tbuckley/cabot-search huggingface dataset:
Frailty and sarcopenia: The potential role of an aged immune system
Authors: Daisy Wilson, Thomas Jackson, Elizabeth Sapey, Janet M. Lord
Journal: Ageing Research Reviews (2017)

Frailty is a common negative consequence of ageing. Sarcopenia, the syndrome of loss of muscle mass, quality and strength, is more common in older adults and has been considered a precursor syndrome or the physical manifestation of frailty. The pathophysiology of both syndromes is incompletely described with multiple causes, inter-relationships and complex pathways proposed. Age-associated changes to the immune system (both immunesenescence, the decline in immune function with ageing, and inflammageing, a state of chronic inflammation) have been suggested as contributors to sarcopenia and frailty but a direct causative role remains to be established. Frailty, sarcopenia and immunesenescence are commonly described in older adults but are not ubiquitous to ageing. There is evidence that all three conditions are reversible and all three appear to share common inflammatory drivers. It is unclear whether frailty, sarcopenia and immunesenescence are separate entities that co-occur due to coincidental or potentially confounding factors, or whether they are more intimately linked by the same underlying cellular mechanisms. This review explores these possibilities focusing on innate immunity, and in particular associations with neutrophil dysfunction, inflammation and known mechanisms described to date. Furthermore, we consider whether the age-related decline in immune cell function (such as neutrophil migration), increased inflammation and the dysregulation of the phosphoinositide 3-kinase (PI3K)-Akt pathway in neutrophils could contribute pathogenically to sarcopenia and frailty.
Changes in the patterns of care for small-cell-lung cancer (SCLC): Results of the 99–01 Patterns of Care Study (PCS) nationwide survey in Japan
Authors: T. Uno, M. Sumi, H. Kawakami, M. Nakamura, Y. Suzumoto, A. Kihara, H. Ikeda, T. Teshima
Journal: Journal of Clinical Oncology (2005)

6085 Background: Several key studies for SCLC preceded 2nd PCS nationwide survey in Japan. This study was undertaken to analyze the process of thoracic radiotherapy (TRT) and to evaluate changes in the patterns of care for SCLC. Methods: Between July 2002 and August 2004, the PCS conducted a second nationwide audit survey of care process for stage I-III SCLC patients treated with TRT between 1999–2001. PCS investigated; 1) patient background, 2) work-up studies, 3) process of RT, and 4) process of chemotherapy. Practice patterns of 99–01 PCS were compared with those of 95–97 PCS. Results: By using two-stage cluster sampling, the PCS expert team collected data for 139 eligible SCLC patients (men to women ratio, 5:1; median age, 69; age>70, 43%; KPS>70, 73%; stage III, 89%) from 73 institutions. Pre-treatment work-up study included chest CT in 96%, fiberoptic scope in 93%, brain CT or MRI in 86%, bone scinti in 79%. The median total dose of TRT was 5000 cGy. Twice-daily radiotherapy (BID) was used in 43%. The median field size of TRT was 12 cm x 14 cm. TRT port included ipsilateral hilus in 96%, ipsilateral mediastinum in 96%, contralateral mediastinum in 84%, and contralateral hilus in 17%. Field reduction during TRT course in 61%. The most predominantly used photon energy was 10 MV (77%), whereas obsolete technique using Co-60 or X-ray energy < 6MV comprised 12%. 3D-conformal therapy was used in 12%. Dose prescription was at an isodose line in 15%. CT-simulation was performed in 40%. Only 12 patients (9%) received prophylactic cranial irradiation (PCI). Ninety-two percent received systemic chemotherapy, of those, platinum based chemotherapy constituted 98%, and 73% were treated by concurrent chemoradiation (CCRT). Treatment by IRB-approved protocol was only 6 cases (4%). Compared with the previous 95–97 PCS, in the management of SCLC, significant increases in the use of CCRT (73% vs 37%, P<0.0001), BID-TRT (43% vs 19%, P<0.0001), and PCI (9% vs 2%, P=0.01) were observed, although the absolute number of patients receiving PCI was still extremely low. Conclusions: Evidence based CCRT and BID-TRT for SCLC had well penetrated into clinical practice, however, PCI has not yet widely accepted in Japan. No significant financial relationships to disclose.
Cervical screening reminder calls pilot: Utilizing EMRs to improve cancer screening.
Authors: Zabin Dhanji, Aaron Randall
Journal: Journal of Clinical Oncology (2016)

163 Background: Cancer screening detects pre-cancerous changes, or cancer at an early stage when there is a better chance of treating it successfully. Research shows that that physician encouragement improves the odds of patients getting screened. Furthermore, systematic reviews demonstrate that efforts to encourage screening can be more effective through telephone reminders when compared to other methods of outreach. Electronic Medical Records (EMRs) are a powerful tool for the coordination, recording, monitoring and reporting of patient care in primary care. In Ontario, 80% of primary care providers (PCPs) have adopted EMRs within their practice. CCO developed the Cervical Screening Reminder Calls (CSRC) pilot to support PCPs in increasing their cervical cancer screening rates. The pilot consisted of two components. First, practice staff were trained to utilize their EMRs to identify eligible patients for cervical screening. Once identified, practice staff invited patients via telephone to get screened. Family Health Team’s (ANFHT) pilot implementation will be presented. Methods: Twelve primary care practices were recruited from across Ontario to participate in the four-month pilot. Each practice was assigned a CCO support person to guide them through the implementation. The practice teams completed the self-directed EMR training. They then generated lists of patients eligible for cervical screening based on CCO’s cancer screening guidelines and telephoned patients to book Pap test appointments. Results: Over the course of the pilot, 1593 (57%) of all eligible patients were reached and 71%, or 798, of them scheduled a Pap test. Overall, participating physicians saw an average 2% increase in their total cervical screening participation rates. Conclusions: From a spread and sustainability perspective, the pilot has provided valuable insights to inform future planning at CCO. The lessons learned have implications for the implementation of a broader range of quality improvement initiatives. Next steps will include the development of an implementation model that is ‘lower touch’ thus allowing for spread to a broader number of practices.
Activity of gemcitabine-oxalipaltin (GemOx) plus prednisolone in patients with castration-resistant prostate cancer (CRPC) for whom docetaxel-based chemotherapy failed.
Authors: Jae-Lyun Lee, Yesul Kim, Jin-Hee Ahn, MeeKyung Choi, Seung-Woo Hong, In Gab Jeong, Cheryn Song, Bum-Sik Hong, Jun Hyuk Hong, Choung-Soo Kim, Hanjong Ahn
Journal: Journal of Clinical Oncology (2013)

108 Background: We assessed the cytotoxic effects of the gemcitabine in combination with oxaliplatin (GemOx) in prostate cancer cell lines and evaluated the efficacy and safety of GemOx in patients with metastatic castration-resistant prostate cancer (CRPC) who failed docetaxel based chemotherapy. Methods: Gemcitabine and oxaliplatin were preclinically tested for their cytotoxic activity in LNCaP, PC3 and DU145 cell lines. The combined drug effects were evaluated using the Chou and Taladay analysis. Clinically, patients with CRPC who failed prior docetaxel chemotherapy were treated with gemcitabine 1,000 mg/m 2 at fixed-dose rate (10 mg/m 2 /min) and oxaliplatin 100 mg/m 2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. Unless disease progression or intolerability develops, treatment could be continued until 12 cycles. Primary endpoint was PSA response rate (PCWG 1.0 criteria). Results: The IC 50 of gemcitabine and oxaliplatin were, respectively, 1.25 μM and 0.69 μM for LNCaP cells; 50.00+ μM and 12.81 μM for PC3 cells; and 11.23 μM and 11.04 μM for DU145 cells. The GemOx combination displayed synergistic effects in all 3 cell lines. In phase II study, 31 patients were accrued. At the time of this analysis 7 patients were still continuing treatment. The median age was 67 years (range 57 ~ 81) and the median dose of docetaxel exposure was 525 mg/m 2 . A total of 231 cycles administered with a median of 9 cycles per patient. PSA responses were observed in 52% (95% CI, 34~69) and partial responses were observed in 7 of 10 patients with measurable disease. Out of 23 patients, 10 patients achieved pain response (44%). With a median FU duration of 8.0 months, the median time to PSA progression was 6.4 months (95% CI, 3.5~9.2). Peripheral neuropathy developed in 78% of patients but remained of grade 1 ~2 intensities. Frequently observed grade 3 or 4 toxicities were neutropenia (10%), thrombocytopenia (10%), anemia (3%), and diarrhea (3%). Conclusions: GemOx is active and well tolerated in patients with CPRC after docetaxel failure and deserves further investigation in this setting (NCT 01487720). Clinical trial information: NCT01487720.
Phase IB trial of EMD 273066 (huKS-IL2) with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.
Authors: J. P. Connor, R. Stupp, M. C. Cristea, N. Lewis, L. D. Lewis, M. R. Mattiacci, M. Felder, S. Stewart, J. Henslee-Downey, R. Neugebauer, P. B. Komarnitsky
Journal: Journal of Clinical Oncology (2011)

2556 Background: EMD 273066 (humanized KS‐interleukin‐2 [huKS-IL2]) is an immunocytokine consisting of a humanized antibody specific for EpCAM fused at its Fc end to two molecules of interleukin‐2 (IL2). Preclinical data provided a rationale to evaluate huKS-IL2 in combination with immune-modulating low-dose cyclophosphamide (CTX) in patients with EpCAM-expressing solid tumors. Methods: Patients with advanced tumors expressing EpCAM received an infusion of CTX (300 mg/m2) on Day 1, followed by daily 4‐hour intravenous infusions of huKS-IL2 on Days 2 to 4, in up to 6 21-day cycles. Following a 3+3 design, doses of huKS-IL2 were to be escalated from 0.5 to 6.0 mg/m2 or MTD if reached earlier. Safety, tolerability, anti-tumor activity, PK, and effect of huKS-IL2 on immune function were evaluated. Results: 27 patients (10 M; 17 F) with a median age of 58.2 (range 46-69) years were enrolled: 15 with ovarian, 4 with lung, 3 with colon, 2 with prostate cancer and one each with melanoma, acinic cell carcinoma and unspecified adenocarcinoma. All except 2 patients had received prior chemotherapy. Four dose levels up to 4 mg/m2 were explored. Median time on study was 25 (range 1-109) days. Patients were exposed to median cumulative doses of 1182 mg CTX (range 440-3841 mg) and 12 mg/m2 huKS-IL2 (range 1-54 mg/m2). The most common treatment-related AEs were nausea, pyrexia, chills, rash, fatigue, diarrhea, and vomiting. Fourteen (52%) subjects experienced Grade 3-4 AEs. DLTs were G3 hypoxia (at 2 mg/m2), G3 dyspnea/bronchospasm/GGT elevation (at 3 mg/m2), G4 thrombocytopenia/G3 neutropenia and G3 anemia (at 4 mg/m2). Changes in total and subset lymphocyte counts were time- and in some cases dose-related and reflected common IL2 effects. PK parameters will be presented. Median OS was 8.8 months. Seven patients were alive at the time of the analysis, with median follow-up of 25.8 months (range 7.4-37.3 months). Conclusions: The MTD of huKS-IL2 in combination with 300 mg/m2 CTX was 3 mg/m2. Four DLTs were observed (2 in the 4 mg/m2 huKS-IL2 dose cohort). Effects on immune function were consistent with those of IL2. As one DLT was observed at 2 mg/m2 and one at 3 mg/m2, the dose of 1.5 mg/m2 was recommended for further development.
Use of the intensity of membranous EGFR staining by immunohistochemistry to predict the efficacy of chemotherapy containing cetuximab in <i>KRAS </i>wild-type patients with metastatic colorectal cancer: A retrospective analysis.
Authors: Naoki Takahashi, Yasuhide Yamada, Hirokazu Taniguchi, Kohei Akiyoshi, Yoshitaka Honma, Satoru Iwasa, Ken Kato, Tetsuya Hamaguchi, Yasuhiro Shimada
Journal: Journal of Clinical Oncology (2012)

516 Background: KRAS mutation status is a strong predictive factor for anti-EGFR monoclonal antibody therapy efficacy in metastatic colorectal cancer (mCRC). In the BOND trial, objective response rates to cetuximab in irinotecan-refractory mCRC were not significantly different based on the intensity of EGFR staining by immunohistrochemistry (IHC). However, this result was not evaluated by KRAS mutation status, so we retrospectively evaluated the relationship between the efficacy of chemotherapy containing cetuximab and the intensity of membranous EGFR staining in KRAS wild type (KRAS-WT) patients. Methods: Between August 2008 and July 2011, specimens of 391 CRC patients were collected by endoscopic biopsy or surgical resection. EGFR staining by IHC and genetic screening for KRAS status were performed and intensity of EGFR staining was scored by the Guidelines for Interpreting EGFR pharmDx, DAKO. We analyzed 94 KRAS-WT patients who received combination chemotherapy with an irinotecan-regimen plus cetuximab or cetuximab monotherapy and met the following criteria: histologically proven mCRC adenocarcinoma , at least 1 previous regimen of standard fluoropyrimidine - containing chemotherapy , ECOG PS score 0-2, and adequate hepatic and renal function. Patients were classified into 2 groups by intensity of EGFR staining: (A) absence of staining and weakly to moderately positive (IHC 1+ and IHC 2+), (B) strongly positive (IHC 3+). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared in Groups A and B by the log-rank test. Results: There was no significant difference in patient characteristics between the 2 groups except for primary site. The median PFS of Groups A (n=76) and B (n=18) were 5.4 months and 9.1 months (p= 0.029), the median OS was 8.1 months and 13.2 months (p=0.054) and response rate was 20.1% and 33.3%, respectively. Conclusions: In KRAS-WT patients with fluoropyrimidine-containing chemotherapy-refractory mCRC, strong intensity of EGFR staining by IHC might be predictive for efficacy of chemotherapy containing cetuximab.
Evaluation of the antitumoral effect sunitinib eluting beads in VX2 liver tumour in a rabbit model.
Authors: Pierre E. Bize, Olivier Jordan, Katrin Fuchs, Olivier Dormond, Rafael Duran, Eric Doelker, Thierry De Baere, Alban Denys
Journal: Journal of Clinical Oncology (2013)

247 Background: We demonstrated that DC Bead (Biocompatibles UK, Ltd) could be loaded with sunitinib and injected intra-arterially in the rabbit without unexpected toxicity. The purpose of this study is to evaluate the antitumoral effect of sunitinib eluting beads in the VX2 tumor model of liver cancer. Methods: VX2 tumors were implanted in the left liver lobe of New-Zealand white rabbits. Animals were assigned to 3 groups: Group 1 (n=6) received 1.5mg of sunitinib loaded in 0.05ml of 100-300um DC Bead, group 2 (n=5) received 0.05ml of 100-300um DC Bead, group 3 (n=5) received 0.05ml NaCl 0.9% in the left hepatic artery. One animal in each group was sacrificed at 24 hours and the others were followed for survival until day 15. Liver enzymes were measured daily. In group 1, plasmatic sunitinib concentration were measured daily by LC MS/MS tandem mass spectroscopy. At day 15 all living animals were sacrificed. After sacrifice, the livers were harvested for determination of the VEGF receptor tyrosine kinase activity by western blot and histopathological examination. Results: In group 1, no animals died during follow-up. In group 2, 2 animals died during follow-up on day x. In control group 3, 3 animals died during follow up on day x. In group 1 plasmatic sunitinib levels remained under therapeutic concentration throughout the experiment. Very high concentrations of sunitinib were measured in the liver tissue 24 and 15 days after embolization. Inhibition of the phosphorylation of the RTK was demonstrated at 24h and 15 days in groups 1. Sunitinib eluting beads seemed to penetrate in the tumor more effectively and there was more necrosis around the beads than their bland counterparts. Conclusions: Administration of sunitinib eluting beads in VX2 carrying rabbits resulted invery high drug concentrations at the site of embolization with minimal systemic passage. Despite the very high tissular sunitinib concentration we did not observe any additional toxicity with loaded beads. Sunitinib eluting beads inhibit the activation of RTK’s triggered by ischemia and seem to prolong survival of the treated animals. Therefore we consider that local treatment with sunitinib may provide a promising approach for the treatment of liver cancer.
Post-diagnosis mammographic density and risk of death in breast cancer survivors: The Health, Eating, Activity, and Lifestyle (HEAL) study
Authors: M. L. Irwin, A. Smith, E. Aiello, K. Cronin, A. McTiernan, L. Bernstein, R. Baumgartner, F. Gilliland, R. Ballard-Barbash
Journal: Journal of Clinical Oncology (2008)

22095 Background: There is evidence that mammographic breast density (BD) is a strong risk factor for breast cancer; however, no study has examined the association between BD and death in breast cancer survivors. We examined the association between post- diagnosis BD and risk of all causes of death and breast cancer death in breast cancer survivors. Methods: Prospective observational study of 524 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study who were diagnosed with breast cancer between 1995 and 1998 and followed until death or September 2004. We collected a mammogram and prognostic, demographic, and lifestyle factors including measured weight and height during a clinic visit two to three years after diagnosis. Mammograms were digitized and the cranio-caudal view contralateral to the breast diagnosed with breast cancer was measured for percent density and dense area using a computer-assisted program developed at University of Toronto. Results: The age and BMI of women were 58.3 ± 10.6 yrs and 27.7 ± 6.7 kg/m2. Women were postmenopausal (81%); non-Hispanic White (59%), African American (25%) or Hispanic White (13%); and diagnosed with Stage I (72%) or Stage II (28%) breast cancer. Seventy-one % of women were diagnosed with tumors that were estrogen receptor-positive. In analyses adjusted for age, menopausal status, race, disease stage, hormone therapy, BMI, physical activity, smoking status, and family history of breast cancer, the adjusted hazard ratio (HR) and 95% confidence interval (CI) for women in the highest vs. the lowest tertile of amount of dense tissue and all causes of death was 2.47 (95% CI, 1.01–6.23), P for trend = 0.049. Similar, yet nonsignificant associations, were observed for amount of dense tissue and breast cancer deaths. The adjusted HR for women in the highest vs. the lowest tertile of percent dense tissue and all causes of death was 1.38 (95% CI, 0.57–3.31), P for trend = 0.48. Similar nonsignificant associations were observed between percent dense tissue and breast cancer deaths. Conclusions: Women with high amounts of dense tissue were at a 2.5 times greater risk of death compared to women with lower amounts of dense tissue. Increased BD may be a marker of tumor aggressiveness or response to therapy. No significant financial relationships to disclose.
Surgical outcomes of colorectal cancer in octogenarians: Survival analysis of the Veteran's Affairs population.
Authors: S. Birdsong, R. Thota, T. Tashi, W. Gonsalves, P. T. Silberstein, S. Subbiah
Journal: Journal of Clinical Oncology (2011)

e14024 Background: Surgical resection of the primary tumor in the absence of metastatic disease is the treatment of choice for colorectal cancer. There is limited data evaluating surgical outcomes in the very elderly patients (≥80years). The purpose of this study was to evaluate surgical practice patterns and their effects on survival for patients ≥80 years of age. Methods: Retrospective analysis of 36,260 patients with colon cancer in the Veteran’s Affairs Central Cancer Registry between 1995 and 2009 was done. Demographic data, location of tumor, grade, stage, co-morbidities, therapy and survival data were extracted. Results: A total of 36,260 patients were identified with colon cancer and 5473 (15%) were octogenarians. Of the entire population, 97.3% were males, 82% were white and 16% were black. Among octogenarians, 4,111 (75%) received surgery while in the younger population, 25,166 (82%) received surgery. Median survival of patients who had surgery among the elderly compared to the younger population was 48 vs 99 mos (P<0.0001). Median survival was significantly higher among octogenarians who received surgery (50 vs 25 mos, P<0.001). The stage specific median survival with surgery among elderly compared to the younger population are stage 1-62 vs 143 mos (P<0.001), stage 2-53 vs 102 mos (P<0.001), stage 3-34 vs 63 mos (P<0.001). Elderly patients who received adjuvant chemotherapy had significantly better survival outcomes compared to those who did not receive adjuvant therapy (23 versus 64 mos). Conclusions: Surgical resection rates and median overall survival are lower in octogenarians compared to their younger counterparts; however fit elderly patients do benefit from surgery and adjuvant therapy.
Preliminary results of a phase I study of stereotactic radiotherapy for unresectable primary and metastatic liver cancer
Authors: M. A. Hawkins, C. Eccles, G. Lockwood, B. Cummings, J. Ringash, J. J. Knox, M. Sherman, P. Greig, S. Gallinger, L. A. Dawson
Journal: Journal of Clinical Oncology (2005)

4127 Purpose: To report initial toxicity and response data from a phase I study of stereotactic radiotherapy (SRT) for unresectable liver cancer. Methods: Eligible patients have unresectable or medically inoperable primary or metastatic liver cancer, Childs score A and KPS ≥ 60. Standard treatment options have been explored. Patients are stratified based on diagnosis (metastases vs. primary cancer) and volume of uninvolved liver treated (< 20%, 20–50%, 50–80%). SRT is delivered in 6 fractions/2 weeks to maximize patient convenience, resource utilization and therapeutic gain. Dose is individualized to maintain the same estimated risk of liver toxicity for patients at each level (level I - 5% risk, level II - 10% risk, level III - 20%, max. dose 60 Gy in 6 fractions). Escalation to level II and III occurs once at least 3 patients have been followed for >3 months without dose limiting toxicity for each stratum at the previous level. Patients are treated during breath hold to reduce organ motion, with daily imaging and repositioning to reduce setup error. Acute toxicity scored using CTC v3.0. Results: From Aug 2003 to Dec 2004, 36 patients completed SRT at levels I and II (14 hepatocellular carcinoma, 6 cholangiocarcinoma, 16 metastases). The median tumor volume was 213.9 cm3 (range 9.2 to 3088cm3). The average SRT dose to tumor was 35.7 Gy (range: 24 to 56.3 Gy). Median follow-up was 5.5 months (1.4 to 14.9 months). No grade 4/5 related toxicity was seen. At 1 month, 4 patients with HCC had a decline in liver function to Child B. No radiation-induced liver disease (RILD) was observed. Toxicity within 3 months included: grade 3 fatigue (1), vomiting (1); grade 2: thrombocytopenia (2), gastritis (4), pruritis (2), vomiting (2), nausea (6), anorexia (2) fatigue (8), hepatic pain (2). One gastrointestinal bleed occurred 6.4 months following SRT in a patient with tumor extension to the stomach on endoscopy. In 28 evaluable patients, in-field response assessed using CT at 3 months was: CR (1), PR (9), MR/SD (14), PD (4) Conclusion: This approach of individualized dose SRT appears safe, with no severe liver toxicity observed to date. More patients and longer follow up are required for a further assessment of late toxicity and efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ASCO CDA, Canadian Institutes of Health Research, NIH (US)/ NCI, NIH (US)/ Ontario portion/year, Ontario Cancer Research Network, Lustgarten Foundation for Pancreatic Cancer Research