tbuckley/cabot-search huggingface dataset:
Impact of the <i>MDM2</i> promoter polymorphisms SNP285 and SNP309 on endometrial cancer risk among caucasians.
Authors: S. Knappskog, J. Trovik, J. Marcickiewisz, S. Tingulstad, A. Staff, K. Hveem, L. Vatten, H. B. Salvesen, P. E. Lonning
Journal: Journal of Clinical Oncology (2011)

5092 Background: MDM2 is a key regulator of p53 and, thus, of cell cycle arrest and apoptosis. The MDM2 intronic promoter polymorphism SNP309T>G increases MDM2 expression through enhanced Sp1 transcription factor binding. Conflicting evidence has linked 309G to elevated risk and early diagnosis of different cancer forms. Recently we reported a second MDM2 promoter polymorphism SNP285G>C, located on the 309G allele (Knappskog et al, Cancer Cell 2011; doi:10.1016/j.ccr.2010.12.019). SNP285C/309G accounts for 12% of the 309G alleles in Western Europeans but is non-existent among Asians. It antagonizes the effect of SNP309G by reducing Sp1 binding and reduces the risk of breast and ovarian cancer. Here, we explored the effect of SNP309 and SNP285 on risk of endometrial cancer in a European population. Methods: We analysed SNP285 and SNP309 status in 915 Norwegian endometrial cancer patients and 2.465 healthy controls. Our primary hypothesis was to examine the effect of the SNP285C/309G haplotype on endometrial cancer risk among individuals carrying the SNP309G allele. Our secondary hypothesis was to explore the effect of SNP309G on endometrial cancer risk and explore the effect of excluding individuals harbouring the SNP285C/309G haplotype from this analysis. Results: The SNP285C/309G haplotype strongly reduces the risk of endometrial cancer among carriers of the SNP309TG genotype (OR: 0.62; CI 0.42-0.91) but not among SNP309GG homozygotes (OR: 1.47; CI 0.89-2.35). SNP309TG and GG genotype carriers revealed a moderately increased risk of endometrial cancer compared to SNP309TT homozygotes (TG: OR 1.17; CI 0.99-1.37; GG: OR 1.21; CI 0.95-1.58; TG + GG combined: OR: 1.18; CI 1.01-1.37). Removing individuals harbouring the SNP309G-counteracting SNP285C from the analysis strengthened this association (TG + GG: OR: 1.20; CI 1.03-1.41). Conclusions: MDM2 promoter haplotypes influence risk of endometrial cancer, mirroring their effect on ovarian cancer. The finding that the SNP285C/309G haplotype reduces the risk of endometrial cancer by 38% among individuals expressing SNP309TG heterozygosity (about 40% of the Caucasian population) reveals ethnic diversity with respect to endometrial cancer risk.
Estimation of risk in cancer patients undergoing palliative procedures by the American College of Surgeons risk calculator.
Authors: Rodrigo Andres Rodriguez, Molly McClain, Bridget N. Fahy, Katherine Teresa Morris
Journal: Journal of Clinical Oncology (2014)

93 Background: Surgical palliation is defined as the use of a procedure in patients with incurable disease to relieve symptoms. The American College of Surgeons Risk Calculator (ACSRC) was created based on data from the National Surgical Quality Improvement Program to predict the risk of surgical complications on a patient specific level. Whether the ACSRC can accurately predict the risk of postoperative complications following palliative procedures in cancer patients is unknown. The purpose of this study was to determine if the ACSRC accurately predicted postoperative complication rates in this setting. Methods: Our surgical oncology database of patients treated from 2011 to 2013 was queried. Thirty-two patients who underwent palliative procedures were identified. Data extracted included: demographics, comorbidities, site and stage of cancer, type of procedure and post-operative complication rate and type. Risk assessment was performed for each patient using the ACSRC. Actual frequency of complications and length of stay (LOS) were compared to ACSRC predicted rate of complications and LOS. Results: See Table. Conclusions: The ACSRC is a powerful tool for aid in surgical decision-making; however, in the case of palliative procedures, it overestimated the risk of postoperative complications and underestimated the LOS. Overestimation of postoperative complications could result in fewer patients being offered potentially beneficial palliative procedures. [Table: see text]
When 'home' means another nation: The power and pitfalls of repatriation at the end of life from a tertiary cancer centre.
Authors: Ros Taylor
Journal: Journal of Clinical Oncology (2016)

46 Background: How people die lives on in the memory of those who survive. It is therefore pivotal for palliative teams to help craft an ending in line with patient and family goals. It has been observed in a tertiary cancer centre that there is often a spiritual imperative for patients to return to their nation of birth, once treatment is stopped and mortality accepted. Methods: Retrospective chart review of 3 patients repatriated for end of life care to their nation of birth (Romania, Portugal, Ireland), focusing on: the conversations about the goal of repatriation and its meaning to the patient; the practical barriers and enablers of repatriation of patients with advanced cancer. Follow-up interview with bereaved families to establish impact of repatriation. Results: Chart review revealed multi-layered hesitant conversations, often facilitated by the palliative care team, to establish that getting ‘home’ meant returning to the country of birth. This became an overarching pre-occupation for the patient, family and team. Patients were not concerned whether they were transferred to a hospital, hospice or family home – it was the country that mattered. There was huge anxiety and little objectivity about fitness to travel. Nurses were more anxious than doctors. Patient and family expressed least anxiety. There was a knowledge deficit regarding fitness to fly, whether an escort was needed, the respiratory and metabolic effects of flight, and how to maximize wellbeing on the journey. Reassurance was gained if the transfer was to a hospital, with greater concern if the transfer was to a community setting. Follow-up interviews with bereaved families are still in progress. Initial findings suggest no regrets in terms of the decision to fly home, and that self-esteem improved with familiarity and social connection. Conclusions: The practical anxieties of health professionals often act as delays to repatriation at the end of life. Checklists to facilitate these journeys would ensure that the process does not need to be learnt each time, and that windows of opportunity are not missed. Achievement of spiritual goals for a loved one is hugely important to those who live on.
Emergence of Indigenous Artemisinin-Resistant <i>Plasmodium falciparum</i> in Africa
Authors: Feng Lu, Richard Culleton, Meihua Zhang, Abhinay Ramaprasad, Lorenz von Seidlein, Huayun Zhou, Guoding Zhu, Jianxia Tang, Yaobao Liu, Weiming Wang, Yuanyuan Cao, Sui Xu, Yaping Gu, Julin Li, Chao Zhang, Qi Gao, Didier Ménard, Arnab Pain, Haitao Yang, Qingfeng Zhang, Jun Cao
Journal: New England Journal of Medicine (2017)

The emergence of artemisinin resistance in Plasmodium falciparum has threatened the effectiveness of malaria treatment in Southeast Asia. In this report, such resistance has been observed in a patient who was working in Equatorial Guinea.
Natural evolution in patients with nonsteroidal anti‐inflammatory drug‐induced urticaria/angioedema
Authors: I. Doña, E. Barrionuevo, M. Salas, J. A. Cornejo‐García, J. R. Perkins, G. Bogas, A. Prieto, M. J. Torres
Journal: Allergy (2017)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequent triggers of drug hypersensitivity with NSAIDs-induced urticaria/angioedema (NIUA) the most common phenotype. Loss of hypersensitivity has been reported for IgE-mediated reactions; however, it has not been assessed in nonimmunological reactions such as NIUA. We evaluated NSAID-hypersensitivity over time in NIUA patients.Patients confirmed as NIUA by positive drug provocation test (DPT) with acetylsalicylic acid (ASA) during 2005-2012 (V1) were included (n=38). Subjects were prospectively re-evaluated by DPT with ASA/other NSAIDs at two time points between 2013 and 2015 (V2 and V3). Atopy was assessed by skin prick test (SPT) using inhalant and food allergens.Patients were evaluated at V1 and re-evaluated after 60 months (V2; IR:48-81) and a further 18 months (V3; IR:14-24). At V2, the majority (24; 63.15%) tolerated ASA and other NSAIDs (Group A) while 14 (36.84%) still reacted (Group B). At V3, all Group A patients remained tolerant; all Group B patients remained hypersensitive. The number of previous episodes reported at V1 and the percentage of reactions induced by ASA/ibuprofen were significantly lower in Group A (P=.005 and P=.006, respectively). Group A patients developed tolerance 72 months (IR:45-87) after their last evaluated reaction (V1); this interval was shorter in nonatopics (P=.003), patients who experienced reactions over 1 hour after NSAIDs administration (P=.001), and those who experienced isolated urticaria after NSAID intake (P=.024).NIUA patients may develop tolerance to NSAIDs over time, a process that seems to be influenced by atopy and type of clinical reaction.
Initial results from ongoing phase I trials of a novel pan bcl-2 family small molecule inhibitor
Authors: J. S. McGreivy, J. Marshall, B. D. Cheson, J. Hwang, S. Malik, P. Lebowitz, J. Mangipudy, C. Soho, J. Viallet
Journal: Journal of Clinical Oncology (2005)

3180 Background: GX15–070 is a small-molecule antagonist of the BH3-binding groove of the bcl-2 family of proteins that are frequently over expressed in cancers. Bcl-2 family protein overexpression has been implicated in the inhibition of apoptosis. GX15–070 has been shown to activate apoptosis in vitro and to exhibit anti-tumor activity in animal models. We report the first in human and first in class initial results of two parallel Phase I studies of GX15–070. Methods: In an accelerated titration design cohorts of 1 patient (pt) were treated with 1.25mg/m2 - 7mg/m2 IV over one hour, weekly in the solid tumor protocol and every 3 weeks in the chronic lymphocytic leukemia protocol (CLL) protocol. Results: N=6 with 5 pts in the solid tumor protocol and 1 pt in the CLL protocol. Mean age 59 (range 25–74). Mean number of prior regimens 3.2 (range 1–5). PK shows rapid initial distribution phases (α t1/2=0.35 hr and β t1/2=1.5 hr), followed by a longer elimination γphase (t1/2=13.4 hr), with a secondary rise following repeated administration possibly due to enterohepatic recirculation. AUC increased in an approximately dose-proportional manner from 17.97 to 38.4 ng.hr/ml over the entire dose range. However, Cmax was not dose proportional. Pharmacodynamic response was evaluated by following plasma oligonucleosomal DNA levels on days 1–5 of cycle 1. The MTD has not been established. Adverse events have mostly been observed during or shortly after the infusion and have been transient: drowsiness (3/6 pts), ataxia (2/6 pts), hypotension (2/6 pts), hypoxia (2/6 pts), allergic reaction (1/6 pts) that was associated with a grade 1 QT prolongation. Most toxicities were mild to moderate, with the exception of 2 episodes of transient grade 2 hypotension, 1 of which was reported as a Serious Adverse Event. Of the 5 solid tumor pts: 3 had progression after 2 cycles, 1 had stable disease at 6 weeks, and for 1 pt response is not yet evaluable. After 2 cycles, the 1 CLL pt had a 60% reduction of bulky lymphadenopathy and a near normalization of peripheral counts. Conclusion: GX15–070 is the first small molecule targeting the bcl-2 pathway to be evaluated clinically and shows evidence of clinical activity at well tolerated doses. Accrual is ongoing. No significant financial relationships to disclose.
Concordance with NCCN practice guidelines for local therapies as a measure of quality of care: Review of practice and identification of quality gaps.
Authors: V. Francescutti, N. L. Watroba, S. B. Edge
Journal: Journal of Clinical Oncology (2011)

6019 Background: Quality of cancer care may be assessed by determining concordance with guidelines. Guideline concordance alone may not be sufficient for determining quality as non-concordant (NC) care may be appropriate for individual cases. This study examined NC with local therapy (LT) breast cancer guidelines of the NCCN at Roswell Park Cancer Institute (RPCI). Methods: Data on all breast cancer patients treated at RPCI are entered into the NCCN Breast Cancer Outcomes Database and concordance with guidelines was determined. Records were reviewed for all NC for LT from 2000-8. Reasons for NC were defined as: documented MD recommendation, patient choice, system failure (lost to followup), and database error. Results: Among 1917 patient encounters there were 411 (21%) instances of NC care for LT; 52 patients had NC care for 2 guidelines. NC care for surgery accounted for 33% and radiation (RT) 67%. Most NC was MD recommended omission of axillary surgery and/or RT in older women with ER + breast cancer or DCIS. Database errors accounted for 5%. System failure was rare, accounting for 0.7%. Conclusions: The majority of NC care was MD recommended or patient choice related. Concordance reports allow objective assessment of quality of cancer care, and can be used for quality assurance. Cancer center program review should be conducted to assure overall appropriateness of MD recommend NC care. Invasive ductal carcinoma group Total (n) NC (%) Physician recommended Patient choice Database error System failure Stage I, II BCS 1,284 19% Axillary surgery omitted 68 7 0 0 RT omitted 118 35 15 2 Stage I, II mastectomy node neg <5cm 150 11% Axillary surgery 0 0 1 0 RT administered 15 0 0 1 Stage I, II mastectomy >5cm or pos margin 17 29% RT omitted 2 0 3 0 Stage I, II SLN + H&E 186 10% Axillary surgery omitted 17 1 0 0 DCIS group Total (n) NC (%) Physician recommended Patient choice Database error System failure DCIS <0.5 cm neg margin 55 47% Axillary surgery 5 0 1 0 RT omitted 14 6 0 0 DCIS unicentric neg margin 124 38% Axillary surgery 12 0 0 0 RT omitted 32 3 0 0 DCIS, BCS 39 10% Axillary surgery 3 0 1 0 DCIS widespread 58 84% Mastectomy omitted or axillary surgery 46 2 1 0 DCIS pos margins 4 100% Mastectomy omitted 4 0 0 0
Clinicopathologic characteristics and survival outcomes in multifocal and multicentric breast cancer.
Authors: Atsushi Fushimi, Atsushi Yoshida, Osamu Takahashi, Naoki Hayashi, Hiroshi Yagata, Koyu Suzuki, Hiroko Tsunoda, Hideko Yamauchi
Journal: Journal of Clinical Oncology (2013)

41 Background: Although multifocal and multicentric (MF/MC) breast cancers are a common entity, their clinical behaviors are not well characterized. We evaluated the impact of MF/MC on the disease-free survival (DFS) and distant disease free survival (DDFS) of breast cancer patients and compared clinicopathological characteristics between MF/MC breast cancers and breast cancers with single lesion. Methods: We retrospectively analyzed 734 consecutive patients who had invasive breast carcinoma and underwent definitive surgery at the St Luke’s International Hospital from January 2004 to December 2006. MF or MC ware defined as more than one lesion in the same quadrant or in separate quadrants, respectively. DDFS and DFS ware calculated by The Kaplan–Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox proportional hazards models. Results: Of 734 patients, 136 (18.5%) had MF/MC disease. MF/MC disease was associated with smaller tumor size (P &lt;0.001). Multivariate analysis shows that MF/MC disease did not have an independent impact on DDFS or DFS adjusting by age, ER status, tumor size, lymphovascular invasion, lymph node metastases and nuclear grade. Conclusions: MF/MC breast cancers were not associated with poor prognostic factors, and were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.
Phase II trial evaluating combination, weekly gemcitabine and docetaxel in progressive, chemotherapy-exposed NSCLC: Preliminary results of OPN 003
Authors: C. H. Huang, C. J. Langer, M. M. Millenson, E. Sherman, J. Seldomridge, J. Schol, A. Rogatko, J. Treat
Journal: Journal of Clinical Oncology (2005)

7295 Background: Docetaxel is the first FDA approved systemic agent for second line therapy (Tx) of NSCLC. In single institution consortium studies, gemcitabine has demonstrated similar activity in the salvage setting. We therefore opted to assess both agents in combination in the salvage Tx of patients (pts) who had received prior systemic chemotherapy. Methods: Eligibility stipulated advanced NSCLC, exposure to one prior platinum based regimen, PS 0–1, and adequate physiologic indices. In radiation-naï ve pts, docetaxel was dosed at 40mg/m2 days 1 & 8 q 3 wks, and gemcitabine at 800mg/m2 days 1 and 8 q 3 wks. RT exposed pts received 40mg/m2 and 600mg/m2 respectively days 1 and 8. In the absence of grade 3 or 4 neutropenia/thrombocytopenia, the gemcitabine dose was escalated to 1 g/m2 days 1 and 8. Results: To date, 25 patients have been enrolled. 17 pts, (8 men, 9 women) enrolled between 6/02 and 1/04, are fully evaluable. The median age is 61 (range, 44 to 79). 12 (71%) are PS 1. All were previously treated with carboplatin, 15 (88%) with paclitaxel, 4 (24%) with docetaxel. 8 (47%) received prior RT, 6 (35%) to brain. Other prior exposures included erolotinib (versus placebo) in 4 pts, CP 547, 632, an experimental oral angiogenesis inhibitor in 2 pts, and bevacizumab in 1. 61 cycles (median 3, range 2–10) have been administered. 6 pts (35%) received ≥ 6 cycles. Grade 3/4 toxicity included neutropenia in 8 (47%) and gemcitabine pneumonitis in 1 (6%). The confirmed response rate is 22%. Median time to progression exceeds 2 mos, and median survival to date exceeds 6 mos. Conclusions: Combination weekly docetaxel and gemcitabine in the salvage setting post carboplatin-taxane failure is well tolerated, with acceptable toxicity, clear activity and promising median survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis AstraZeneca, Aventis, Bristol-Myers Squibb, Genentech, ImClone, Novartis Lilly Oncology AstraZeneca, Aventis, Bristol-Myers Squibb, Genentech, Lilly Oncology, Pfizer
Phase II study of loading-dose ibandronate treatment in patients with breast cancer and bone metastases suffering from moderate to severe pain.
Authors: O. Dizdar, M. K. Altundag, S. Ozkok, Z. Ozsaran, P. Saip, Y. Eralp, S. Komurcu, O. Kuzhan, M. Ozguroglu, M. Karahoca
Journal: Journal of Clinical Oncology (2010)

e19507 Background: Ibandronate is a third generation bisphosphonate with analgesic effects demonstrated in previous phase III trials. Renal safety of ibandronate enables using higher-dose regimens. We aimed to investigate whether high doses of ibandronate is effective and safe in patients with breast cancer and bone metastases suffering from moderate to severe pain. Methods: Female breast cancer patients with moderate to severe metastatic bone pain diagnosed with visual analogue scale (VAS) >5 (range: 0 (no pain) to 10 (maximum pain)) were included in this phase II single arm multicenter study. Patients were treated with intravenous ibandronate 6mg infused over 15 minutes on 3 consecutive days. Patient visits were made on days 1, 2, 3, 4, 7, and 14, and vital signs, physical examination, analgesics used, blood counts and serum biochemistries, pain assessment with VAS and Karnofsky performance status were evaluated. Patients were given diaries to rate the intensity of pain on a VAS chart and note the analgesics they have used daily for 14 days. Results: Thirteen patients were included in the study. Median age was 51. Five patients (30,8%) had a history of bisphosphonate use. The rate of analgesic use was 69,2%, 0%, 7,7%, 15,4%, 16,7% and 15,4% on days 1, 2, 3, 4, 7 and 14, respectively. Pain intensity based on VAS scores significantly decreased on day 7 (3.2 ± 2.2, p<0.01) and day 14 (3.0 ± 2.1, p<0.01) compared with day 1 (6.1±0.9). Time to pain response was 8.2 days in ITT population. Adverse events were observed in 5 patients (38.5%), with vomiting being the commonest one, and with mild to moderate severity in most cases. Only one patient (7.7%) experienced severe headache, which spontaneously resolved on follow up. Majority of the adverse events were deemed unrelated to the study drug. No serious adverse events were observed. No significant change was detected in laboratory parameters throughout the study. Conclusions: Administration of loading dose ibandronate resulted in significant reduction in bone pain and analgesic use by the patients. The intensive dosing schedule was not associated with any deterioration in renal function and was generally well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharma AG
Randomized phase II trial of tegafur-uracil (UFT) and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small cell lung cancer: NJLCG 0601.
Authors: M. Maemondo, S. Sugawara, T. Ishida, A. Inoue, K. Usui, O. Ishimoto, N. Matsubara, M. Tachihara, Y. Saijo, T. Nukiwa
Journal: Journal of Clinical Oncology (2010)

7083 Background: A treatment (UP) with tegafur-uracil (UFT) and cisplatin in combination with concurrent thoracic radiotherapy (c-TRT) could have favorable efficacy with less toxicity for locally advanced non-small cell lung cancer (LA-NSCLC). We conducted this randomized phase II study to compare this regimen to a treatment (VC) with vinorelbine and cisplatin, which is a commonly used regimen with c-TRT for LA- NSCLC in Japan. Methods: Patients (pts) with LA-NSCLC were randomized to receive UP (UFT400 mg/m2 on days 1-14 and 29-42 and cisplatin 80 mg/m2 on days 8 and 36) or VC (vinorelbine 20 mg/2 on days 1, 8, 29, and 36 and cisplatin 80 mg/m2 on days 1 and 29), stratified by age, gender, histology, and stage. In both arms, c-TRT began on day 1 (total 60Gy in 30 fractions). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 80% in eligible pts would indicate potential usefulness while ORR of 60% would be the lower limit of interest, the estimated accrual was 33 pts in each arm. Results: From February 2006 to May 2009, 70 pts were enrolled from 5 institutions. Finally 66 pts were evaluable for efficacy and safety. Patient characteristics were: Male/Female 54/12; median age 62 (range 40-75); Performance status 0/1 31/35; IIIA/IIIB 24/42. ORRs were 80% (95%CI: 67-93) and 71% (95%CI: 55-87) for the UP arm and the VC arm, respectively. With a median follow-up of 11.8 months, median PFS in the UP arm was 7.9 months and in the VC arm was 5.9 months. grade 3/4 neutropenia occurred in 20% and 58% of pts in the arms UP and VC, respectively. There was no remakable difference in other toxicities between both arms. Two pts in the VC arm died of radiation pneumonitis. Conclusions: Combined with c-TRT, UP achieved more preferable efficacy and safety compared with VC, suggesting a promising candidate as a standard regimen with c-TRT for LA-NSALC. Further evaluation of UP with c-TRT is warranted in a phase III setting in comparison with cisplatin-based second generation chemotherapy with c-TRT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Chugai Pharma, Daiichi Sankyo, Lilly, Novartis, sanofi-aventis