tbuckley/cabot-search huggingface dataset:
A phase I study of a novel taxane, TL310, orally administered every week in patients (pts) with advanced solid tumors
Authors: R. M. Glasspool, A. V. Boddy, T. R. Evans, M. J. Griffin, A. Anthoney, A. Barker, R. E. Longley, C. J. Twelves, C. J. Edwards, H. E. Wilcox
Journal: Journal of Clinical Oncology (2007)

2544 Background: TL310 is a novel, oral taxane with potent pre-clinical activity in taxane-resistant model systems. This is the first study to evaluate the safety, tolerability and pharmacokinetics (PK) of TL310 in pts with advanced refractory solid tumors. Methods: Pts with adequate hematologic, renal, and liver function received TL310 administered orally on days 1, 8 and 15 of a 28-day cycle. Pts were continuously assessed for safety and dose-limiting toxicity (DLT) was based on first cycle toxicity only. A rapid dose escalation schedule was used (1 pt per dose level until ≥ grade 2 toxicity then 3–6 patients per cohort). The maximum tolerated dose (MTD) was defined as the dose level below that at which ≥ 2 of 3–6 pts experienced DLT. PK sampling was performed on days 1, 2, 3–4, 8, 15, 16, 17–18, 22 of cycle one. Serial imaging with CT was performed every 8 weeks to assess response. Results: 18 patients [M=11, F=7], ECOG PS ≤ 2 were treated with doses of 5 (1 pt), 10 (1pt), 20 (1pt), 40(2pts), 80 (5pts), 120 (3pts) and 160 mg/m 2 (5pts). 1 pt had grade 2 vomiting at 80mg/m 2 . This, and subsequent, dose levels were expanded to include 3 pts. 3 pts (2 at 80 and 1 at 160 mg/m 2 ) vomited immediately after drug administration during cycle 1 and were replaced. 1/5 patients experienced a DLT at 160 mg/m2 with G5 neutropenic sepsis, G4 neutropenia and G4 thrombocytopenia. No other grade 3/4 toxicities attributed to study drug have occurred. Of 18 patients assessable for response, 1 had a partial response (gastric cancer) at 80 mg/m 2 and 6 had stable disease for &gt; 2 cycles (esophageal 3, melanoma 1, ovary 1, cervix 1). The maximum concentration (Cmax) increased with dose up to 120 mg/m 2 , but appeared to plateau (86±6 ng/ml) in 4 of 5 patients at 160 mg/m 2 . TL310 has a half-life of up to 80 hours, but PK were very similar on successive courses of treatment. Conclusions: TL310 can be administered orally up to 160 mg/m 2 on day 1, 8, 15 of a 28 day cycle and shows promising activity at doses below the MTD. The MTD has not yet been defined and dose escalation continues. No significant financial relationships to disclose.
Empiric dose reduction of pegfilgrastim in breast cancer patients receiving cytotoxic chemotherapy
Authors: C. Paba, J. Sachdev, L. Kronish, M. Jahanzeb, S. Waheed
Journal: Journal of Clinical Oncology (2008)

20636 Background: Pegfilgrastim greatly reduces the incidence of febrile neutropenia in patients receiving myelosuppressive chemotherapy, but is associated with side effects such as bone pain often requiring analgesics. Empiric dose reduction from 6mg to 4mg administered on the day after chemotherapy was used to ameliorate pain while maintaining count recovery in these patients. Methods: We retrospectively reviewed 25 female breast cancer patients who were undergoing adjuvant or neoadjuvant chemotherapy with pegfilgrastim support who had empiric dose reductions because of bone pain with concomitant normal or high leukocyte counts during recovery. Data of blood counts, complaints of bone pain and analgesic use were collected. Weekly complete blood counts (CBC's) were analyzed. White cell counts and ANC before and after pegfilgrastim dose reduction and treatment delays post dose reduction were recorded. Results: Median age was 52 yrs (5 < 40, 6 < 50, 6 < 60, 4 < 70 while 2 were more than 70); 18 were African Americans, 7 Caucasians; 4 stage I, 13 were stage II and 8 were stage III. Seven patients received neoadjuvant chemotherapy and 18 received it in the adjuvant setting. Thirteen patients (52%) were estrogen receptor positive; 56% patients received Doxorubicin and cyclophosphamide (60/600 mg/m2) followed by docetaxel (100 mg/m2). Median number of cycles given was 7 (range 4–10) and total number of CBC's recorded were 397. After dose reduction, the highest white cell count noted on day 8 of the cycle was 48,600 and 41,300 on day 15; 8 patients had WBC >20,000. The lowest nadir WBC count after dose reduction was 800 with an ANC of 200 on day 8. Seven patients required narcotics for pain control at standard dose of pegfilgrastim. None of the 25 patients experienced bone pain after dose reduction. We were able to give 100% of the planned doses without dose delays in all cases after a dose reduction to 4 mg per cycle. Conclusions: From this small experience, it appears that dose reduction may be a viable and safe option to avoid the undesirable side effects of pegfilgrastim especially bone pain in patients receiving cytotoxic chemotherapy. A prospective well designed study in appropriately selected patients is warranted to investigate the optimal dose in these patients. No significant financial relationships to disclose.
Pancreatectomy for neoplasm: National outcomes in mortality
Authors: J. T. McPhee, M. Zayaruzny, G. F. Whalen, D. E. Litwin, M. E. Sullivan, F. A. Anderson, J. F. Tseng
Journal: Journal of Clinical Oncology (2006)

4035 Background: Pancreatic resection remains the only potentially curative intervention for pancreatic cancer. The goal of this study was to evaluate factors affecting outcomes after pancreatectomy for neoplasm using a large national database. Methods: This is a retrospective analysis of 6,091patients (pts) undergoing pancreatic resection for non-endocrine neoplastic disease obtained from the National Inpatient Sample 1998–2003 (≈ 30,241 pts nationally by weighted analysis). Crude primary outcome measures of in-hospital mortality and postoperative disposition were analyzed by chi-square. A proportional hazards model was then constructed to adjust outcomes for age, sex, hospital teaching status, hospital surgical volume and selected co-morbid conditions. Results: 42,380 patient discharges (≈209,016 nationally) occurred with a primary diagnosis of pancreatic neoplasm. 6,091 (14%) pts underwent resection during that hospitalization. In-hospital mortality was 5.8% with a significant decrease of 7.7% - 4.4% from 1998–2003 (p=.016, regression coefficient .0042). In the univariate analysis pts treated at a non-teaching hospital had higher mortality rates (9.4% vs. 4.4% p&lt;.0001). However, when adjusted for covariates including hospital surgical volume [low (&lt;4 resections/year), medium (4–13/year), high (&gt;13/year)] teaching status became insignificant in predicting mortality. Resections done at low and medium volume centers were predictive of higher mortality compared to high volume centers (OR 4.1 [2.7, 6.1] and OR 2.4 [1.6, 3.6]). Female gender was predictive of lower mortality (OR 0.58 [0.46, 0.74]). Younger pts (40–69) had lower mortality than pts 70 years or older. Overall, median post-operative length of stay (LOS) was 11 days (SD 23.9). LOS was shorter for female patients (median 10 days vs. ll days) and for resections done at high volume centers (median 10 days vs. ll days). Conclusions: This large observational study demonstrates an improvement in operative mortality for patients undergoing pancreatectomy for neoplastic disease 1998–2003. Furthermore, it demonstrates superior adjusted outcomes in terms of mortality, and LOS, for females, younger patients, and those treated at high volume surgical centers in the United States. No significant financial relationships to disclose.
GW26-e1032 Renal Sympathetic Denervation Improves Cardiac Dysfunction in Rats with Chronic Pressure Overload
Authors: Zhenzhen Li, Hui Jiang, Dan Chen, Qian Liu, Jie Geng, Jiqun Guo, Renhua Sun, Guoqing Zhu, Qijun Shan
Journal: Journal of the American College of Cardiology (2015)
Tracking the fate of antigen-specific versus cytokine-activated natural killer cells after cytomegalovirus infection
Authors: Tsukasa Nabekura, Lewis L. Lanier
Journal: The Journal of Experimental Medicine (2016)

Natural killer (NK) cells provide important host defense and can generate long-lived memory NK cells. Here, by using novel transgenic mice carrying inducible Cre expressed under the control of Ncr1 gene, we demonstrated that two distinct long-lived NK cell subsets differentiate in a mouse model of cytomegalovirus (MCMV) infection. NK cells expressing the MCMV-specific Ly49H receptor differentiated into memory NK cells by an activating signaling through Ly49H and Ly49H− NK cells differentiated into cytokine-activated NK cells by exposure to inflammatory cytokines during infection. Interleukin-12 is indispensable for optimal generation of both antigen-specific memory NK cells and cytokine-activated NK cells. MCMV-specific memory NK cells show enhanced effector function and augmented antitumor activity in vivo as compared with cytokine-activated NK cells, whereas cytokine-activated NK cells exhibited a more robust response to IL-15 and persisted better in an MCMV-free environment. These findings reveal that NK cells are capable of differentiation into distinct long-lived subsets with different functional properties.
Randomized clinical trial of medical qigong on quality of life, fatigue, side effects, mood, status, and inflammation of cancer patients
Authors: B. Oh, P. Butow, B. Mullan, S. Clarke, P. Beale, N. Pavlakis, D. Rosenthal
Journal: Journal of Clinical Oncology (2009)

9617 Background: The quality of life (QOL) of cancer patients is often diminished due to the side effects of treatment and symptoms of the disease itself. This study examines the impact of Medical Qigong (MQ), including gentle exercise and relaxation through meditation and breathing exercise based on the Chinese Medicine theory of energy channels, on quality of life (QOL), fatigue, side effects, mood status and inflammation. Methods: One hundred sixty two patients diagnosed with a range of cancers recruited from three university teaching hospitals were randomly assigned to two groups: a control group (n=83) that received usual health care and an intervention group (n=79) who participated in a MQ program for 10 weeks in addition to receiving usual health care at the hospital. Quality of life and symptoms were measured by the FACT-G, cancer related fatigue by FACT-F and mood status by POMS. The inflammatory marker serum C-reactive protein (CRP) was also monitored serially. Results: Regression analysis indicated that the MQ intervention group significantly improved on measures of overall QOL (t 144 = -5.761, p&lt;0.001), fatigue (t 153 = -5.621, p&lt;0.001), mood disturbance (t 122 =2.346, p=0.021) and inflammation (CRP) (t 99 =2.042, p&lt;0.044) compared to the usual care control group after controlling for baseline variables. Analysis of the FACT-G subscales revealed that the MQ intervention group also significantly improved in satisfaction with sex life (t 92 =-3.783, p&lt;0.001) and reduced side effects of nausea (t 152 =-2.071, p=0.040) and sleep disturbance (t 150 =-2.603, p=0.010) compared to the usual care control group. Pain was improved in both intervention and control groups. Conclusions: This study suggests that MQ with usual health care can improve overall QOL, fatigue, positive mood status and reduce the side effects of nausea, sleep disturbance and inflammation of cancer patients. This study supports the use of MQ as an intervention for cancer care. No significant financial relationships to disclose.
Upgraded hardware─What about the software? Brain updates for return to play following ACL reconstruction
Authors: Dustin R Grooms, Gregory D Myer
Journal: British Journal of Sports Medicine (2016)

The ‘release for full activity’ or the determination of ‘return to sport’ (RTS) is an important landmark for any athlete following anterior cruciate ligament reconstruction (ACLR). The ‘clearance’ to RTS following ACLR is not the golden ticket back to safe and successful preinjury level activity. Unfortunately, the ‘cleared’ status is accompanied by an up to 40-fold elevated risk of second ACL injury (relative to peers without a history of ACL injury) despite accepted ‘time’ postsurgery.1

The reliance on time since surgery is too common, with the majority of investigations using time postoperative as a key criterion for RTS. Even more concerning, one-third of the investigations indicated that time from surgery was the only determinant for RTS decision-making.2 The insistence of a time-based and accelerated RTS may be heightened with pressures from coaches, parents and/or teammates to meet specific sport timelines. However, reliance on time as distinct from function to drive sport reintegration contributes to the gap between the athletes' perceived versus actual sports readiness.

Historically, little attention has been focused on late-phase rehabilitation …
Incidence and management of bone metastases digestive cancer.
Authors: F. Portales, S. Thézenas, E. Samalin, E. Assenat, P. Senesse, M. Ychou
Journal: Journal of Clinical Oncology (2011)

e14110 Background: Gastrointestinal (GI) cancer rarely metastasizes to the bones. This retrospective study aimed to determine the incidence and management of bone metastases (BM) from GI cancers. Methods: Among 3438 patients (pts) with primary GI tumors (2,434 colorectal and 1,004 gastroesophageal cancer) treated between 1996 and 2006, at the Montpellier Cancer institute,189 pts (5.5%) developed bone metastases (BM). Clinical and biological data were collected in data base. Results: Median age was 60 yrs (range 27-92), 123 (65%) were male. Histology was adenocarcinoma in 157 pts, squamous cell carcinoma in 30 pts, undifferentiated in 1 pt. Primary tumor (PT) sites were: colon 69 pts (36%), rectum 41 pts (22%), gastroesophageal (GE) 79 pts (42%), and initial staging was T3-T4 in 107 pts (85%), positive nodal status in 53 pts (71%). and 85 pts (45%) were metastatic. 38 pts / 85 had synchronous BM: 63 % in GE 34% in colorectal cancers (p=0.01). Median time between PT diagnosis and bone spreading was 12.2 months (range 0-236) and was significantly different with tumor site (colorectal: 25 months [0-236], GE: 4 months [0-170], p= 0.0001), nodal spreading (N0: 35 months [0-208] and N+: 19 months [0-170], p=0.02), and tumor stage (T0-2: 21months [2-208] and T3-4: 18 months [0-138], p=0.047). Chemotherapy was administered to 166 pts (88%). Pain was the most frequent clinical sign leading to BM diagnosis in 144 pts (76%). Hypercalcemia was an uncommon event with only 2 cases. In 173 pts (92%), the diagnosis was confirmed by bone scan. Pain management of BM included analgesic agents in 168 pts (89%), biphosphonates in 19 pts (10%), local radiation therapy in 95 pts (50%). Twelve pts (6%) had surgery for pathological fracture or medullar compression. With a median follow up of 91.7 months [0.2-91.7], median survival after BM diagnosis was 9.4 (6.3-11.4) and 3.3 months (2.5-9.0) for colorectal and GE cancer, respectively. Significant favorable prognostic factors for 1-year survival were: surgical treatment of PT and metastases (40% Vs 23% p=0.012) and a number of BM less than 3 (36% Vs 22 % p= 0.0016). Conclusions: This retrospective study shows a relatively high incidence of BM in GI cancer (5.5%) and confirms its poor prognosis, specially in GE cancer and justify a prospective study.
Maternity services will be rated as part of safety improvement drive
Authors: Ingrid Torjesen
Journal: BMJ (2016)

Clinical commissioning groups in England will be rated on the safety of their maternity services, and £8m (€9m; $10m)—at least £40 000 per trust—will be made available through Health Education England to improve multidisciplinary training as part of a government action plan to improve maternity services.1

As part of the plan, which was launched by Jeremy Hunt, health secretary for England, on 17 October, every maternity unit in England will be expected to participate in a National Maternal and Neonatal Health Quality Improvement Programme; a similar scheme in Scotland was linked to a 19% fall in stillbirths over three years. A £250 000 maternity safety innovation fund will be available to help create and pilot new ideas for improving maternity care.

Hunt also announced a consultation later this year on …
Outcomes in patients with stage III non-small cell lung cancer (NSCLC) treated with cisplatin and irinotecan with concurrent thoracic radiotherapy (CRT): A multi-disciplinary thoracic oncology experience at East Carolina University.
Authors: Jessica R. Hildebrand, Sulochana Devi Cherukuri, Hyder Husain Arastu, Clinton Leinweber, Chipman Robert Geoffrey Stroud, Teresa Parent, Cynthia R. Cherry, Jessica Hardin, Paul R. Walker
Journal: Journal of Clinical Oncology (2016)

e20019 Background: Platinum-based doublet chemotherapy with concurrent radiation is the standard of care for unresectable locally advanced NSCLC. The National Cancer Database reports a median overall survival (MOS) for stage III NSCLC of 12months and 3 year OS of 20%. Approximately 40-50% of patients with locally advanced NSCLC will develop brain metastasis during the course of their disease (Mamon et al JCO 2005). Prophylactic cranial irradiation (PCI) has been reported to reduce the incidence of brain metastasis to 9% (Pottgen et al, JCO 2007). We reviewed patient outcomes from our multi-disciplinary thoracic oncology program database of cisplatin-irinotecan with concurrent RT in stage III NSCLC. Methods: Patients with unresectable stage IIIa/b NSCLC who were treated with definitive cisplatin and irinotecan with CRT between 2011 and 2015 were identified through a search of our thoracic oncology database. 61 patients were identified. Treatment consisted of cisplatin 30mg/m2 and irinotecan 65 mg/m2 on days 1 and 8 every 21 days for 4 cycles. Concurrent thoracic radiation therapy to ≥ 60 Gy started with cycle 2. Survival curves were estimated by Kaplan Meier analysis. Our primary end point was MOS and our secondary endpoint was rate of brain metastasis. Results: Patient characteristics: 56.7% squamous, 36.7% adenocarcinoma, 6.6% other histology, 56.7% stage IIIA, 43.3% Stage IIIB. MOS was 14.4 months and 3 year overall survival was 32.9% (p = 0.037). Rate of brain metastasis was 11.6% (p < 0.05) Conclusions: Definitive cisplatin and irinotecan with CRT is effective for treating locally advanced NSCLC and reduces the incidence of brain metastasis at a rate comparable to PCI.
Reactivation of Human Herpes Virus 6 (HHV6) during Hematopoietic Stem Cell Transplantation: Risk Factor Analysis of HHV6 Encephalitis and Survival.
Authors: Yutaka Shimazu, Takayuki Ishikawa, Tatsuo Ichinohe, Tadakazu Kondo, Kouhei Yamashita, Wataru Maruyama, Takashi Uchiyama
Journal: Blood (2008)
Esculetin induces antiproliferative and apoptotic response in pancreatic cancer cells by directly binding to KEAP1
Authors: Rashi Arora, Sharad Sawney, Vikas Saini, Chris Steffi, Manisha Tiwari, Daman Saluja
Journal: Molecular Cancer (2016)

A handful of studies have exploited antitumor potential of esculetin, a dihydroxy coumarine derivative; the targets to which it binds and the possible downstream mechanism for its cytotoxicity in cancer cells remain to be elucidated. Using pancreatic cancer cell lines as a model system, herein the study was initiated to check the efficacy of esculetin in inhibiting growth of these cancer cells, to decipher mechanism of its action and to predict its direct binding target protein.The cytotoxicity of esculetin was determined in PANC-1, MIA PaCa-2 and AsPC-1 cell lines; followed by an inspection of intracellular levels of ROS and its associated transcription factor, p65-NF-κB. The interaction between transcription factor, Nrf2 and its regulator KEAP1 was studied in the presence and absence of esculetin. The effect of Nrf2 on gene expression of antioxidant response element pathway was monitored by real time PCR. Thereafter, potential binding target of esculetin was predicted through molecular docking and then confirmed in vitro.Esculetin treatment in all three pancreatic cancer cell lines resulted in significant growth inhibition with G1-phase cell cycle arrest and induction of mitochondrial dependent apoptosis through activation of caspases 3, 8 and 9. A notable decrease was observed in intracellular ROS and protein levels of p65-NF-κB in PANC-1 cells on esculetin treatment. Antioxidant response regulator Nrf2 has been reportedly involved in crosstalk with NF-κB. Interaction between Nrf2 and KEAP1 was found to be lost upon esculetin treatment in PANC-1 and MIA Paca-2 cells. Nuclear accumulation of Nrf2 and an upregulation of expression of Nrf2 regulated gene NQO1, observed on esculetin treatment in PANC-1 further supported the activation of Nrf2. To account for the loss of Nrf2-KEAP1 interaction on esculetin treatment, direct binding potential between esculetin and KEAP1 was depicted in silico using molecular docking studies. Pull down assay using esculetin conjugated sepharose beads confirmed the binding between esculetin and KEAP1.We propose that esculetin binds to KEAP1 and inhibits its interaction with Nrf2 in pancreatic cancer cells. This thereby promotes nuclear accumulation of Nrf2 in PANC-1 cells that induces antiproliferative and apoptotic response possibly by attenuating NF-κB.
In type 2 diabetes treated with high-dose insulin, liraglutide reduced HBA<sub>1c</sub>
Authors: Krista Gonzales, Gunjan Y. Gandhi
Journal: Annals of Internal Medicine (2016)

Source Citation Vanderheiden A, Harrison L, Warshauer J, et al. Effect of adding liraglutide vs placebo to a high-dose insulin regimen in patients with type 2 diabetes: a randomized clinical trial. JAMA Intern Med. 2016;176:939-47. 27273731
The Ethics of Organ Donor Registration Policies: Nudges and Respect for Autonomy
Authors: Douglas MacKay, Alexandra Robinson
Journal: The American Journal of Bioethics (2016)

Governments must determine the legal procedures by which their residents are registered, or can register, as organ donors. Provided that governments recognize that people have a right to determine what happens to their organs after they die, there are four feasible options to choose from: opt-in, opt-out, mandated active choice, and voluntary active choice. We investigate the ethics of these policies' use of nudges to affect organ donor registration rates. We argue that the use of nudges in this context is morally problematic. It is disrespectful of people's autonomy to take advantage of their cognitive biases since doing so involves bypassing, not engaging, their rational capacities. We conclude that while mandated active choice policies are not problem free—they are coercive, after all—voluntary active choice, opt-in, and opt-out policies are potentially less respectful of people's autonomy since their use of nudges could significantly affect people's decision making.