang, Brian Joseph Moran, Michelle H. Braccioforte, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2015)

27 Background: We assessed the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable and favorable intermediate-risk prostate cancer (PC) who received dose-escalated radiotherapy (RT) with or without short-course androgen deprivation therapy (ADT). Methods: The cohort consisted of 2,668 men with intermediate-risk PC (71.3% favorable, 28.7% unfavorable) who were treated with dose-escalated RT with or without ADT (median 4 mos.) from 1997 - 2013. Fine and Gray's competing risks regression was used to assess whether ADT decreased PCSM-risk in an adjusted multivariable model (Table). An interaction term was included to assess for potential differences in the impact of ADT on PCSM risk in men with favorable versus unfavorable intermediate-risk PC. Results: After a median follow-up of 7.84 years, there were 393 deaths (14.73%), of which 33 were from PC (8.40%). There was significant reduction in PCSM-risk in men with unfavorable intermediate-risk PC who received ADT (AHR 0.39, 95% CI 0.16 to 0.92, P=0.033), but no significant difference in PCSM-risk in men with favorable intermediate-risk PC who received ADT (AHR 0.68, 95% CI 0.19 to 2.49, P=0.561). Conclusions: While ADT reduced PCSM-risk in men with unfavorable intermediate-risk PC, there was no significant improvement in men with favorable intermediate-risk PC, suggesting that for these patients ADT in addition to dose-escalated RT may not be required to minimize PCSM-risk. [Table: see text]
Patients with Mature T-Cell Lymphoma Show High Relapse Rates after High Dose Therapy and Autologous Stem Cell Transplantation
Authors: Maike Nickelsen, Carmen Canals, Norbert Schmitz, Charalampia Kyriakou, Monika Engelhardt, Thomas Relander, Werner Linkesch, Vladimir Koza, Giovanna Meloni, Armando Lopez-Guillermo, Karel Indrac, Dolores Caballero, Hannes Wandt, Niklas Theorin, Bertram Glass, Anna Sureda
Journal: Blood (2008)
A phase I study of FOLFOX administered with flavopiridol (F) in patients with refractory solid tumors
Authors: M. A. Dickson, R. D. Carvajal, M. A. Shah, L. M. Cane, H. J. Dials, G. K. Schwartz
Journal: Journal of Clinical Oncology (2008)

3569 Background: F, a cyclin-dependent kinase inhibitor, shows promising solid tumor activity when combined with CPT-11 (Shah et al, CCR 2005) and docetaxel (Fornier et al, CCR 2007). Preclinical data indicate that F enhances oxaliplatin (OX)-and 5FU-induced apoptosis. Methods: We conducted a phase I trial of FOLFOX + F every two weeks in patients with refractory solid tumors. F was administered with OX but before 5FU based on sequence dependent growth inhibition. Dose escalation of 5FU and OX was initially performed with F fixed at 40 mg/m2. 5FU was then de-escalated to allow dose escalation of F. F pharmacokinetics were determined. Results: 40 patients were enrolled. Patient characteristics: median age 54 (range 20–77), KPS 90 (80–90), prior regimens 3 (0–10). 11 pts received prior OX. Tumor types included colon, pancreas, gastric, germ cell, ampullary, rectal, breast, anal, head & neck, and renal. With F 40 mg/m2 over 1 hr and dose escalation of 5FU and OX, the maximum tolerated dose (MTD) was F 40mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus and 2400mg/m2 over 48h. Dose-limiting toxicities (DLT) were nausea, vomiting, hyponatremia and neutropenia. With 5FU de-escalation and F dose escalation, the MTD was F 80mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU: 400mg/m2 bolus and 1,800mg/m2 over 48h. DLTs were diarrhea, nausea and vomiting. Clinical activity was noted in patients with platinum-refractory metastatic germ cell tumors. This included 1 PR (4.7 months) and 1 MR (9.1m). A third patient who had prior OX had a decline in AFP but discontinued therapy due to OX hypersensitivity. PRs were also observed in pancreas (7.9m), gastric (6.4m) and ampullary carcinoma (7.7m). F PK was noted to have significant interpatient variability. However, F Cmax increased with dose (1.95μM ± 0.56 at 70–80mg/m2 vs 1.23μM ± 0.56 at 40mg/m2, p=0.002). At the MTD, DLT was associated with higher F Cmax (2.26μM ± 0.03 vs 1.45μM ± 0.44 for other patients in the cohort, p=0.07). Conclusions: The recommended phase II dose (one level below MTD) is F 70mg/m2 with OX 85mg/m2, LV 400mg/m2, 5FU 400mg/m2 bolus and 1,800mg/m2 over 48h. This regimen shows promising clinical activity especially in platinum- refractory germ cell tumors. (Supported by NCI R01CA67819) No significant financial relationships to disclose.
Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy
Authors: Frédéric Amant, Tineke Vandenbroucke, Magali Verheecke, Monica Fumagalli, Michael J. Halaska, Ingrid Boere, Sileny Han, Mina Mhallem Gziri, Fedro Peccatori, Lukas Rob, Christianne Lok, Petronella Witteveen, Jens-Uwe Voigt, Gunnar Naulaers, Lore Vallaeys, Frank Van den Heuvel, Lieven Lagae, Luc Mertens, Laurence Claes, Kristel Van Calsteren
Journal: New England Journal of Medicine (2015)

Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking.In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months.A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings.Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).
Phase I/II study of docetaxel and atrasentan in men with metastatic hormone-refractory prostate cancer (HRPC)
Authors: C. N. Moore, P. Creel, W. P. Petros, T. Torain, S. Yenser, J. Gockerman, H. Hurwitz, A. Garcia Turner, D. J. Sleep, D. J. George
Journal: Journal of Clinical Oncology (2006)

14504 Background: Docetaxel is first-line standard treatment for metastatic HRPC. New combinations with targeted therapies may improve clinical responses. . Atrasentan is an endothelin receptor A (ET A ) inhibitor with an IC 50 in the pM range. Clinical studies suggest atrasentan delays time to disease progression, bone turnover markers and PSA kinetics. Methods: We conducted a Phase I/II trial of docetaxel and atrasentan to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and treatment response of this regimen. Patients were treated with docetaxel IV every 3 weeks at doses ranging from 60 to 75 mg/m 2 . Atrasentan was given orally at 10 mg daily starting on Day 3 and continuously thereafter. Initially, we defined DLT as grade IV neutropenia, but subsequently amended the protocol to redefine DLT as grade IV neutropenia lasting ≥ 7 days. Plasma PK evaluations were conducted for each drug when administered alone (Cycle 1 Day 1, 21) and together (Cycle 2 Day 1). Serial samples were evaluated by LC-MS and data were modeled using a standard, two-stage approach. Results: 18 patients were enrolled over 3 dose levels (9 at 60 mg/m 2 ; 6 at 70 mg/m 2 and 3 at 75 mg/m 2 ) in the phase I portion and to date 9 more patients have been enrolled in a dose expansion cohort at a docetaxel dose of 70 mg/m 2 . Patient demographics include median age 69, PSA level 87.3 ng/ml, hemoglobin 12.7 g/dl, and KPS 90%. DLT, initially any grade IV neutropenia, was seen at every dose level, however no grade IV neutropenia has lasted ≥ 7 days and no MTD has been defined to date. Drug-related grade III/IV toxicities included only neutropenia (42%); grade I-II toxicities included fatigue, peripheral edema, and nausea. To date, 5 of 15 evaluable patients who have been treated with 70–75 mg/m 2 of docetaxel and 10 mg of atrasentan demonstrate a sustained PSA response. Preliminary PK data in 11 patients show a mean docetaxel terminal half-life of 46 hr and systemic clearance of 55 L/hr. The median difference in systemic clearance between the cycles was 18% with values increasing in 67% of subjects. Conclusions: The combination of docetaxel and atrasentan appears to be well tolerated to date. The study is ongoing to more accurately determine safety, response and potential pharmacokinetic interactions. [Table: see text]
Results of a phase I/II clinical trial with OncoVEX<sup>GM-CSF</sup>, a second generation oncolytic herpes simplex virus
Authors: R. S. Coffin, J. C. Hu, C. J. Davis, N. D. James, C. Love, A. Michael, H. Pandha, J. Steiner, N. M. Steven, C. Coombes
Journal: Journal of Clinical Oncology (2005)

3099 OncoVEXGM-CSF is a second generation oncolytic HSV expressing GM-CSF. Deletion of ICP34.5 provides tumour selectivity. Oncolytic potency is increased using a clinical virus strain, and by expression of US11 as an IE rather than L gene. Immune stimulation is improved by deleting ICP47, and expression of GM-CSF. Following intra-tumoral injection, OncoVEXGM-CSF is, therefore, intended to stimulate a GM-CSF-enhanced immune response to tumour antigens released by oncolysis. A Phase I/II clinical trial in 26 evaluable patients enrolled with cutaneous or sub-cutaneous melanoma (8), breast (13), head and neck (3), and colon cancer (2) has now been completed. 9 patients were HSV sero -ve and 17 sero +ve. Patients received single doses of 106, 107 or 108 pfu/ml of OncoVEXGM-CSF, volume depending on tumour size, followed by a multi-dosing phase using a number of regimes. The most common side effects were transient grade I/II pyrexia/flu-like symptoms and injection site inflammation which were more marked and/or extensive at higher doses and in patients who were sero -ve at dosing, including one Grade III pyrexia. This led to the development of a tolerising regime of one 106 pfu/ml dose followed by two 108 pfu/ml doses ∼3 wks later. The only biochemical change was one transient Grade II transaminitis. Virus/DNA was detected transiently in the blood of 10 patients and at the injected site of 3 patients. Dose related GM-CSF expression was detected in injected tumours by RT-PCR and by ELISA at low levels in serum from some patients which was more evident following multiple doses. Tumour necrosis was evident clinically and/or by histology in biopsies taken ∼2 wks after the final dose in most patients which was in some cases considerable. Infiltration of T cells and macrophages was also observed. In two cases both injected tumours and tumours nearby flattened, and in some cases non-contiguous tumours became mildly inflamed. There was no obvious difference in the effects on the different tumour types. In conclusion, OncoVEXGM-CSF has been well tolerated and biological activity observed, including virus replication, tumour necrosis, and GM-CSF expression. Following this promising data, OncoVEXGM-CSF is now in Phase II development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BioVex Ltd. BioVex Ltd. BioVex Ltd.
The use of single-fraction radiation therapy in cutaneous T-cell lymphoma
Authors: A. M. Babbo, M. Chokshi, A. Rademaker, B. Mittal
Journal: Journal of Clinical Oncology (2009)

e19505 Background: Primary cutaneous lymphomas occur in 0.5 to 1 per 100,000 people every year in developed countries. Less than 1,000 cases of Mycosis Fungoides are diagnosed each year in the United States, with approximately 3 cases per 1,000,000 per year. Cutaneous T-cell lymphomas are responsive to radiation therapy, and local radiation therapy, total skin electron beam therapy, phototherapy (with UVB or PUVA), chemotherapy agents (nitrogen mustards, BCNU), retinoids, and steroids have all been used with varying degrees of success. Methods: This is a retrospective review of all cases of histology-proven cutaneous T-cell lymphoma treated with single-fraction radiation therapy at Northwestern Memorial Hospital in the Department of Radiation Oncology since 1990. We looked at response to treatment and local control. We reviewed the charts of 67 patients with cutaneous T-cell lymphoma, of which 40 patients and a total of 130 sites of disease received single-fraction radiation therapy and had available follow-up data. Results: Of the 130 lesions receiving a single-fraction of radiation, 86 (66%) received 800cGy in 1 fraction and 38 (29%) received 700cGy. 4 patients (3%) received 750cGy, 1 (&lt;1%) received 550cGy and 1 (&lt;1%) received 500cGy. Patients were treated with electron energies ranging from 6–18 MeV or photon energies ranging from 4–10 MV. Out of 130 lesions, 119 (92%) achieved a complete response (CR) to single-fraction radiation and 11 (8%) achieved a partial response (PR). There were 2 sites of relapse out of 130 treated sites, involving 2 patients. The median follow-up time was 4 months, mean follow-up time was 14 months, and 44% of patients had greater than 6 months of follow-up. Conclusions: This review of the experience at our institution since 1990 shows single-fraction radiation therapy to be an effective treatment for cutaneous T-cell lymphoma, with high response rates and very low relapse rates. No significant financial relationships to disclose.