tbuckley/cabot-search huggingface dataset:
Image-guided radiation therapy for functional bone marrow sparing in patients with pelvic malignancies.
Authors: L. K. Mell, Y. Liang, M. Bydder, G. Bydder, C. Hoh, G. White, J. Lawson, C. M. Yashar, A. J. Mundt
Journal: Journal of Clinical Oncology (2010)

e13570 Background: Hematologic toxicity (HT) is a significant problem in patients undergoing chemoradiotherapy (CRT) for pelvic malignancies. We tested the hypothesis that image-guided radiation therapy (IGRT) could reduce functional bone marrow (FBM) radiation dose, potentially reducing HT. Methods: We enrolled 10 patients with cervix (n=5) or anal (n=5) cancer onto a prospective IRB-approved protocol. Patients underwent CT simulation plus (1) whole body 18F-FDG-PET/CT and (2) quantitative MRI using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (MRI-IDEAL). Regions of high standardized uptake value (SUV) (increased glucose metabolism) on PET and low fat fraction (high cellularity) on MRI-IDEAL indicated higher FBM concentrations. The PET/CT and MRI-IDEAL were registered with the simulation CT, and FBM was automatically segmented based on the mean SUV and fat fraction within the pelvic bone. For each patient, 4 plans were compared: intensity modulated radiation therapy using pelvic bone as the sparing objective (IMRT), volumetric modulated arc therapy using pelvic bones as the sparing objective (VMAT), IMRT using FBM as the sparing objective (IG-IMRT), and VMAT using FBM as the sparing objective (IG-VMAT). Results: The mean FBM volume, as a proportion of pelvic bone, was 29.5% (s.d. 5.0%). IGRT plans (IG-IMRT or IG-VMAT) significantly reduced the volume of FBM receiving ≥ 10 Gy and ≥ 20 Gy (V10 and V20), which are key predictors of HT. The mean reductions in FBM V10 and V20 with IGRT compared to non-IGRT were 3.9% (p=.04) and 9.7% (p<.001), respectively. FBM sparing with IGRT was greater for cervical than anal cancer. No significant differences between IMRT and VMAT were observed. IGRT plans did not compromise target coverage or increase dose to other organs at risk. One cervix cancer patient was successfully treated with IG-IMRT, with FBM V10 and V20 of 86% and 70%, respectively. She received all 5 cycles of weekly cisplatin (40 mg/m2) and had grade 2 HT during CRT. Conclusions: IGRT for bone marrow sparing is clinically feasible and significantly reduces dose to FBM compared to standard IMRT. This novel technique may reduce HT and is being tested in a clinical trial. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GE Healthcare, Varian Medical Systems
Pharmacogenetic biomarkers for predisposition to toxicity to adjuvant FOLFOX/XELOX in colorectal cancer.
Authors: Pilar Garcia Alfonso, Andres J. Muñoz, Montse Blanco Codeisido, Daniel Lopez-Trabada Ataz, Lucia Cortejoso-Fernandez, Maria-Isabel Garcia-Garcia, Eva Gonzalez-Haba, Maria Sanjurjo-Saez, Miguel Martin, Luis A. Lopez-Fernandez
Journal: Journal of Clinical Oncology (2013)

390 Background: 5-fluorouracil and capecitabine are the gold standards in colorectal cancer (CRC) treatment and are often combined with oxaliplatin (FOLFOX and XELOX chemotherapy, respectively). Our purpose was to analyze associations between severe adverse reactions to these regimes and polymorphisms in genes related to these drugs Methods: Retrospective study with 47 adult CRC patients treated with adjuvant FOLFOX/XELOX. 20 polymorphisms in 14 genes were selected: 6 genes [XRCC1 (rs25487), ERCC2 (rs131181), ERCC1 (rs11615), GSTP1 (rs1695), EGFR (rs4559542) and GSTT1 (copy number variation)] related to the pharmacokinetics and dynamics of oxaliplatin and 8 related to fluoropyrimidines [MTHFR (rs1801131 and rs1801133), DPYD (rs2297595 and rs3918290), TYMS (rs34743033 and rs34489327), ABCB1 (rs1128503, rs2032582 and rs1045642), ABCC4 (rs4148551 and rs3742106), ABCC5 (rs3805114), CYP2A6 (rs3742106 ) and CDA (rs2072671)]. Linear by linear association chi-square test (SPSS v.18.0.) was used to study associations. A multivariate analysis including sex and performance status was also conducted. p&lt; 0.05 was considered significant. Results: Mean age was 62 (SD: 12) years and 78.7% male. Univariate analysis: statistically significant associations were obtained between rs11615 (ERCC1), neutropenia and hand-foot syndrome; rs3742106 (CYP2A6) and neutropenia; rs34743033 and rs34489327 (TYMS) and nausea/vomiting; and CNV of GSTT1 and neutropenia. Multivariate analysis: statistically significant associations were obtained between rs3742106 (CYP2A6) and neutropenia (GT vs. TT: OR, 0.042, 95% CI, 0004-0499, p = 0.012); rs2297595 (DPYD) and nausea/vomiting (GA vs AA: OR, 0.051, 95% CI, 0003-0772, p = 0.032); and rs11615 (ERCC1) and neutropenia (CC vs CT / TT: OR, 0.099, 95% CI, 0016-0615, p = 0.013) Conclusions: These results could help oncologists reduce adverse reactions associated to FOLFOX and XELOX chemotherapy by giving patients the best possible option, thus, improving their quality of life. Bigger cohorts are needed to verify the polymorphisms in ERCC1, CYP2A6, TYMS, DPYD and GSTT1 prior application in clinical practice.
EXPERT-C: A randomized, phase II European multicenter trial of neoadjuvant capecitabine plus oxaliplatin chemotherapy (CAPOX) and chemoradiation (CRT) with or without cetuximab followed by total mesorectal excision (TME) in patients with MRI-defined, high-risk rectal cancer.
Authors: A. Dewdney, J. Capdevila, B. Glimelius, A. Cervantes, D. M. Tait, G. Brown, A. Wotherspoon, D. Gonzalez de Castro, Y. J. Chua, R. Wong, Y. Barbachano, J. R. Oates, I. Chau, D. Cunningham
Journal: Journal of Clinical Oncology (2011)

3513 Background: This trial evaluates the addition of C to our previously described treatment strategy of neoadjuvant chemotherapy before CRT and TME in patients with MRI selected high-risk operable rectal adenocarcinoma (Chua et al 2010). Methods: Eligible patients were randomised to 4 cycles of CAPOX followed by CRT (with concurrent capecitabine), TME and 4 cycles of adjuvant CAPOX (CAPOX) or the same regimen with weekly C (CAPOX + C). The primary endpoint was complete response (pCR or radiological CR in those not having surgery) in the KRAS + BRAF wild type (wt) population. Secondary endpoints included radiological response (RR), PFS, OS, safety and QoL. Molecular analysis was performed for PIK3CA, PTEN loss, EGFR and NRAS. Results: Between 2005-2008, 164 patients were recruited from 15 centres. Molecular analysis was performed on 149 patients, 90 (60%) had KRAS + BRAF wt tumours (CAPOX n=44, CAPOX +C n=46). In 15 patients, insufficient tissue was available for analysis, 8 of whom achieved a pCR. In the wt population the RR was significantly improved with the addition of C to neoadjuvant chemotherapy (50% vs 70% p=0.038) and CRT (72% vs 89% p=0.028). There was no significant difference in CR (9% vs 11%) or pCR (7% vs 11%). PFS curves separated at 1 and 2 years in favour of C but 3 year PFS was 81% vs 80% HR 0.81 p=0.668. There was a significant improvement in 3 year OS with the addition of C (81% vs 96%; HR 0.27, p=0.035). In the all treated population there was no difference in any of the endpoints. Skin toxicity was increased with C during neoadjuvant chemotherapy and CRT and diarrhoea was increased during CRT. Conclusions: The addition of cetuximab in wt patients significantly improved RR and OS. The low pCR rate may be explained by the 8 patients with a pCR but insufficient tissue for molecular analysis, 6 of whom received cetuximab. The high overall survival demonstrated in both arms, in this selected poor risk group supports further evaluation of neoadjuvant chemotherapy in rectal cancer. The molecular analysis of PIK3CA, PTEN loss, EGFR and NRAS will be presented at the meeting.
Correlation between fatigue level and irradiated volume of the whole body, lung and heart in breast cancer patients receiving adjuvant radiotherapy after breast-conserving surgery
Authors: M. Rucinska, S. T. Langkjer
Journal: Journal of Clinical Oncology (2007)

19608 Background: Fatigue - an unpleasant, persistent, subjective sense of tiredness - is one of the most common symptoms experienced by cancer patients. It is multidimensional and is associated with both - malignancy itself and the anti-neoplastic treatment. The aim of the study was to assess the level of fatigue during and after adjuvant postoperative radiotherapy in breast cancer patients and evaluate its correlation with the irradiated volume of the whole body, lung and heart. Methods: 48 patients (age 33–76 years, mean 57 years) with early breast cancer after breast-conserving surgery were treated with adjuvant radiotherapy (48Gy/24fractions/5weeks; 12 patients received boost 10Gy/5fractions/1week to the tumor-bed). The patients′ subjective feeling of fatigue intensity was measured according to 10- score visual analog scale (VAS) before the start and weekly during radiotherapy, as well as 14 days and 3 months after radiotherapy. Results: Fatigue intensity increased gradually during radiotherapy (mean fatigue-VAS before and in the last week of treatment was 1.21 and 2.31 respectively; p=0.004). 14 days after the end of radiotherapy, the fatigue intensity was still higher than before treatment (1.88 and 1.21 respectively; p=0.04), but 3 months later, fatigue was lower than at the pretreatment level (n.s.). Irradiation of the large volume of the whole body was correlated with higher fatigue level during and after radiotherapy. If 15% or more of the unilateral lung volume received 20Gy, patients reported higher fatigue level than patients receiving 20Gy for less than 15% of the unilateral lung volume. There were no statistical differences in fatigue level between patients with different percentage of the heart volume receiving irradiation. Patients with boost did not manifest higher fatigue level. Conclusions: Fatigue increased over the course of radiotherapy, but 3 months after the end of therapy it was reduced to lower than at the preliminary level. There was a positive correlation between fatigue level during and after radiotherapy and the irradiated whole body and lung volume, but not heart volume. No significant financial relationships to disclose.
Renal Function Profile in White Kidney Donors: The First 4 Decades
Authors: Hassan N. Ibrahim, Robert N. Foley, Scott A. Reule, Richard Spong, Aleksandra Kukla, Naim Issa, Danielle M. Berglund, Gretchen K. Sieger, Arthur J. Matas
Journal: Journal of the American Society of Nephrology (2016)

Previous studies reported the risk of ESRD after kidney donation, but not the renal outcomes that precede ESRD. Here, we estimated the risk of proteinuria, reduced GFR, and ESRD in 3956 white kidney donors, assessed the contribution of postdonation hypertension and diabetes to these outcomes, and developed a risk calculator. After a mean±SD follow-up of 16.6±11.9 years, 215 (6.1%) donors developed proteinuria. Men had a higher risk of proteinuria (hazard ratio [HR], 1.56; 95% confidence interval [95% CI], 1.18 to 2.05; P &lt;0.001) as did those with higher body mass index (HR, 1.10; 95% CI, 1.06 to 1.13; P &lt;0.001). In all, 1410 (36%) donors reached an eGFR&lt;60 ml/min per 1.73 m 2 , and 112 (2.8%) donors had either an eGFR&lt;30 ml/min per 1.73 m 2 or ESRD (28 donors developed ESRD). An eGFR&lt;30 ml/min per 1.73 m 2 or ESRD associated with older age (HR, 1.07; 95% CI, 1.05 to 1.09; P &lt;0.001), higher body mass index (HR, 1.08; 95% CI, 1.04 to 1.13; P &lt;0.001), and higher systolic BP (HR, 1.02; 95% CI, 1.00 to 1.04; P =0.01) at donation. Postdonation diabetes and hypertension associated with a fourfold higher risk of proteinuria and a &gt;2-fold higher risk of ESRD. Models predicting proteinuria and reduced eGFR performed well (C-index 0.77–1.00). In conclusion, severe reduction in GFR and ESRD after kidney donation were uncommon and were highly associated with postdonation diabetes and hypertension. Furthermore, information available before donation may predict long-term renal outcomes in white living kidney donors.
A randomised phase II trial assessing the impact of the addition of gefitinib to the combination of radiotherapy and short-term maximal androgen blockage in high-risk localised prostate cancer: Safety evaluation
Authors: P. Thirion
Journal: Journal of Clinical Oncology (2006)

14613 Background: Given the in-vitro evidence of potential increase in tumour radiosensitisation and hormonal deprivation-related tumour growth inhibiting effect by the addition of EGFR inhibitors, a randomised unblinded phase II trial was initiated to evaluate the impact of the addition of gefitinib to a combination of radiotherapy (RT) and maximal androgen blockage (MAB) in patients (pts) with high-risk localised prostate cancer. Methods: Eligible pts had biopsy proven localised prostate carcinoma Gleason score ≥7 and/or cT3 stage and/or initial PSA ≥ 20; without nodal and distant metastases. All pts were treated by 8 months MAB using LH-RH agonist (Zoladex 3.6 mg/month) and peripheral anti-androgen (Casodex 50 mg/day), and localised Conformal RT (Prostate + Seminal Vesicles, 75.6 Gy/42 daily fractions), initiated after 4 months of MAB. Pts were randomised to receive or not gefitinib 250 mg/day concomitantly for 8 months. The planned accrual was 98 pts. The end-points were ASTRO defined PSA-relapse-free survival at 18 months and toxicity. A safety evaluation was performed mid 2005. Results: 20 pts (10 per arm) were included from 10/2003 to 02/2005. No significant difference in RT or MAB-related toxicity was seen between the 2 arms. The addition of gefitinib significantly increased the frequency and intensity of reversible skin toxicity events (Rash-CTC grade 3–4: 4 pts Vs O pts, p = 0.04), with a trend for reversible transaminase enzymes elevation (TEE) (CTC grade 3–4: 2 pts Vs 0 pts). No treatment interruption was reported in the control arm. In the experimental arm, 3 pts completed treatment, 3 pts had a temporary (&lt;10 days) gefitinib discontinuation (reversible asthenia and skin rash) and 4 pts had a permanent gefitinib discontinuation for reversible CTC grade 3 toxicity (skin rash: 2 pts, TEE: 2 pts). Conclusions: Gefitinib-related toxicity led to treatment discontinuation in 4 out of 10 patients. The trial is under review. This trial was supported by AstraZeneca. No significant financial relationships to disclose.
David Oliver: Senior nurses should stand up for nursing
Authors: David Oliver
Journal: BMJ (2016)

BerkshireIn my 27 years as an NHS hospital doctor, my admiration for nurses in hands-on clinical roles has only grown.Whether staff nurses, ward sisters, charge nurses, specialist practitioners, or consultants, they're dedicated, skilled, underpaid, and often undervalued.I can't muster such consistent respect for their senior managers.
A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer
Authors: K. L. Blackwell, E. H. Kaplan, S. X. Franco, P. K. Marcom, J. E. Maleski, M. J. Sorensen, M. S. Berger
Journal: Journal of Clinical Oncology (2004)

3006 Background: GW572016 is an oral, reversible and specific receptor tyrosine kinase inhibitor of both ErbB1 (EGFR) and ErbB2 (HER-2/neu). Signaling through these receptors regulates tumor cell proliferation and survival. Results of Phase I trials suggest activity of GW572016 in a number of tumor types including breast cancer. The primary objectives of this study are the assessment of safety and efficacy of monotherapy GW572016 at 1500 mg daily in women with trastuzumab-refractory metastatic breast cancer (MBC). Initially 1250 mg of GW572016 was utilized; the study was amended after 13 patients to administer 1500 mg daily. Methods: Eligible patients had ErbB2 overexpressing (IHC) MBC with disease progression following either 1 or 2 prior trastuzumab-containing regimens. Safety (NCI CTC criteria) and efficacy (RECIST criteria) assessments were performed by the attending physician on all patients at 4- and 8-week intervals on treatment. Results: As of Dec. 2003, 44 patients were enrolled. Preliminary efficacy results regarding the initial 36 patients include 3 partial responses (PR) (8+ weeks, 16+ weeks and 44 weeks) and 5 stable disease (SD) (range 12–36+ weeks). For 15 patients with preliminary safety data, adverse events (AEs) considered by investigators to be study drug related were all grades 1–2 except for one grade 3 rash. For these 15 patients, study drug related AEs that were observed in more than 1 patient were anorexia, nausea, rash, vomiting, diarrhea and weight loss. Conclusions: GW572016 1500 mg daily demonstrates preliminary evidence of efficacy in patients with ErbB2-overexpressing MBC refractory to trastuzumab-containing regimens. In the first 36 patients evaluated for efficacy, the clinical benefit rate (PR + SD) is 22%. GW572016 appears well tolerated in this population. Inhibition of both ErbB1 and ErbB2 with GW572016 represents a promising approach in the treatment of breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
The Rotterdam study: why fall in COPD?
Authors: Lies Lahousse, Vincentius J.A. Verlinden, M. Arfan Ikram, Guy G. Brusselle
Journal: European Respiratory Journal (2015)

We thank De and Bhuniya for their interesting comments on our study that investigated gait patterns in chronic obstructive pulmonary disease (COPD) [1]. We measured 30 gait parameters during normal walking, turning and tandem walking in 1500 persons (mean age 74 years), and summarised these parameters into seven independent gait domains. Importantly, only the gait domain Rhythm (reflecting how quickly steps are taken) was significantly impaired in persons with COPD [1, 2]. We fully support the call to investigate the causes of this disturbed Rhythm in COPD thoroughly and to elucidate why fallers with COPD exhibit especially worse Rhythm. Musculoskeletal pain may contribute to worse Rhythm in gait analysis of COPD patients <http://ow.ly/RWtMF>
III-IV line of target therapy in advanced renal cell carcinoma (RCC).
Authors: V. D. Ferrari, G. Fogazzi, F. Valcamonico, V. Amoroso, G. Procopio, D. Nonnis, L. Vassalli, P. Marpicati, S. Grisanti, E. Simoncini
Journal: Journal of Clinical Oncology (2010)

e15148 Background: Rapid development of treatment strategies for renal cell cancer (RCC) has occurred in recent years. The mammalian target of rapamycin (mTOR) and its molecular pathways are supposed to be activated frequently in RCC. mTOR inhibitors such as temsirolimus (CCI779) and everolimus (RAD001) are effective for suppressing cell growth. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. We describe our experience in the treatment of pts refractory to TKI therapy. Methods: From September 2008 to December 2009 we administered mTOR inhibitors to 23 pts as III line (10 pts) or IV line (13 pts) therapy for advanced RCC. Median age was 71 yrs (range 40–74). Gender was M/F in 11/12 pts. Histology included 1 squamous cell carcinoma and 22 clear cell carcinoma. Metastatic sites included liver (4 pts), brain (4 pts), pancreas (7 pts), bone (11 pts), nodes and lung (17 pts). We treated 6 pts with temsirolimus and 17 pts with everolimus. Results: We had no hematological toxicity; 3 pts experienced grade 2 asthenia, 2 pts had grade 2 skin reactions, 2 pts grade 2 diarrhea. 3 pts had cough, dyspnea, fever and stopped everolimus because chest x-rays was suggestive of interstitial pneumopathy. We did not found neurotoxicity. 2 pts reduced the dose of mTOR inhibitor for toxicity. We obtained disease control in 9 pts (39%). Best responses were PR in 3 (13%) pts and SD in 6 pts (26%). Median progression-free survival was 6 months (range 2-13.5). Conclusions: Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. In this study we observed that the treatment of advanced RCC in pts with good performance status is feasible, III or IV line target therapy could increase survival. In the future we could probably define a sequence of treatment to optimize therapy in advanced RCC. No significant financial relationships to disclose.
Quantitative evaluation of heterogeneities in treatment effects and baseline risks among hospitals from a phase III surgical trial of gastric cancer
Authors: Y. Kurokawa, T. Yamaguchi, K. Yoshimura, S. Yamamoto, K. Nakamura, M. Sasako, H. Fukuda
Journal: Journal of Clinical Oncology (2007)

6553 Background: Although the JCOG9501 phase III trial demonstrated that standard D2 plus extended lymphadenectomy (D3) could not improve the survival in cT2b-T4 gastric cancer (ASCO2006 Abs#LBA4015), it is important to examine the variation in the treatment effects for evaluating the generalizability, as written in international statistical guideline (ICH-E9). In addition, investigating the ranges of baseline risks among hospitals gives important information for the standardization of cancer treatment. Methods: Mixed effect models were applied to survival and surgical outcome data for 521 (D2: 263, D3: 258) gastric cancer patients from 23 Japanese hospitals, which were the leading institutions of gastric cancer surgery in Japan. After adjustment with 10 clinicopathological factors, the variation in the treatment effects and the baseline risks among hospitals were estimated. If heterogeneity was identified, we further estimated the Spearman’s correlation coefficients between the variation and hospital characteristics. Results: In the treatment effects, the ranges of the hazard ratio of overall survival (OS) and recurrence-free survival (RFS) for D3 compared with D2 were 1.05–1.48 and 1.03–1.77, respectively. The ranges of baseline risks for D2 were shown in Table . The correlation coefficients between hospital volume of gastrectomy and the heterogeneity in operation time, blood loss and postoperative complication were -0.31 (p=0.15), −0.40 (p=0.06), −0.52 (p=0.01), respectively. Any institutional characteristics showed little correlation with OS or RFS. Conclusions: The final result of JCOG9501 seemed to be generalizable to the target populations, although some degree of heterogeneity of treatment effects existed. The hospitals entered in this trial had some variation also in the baseline risks for D2. The heterogeneities of some surgical outcomes may be correlated with hospital volume of gastrectomy. No significant financial relationships to disclose. [Table: see text]