tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA CD3 TCB) for the treatment of CEA-expressing solid tumors.
Authors: Ignacio Melero, Neil Howard Segal, Jose M. Saro Suarez, Willeke Ros, Maria Martinez Garcia, Emiliano Calvo, Victor Moreno, Santiago Ponce Aix, Aurelien Marabelle, James M. Cleary, Herbert Hurwitz, Joseph Paul Eder, Cancize Jamois, Anton Belousov, Said Bouseida, Federico Sandoval, Marina Bacac, Tapan K. Nayak, Vaios Karanikas, Guillem Argiles
Journal: Journal of Clinical Oncology (2017)

2549 Background: CEA CD3 TCB (RO6958688) targets CEA on tumor cells and is agonistic for CD3e on T cells. In mouse models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and up-regulates the PD-1/PD-L1 pathway. Methods: Biodistribution was assessed in mice using SPECT/CT. Patient (pts) samples correspond to 2 dose-escalation studies in CEA+ solid tumors. Study 1 (S1): single agent weekly (qW) (0.052 to 600 mg, iv, n = 80), and Study 2 (S2): combination of RO6958688 qW (5 to 160 mg, iv) with 1200mg atezolizumab q3W (n = 38). Analytical methods: PK - population modeling approach; anti-drug antibodies (ADA) - ELISA; immunophenotyping in peripheral blood (PB) by flow cytometry (FCM), in pre- (BSL) and on-treatment (OT) biopsies by immunohistochemistry (IHC) and FCM; plasma cytokines - multiplex assays; PD-L1 - SP142 assay. Results: In mice, RO6958688 preferentially accumulated in CEA+ tumors. In pts with no ADAs tested thus far in both studies (S1 29; S2 21), RO6958688 showed near linear PK and exposure. In S1, OT biopsies demonstrated a statistically significant increase in density and activation profile of T cells (CD3: 2.6-fold, n = 21; CD3/CD8: 3.7 fold, n = 17; CD3/Ki67: 4-fold, n = 20; CD8/PD1: 1.7-fold, n = 15) without dose-dependence. In S2, preliminary data of T cell density (5-80mg) were similar to S1 (2-fold). In S1, a significant correlation was observed between treatment-induced tumor lesion reduction and increases of OT CD8/CD25 fluorescence intensity from BSL (p = 0.028). PD-L1 expression increased in OT biopsies in both studies. In S1, from week 4, a moderate expansion of activated CD8 T cells (HLA-DR/Ki67) but not of CD4, was detected in PB at doses &gt; 60mg ( &gt; 3.3 fold). Transient increases of several cytokines were seen in both studies with levels peaking within 24hrs. Conclusions: PK and PD results consistent with tumor inflammation and mechanism of action support that RO6958688 is the first tumor-targeted T cell bispecific to show intra-tumoral biological activity in pts with CEA+ solid tumors. Updated data will be presented. Clinical data are reported separately.
Outcome of Autologous Stem Cell Transplantation in Myeloma Patients Aged ≥ 75 Years
Authors: Qaiser Bashir, Mohammed El Shazly, Denái R. Milton, Krina Patel, Nina Shah, Yago Nieto, Partow Kebriaei, Uday R. Popat, Simrit Parmar, Betul Oran, Stefan O. Ciurea, Chitra Hosing, Hans Lee, Elisabet E. Manasanch, Robert Z. Orlowski, Richard E. Champlin, Muzaffar Qazilbash
Journal: Blood (2016)
Randomized phase III trial of utidelone, a genetically engineered epothilone analog, in combination with capecitabine versus capecitabine alone for metastatic breast cancer patients with previous taxane and anthracycline treatment.
Authors: Binghe Xu, Tao Sun, Qingyuan Zhang, Zhongyu Yuan, Pin Zhang, Wang Xiao Jia, Shude Cui, Zefei Jiang, Yuee Teng, Xi-Chun Hu
Journal: Journal of Clinical Oncology (2016)

1004 Background: Utidelone, a genetically engineered epothilone analog, is a microtubule stabilizing agent that showed promising activities in phase I and phase II trials. In this report, a multi-center, randomized phase III trial of utidelone plus capecitabine (CAP) vs CAP alone wascarried out to assess the efficacy and safety. Methods: Patients with metastatic breast cancer (MBC) previously treated with anthracycline and taxanes were randomized to utidelone (30mg/m2/d intravenously on d1-d5) plus CAP (1,000 mg/m2 orally bid on d1-d14) or CAP alone (1,250 mg/m2 orally bid on d1-d14) given every 21 days, until disease progression or unacceptable toxicity occurred. The two arms were enrolled with 2:1 ratio. The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), safety, and overall survival (available by 2017). PFS was estimated using the Kaplan-Meier product-limit method. Results: Of 405 patients randomized, about 80% had more than two prior chemotherapy regimens. Median of 6 and 5 cycles of utidelone plus CAP and CAP alone, respectively, were administered. The combination of utidelone with CAP was superior to CAP alone for both PFS (hazard ratio= 0.58; 95% CI, 0.44 to 0.75; log-rank P <0.0001) and ORR (39.4% with 2 complete responses vs 28.9% in the monotherapy arm). Utidelone plus CAP showed low level of liver and renal toxicities, and did not have significant increase in myelosuppression. Grade3/4 adverse events included peripheral neuropathy (14.2% in combination arm vs 0% in CAP alone), hand-foot syndrome (10% vs 6.7%), nausea (1.5% vs 1.5%), hyperbilirubinaemia (0% vs 1.5%), diarrhea (5% vs 0%), anaemia (3.1% vs 3%), leukopenia(4.2% vs 5.2%) and neutropenia (6.5% vs 5.2%). Conclusions: Utidelone plus CAP significantly improved PFS and ORR and had a manageable safety profile in this heavily pretreated population. It had very limited myelosuppression in addition to low liver and renal toxicities, in contrast to ixabepilone and other epothilone analogs. It offers a new potential therapeutic option for patients with MBC. Clinical trial information: NCT02253459.
Another Beginning for Cystic Fibrosis Therapy
Authors: Pamela B. Davis
Journal: New England Journal of Medicine (2015)

Treatments for the fundamental defect in cystic fibrosis are beginning to come to fruition. Cystic fibrosis, an autosomal recessive disease of epithelial chloride transport, can be caused by more than 1000 mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). However, these mutations fall into six functional categories,1 which gives hope that therapies specific to particular mutant categories can be developed. The first success, ivacaftor, was approved by the Food and Drug Administration (FDA) in 2012 for treatment of the 4 to 5% of patients who have the Gly551Asp mutation in CFTR and later for . . .
Epidemiology of lung cancer: A joinpoint analysis of temporal incidence and mortality trends in 38 countries.
Authors: Martin CS Wong, Stephen Lam Chan, Xiang Qian Lao, Lap Ah Tse, KF Ho, William Goggins
Journal: Journal of Clinical Oncology (2017)

e13091 Background: Lung cancer is the leading cause of cancer death worldwide. We examined the correlation between lung cancer incidence/mortality and country-specific socioeconomic development, and evaluated the most recent global patterns and trends of this cancer in 38 countries. Methods: We retrieved age-standardized incidence rates of lung cancer in 2012 from the GLOBOCAN database. Temporal patterns were assessed for all countries obtained from the Cancer Incidence in Five Continents volumes I-X and the WHO mortality database. Simple linear regression analysis was used to evaluate their correlations with Human Development Index (HDI) and Gross Domestic Product (GDP) per capita. The average annual percent change (AAPC) of the incidence and mortality trends in the most recent 10 years were evaluated from join-point regression analysis according to country and gender. The statistical significance of AAPC was ascertained comparing with zero, and all insignificant AAPCs were regarded as having “stable trends”. Results: The global incidence and mortality of lung cancer varied by 31-fold. Country-specific HDI was strongly correlated with age-standardized incidence (r = 0.70) and mortality (r = 0.67), and so was GDP per capita to a lesser extent (r = 0.24 to 0.55) (all p &lt; 0.001). Among men, 22 and 30 (out of 38 and 36) countries showed declining incidence and mortality trends, respectively; whilst among women, 19 and 16 countries showed increasing incidence and mortality trends, respectively. The AAPCs ranged from -2.8 to -0.6 (incidence) and -3.6 to -1.1 (mortality) among countries with declining trend in men, whereas the AAPC range was 0.4 to 8.9 (incidence) and 1 to 4.4 (mortality) among countries with increasing trends in women. Among women, Brazil, Spain and Cyprus had the greatest incidence increase, and all countries in Western, Southern and Eastern Europe had increasing mortality. Conclusions: Countries with higher socioeconomic development had higher lung cancer incidence and mortality. The incidence and mortality rates of lung cancer were increasing in many countries among women but declining in most countries among men, highlighting the need for regular surveillance and global preventive measures.
Regional nodal irradiation after breast conserving surgery for HER2-positive breast cancer: Results of a sub analysis from the ALTTO trial.
Authors: Isabelle Gingras, Eileen McCormick Holmes, Evandro De Azambuja, David H. A. Nguyen, Miguel A. Izquierdo, Jo Anne Zujewski, Moshe J. Inbar, Bjorn Naume, Gianluca Tomasello, Michael Gnant, Alvaro Moreno-Aspitia, Martine J. Piccart-Gebhart, Hatem A. Azim
Journal: Journal of Clinical Oncology (2016)

604 Background: The optimal treatment of regional nodal areas following breast-conserving surgery (BCS) is a source of debate. Two randomized trials recently demonstrated that regional nodal irradiation (RNI) can reduce the risk of recurrence in early breast cancer; however,these trials were conducted in the pre-trastuzumab era.Whether these results are applicable to HER2-positive breast cancer patients treated with anti-HER2 targeted therapy, is unknown. Methods: This retrospective analysis was performed on patients with node-positive breast cancer, who were enrolled in the ALTTO phase III adjuvant trial and subjected to BCS. The primary objective of the present study was to examine the effect of RNI on disease-free survival (DFS). Secondary objectives included regional recurrences and overall survival (OS). A multivariate cox regression analysis adjusted for number of positive lymph nodes, tumor size, grade, age, hormone receptors status, presence of macrometastatis, treatment arm, and chemotherapy timing was carried out to interrogate the relation between RNI and DFS. Results: 1,664 HER2-positive breast cancer patients were included, of whom 878 patients (53%) had received RNI to the axillary, supraclavicular and/or internal mammary lymph nodes. Patients in the RNI group had higher nodal burden (55% vs 13% patients with ≥ 4 positive lymph nodes) and more frequently tumors larger than 2cm (53% vs 44%). At a median follow-up of 4.5 years, DFS was 84% in the RNI group and 88% in the non-RNI group. No differences in regional recurrence (1% vs 1%) and in OS (94% vs 95%) were observed between the two groups. In the multivariate analysis, there was no significant association between RNI and DFS (HR 0.96, 95% CI 0.71-1.29). Conclusions: Our analysis did not demonstrate a DFS benefit of RNI in HER2-positive, node positive patients treated with adjuvant HER2-targeted therapy. The benefit of RNI in HER2-positive breast cancer needs further testing within randomized clinical trials.
US judicial guidelines on sentencing could show way forward for NHS
Authors: L T Wilkins, A J Wilkins
Journal: BMJ (1996)

EDITOR,—Allocation of scarce medical resources presents problems that have striking similarities to judicial sentencing or the decisions of parole boards. Both the medical and judicial decisions involve ethical and technical constraints. Both must avoid disparity. Both must in principle be accountable to the public, and both must be seen to be fair.

In some states of the United States, notably Minnesota, judicial sentencing guidelines have been developed by the Sentencing Commission to ensure that the punishment allocated both fits the …
Stable centromere positioning in diverse sequence contexts of complex and satellite centromeres of maize and wild relatives
Authors: Jonathan I. Gent, Na Wang, R. Kelly Dawe
Journal: Genome biology (2017)

Paradoxically, centromeres are known both for their characteristic repeat sequences (satellite DNA) and for being epigenetically defined. Maize (Zea mays mays) is an attractive model for studying centromere positioning because many of its large (~2 Mb) centromeres are not dominated by satellite DNA. These centromeres, which we call complex centromeres, allow for both assembly into reference genomes and for mapping short reads from ChIP-seq with antibodies to centromeric histone H3 (cenH3). We found frequent complex centromeres in maize and its wild relatives Z. mays parviglumis, Z. mays mexicana, and particularly Z. mays huehuetenangensis. Analysis of individual plants reveals minor variation in the positions of complex centromeres among siblings. However, such positional shifts are stochastic and not heritable, consistent with prior findings that centromere positioning is stable at the population level. Centromeres are also stable in multiple F1 hybrid contexts. Analysis of repeats in Z. mays and other species (Zea diploperennis, Zea luxurians, and Tripsacum dactyloides) reveals tenfold differences in abundance of the major satellite CentC, but similar high levels of sequence polymorphism in individual CentC copies. Deviation from the CentC consensus has little or no effect on binding of cenH3. These data indicate that complex centromeres are neither a peculiarity of cultivation nor inbreeding in Z. mays. While extensive arrays of CentC may be the norm for other Zea and Tripsacum species, these data also reveal that a wide diversity of DNA sequences and multiple types of genetic elements in and near centromeres support centromere function and constrain centromere positions.
The value of <sup>18</sup>F-fluordesoxyglucose positron emission tomography (FDG-PET/CT) in the detection of the primary lesion and for staging in brain metastasis (BM) patients with cancer of unknown primary site (CUPS).
Authors: Emilie Le Rhun, Michael Weller, Anna Sophie Berghoff, Elisabeth Jane Rushing, Lisa Fuereder, Gregory Petyt, Henning Leske, Nicolaus Andrastschke, Luca Regli, Marian Christoph Neidert, Roger Stupp, Reinhard Dummer, Thomas Frauenfelder, Patrick Roth, Nicolas Reyns, Philipp Antonio Kaufmann, Matthias Preusser, Fabian Wolpert
Journal: Journal of Clinical Oncology (2017)

2076 Background: Brain metastasis (BM) are the first clinical presentation of cancer in around 30% of patients. They are then referred as BM from cancer of unknown primary site (BM-CUPS). The value of 18 F-fluordesoxyglucose positron emission tomography (FDG-PET)/CT has not yet be determined for the management of these patients. Methods: A total of 566 patients were operated for BM at the University Hospital Zurich between 2004 and 2014, of whom 127 were identified as BM-CUPS patients. Two cohorts from other independent centers (n = 100 and 120) were used for the validation of data. Results: No difference in determining the localization of the primary lesion was observed between FDG-PET/CT and CT (FDG-PET/CT: 73/78, 93.6%; CT: n = 70/78, 89.7%; p = 0.25, McNemar’s test). The same pattern of primary lesion and other extracranial lesions was observed in 36 of 64 patients (56.3%). Additional suspicious extracranial metastases were identified by FDG-PET/CT in 28 patients (43.7%). The median graded prognostic assessment (GPA) scores were 2.5 determined according to FDG-PET/CT and 3 according to CT alone (p = 3.8x10 -5 ), resulting in predicted survival times of 3.8 versus 5.3 months (p = 6.1x10 -5 ; Wilcoxon’s test). Conclusions: A similar sensitivity of FDG-PET/CT and chest CT was observed for the detection of the primary tumor in BM-CUPS, however, FDG-PET/CT significantly improved the accuracy of staging. FDG-PET/CT should be preferred for the management of BM-CUPS and may help to avoid redundant CT imaging.
Increased Activity in the Lung Field on Gastroesophageal Scintigraphy Is Not Always Due to Aspiration
Authors: Xiaofei Zhao, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2017)

Elevated activity in the lung field on gastroesophageal scintigraphy (milk scan) generally indicates aspiration of the gastric content that has refluxed to the pharynx. An 18-year-old man underwent to gastroesophageal scintigraphy to assess the rate of gastric emptying. Increased activity was noted in the left lower lung field during the image acquisition. Careful analysis of the images showed that this activity was caused by hiatal herniation.
Successful Treatment of Cutaneous Small Vessel Vasculitis With Leflunomide
Authors: Julia D. Stiegler, Naveed Sami
Journal: JAMA Dermatology (2017)

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Inspiratory muscle training in patients with Parkinson's disease
Authors: Silvana Loana Oliveira Sousa, Martha Cecília León Garzón, María Gómez-Gallego, Juan José Bellester Cerezo, Lourdes Gómez-Amorós, José Luis Martínez-Gil, Fulgencio Buendía-López
Journal: European Respiratory Journal (2012)

Background: Respiratory muscle weakness is a common impairment in patients with Parkinson's disease (PD). This is muscle weakness is exacerbated by increased chest wall rigidity that potentially contribute to reduced lung volumes and respiratory pressures and may be an important factor in the respiratory complications in this population.

Objective: This study investigated the effect of specific inspiratory muscle training (SIMT) on maximum inspiratory pressure in patients with PD.

Methods: Thirteen participants (7 males and 6 females) with PD (mean age of 69.6 years (SD=7.7 years) referred from the On-Off Parkinson's Association in Murcia, Spain, were involved in this study. Maximum inspiratory pressure (MIP) was considered the indice of inspiratory muscle strength and measured before and within one week after the training period and. All subjects trained daily at home, six times a week, each session consisting of 3 sets of the 15 times, for 8 week. The training was performed using an inspiratory muscle trainer.

Results: Following the training period there was a significant improvement in inspiratory muscle strength. The mean inspiratory muscle strength pre-intervention was 58.6 cmH20 (SD=12.3) and post-intervention was 72.4 cmH20 (SD=14.1) (p<0.01).

Conclusions: The results of this study demonstrate that muscle strength training has the potential to improve inspiratory muscle strength in patients with Parkinson's disease.
Experience with perioperative chemotherapy (ECC or ECF) for gastroesophageal cancer in British Columbia: A multicenter experience.
Authors: Howard John Lim, Jasem Al-Barrak, Winson Y. Cheung, Renata D'Alpino Peixoto
Journal: Journal of Clinical Oncology (2013)

e15153 Background: In 2006, the MAGIC trial demonstrated a significant overall survival benefit for perioperative ECF among patients with resectable gastro-esophageal cancer when compared to surgery alone. Since 2008, perioperative chemotherapy has become the standard of care for resectable gastro-esophageal cancer in our institution. We report the results of our experience with this protocol. Methods: The BC Cancer Agency is a multi-centre institution treating the majority of oncology patients for the province. A total of 83 consecutive patients with localized gastric, gastro-esophageal junction (GEJ) or lower esophageal cancer who initiated ECC/ECF perioperative chemotherapy from March 2008 to June 2011 were identified using the pharmacy database. Patient’s characteristics were abstracted to an anonymous database and analyzed. Results: In our cohort, 83 patients (66 males and 17 females) with a median age of 62 years (range 37 – 79) began preoperative chemotherapy, of whom 73 (87.9%) completed 3 cycles. The response rate was 49.3%. Among the 83 patients, 78 (93.9%) underwent surgery (2 patients died of chemotherapy toxicities, 1 refused surgery and 2 developed disease progression before surgery), of whom 11 (14.1%) could not have their tumors resected (1 unresectable, 1 with liver metastasis and 9 with peritoneal carcinomatosis). Only one patient died of surgical complications. Six patients (7.69%) achieved pathologic complete response (ypCR) and all of them are alive and recurrence-free. Forty-eight patients (57.8%) subsequently began postoperative chemotherapy, of whom 37 (44.5%) completed 3 cycles. Thirty-nine patients have died as of December 4 th , 2012. The observed median survival was 38 months. Conclusions: In our multi-center experience, the results reported in the MAGIC trial were reproduced.