tbuckley/cabot-search huggingface dataset:
National Trends in Colorectal Cancer Incidence Among Older and Younger Adults in Canada
Authors: Darren R. Brenner, Emily Heer, R. Liam Sutherland, Yibing Ruan, Jill Tinmouth, Steven J. Heitman, Robert J. Hilsden
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Recent evidence has shown that although the incidence of colorectal cancer (CRC) is decreasing among older adults, rates have increased in adults younger than 50 years. Given that younger adults are typically classified as at low risk for the disease, this epidemiologic shift is cause for concern. <h3>Objective</h3> To analyze Canadian national cancer incidence registries to determine incidence trends for CRC among older and younger adults, updated to 2015. <h3>Design, Setting, and Participants</h3> This cohort study determined the incidence of CRC using data from the National Cancer Incidence Reporting System (1969-1992) and the Canadian Cancer Registry (1992-2015). All Canadians diagnosed with CRC from January 1, 1969, through December 31, 2015, were included in this study. Trends among men and women were examined separately and by age category (&gt;50 vs &lt;50 years). Birth cohort models were fit using 5-year groups starting in 1886, with 1936 as the reference cohort. Data were analyzed from May 13, 2018 to May 16, 2018. <h3>Main Outcomes and Measures</h3> Annualized percentage changes and incidence rate ratios of CRC. <h3>Results</h3> From 1971 to 2015, 688 515 incident cases (52.9% women) of CRC were identified. Although the incidence of CRC has decreased in older men and women, rates among younger men and women have increased since 2006 and 2010, respectively. For women younger than 50 years, incidence has increased with a mean annual percentage change of 4.45% since 2010; for men younger than 50 years, a mean annual percentage change of 3.47% from 2006 through 2015. There was an association between CRC incidence and birth cohort, with more recent cohorts being at greater risk than those born earlier. For men, the risk of colorectal cancer in the youngest cohort is more than double that of the reference (incidence rate ratio, 2.57; 95% CI, 1.32-5.02). Incidence rate ratios were not significant for women (IRR, 2.12; 95% CI, 0.95-4.70) but increased in successively younger cohorts. <h3>Conclusions and Relevance</h3> This study found increasing incidence of colorectal cancer diagnoses among Canadian men and women younger than 50 years of age. This increase in incidence among a low-risk population calls for additional research on possible risk factors that may be affecting these younger cohorts. It appears that primary prevention should be the highest priority to reduce the number of younger adults developing CRC in the future.
Erlotinib as first-line treatment for untreated advance stage NSCLC with good prognosis
Authors: W. L. Akerley
Journal: Journal of Clinical Oncology (2006)

7178 Background: Erlotinib demonstrated improved survival in previously treated NSCLC, but did not affect survival in untreated NSCLC when used with concurrent chemotherapy. A potential hypothesis for this paradox is erlotinib may be more effective for patients with less aggressive tumors (i.e. those still surviving after multiple chemotherapy treatments). The current trial was designed to evaluate erlotinib before initial chemotherapy in a population of patients with less aggressive tumors based on clinical criteria. Methods: Eligibility criteria included stage IIIB/IV or recurrent NSCLC, no prior chemotherapy for systemic disease, PS = 0–1, weight loss less than 10%, and no urgent symptoms. Patients received erlotinib 150 mg po/day until objective or symptomatic progression before they were switched to chemotherapy. The 1 0 endpoint was time-to-progression after 1st chemotherapy. Results: 40 patients have been accrued. The median age was 65, 35 had PS = 1, 8 were never-smoker, and 23 were former smokers. Histologies were: Adeno 20, BAC 2, Sq 6, NSCLC 11, Other 1. The major toxicity was rash (Gr0 in 4, Gr1in 15, Gr2 in 14, Gr3 in 3, 4 too early. Other toxicity included liver (Gr 1 in 2, Gr2 in 1), mucositis (Gr1 in 1, Gr2 in 1) and diarrhea (liver (Gr1 in 10, Gr2 in 1, Gr3 in 2). 34 have been followed long enough for response evaluation, which identified 4 (12%) with PR (median 37 wks), 8 with stable (median 20 wk) and 22 with progression. At progression only 2 patients were too ill to start chemotherapy due to inadequate performance status. The median time on erlotinib was 8 wks overall: for rash Gr 0–1 8 wks, Gr 2–3=43 wks (p = 0.03). The median and 6-month PFS for chemotherapy are 22 wks and 45% with17 still on treatment. The median and 1-yr survivals are 50 wks and 47% with 24 pts still alive. Conclusions: Mid-term safety analyses exceeded expectations. Rash predicts duration of erlotinib effectiveness. Preliminary results suggest single agent, erlotinib may be as effective (PFS and survival) as initial chemotherapy with less toxicity and merits randomized testing as first treatment for advanced lung cancer. No significant financial relationships to disclose.
Differential Outcomes of Synchronous and Metachronous Diffuse Large B-Cell Lymphoma Transformed from Follicular Lymphoma
Authors: Natalie Pei Xin Chan, Ryan Mao Heng Lim, Lay Poh Khoo, Chee Leong Cheng, Leonard Kwan Cheong Tan, Eileen Yi Ling Poon, Nagavalli Somasundaram, Mohamad Farid, Tiffany Tang, Miriam Tao, Soon Thye Lim, Jason Yongsheng Chan
Journal: Blood (2018)
Frequency of second- and third-line treatment among elderly Medicare stage IV colon cancer patients.
Authors: C. Daniel Mullins, Kaloyan A Bikov, Ebere Onukwugha, Brian S. Seal, Nader Hanna
Journal: Journal of Clinical Oncology (2012)

e14035 Background: Stage IV colon cancer (CC4) patients may receive multiple lines of chemotherapy and/or biologics as treatment (TX) to improve survival or quality of life, yet elderly patients generally receive less aggressive cancer TX. Methods: Elderly (65+) SEER-Medicare patients diagnosed with CC4 in 2003-7 were followed through death or 2009 to examine variation across sub-groups in the number of TX lines. TX included 5-fluorouracil and (levo)leucovorin-based (5FU/LV); irinotecan (IRI) and/or oxaliplatin (OX) with/out 5FU/LV; bevacizumab, cetuximab, or panitumumab (MNCLA), alone or in combination with chemotherapy; and other TX. A hierarchy categorized treatments as: 1) IROX (IRI+OX); 2) IRI or OX; 3) 5FU/LV; 4) MNCLA without chemotherapy; and 5) other TX. Gaps in TX or changes from OX or IRI to 5FU/LV were not considered new lines. Results: Of 7,937 elderly CC4 patients, 3,263 (41%) received any TX, while 1,541 (19%) and 570 (7%) received second and third line TX, respectively. Among the TX group, younger (p&lt;0.01), married (51 vs. 42%, p &lt; 0.01) and male (49 vs. 45%, p = 0.02) patients were more likely to go on to second line TX. Medicare buy-in coverage, which generally indicates dual Medicaid-Medicare coverage (42 vs. 48%, p = 0.03), lowered the likelihood of second line TX. Having comorbidities impacted initial TX (CCI=0: 44.5%, CCI=1: 41.9%, CCI=2: 28.4% ; p&lt;0.01) more so than the likelihood of second (CCI=0: 48.6%, CCI=1: 45.9%, CCI=2: 42.4% ; p=0.06) or third (CCI=0: 37.2%, CCI=1: 39.9%, CCI=2: 29.9% ; p=0.09) line TX conditional upon receipt of prior line treatment. There was no significant association between second line TX and race/ethnicity, urbanicity or year of cancer diagnosis. Among those with second line TX, only age (p=0.05) and urbanicity (38 urban vs. 25% non urban, p &lt; 0.01) were significantly associated with higher likelihood of third line TX. Conclusions: Among CC4 patients with TX, married patients and men receive more TX lines, while number of treatment lines decreases with age. Tendency to use less aggressive treatment with elderly CC4 patients, combined with our observed results, suggests that a substantial proportion of elderly CC4 patients receive fewer TX lines than equivalent younger patients.
A single arm phase II trial of gemcitabine (G) and irinotecan (I) in metastatic breast cancer: Can localization of topoisomerase I (topo I) predict response to topo I inhibitors?
Authors: S. L. Moulder, N. Valkov, S. Minton, P. Munster, J. Gump, M. Lacevic, C. Rocha-Lima, J. Horton, R. Lush, D. Sullivan
Journal: Journal of Clinical Oncology (2006)

661 Background: The incorporation of G into DNA enhances cleavage complexes in vitro when combined with a topo I inhibitor. Topo I poisons require enzyme interaction with DNA to exert activity. Methods: Two stage accrual design, primary endpoint: response (RR) using RECIST criteria. Inclusion criteria: male and female patients (pts) with MBC, prior anthracycline therapy, measurable disease, ECOG PS of ≤ 2, adequate organ function, and ≤ 3 prior chemotherapy regimens for MBC. 51 eligible pts received therapy with G at 1000mg/m 2 and I at 100mg/m 2 on days 1 and 8 of a 21-day cycle. Optional tumor biopsies were obtained in 9 pts (18%) prior to therapy to determine localization of topo I using immunofluorescence. PK: Irinotecan: A validated limited sampling strategy was used. Gemcitabine: Serial blood samples were collected over 24 hrs following the first dose. Intracellular nucleotides were quantitated in PBMCs. Results: 45 pts have been evaluated with a RR of 27% (CR=0, PR=12; 95% CI 13–37%). 4 pts had SD for ≥6 months for a clinical benefit rate (PR+SD) of 36%. 3 pts received &lt; 1 cycle of therapy before protocol withdrawal and were not evaluable for RR. RR for the final 3 patients will be available at the time of presentation. 7/9 tissue biopsies were assessable for topo I with results listed below. PK and toxicity data will be available at presentation.Conclusion: GI is active in MBC. Topo I localization can be measured in MBC. In this limited data set, the two lowest nuclear to cytoplasmic (N/C) ratios were associated with lack of response to irinotecan. Further validation is needed. [Table: see text] [Table: see text]
Randomized phase II trial of multipeptide vaccination with or without a single pre-vaccine dose of denileukin diftitox in advanced melanoma.
Authors: Thomas Gajewski, Karen Matijevich, Yuanyuan Zha
Journal: Journal of Clinical Oncology (2012)

2582 Background: The efficacy of immunotherapy approaches such as vaccines in melanoma appears limited, in part, due to immune suppressive mechanisms in the tumor microenvironment. One of these mechanisms is the presence of CD4+CD25+FoxP3+ regulatory T cells (Tregs). It has been hypothesized that strategies to reduce Treg numbers should improve the efficacy of melanoma vaccines. Methods: The study design was to randomize 24 HLA-A2+ patients to receive vaccine alone or denileukin diftitox (18 mcg/kg i.v.) as a single dose 4 days prior to the first vaccination. The vaccine formulation consisted of 4 melanoma antigen peptides (derived from MelanA, gp100, MAGE3, and NA17A) emulsified in Montanide and GM-CSF, administered i.d./s.c. every 2 weeks. The primary endpoints were assessment of depletion of Tregs from the peripheral blood, and measurement of antigen-specific CD8+ T cell responses by ELISPOT. Secondary endpoints included clinical response and analyses of the tumor microenvironment for changes in Treg infiltration. Results: The treatment was well tolerated. Enrollment was halted at 16 patients when it was clear that immune response endpoints would not be reached. There was no significant decrease in Treg numbers, nor was there an increase in vaccine-induced T cell responses, when patients received denileukin diftitox prior to vaccination. In patients with biopsiable tumors, there was no decrease in Tregs in metastatic lesions post-versus-pre-treatment. Of the 9 patients who showed clinical benefit (1 PR, 8 SD), 4 of them received denileukin diftitox and 5 did not. Estimated time to progression was 146 days in the group that received denileukin diftitox and 131 days in the group that did not. Conclusions: Denileukin diftitox given as a single dose prior to vaccination was not sufficient to deplete Tregs or improve the potency of this melanoma vaccine. Alternative strategies to reduce Tregs, such as multiple doses of denileukin diftitox or anti-CD25 mAbs, should be considered.
Doctors to get flexibility on pension contributions from next year
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Doctors in England and Wales will be able to control how much they pay into their pensions when the new financial year starts next April, to avoid punitive tax charges, under new government proposals.

The new approach, which will be put out for consultation shortly, replaces the 50:50 proposal announced in June,1 which suggested that doctors could halve their pension contributions to avoid tax charges. This was criticised by the BMA, which said that it would just leave doctors with smaller pensions.

The same problem could arise in the new proposal, however, because although doctors will be able to reduce the amount they pay into their pension, the employer contribution will also reduce, meaning their pensions will grow at a slower rate. This would mean that if a doctor cut their pension payment to …
التأثيرات الصحية للحبيبات العالقة بالهواء على التنفس: دور حجم الجزيئات وتركيبها وجهدها المؤكسد (مشروع الرابتس)
Authors: Maciej Strak, A.H. Janssen Nicole, J. Godri Krystal, Gosens Ilse, S. Mudway Ian, R. Cassee Flemming, Lebret Erik, J. Kelly Frank, M. Harrison Roy, Brunekreef Bert, Steenhof Maaike, Hoek Gerard
Journal: Environmental Health Perspectives (2012)

Background: Specific characteristics of particulate matter (PM) responsible for associations with respiratory health observed in epidemiological studies are not well established. High correlations among, and differential measurement errors of, individual components contribute to this uncertainty.
O
b
jectives: We investigated which characteristics of PM have the most consistent associations with acute changes in respiratory function in healthy volunteers.
Methods: We used a semiexperimental design to accurately assess exposure. We increased exposure contrast and reduced correlations among PM characteristics by exposing volunteers at five different locations: an underground train station, two traffic sites, a farm, and an urban background site. Each of the 31 participants was exposed for 5 hr while exercising intermittently, three to seven times at different locations during March–October 2009. We measured PM10, PM2.5, particle number concentrations (PNC), absorbance, elemental/organic carbon, trace metals, secondary inorganic components, endotoxin content, gaseous pollutants, and PM oxidative potential. Lung function [FEV1 (forced expiratory volume in 1 sec), FVC (forced vital capacity), FEF25–75 (forced expiratory flow at 25–75% of vital capacity), and PEF (peak expiratory flow)] and fractional exhaled nitric oxide (FENO) were measured before and at three time points after exposure. Data were analyzed with mixed linear regression.
R
esults: An interquartile increase in PNC (33,000 particles/cm3) was associated with an 11% [95% confidence interval (CI): 5, 17%] and 12% (95% CI: 6, 17%) FENO increase over baseline immediately and at 2 hr postexposure, respectively. A 7% (95% CI: 0.5, 14%) increase persisted until the following morning. These associations were robust and insensitive to adjustment for other pollutants. Similarly consistent associations were seen between FVC and FEV1 with PNC, NO2 (nitrogen dioxide), and NOx (nitrogen oxides).
C
onclusions: Changes in PNC, NO2, and NOx were associated with evidence of acute airway inflammation (i.e., FENO) and impaired lung function. PM mass concentration and PM10 oxidative potential were not predictive of the observed acute responses.
SSRIs in children: NICE guidelines may have increased their use
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Guidelines from the National Institute for Health and Care Excellence (NICE) on antidepressant treatments in children and adolescents may have encouraged doctors to prescribe selective serotonin reuptake inhibitors (SSRIs) despite warnings from drug regulators, a study has found.1

Researchers from five UK universities assessed the impact that the Committee on Safety of Medicines’ (CSM) 2003 warning and the 2005 NICE guidance had had on antidepressant prescription rates in children and adolescents in UK primary care.

They found that an increasing trend in SSRI prescriptions had reversed after the CSM warning. But the publication of NICE guidance two years later led to newly increased SSRI prescribing of the three drugs studied: fluoxetine, citalopram, and sertraline.

During the late 1990s …
Chemotherapy selection by gene expression profiling (MAGE) in resistant/refractory (R/R) patients with solid tumors: A feasibility study.
Authors: Joseba Rebollo, Ramon Gonzalez-Manzano, Francisco J. Fernandez-Morejon, Severino Rey, Jose Farre, Manuel Sureda, Antonio Brugarolas
Journal: Journal of Clinical Oncology (2013)

e22120 Background: Genomic-based profiling of tumors is a promising approach that allows the selection of the optimal chemotherapy regimen minimizing the possibility of futile therapies. Preliminary clinical results by our group showing a 23% response rate were presented at ASCO’12 (abstract 3,064). However, RNA isolation is a challenging technical step that requires a high quality specimen and takes 2-4 weeks interval to be finished. For this reason we analyzed the feasibility conditions in our series. Methods: Patients (pts) with R/R solid tumors had immediately frozen biopsies, underwent RNA isolation and quality validation after a pathologic confirmation of viable tumor in more than 30% of the sample. Results: From August 2010 to December 2012, 138 patients accepted the MAGE chemotherapy profiling. The median time from biopsy to MAGE analysis has been 4 weeks (ranging 2 to 6). In 17 (12%) pts the procedure was aborted for technical reasons. In these cases tumor samples were obtained from liver in 7 pts, local recurrence in 3 pts, soft tissues in 3 pts, peritoneum in 2 pts, and nodes in 2 pts. Reasons for canceling the assay were mainly a very low tumor cells rate (less than 30%) in 10 pts (fibrotic changes in 5 pts and predominance of necrosis in 5 pts), 2 pts with no tumor, 1 pt with a non-radiologically identifiable lesion, 1 pt with radiofrequency deterioration of the specimen and 3 pts with poor quality RNA. Among the remaining 121 pts who completed the procedure only 74 (61.2%) were treated according to the selected chemotherapy agents achieving a clinical benefit rate of 60%. The high attrition rate (38.8%) was due to poor clinical condition, refusal of recommendations and/or short life expectancy. Conclusions: MAGE-based chemotherapy profiling of tumors was feasible to guide antitumor therapy in selected patients. We recommend performing the study in untreated patients or earlier in the course of their disease (i.e. after failure to first line chemotherapy) in patients with a life expectancy of more than 3 months.
Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study
Authors: John G. Hanly, Qiuju Li, Li Su, Murray B. Urowitz, Caroline Gordon, Sang‐Cheol Bae, Juanita Romero‐Diaz, Jorge Sanchez‐Guerrero, Sasha Bernatsky, Ann E. Clarke, Daniel J. Wallace, David A. Isenberg, Anisur Rahman, Joan T. Merrill, Paul R. Fortin, Dafna D. Gladman, Ian N. Bruce, Michelle Petri, Ellen M. Ginzler, M. A. Dooley, Kristjan Steinsson, Rosalind Ramsey‐Goldman, Asad A. Zoma, Susan Manzi, Ola Nived, Andreas Jonsen, Munther A. Khamashta, Graciela S. Alarcón, Elisabet Svenungsson, Ronald F. van Vollenhoven, Cynthia Aranow, Meggan Mackay, Guillermo Ruiz‐Irastorza, Manuel Ramos‐Casals, S. Sam Lim, Murat Inanc, Kenneth C. Kalunian, Soren Jacobsen, Christine A. Peschken, Diane L. Kamen, Anca Askanase, Chris Theriault, Vernon Farewell
Journal: Arthritis & Rheumatology (2019)

Objective To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. Methods Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. Results Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow‐up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF‐36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF‐36 summary scores for peripheral neuropathy and mononeuropathy. Conclusion PNS disease is an important component of total NPSLE and has a significant negative impact on health‐related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.
Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma
Authors: Jinhong Park, Hyun Jae Lee, Doona Song, Mia Gi, Sungwoo Jo, Dong-kyu Jeon, Yohan Seo, Bomin Kim, Ho Lee, Wan Namkung, Gyoonhee Han, Jae Young Choi
Journal: Journal of Allergy and Clinical Immunology (2019)
Immune Desertic Landscapes in Hepatocellular Carcinoma Shaped by β-Catenin Activation
Authors: Pedro Berraondo, Maria C. Ochoa, Irene Olivera, Ignacio Melero
Journal: Cancer Discovery (2019)

Abstract Summary: About one third of cases of hepatocellular carcinoma (HCC) show gain-of-function mutations of CTNNB1 (β-catenin) that correlate with sparse intratumoral T-cell content, as observed previously in an ample spectrum of malignancies, and there is mounting preliminary evidence that such HCC cases are refractory to treatment with PD-1 checkpoint inhibitors. Elegant hepatocarcinogenesis experiments by in vivo gene transfer to mouse hepatocytes show that coexpression of active forms of β-catenin result in poor T-cell infiltrates, faster progression in immunocompetent hosts, and unresponsiveness to immunotherapy with checkpoint inhibitors. See related article by Ruiz de Galarreta et al., p. 1124.