tbuckley/cabot-search huggingface dataset:
Association of resistance to antiangiogenic therapy with an immunosuppressive tumor microenvironment in metastatic renal cell carcinoma.
Authors: Xiande Liu, Anh Hoang, Lijun Zhou, Sarathi Kalra, Alper Yetil, Mianen Sun, Zhiyong Ding, Pheroze Tamboli, Priya Rao, Jose A. Karam, Christopher G. Wood, Surena F. Matin, Amado J. Zurita, Axel Bex, Arjan W. Griffioen, Jianjun Gao, Padmanee Sharma, Nizar M. Tannir, Kanishka Sircar, Eric Jonasch
Journal: Journal of Clinical Oncology (2015)

419 Background: Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers which predict therapeutic resistance and guide combination therapy. Methods: Tissue microarrays with triplicate cores for each case were generated from 33 unaffected kidneys, 41 untreated primary RCC, and 42 bevacizumab and 39 sunitinib pretreated primary RCC from patients with metastatic RCC. Immunohistochemistry was used to visualize immune cell infiltration. Staining quantitation was performed using a Vectra multispectral system. Statistical analysis was performed using unpaired Student´s t-test. Results: We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. Here we found that anti-angiogenic therapy treated RCC primary tumors demonstrated increased infiltration of CD4 + and CD8 + T lymphocytes, which was inversely related to patient survival. Furthermore, anti-angiogenic therapy treated specimens showed higher infiltration of CD4 + FOXP3 + regulatory T cells (Tregs) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T lymphocyte infiltration and were negatively related to patient overall survival (OS) and/or progression free survival (PFS). Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Conclusions: This study indicates that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents.
Does multidimensional geriatric assessment influence the prescription of adjuvant chemotherapy to elderly women with early breast cancer in a multivariate model?
Authors: U. Basso, C. Bassi, C. Falci, D. Sambiasi, D. Crivellari, A. Molino, S. Lonardi, P. Fiduccia, A. Jirillo, S. Monfardini
Journal: Journal of Clinical Oncology (2008)

20541 Background: To evaluate in a multivariate model if the outcome of Multidimensional Geriatric Assessment (MGA) influences the prescription of adjuvant chemotherapy (as a binary outcome) to elderly women with intermediate-high risk early breast cancer enrolled in a observational, prospective, multicenter study. Methods: MGA was performed at first diagnosis [Basso Eur J Cancer Care 2004] and pts were classified as Frail if ADLs dependent or with three or more severe comorbidities, or with one or more geriatric syndromes, or ≥85 years. Pts without relevant comorbidities and fully independent were classified as Fit and pts with only one or two significant comorbid conditions, or only IADLs but no ADLs deficit, as Vulnerable [Balducci Cancer Control 2001]. Results: Out of 195 pts so far enrolled, 148 had at least one risk factor (T≥ 2 cm, positive lymph nodes, tumor grade G2 or G3, Estrogen receptor-ER negative) and were eligible for this study. Median age was 76 years (range, 70–91.5). After MGA, 32.5% were deemed Fit, 38.5% Vulnerable and 29% Frail. Chemotherapy was prescribed to 30 pts (20.3%). Univariate analysis demonstrated a correlation of chemotherapy with age <80 years, node positive, and ER negative disease. Outcome of MGA was not significant either comparing the choice in Fit vs non-Fit patients (OR for fit =1.27) or Frail vs not-Frail patients (OR for frailty=1.06) (table 1). We then assessed the same factors in a backward multivariate model. Age < 80 years, N positive and ER- retained prognostic relevance, while outcome at MGA did not appear to correlate with chemotherapy. Conclusions: Older breast cancer women are evenly distributed among the three classes of elderly patients but MGA does not appear to impact on the choice for chemotherapy either because biological factors are perceived to be more relevant or because current criteria of frailty and ’fitness’ do not coincide with clinical parameters used by Oncologists for this therapeutic choice. OR for prescription of chemotherapy 95% CI Age < 80 years 5.75 1.65–20.05 Positive lymph nodes 8.67 3.45–21.8 ER negative 10.36 2.87–37.4 T ≥ 2 cm 1.8 0.79–4.07 G2 or G3 0.5 0.08–2.87 Fit at MGA 1.27 0.55–2.93 Frail at MGA 1.06 0.45–2.55 No significant financial relationships to disclose.
Ten-year reproduction rates (10-RR) after cancer treatment: Comparison between patients (cases) and the normal population (controls)
Authors: M. S. Cvancarova, H. Magelssen, S. Fossa
Journal: Journal of Clinical Oncology (2007)

9075 Background: Reproduction rates in cancer survivors are sparse, and the impact of the number of pre-diagnosis children and age at diagnosis on post-diagnosis parenthood is unknown. We assessed 10-RRs in cases and age- and gender- matched controls. Methods: After merging the Hospital Registry and the Medical Birth Registry of Norway, we analyzed 6,071 cases treated from 1971 to 1997 and aged 15–45 at diagnosis, and 30,355 controls, all born after 1950. All were followed from the recorded or simulated date of diagnosis. The primary outcome was the first post-diagnosis pregnancy (median observation time: 10 years, range: 0–35 years). 10-RRs and hazard rates (HRs, controls as reference) were computed by Cox proportional hazard multivariate regression models adjusted for age at diagnosis, stratified by gender and number of pre-diagnosis children. Results: 45% of cases and 56% of controls were childless at diagnosis. The table below displays 10- RRs and HRs for all cases and controls and the most frequent cancer types (cases given first). When 10-RR of cases is higher or not significantly different from the rates for controls, the cell is highlighted. In general, 10-RRs are the highest for those with one-time pre-diagnosis paternity. Conclusion: Contrary to observations in females, 10-RRs of the first post-cancer paternity in males are significantly increased for cases compared to controls. In addition, the 10-RR for male cases with one pre-diagnosis child exceeded the rates for males who were childless at diagnosis. Overall, 10-RRs are associated with gender, cancer type and pre-diagnosis parenthood. [Table: see text] No significant financial relationships to disclose.
A randomized trial of computer and pamphlet-based versions of the Decision Board (DB)
Authors: T. J. Whelan, A. Gafni, J. Julian, R. J. Sebaldt, R. Tozer, B. Heller, P. Ellis, N. Hodgson, S. Mukherjee, M. N. Levine
Journal: Journal of Clinical Oncology (2007)

6508 Background: Many women with breast cancer want to be involved in treatment decision making. The DB is a visual aid poster board which sequentially presents written and graphical information from clinical trials regarding treatment options for early breast cancer. The physician presents the DB to the patient during the consultation. Randomized trials have demonstrated that the standard version of the DB improves patient comprehension, satisfaction and comfort with decision making. The standard DB is cumbersome to use and hard to update. Computer based instruments are attractive as they provide more flexibility in presenting information, and can be easily updated and accessed via the Internet. On the other hand pamphlet based versions may be easier to use. We developed computer versions of the DB for breast cancer surgery and adjuvant chemotherapy options using a Windows type format. Pamphlet versions were also developed. The objective of this study was to compare the computer and pamphlet versions of the DB to the proven standard version. Methods: 309 women were randomized to the physician consultation plus the standard (105), computer (103) or pamphlet (101) versions of the DB. Patients were stratified according to type of decision: surgical treatment or adjuvant chemotherapy. Patients were evaluated following the consultation for their knowledge about the breast cancer treatments offered, decisional conflict, and satisfaction with preparation for decision making using established validated instruments. Usefulness of the instrument for the patient and physician was also assessed. Results: Study outcomes were similar between the three versions of the DB ( Table ). Usefulness of the instrument for the patient and physician was also similar for the different versions. Conclusions: The different versions of the DB appeared equally effective in facilitating shared decision making. Physicians and patients now have the option of choosing which instrument best suits their needs. Such versatility may encourage wider use of the DB. No significant financial relationships to disclose. [Table: see text]
Hands-On Endoscopy Training: An Evaluation of the SADE Endoscopy Course
Authors: L Aabakken, M Osnes, A R Rosseland, F T Fork, G Liedberg, P Matzen, A Kruse
Journal: Endoscopy (1995)

The Scandinavian Association of Digestive Endoscopy course in advanced practical endoscopy has been arranged on a regular basis since 1980, representing a joint Scandinavian effort to offer hands-on endoscopy training with expert supervision at major endoscopy centers. The course has been aimed at gastroenterologists with previous endoscopic experience, focusing on special techniques, practical hints and expert solutions in special cases. Three days of practical training throughout Scandinavia are completed with two days of review lectures, case reports and special techniques. An inquiry among previous course participants indicates that the course has indeed been of practical value for their daily work, and that personal training as well as watching “experts at work” were useful for their ensuing endoscopic practice. The course model does, however, require close co-operation with the endoscopy units hosting the practical part of the course.
The RNA-Binding Protein Quaking Regulates Alternative Splicing Events in Myocardin That Determine Vascular Smooth Muscle Cell Phenotype
Authors: R.G. de Bruin, E.P. van der Veer, M. de Vries, J. van Gils, A. Kraaijeveld, T. Rabelink, P.H. Quax, W. Jukema, E.A. Biessen, A.J. van Zonneveld
Journal: Circulation (2013)
Intravenous immunoglobulin in community acquired pneumonia
Authors: Usman Farkhutdinov, Albert Mirchaidarov, Shamil Farkhutdinov
Journal: European Respiratory Journal (2011)

Immunity disorders play an important role in the inflammatory formation in patients with lung diseases.

The aim was to study the efficacy of i.v. immunoglobulin immunovenin (IMV) in patients with community acquired pneumonia (CAP).

Methods: The study included 35 patients with CAP. The patients blood was tested to estimate the level of CD3+, CD4+, CD8+, CD16+, CD20+ lymphocytes, the content of A,G,M immunoglobulins (Ig), circulating immunocomplexes (CIC), γ-interferon and TNFa. 17 patients with CAP were treated with standard therapy. The other 18 patients received combined treatment with IMV.

Results: Compared to healthy subjects in patients with CAP the level of CD3+,CD4+,CD8+, CD16+ lymphocytes was lower by 1,2-1,4 times, the content of IgA, IgG and γ-interferon was lower by 1,3 times. Conversely, the level of CD20+ lympocytes, IgM, CIC was higher by 1,3-1,8 times, and the level of TNFa was higher by 1,9 times. Symptoms of inflammation and impairment of the immune status have been found in patients who received standard therapy. The use of IMV in patients with CAP eliminated immunity disorders, improved the results of the treatment.

Conclusion: In patients with CAP immunovenin improved the immunity status and increased the treatment efficacy.
Enhanced gemcitabine (G) exposure in combination with escalating doses of paricalcitol [19-nor-1 alpha, 25-(OH)2 D2] (P) in patients with advanced malignancies.
Authors: R. V. Iyer, G. J. Fetterly, M. M. Javle, W. Tan, G. E. Wilding, J. Muindi, M. Fakih, N. Ramnath, C. S. Johnson, D. L. Trump
Journal: Journal of Clinical Oncology (2010)

e13031 Background: Calcitriol+ gemcitabine (G) combination results in synergistic antitumor effects in preclinical models. Cytidine deaminase (CDD) inactivates G into 2′,2′-difluorodeoxyuridine (dFdU) and its overexpression may lead to G resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). P is a potentially less hypercalcemic calcitriol analogue that is cytotoxic in vitro, and synergistic with several chemotherapeutic agents, including G. We are conducting a phase I study of P + fixed-dose G. The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of P on PK of G, CDD activity in PBM and clinical outcomes. Methods: Each cycle is 4 weeks: G 800 or 1,000 mg/m2 (over 80 or 100 min) weekly × 3, starting on day 1; P weekly, 24 h prior to G, starting on day 7. A standard 3+3 dose escalation schema was used. Planned P dose levels (DL) are 0.24, 0.72, 1.20, 1.8, 2.4, 3, 3.75, 4.69, 7μg/kg, and 50% increments till MTD. PK of G and CDD activity (PBM) were studied on days 1 and 8. PK of P are obtained on day 7. Results: Thirty-eight pts with the refractory solid tumors have been enrolled. Tumor types were lung 9, gastroesophageal 8, pancreas 7, liver 3, prostate 2, colorectal 3, unknown 2, breast, bladder, other GI and endocrine 1 each. Median age 62 yrs (range 26-80); M/F were 21/17; ECOG PS 0/1/2: 17/20/1; median cycle 2 (range 1-9). Two DLTs have occurred: 1 (thrombocytopenia, dose delay > 2 weeks) at DL6 and 1 (grade 3 somnolence) at DL9. Currently 3 of 6 pts have been enrolled at DL9. Best response was stable in 10/ 38 (26%) (median duration of 5.3 months) and partial response in 1(3%) for a disease control rate of 29% in refractory patients. Median (range) G exposure increased from 12 (6-16) to 25 (19-30) ug-hr/mL following doses of 1.2 and 7 ug/kg of P. Interestingly, dFdu also increased by less than 50% over the entire dose range tested. Inadequate yield of PBM limited the assessment of P effect on CDD levels. Conclusions: MTD has not been reached at 7μg/kg of P with G 800 mg/m2/week. G drug exposure increased in combination with P. Dose escalation is ongoing. No significant financial relationships to disclose.
Topical vitamin K3 (Vit K3, Menadione) prevents erlotinib and cetuximab-induced EGFR inhibition in the skin
Authors: R. Perez-Soler, Y. Zou, T. Li, C. Tornos, Y. Ling
Journal: Journal of Clinical Oncology (2006)

3036 Background: The EGFR inhibitors erlotinib and cetuximab cause skin toxicity in about 75% of patients. The occurrence of skin toxicity correlates with clinical benefit. About half the patients with skin toxicity report significant discomfort. There are currently no scientifically based or proven methods for preventing or treating effectively the skin toxicity secondary to EGFR inhibitors. Methods: We screened a number of EGFR activators and phosphatase inhibitors for their ability to abrogate EGFR inhibition secondary to erlotinib and cetuximab in A431 cells. P-EGFR expression was assessed by western blot analysis. Vit K3 was selected for further in vivo studies. The skin toxicity secondary to the topical application of Vit K3 was evaluated in nude mice. The highest non-toxic concentration was used to determine the ability of topical Vit K3 to prevent EGFR inhibition in the skin of nude mice treated with EGFR inhibitors. Results: Vit K3 was the most potent EGFR activator identified, the maximum effect being observed at concentrations of 0.1–0.5 mM. In the presence of erlotinib or cetuximab, 0.1- 0.5 mM Vit K3 completely prevented EGFR inhibition. The maximum non-toxic concentration of Vit K3 applied topically BID × 10 days to nude mice was 15 mM. At this concentration, topical Vit K3 caused P-EGFR upregulation in the skin. In animals treated with erlotinib (100 mg/kg daily × 5 days), there was no detectable P-EGFR expression in the skin not treated with topical Vit K3 whereas P-EGFR expression was completely restored in the skin treated BID x 5 days with topical Vit K3. Conclusions: Vit K3 is one of the first reported agents to prevent/reverse EGFR inhibition secondary to anti-EGFR agents. The results strongly justify the development of a topical formulation of Vit K3 to treat and prevent the cutaneous toxicity secondary to EGFR inhibitors. [Table: see text]
Metachronous colorectal cancer in mismatch repair gene mutation carriers: The advantage of more extensive surgery.
Authors: S. Parry, A. Win, F. Macrae, B. Parry, N. M. Lindor, S. Gallinger, J. L. Hopper, M. A. Jenkins
Journal: Journal of Clinical Oncology (2010)

3515 Background: Appropriate surgical management of colorectal cancers (CRC) in Lynch syndrome patients, i.e., carriers of a mutation in a mismatch repair (MMR) gene, is still controversial. The decision to remove more or less of the colon requires consideration of the relatively high risk of metachronous colorectal cancer with the functional consequence of more extensive surgery. Our aim was to estimate and compare the risks of a second CRC for MMR mutation carriers following partial or segmental versus subtotal or total removal of colon for their first colon cancer. Methods: Risk of second CRC was estimated for a cohort of 348 carriers of MMR gene mutations (158 MLH1, 148 MSH2, 23 MSH6 and 19 PMS2) from the Colon Cancer Registry, who had colorectal surgery for their first colon cancer. Retrospective cohort analysis was used for the total of 3,113 person-years of follow-up by a Cox proportional hazards regression. Results: Of 41 individuals who had subtotal or total colectomy for first colon cancer we observed no diagnosis of second CRC over 325 person-years (97.5% one-sided CI 0 to 11.3 per 1,000 person-years). Of 307 individuals who had partial or segmental colectomy for first colon cancer, there were 58 (19%) diagnoses of second CRC (incidence rate 20.8 per 1000 person-years; 95%CI 16.1 to 26.9 per 1,000 person-years). Cumulative risk of second CRC was 19% (95%CI 15%-24%) at 10 years, 34% (95%CI 28%-42%) at 20 years and 46% (95%CI 38%-55%) at 30 years after partial or segmental colectomy for a first colon cancer. Females were more likely to have a second CRC following partial colectomy compared to males by an adjusted hazard ratio of 3.54 (95%CI 1.15-10.89; p = 0.027). Risk of second CRC was reduced by 5% (adjusted hazard ratio 0.95; 95%CI 0.92-0.99; p = 0.005) for every 10 cm of bowel removal. Conclusions: Lynch syndrome patients with CRC who have had a partial or segmental colectomy, especially women, have a high cumulative risk for a second CRC. More extensive resection of the index CRC leads to a quantifiable reduction in risk. These findings will better inform decision making about the extent of primary surgical resection and the confounding issue of worse functional outcome. No significant financial relationships to disclose.
Accrual of under-represented minority women to breast cancer clinical trials in Inland Empire, California.
Authors: Yuan Yuan, Padma Tadi Uppala, Sharon S. Lum, John W. Morgan, Carlos Garberoglio
Journal: Journal of Clinical Oncology (2012)

64 Background: Ethnic minority women are currently underrepresented in breast cancer clinical trials. The age-adjusted incidence and mortality rates for breast cancer are higher in Riverside and San Bernardino Counties (Inland Empire), California, than the statewide average. During the 10 years of enrollment at Loma Linda University Cancer Center (LLUCC) between 1999 and 2009, a total of 151 patients were enrolled to breast cancer clinical trials. Among the enrolled patients, only 26.7% were ethnic minority women in contrast with the 59% of ethnic minority women living in Inland Empire. Methods: A countywide breast cancer awareness campaign using billboard, print ads, and newsletters, combined with direct mailing sent to regional physician offices and breast imaging centers was launched. We specifically addressed previously identified barriers to participation in clinical trials, such as lack of medical insurance, time, invitation, awareness of available studies, access to the institution or doctors conducting the trial, and coordination among clinics. In addition, we utilized a culturally sensitive multidisciplinary team to address the breast cancer care for minority women. Results: During the two year period since implementation of the regional culturally sensitive breast cancer awareness campaign, we successfully enrolled 32 patients into breast cancer clinical trials. Minority breast cancer patient accrual increased from a 10-year average of 26.7% to 46.9% in comparison with non-Hispanic white patients (p=0.02). The accrual rate of Hispanic population increased from 10% to 21.9%. The accrual rate of black patients increased from 5.3% to 12.5%. Conclusions: The use of materials specifically targeting known barriers to participation in clinical trials successfully improved accrual of minority women, and has the potential to improve the cure rate, decrease disparities in breast cancer care, and eventually decrease the breast cancer burden particularly in underserved minority groups in Inland Empire, California.