tbuckley/cabot-search huggingface dataset:
Surviving paediatric sepsis in Tanzania: a prospective cohort study to identify risk factors
Authors: Teresa B Kortz, Hendry Sawe, Brittany Murray, Michael Matthay, Teri Reynolds
Journal: The Lancet Global Health (2017)

BackgroundIn 2015, there were 5·9 million deaths in children aged under 5 years worldwide: mortality is highest in sub-Saharan Africa (81 per 1000 livebirths) and sepsis is an important cause of these deaths. Paediatric sepsis is preventable and treatable, yet remains a serious and life-threatening condition. Prompt recognition and early treatment can improve survival; however, the understanding of how to identify and manage paediatric sepsis in sub-Saharan Africa is poor because of a lack of regional data. These data are crucial for the identification of high-risk patients, development of triage systems, and the reduction of barriers to care. In this study, we aim to identify mortality risk factors for paediatric sepsis patients at a national referral hospital in Tanzania.MethodsWe conducted an exploratory analysis of prospective cohort pilot data. We included children aged between 28 days and 14 years in the emergency medicine department at Muhimbili National Hospital in Dar es Salaam with sepsis (defined as ≥2 clinical criteria for systemic inflammatory response syndrome). The primary outcome was in-hospital mortality and secondary outcomes included mortality in the emergency department and length of stay. We used t-tests and Wilcoxon rank-sum, Kruskal Wallis, χ2, and Fisher's exact tests for data analysis.FindingsOf the 2232 children screened between July 1 and September 30, 2017, 433 were eligible, 405 were enrolled, and 402 were followed to discharge or death. Median age was 25·2 months (IQR 11·4–63·5) and prevalence of malaria and HIV was 9·1% (28/307) and 1·7% (n=7), respectively. 247 (61·0%) patients were referred from outside health facilities and 116/244 (47·5%) had received antibiotics before arrival. Mortality was 14·2% (n=57): 89·5% (n=51) died on a hospital ward and 10·5% (n=6) died in the emergency department. Non-survivors were younger than survivors (median age 16 and 27 months, respectively, p=0·002), and more likely to have respiratory insufficiency (54 (94·7%) vs 293 (84·9%), p=0·046) or altered mental status (43 (75·4%) vs 171 (49·6%), p<0·001). 52 non-survivors (91·2%) were referred from another facility compared with 193 survivors (55·9%; p<0·001).InterpretationWe identified several risk factors for mortality, but only that of referral status can be modified. Most children—and a disproportionately high number of non-survivors—were assessed at other health facilities before coming to Muhimbili, suggesting that there could be an opportunity for improved sepsis identification and earlier intervention. Next steps include development of a clinical illness severity score to allow risk stratification of patients and also investigation of barriers to care. Data collection is ongoing.FundingUniversity of California, San Francisco, Department of Pediatrics Clinical-Translational Pilot.
A method to integrate an institutional database with multiple practice EHRs.
Authors: Louis H. Barr, Meiling Wu, Heather Burner
Journal: Journal of Clinical Oncology (2017)

248 Background: Survivorship care plans (SCP) are endorsed or required for accreditation by many organizations including ASCO, NCCN and ACoS. SCP elements include a treatment summary and follow up plan. Information for these elements is usually found in a practice’s electronic health record (EHR), but is not always readily identifiable. Practitioners get information from multiple EHRs across practices and hospitals. Barriers include EHRs not readily accessible to all staff or don’t communicate with each other. No simple means exists for the required data points to auto-populate from practice-based databases. Methods: We approached this by combining Cancer Registry data with an online template to populate a SCP, utilizing the Electronic Registry System, Inc. (ERS), a Cancer Registry software company, and a survivorship template provided by a free online open source company Journey Forward (JF). The Registry is told when a patient is scheduled for a survivorship appointment. A file is created of the patient’s demographics, specific cancer characteristics, and treatment summary. This is sent to the practitioner through a shared drive or secure email. The tumor site-specific JF template is then selected by practice staff who import the Registry file created from ERS. Information required for the SCP is auto-populated in the template during this process. Results: The remainder of the template contains recommendations for follow up and is completed by a physician or designated practitioner working with their EHR. Supplemental tumor site-specific education materials are available in the JF Library. Patient-specific concerns such as cancer recurrence or treatment side-effects can be addressed as well. Any of these prepared documents may be incorporated into the SCP follow up recommendation section with a mouse-click. The printed SCP is given to the patient and forwarded to care providers. A notice of SCP given to the patient is then sent to the Registry which closes the loop. Conclusions: This process utilizes the Cancer Registry, allows specific input from patient care providers, and eliminates the necessity to access multiple EHRs to complete SCPs.
FDA Approval of Desmopressin for Nocturia
Authors: Michael Fralick, Aaron S. Kesselheim
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Nivolumab in resected and unresectable melanoma: Immune-related adverse events and association with survival outcomes.
Authors: Morganna L Freeman-Keller, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2015)

9028 Background: In metastatic melanoma, immune checkpoint blockade has generated excellent response rates and prolonged survival. As the depth of immune activation may correlate with occurrence of immune related adverse events (irAEs), an association between irAEs and disease outcomes might also exist. We describe herein the irAE toxicity profile of 148 patients with resected and unresectable melanoma treated with nivolumab at our institution, and the association of irAEs with progression-free (PFS) and overall survival (OS). Methods: Data was pooled from 148 patients (33 resected, 115 unresectable) treated at 1-, 3-, or 10mg/kg doses (with or without peptide vaccine) every 2 weeks for 12 weeks, then an additional 12 weeks if stable or better, and up to 2 additional years if stable or better. Frequency, grade, and irAE characteristics were analyzed, including kinetics of onset, resolution, and need for steroid therapy. We conducted a 12-week landmark OS analysis, with a multivariate time-dependent Cox proportional hazard model to assess differences in PFS (for 115 unresectable patients) and OS (all 148 patients) in the presence or absence of irAEs. Results: IrAEs of any grade were observed in 68.2% of patients (101/148). Grade III/IV irAEs were infrequent: 3 patients (2%) had Grade III rash, 2 (1.4%) had asymptomatic Grade III amylase/lipase elevation, and 2 (1.4%) had Grade III colitis. Of the irAEs, colitis and pneumonitis required steroids (median duration = 5 wks). Statistically significant PFS and OS differences were seen in patients who experienced any grade of irAE (p = < 0.001 and p = 0.078, respectively). Improved PFS was associated with rash (p = < 0.001 [HR 0.237, 95% CI 0.098 to 0.573]) and vitiligo (p = 0.005 [HR 0.121, 95% CI 0.024 to 0.62]). Rash was associated with improved OS (p = 0.005 [HR 0.098, 95% CI 0.006 to 1.711]), with non-significant association between vitiligo and OS (p = 0.081 [HR 0.146, 95% CI 0.009 to 2.488]. No survival differences were seen with other irAEs (endocrinopathies, diarrhea, or pneumonitis). Conclusions: Rash and vitiligo are associated with prolonged PFS and OS in melanoma patients treated with nivolumab, which should be validated in subsequent prospective analyses.
Prognostic and predictive value of tumour budding in stage II colorectal carcinoma.
Authors: Bojana Mitrovic, Kelly Handley, Naziheh Assarzadegan, Hector Hugo Li Chang, Heather Dawson, Andrea Grin, Gordon Hutchins, Laura Magill, Philip Quirke, Robert Riddell, Richard G. Gray, Richard Kirsch
Journal: Journal of Clinical Oncology (2015)

3605 Background: High-grade tumor budding (HGTB) is reported to be an independent adverse prognostic factor in colorectal cancer (CRC). Its presence is not routinely assessed by pathologists due to uncertainties about its clinical value, risk group thresholds, and the reproducibility of its assessment. Moreover, the benefit of chemotherapy in stage II CRC with HGTB remains to be demonstrated. This study aimed to (1) confirm the prognostic significance of HGTB in stage II CRC (2) determine the optimum threshold for HGTB reporting and (3) determine the responsiveness of stage II CRC with HGTB to chemotherapy. Methods: Whole slide images from CRC resections of 979 QUASAR trial patients (majority stage II) were evaluated for tumor budding as per the method of Ueno (2002). A tumor bud was defined as a single cell or a cluster of < 5 cells on a hematoxylin and eosin stained section. The highest tumor bud count per 1.23 mm2field was recorded. The optimal cutoff for HGTB was determined by maximal likelihood methods. Influence of risk group on recurrence and all-cause mortality was investigated in stratified logrank analyses in 'training' (n = 501) and then 'test' (n = 478) data sets. Results: The optimal cut-off for HGTB was determined to be 10+ buds/1.23 mm2field. Defined as such, HGTB was associated with significantly worse outcome: 10-year recurrence 35% vs 22% (risk ratio [RR] = 1.93 [95%CI 1.48–2.51], 2p < 0.00001) and mortality 51% vs 36% (RR = 1.73 [1.38–2.16], 2p < 0.00001), which was largely independent of other factors, including N and T-stage, grade, MMR, KRAS and BRAF status. There was a non-significant trend towards increasing chemotherapy efficacy with increasing bud counts (p = 0.12). Conclusions: HGTB is a strong independent predictor of disease recurrence and survival in stage II CRC. The proportional reductions in recurrence with chemotherapy in patients with higher bud counts appear at least equivalent to those with low counts, hence the absolute reductions in recurrence with chemotherapy should be about twice as large in patients with 10+ than < 10 tumor bud counts.
Pharmacogenetic correlates of clinical benefit from gemcitabine and platinum in patients with advanced bladder cancer
Authors: M. Castro, A. Neumann, M. Konichezky, K. Danenberg, S. Stemmer
Journal: Journal of Clinical Oncology (2004)

3202 Background: The expression level of the DNA excision repair gene ERCC1 has been correlated with outcome in pts receiving platinum agents for a variety of malignancies. While ribonucleotide reductase (RRM1) levels have been associated with responsiveness to gemcitabine (G), deoxycytidine kinase (DOCK), cytidine deaminase (CD), and other enzymes may also be useful to predict response to G. Therefore, pharmacogenetic correlations were carried out in pts with transitional cell bladder cancer (BC). Methods: mRNA enzyme levels (MEL) of ERCC1, RRM1, DOCK, and CD were determined using quantitative realtime PCR (Taqman) in microdissected paraffin-embedded tumor from treatment-naïve patients with locally advanced or metastatic BC who received G and a platinum agent. The result was expressed as a ratio of the PCR product of each enzyme compared to the β-actin gene. Thresholds for chemotherapy (CT) resistance were determined using the bootstrap technique. Statistical correlations between MEL and clinical endpoints were performed using the Chi square method. Results: 50 consecutive pts with locally advanced or metastatic BC (41 M, 9 F) received G and cisplatin or carboplatin. Among 18 pts with metastatic disease, there were 6 PD, 3 SD, 5 PR, and 2 CR. The median survival for pts with SD, PR, and CR was 13.4 m (range 6.5–25.0); and for pts with PD, 7.6 m (range 3.3–13.5). Among 25 pts who received adjuvant post-operative therapy, 7 died of disease an average of 10.6 m from the start of CT. An additional 4 pts relapsed and are receiving treatment, while 14 remain disease free with a median F/U of 19 m. Among 4 pts with bladder sparing CT-XRT, 3 are alive and disease free and 1 has succumbed to disease with a median F/U of 23.6 m. Among 2 pts with neoadjuvant CT, downstaging occurred in both cases, and both are alive with a median F/U of 12.3 m. Correlations with MEL will be presented at the meeting. Conclusions: MEL may permit the identification pts with a high probability of benefit before CT and avoid ineffective CT when the enzyme profile indicates resistance. Prospective validation of these results would establish MEL for treatment selection in patients with BC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Response Genetics Response Genetics Eli Lilly
Engineering self-assembled materials to study and direct immune function
Authors: Lisa H. Tostanoski, Christopher M. Jewell
Journal: Advanced Drug Delivery Reviews (2017)

The immune system is an awe-inspiring control structure that maintains a delicate and constantly changing balance between pro-immune functions that fight infection and cancer, regulatory or suppressive functions involved in immune tolerance, and homeostatic resting states. These activities are determined by integrating signals in space and time; thus, improving control over the densities, combinations, and durations with which immune signals are delivered is a central goal to better combat infectious disease, cancer, and autoimmunity. Self-assembly presents a unique opportunity to synthesize materials with well-defined compositions and controlled physical arrangement of molecular building blocks. This review highlights strategies exploiting these capabilities to improve the understanding of how precisely-displayed cues interact with immune cells and tissues. We present work centered on fundamental properties that regulate the nature and magnitude of immune response, highlight pre-clinical and clinical applications of self-assembled technologies in vaccines, cancer, and autoimmunity, and describe some of the key manufacturing and regulatory hurdles facing these areas.
Neoadjuvant and adjuvant chemotherapy without radiation for esophageal cancer
Authors: B. Ardalan, S. Spector, A. S. Livingstone, D. Franceschi, P. Ganjei-Azar, M. Lima, L. Sparling, G. Walker, C. P. Bowen-Wells
Journal: Journal of Clinical Oncology (2006)

4054 Background: A Phase II trial to evaluate neoadjuvant (NAD) and adjuvant (AD) combination chemotherapy (CT) without radiation therapy (RT), for Stage III esophageal adenocarcinoma. Methods: Stage III disease by CAT scan or EUS and ECOG performance status 0–1. The CT cycles included Cisplatin, Taxol, FUDR and Leucovorin. The chemotherapy was given for 16 weeks prior to surgery, followed by adjuvant chemotherapy for patients whose pathology at the time of surgery demonstrated microscopic disease. Survival was estimated via Kaplan Meier. Results: 33 patients were enrolled: 28 completed NAD, 15 received AD. Of 33 pts given NAD, 16 had grade I/II toxicity and 14 had grade III/IV. In addition, 6 of 15 pts receiving AD had grade I/II toxicity and 3 had grade III/IV during that phase of treatment. Thirty-two (32) patients went to surgery, 30 patients were resected: 24 transhiatial and 6 transthoracic. Of the 28 patients who completed NAD, 19 (68%) demonstrated improvement in dysphagia; 11 (41%) gained weight, and 7 (26%) had no weight change. Pathologic response to NAD: 30 patients had partial response and 2 patients had progressive disease, one died prior to surgery, post carotid endarterectomy. Ten (10) patients showed no gross disease. Twenty-three (23) patients have expired, 17 disease related with distant metastasis, 1 with local recurrence and distant metastasis, 3 non-disease related and 2 unresectable cases. Kaplan-Meier estimates of overall survival at 1, 3, and 5 years were 73% (95% CI: 58 to 88%), 52% (95%CI: 34 to 69%), and 29% (95% CI: 13 to 45%), respectively. Median survival was 42 months (95% CI: 14 to 52 months). Ten (10) patients are alive after a median follow up of 73 months (range 45 to 89). Seven (70%) of the surviving patients received both NAD (2 cycles) and AD (1 to 2 cycles) and all had no evidence of disease as of last clinical and radiological evaluation. Conclusions: This regimen of combination CT for locally advanced esophageal adenocarcinoma is safe and comparable with those regimens that contain RT. There has been 1 local recurrence; 17 patients have recurred distantly. Omission of RT may allow for a more aggressive CT and reduction in the local complications post-surgery. This study needs to be confirmed in a larger phase II or in randomized phase III trial. No significant financial relationships to disclose.
Preclinical evaluation of anti-RON antibody-drug maytansinoid conjugates (anti-RON ADC) for targeted colorectal cacner therapy.
Authors: Liang Feng, Hang-Ping Yao, Wei WANG, Sharad Sharma, Ruiwen Zhang, Ming-Hai WANG
Journal: Journal of Clinical Oncology (2014)

3048 Background: The receptor tyrosine kinase RON is critical in tumorigenesis and a validated drug target for cancer therapy. Here we report the development and therapeutic efficacy of anti-RON mAb Zt/g4-maytansinoid conjugates (Zt/g4-DM1) with enhanced cytotoxicity against colorectal cancer cells (CRC) in mouse xenograft tumor models. Methods: Zt/g4 (IgG1a/κ) was selected as the drug carrier for its ability to induce RON endocytosis in CRC cells. Zt/g4 was conjugated to DM1 via the thioether link to form antibody-drug conjugate Zt/g4-DM1 with an antibody-drug ratio of 1:4 molecules. CRC HCT116, HT29, and SW620 cells were used as the model for in vitro and in vivo studies. Results: Zt/g4-DM1 retains the intrinsic activity that causes rapid RON internalization. Targeted payload delivery induced cell cycle arrest at G2/M phase, reduced cell viability with IC50 values at ~1.2 μg/ml, which results in massive cell death within a period of 72h. The cytotoxic effect of Zt/g4-DM1 was negligible in cancer cells with minimal RON expression. Studies from the mouse CRC xenograft model revealed that Zt/g4-DM1 is highly effective in delaying HT29 cell-mediated tumor growth in athymic nude mice. In a single cycle of q 4 days x 5 with Zt/g4-DM1 at 1, 3, 7, 10, and 15 mg/kg body weight, we observed significant tumor inhibition (>70% tumor growth delay) when Zt/g4-DM1 was used at 7 mg/kg. Significantly, more than 95% of tumor growth was inhibited at 10 mg/kg or 15 mg/kg of Zt/g4-DM1. Continued observation after last treatment showed that the inhibitory effect of Zt/g4-DM1 is long lasting up to 20 days without signs of tumor regrowth. The prepared Zt/g4-DM1 is stable in vitro and has a minimal toxic effect in vivowhen Zt/g4-DM1 was used below 40 mg/kg. Zt/g4 has been sequenced and a 3D model of antigen-binding domains in variable regions in both heavy and light chains has been created. Zt/g4 is currently under humanization for potential clinical trials. Conclusions: Zt/g4-DM1 is a highly effective biotherapeutics for inhibition of CRC growth in mouse xenograft models. The development of humanized Zt/g4-DM1 opens an avenue for potential clincal trials for various types of cancers harboring aberrant RON expression.
Analysis of clonal evolution in colorectal cancer.
Authors: Donna M. Graham, Madeleine Arseneault, Mahadeo A. Sukhai, Louis Letourneau, Mehran Karimzadeh, Tong Zhang, Mariam Thomas, Michael H. A. Roehrl, Eric Xueyu Chen, Monika K Krzyzanowska, Malcolm J. Moore, Amanda Giesler, Celeste Yu, Philippe L. Bedard, Suzanne Kamel-Reid, Lillian L. Siu, Yasser Riazalhosseini
Journal: Journal of Clinical Oncology (2014)

3510 Background: Comparisons of primary tumor and metastases (met) from the same individual patients (pts) highlight intratumor heterogeneity and clonal evolution with treatment. Results of genomic mutation analysis may guide treatment decisions in colorectal cancer (CRC). Methods: Ultra-deep (mean 35,000x coverage) amplicon sequencing was performed for hotspot regions of TP53, APC, KRAS, NRAS, PIK3CA, and BRAF on 36 DNA samples isolated from metachronous FFPE tumor specimens from 15 pts with CRC. The cohort included 10 pts with tissue from the primary and ≥1 met, four pts with pairs of mets, and one pt with a recurrent tumor at the primary site. One sample from each pt had prior analysis with a customized 23-gene panel for Sequenom. Samples were compared for presence of mutation and variant allele frequency (all-freq). Results: All KRAS, NRAS, PIK3CA, and BRAF mutations identified using Sequenom were confirmed by ultra-deep sequencing. Analysis for the six pts with KRAS codon 12 mutation, three pts with TP53 mutation, and one pt with NRAS mutation confirmed mutation persistence from primary to met. Seven of the 15 pts had interval treatment with chemotherapy +/- bevacizumab. KRAS all-freq differed between primary and met based on interval treatment. Elevated all-freq (2.4 fold) between primary and met was found for three pts who received interval chemotherapy compared with a 0.6 fold average change in all-freq for three pts with no interval treatment (p=0.05 by Mann-Whitney U test). All-freq of TP53 R273H mutation also increased (4.2 fold change) between primary and met in one treated pt. No low-frequency KRAS mutations or other mutations were identified in either sample of 3 pts previously found to be wild-type for KRAS; none had received anti-epidermal growth factor receptor therapy. One pt with anastomotic recurrence at 5 years had discordant TP53, PIK3CA, and BRAF mutation status from the primary suggesting the possibility of new CRC primary. Conclusions: Ultra-deep sequencing confirmed persistent clinically-relevant mutations between CRC primary and met. KRAS mutated subclones may be enriched in metastases following systemic chemotherapy. Targeted deep sequencing of driver mutations provides a powerful tool to monitor tumor behavior, and to identify recurrent lesions that are molecularly distinct from primary tumors.