tbuckley/cabot-search huggingface dataset:
Limitations of Fractional Excretion of Urea in Clinical Practice
Authors: Anawin Sanguankeo, Sikarin Upala
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To The Editor: We read an article written by Patidar et al.1 with interest. The researchers performed an analysis in patients with cirrhosis who were taking diuretics and diagnosed with acute kidney injury (AKI). The objective was to determine the diagnostic ability of fractional excretion of urea (FEUrea) to differentiate prerenal azotemia (PRA), type 1 hepatorenal syndrome (HRS), and acute tubular necrosis (ATN). The researchers concluded that FEUrea was an excellent tool for differential diagnosis of AKI in patients with cirrhosis. However, there are limitations of applying FEUrea in clinical settings that should be considered. FEUrea is one of several diagnostic tools to differentiate causes of AKI. Low FEUrea (≤35%) has greater sensitivity and specificity than fractional excretion of sodium (FENa) in differentiating between AKI attributed to PRA and ATN when diuretics are used.2 The diagnostic ability to diagnose PRA for both FENa and FEUrea were assessed in the oliguric state (urine output <500 mL/day). As urine flow increases, FENa and FEUrea are lower and therefore the calculated cutoffs might have to be decreased.3 In this study, urine output was not documented, and it is unknown whether the cutoffs for FEUrea would be different between patients with oliguric and nonoliguric AKI. Therefore, the diagnostic accuracy of FEUrea may vary in nonoliguric AKI. Moreover, using FEUrea to differentiate HRS versus PRA will be challenging because of poor sensitivity (68%) and moderate specificity (80%) in the validation cohort. Other limitations of FEUrea include its interpretation when patients are taking medication that interfere with tubular secretion of creatinine, such as cimetidine and trimethoprim, and clinical situations that interfere with urea transporters or urea cycling, such as infectious diarrhea or sepsis.4 Including these limitations in the study would be worthwhile. Apart from FEUrea, urine microscopy can be an invaluable diagnostic tool to differentiate PRA versus ATN. Evidence showed that the urinary sediment scoring system was highly predictive of diagnosis of ATN. Urine sediment examination can also provide information for other causes of AKI, such as acute glomerulonephritis and acute interstitial nephritis. Because the test can provide very quick information and is relatively cheaper than FEUrea, it should be emphasized as one of the first tools in diagnosis of AKI. In conclusion, there are limitations in using and interpreting FEUrea to differentiate cause of AKI. Clinical advantages of urine microscopy and examination should be stressed.
Prostate cancer brain metastasis in a contemporary cohort.
Authors: Paul Brittain, Derek Smith, Dexiang Gao, Elizabeth Riley Kessler, Brandon David Bernard, D. Ryan Ormond, Elaine Tat Lam, Brian D. Kavanagh, Thomas W. Flaig
Journal: Journal of Clinical Oncology (2018)

e14011 Background: The rarity of brain metastases from prostate cancer (PCA) limits our understanding of the impact of modern treatments on its development. The potential impact of new, highly active hormonal agents in brain metastases is unknown. We performed a retrospective institutional review to examine PCA brain metastasis in the era of modern therapy. Methods: All institutional cases of prostate cancer were reviewed to identify cases with concurrent CNS metastasis from 2011-2017 using an electronic search. A chart review was performed to confirm clinical evidence for PCA brain metastasis in each case. Results: 6,596 cases of PCA were identified, with 31 cases having confirmed CNS metastases. Nineteen of these were dural and 12 were intraparenchymal metastases. Four total cases had small cell histology. The total median Gleason score was 8.5. The median time from PCA diagnosis to the development of CNS metastasis was 39 months for dural and 75 months for intraparenchymal metastases. The median survival time post CNS metastasis was 3.5 months for the dural and 4.0 months for the intraparenchymal metastases. 14/19 cases of dural metastases had > 6 months of abiraterone (ABI) or enzalutamide (ENZ) exposure, prior to CNS metastasis. The median time to CNS metastasis was 85 months in these patients vs 65 months in the 5/19 cases with limited or no exposure. Within the intraparenchymal metastasis 9/12 cases had > 6 months of exposure with their median time to CNS metastasis 50.5 months vs 24 months for the 3/12 with limited or no ABI/ENZ exposure. Conclusions: CNS metastases in prostate cancer remain a rare event with a < 1% incidence in our cohort. The proportion with dural metastases may be higher than historical controls. The prognostic impact of the condition remains significant regardless of the treatment history or location of CNS involvement. Dural Metastases (19) Intraparenchymal Metastases (12) Median Gleason Score 8.0 (range, 6-9) 9.0 (7-10) Median Time to Diagnosis of CNS Metastases 39m (0-186) 75m (0-183) Median Survival After CNS Metastases 3.5m (1-11) 4.0m (1-11)
Autophagy in Cardiovascular Aging
Authors: Mahmoud Abdellatif, Simon Sedej, Didac Carmona-Gutierrez, Frank Madeo, Guido Kroemer
Journal: Circulation Research (2018)

Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
The prostate clinical outlook (PCO) classifier for predicting biochemical recurrences in patients treated by stereotactic body radiation therapy.
Authors: Mi Jung Rho, Jihwan Park, Anatoly Dritschilo, Sean P. Collins, Simeng Suy, In Young Choi, Seong K. Mun
Journal: Journal of Clinical Oncology (2017)

e16552 Background: Although prostate cancer risk classifiers have been developed for predicting surgical and radiation therapy outcomes, a classifier suitable for predicting biochemical recurrence (BCR) in patients undergoing stereotactic body radiation therapy (SBRT) remains to be defined. SBRT is delivered in large fractions of highly conformal radiation therapy and such treatments are believed to be radiobiologically more effective in treating prostate cancers. The aim of this study is to develop a new classifier specifically for informing patients electing to undergo prostate cancer treatment with SBRT. Methods: We have studied outcomes of 809 patients treated with SBRT between August 2007 and November 2016 at MedStar-Georgetown University Hospital. A Cox regression to BCR was performed and the Prostate Clinical Outlook (PCO) score was calculated at diagnosis based on age at diagnosis, clinical-radiological staging, pre-treatment PSA and Gleason score. Accuracy of the PCO classifier was assessed with concordance (c)-indexes. The results were also compared to classifications by D’Amico and National Comprehensive Cancer Network (NCCN) recurrence risk groups. Results: PCO total scores range from zero to 156 points. The PCO classifier splits patients into 3 risk-groups with the following 5-year BCR-free survival: for low-risk 98%; for intermediate-risk 95%; for high-risk 86%. Our classifier outperforms D’Amico and NCCN for all of the evaluated end-points, with concordance indices of 74 % versus 64 % and 66%, respectively. Conclusions: The PCO classifier is a potential tool for employing readily available parameters to stratify prostate cancer patients and to predict probabilities of BCR after SBRT.
Harnessing IMGN853-mediated cell cytoxicity response by modulating FRα expression in ovarian cancer.
Authors: Rajesh Kumar, Wei Wei, Sam Lauffer, Giulia Fulci, Michael J. Birrer
Journal: Journal of Clinical Oncology (2017)

e17061 Background: Ovarian cancer (OC) is the fifth leading cause of cancer-related death among women in the United States. Standard treatment includes debulking surgery followed by platinum based chemotherapy. While most tumors respond to this treatment, 70% of the tumors recur and develop into a chemo-resistant disease. There is a need for new therapies targeting recurrent chemoresistant OC. To address this need, Mirvetuximab Soravtansine (ImmunoGen, Waltham, MA) has developed an antigen-drug conjugate (ADC) containing DM4, a highly potent maytansinoid derivative that induces the cell cycle arrest, conjugated to an antibody targeting folate receptor alpha (FRα). Mirvetuximab Soravtansine (IMGN853), was tested in Phase I clinical trials on women with recurrent OC and showed low grade toxicity profile and activity in platinum-resistant disease. The goal of this study is to characterize the mechanism(s) leading to IMGN853 resistance in OC and test whether anticancer drugs targeting these mechanisms could be used in combination with IMGN853 for an additive/synergistic therapeutic effect. Methods: In vitro experiments were performed to detect and modulate FRα expression. Results: We show that sensitivity of OC cell lines to IMGN853 correlates with the expression levels of FRα (R = 0.82). Long-term exposure of sensitive cells to sublethal doses of IMGN853 induces drug resistance which correlates with decreased FRα expression. Anti-cancer drugs such as dexamethasone (Dex), which induces glucocorticoid receptors, or epigenetic modulators (Trichostatin A and 5-Azacytidine) induce FRα expression in SKOV3 and OVCAR8 OC cells, suggesting the possibility to use these drugs to maintain sensitivity of OC cells to IMGN853 and increase its therapeutic window. The therapeutic benefits of combining each of these drugs with IMGN853 will be further tested in mice using ovarian cancer patients’ derived xenografts with different FRα expression levels. Conclusions: These findings have clinical implications as they indicate that OC sensitivity to IMGN853 is modulated in part by changes in FRα levels. Resistance to this drug may be overcome by simultaneous treatment with Dex or other anti-cancer drugs such as TSA or AZA.
Changes in patient (pt), tumor, and treatment characteristics over time in 1<sup>st</sup> line (1L) trastuzumab (H) plus taxane (T; paclitaxel/docetaxel) arms in HER2-positive metastatic breast cancer (MBC) trials.
Authors: Tanja Badovinac Crnjevic, Eleonora Restuccia, Francesca Michielin, Jennifer Eng-Wong, Eveline Nüesch
Journal: Journal of Clinical Oncology (2018)

e13024 Background: A retrospective analysis showed improved progression-free survival and consistent underestimation of H+T efficacy assumptions in 1L HER2+ MBC trials over time (ISCB 2016). We evaluated changes in baseline/treatment characteristics and safety profile of H+T in 1L HER2+ MBC trials conducted 1995–2015. Methods: Trial-level data on pt/tumor/treatment characteristics and safety profile in H+T arms of 15 randomized trials were extracted from published data/clinical study reports. Characteristic/safety profile changes over time were explored by weighted regression; relevance was assessed by F-test. Results: Pt/tumor characteristics were generally stable over time. We observed relevant changes in types of adjuvant therapy used (Table). Serious adverse events (SAE) and study withdrawals due to AE decreased over time; rates of treatment discontinuation due to AE increased. Conclusions: In pts enrolled in 1L HER2+ MBC trials, use of adjuvant chemo-, hormonal, and radio-therapy decreased from 1995–2015; adjuvant H use increased following approval in 2005. These changes in treatment patterns suggest a shift towards a higher % pts with de novo metastatic v recurrent disease in 1L MBC trials; possibly due to improved early BC therapies and earlier detection of BC. While SAE decreased over time, no firm conclusions on safety management can be made. No. of trials (pts) Difference in pts with characteristic per 5 years, % (95% CI) P value Baseline characteristics Median age 15 (2895) 0.5 (0.1, 0.9)* .28 ECOG status 0 12 (2472) 0.2 (-1.1, 1.6) .87 Hormone-receptor positive 11 (2124) 1.3 (-1.1, 3.6) .61 HER2 IHC 3+ 8 (1657) 5.8 (3.0, 8.6) .08 Visceral disease 10 (1970) 0.5 (-2.5, 3.6) .86 Adjuvant therapy Hormonal therapy 11 (2194) -10.1 (-12.4, -7.8) .002 Radiotherapy 9 (2010) -4.2 (-5.8, -2.6) .035 HER2-targeted therapy 9 (2176) 20.2 (13.0, 27.4) .026 Chemotherapy 15 (2893) -7.0 (-9.2, -4.7) .008 Safety Grade 3+ AE 6 (1342) -15.4 (-28.4, -2.5) .30 SAE 7 (1462) -12.6 (-15.4, -9.8) .006 Study withdrawal due to AE 8 (1525) -6.8 (-9.0, -4.5) .023 Treatment discontinuation due to AE 6 (1370) 11.5 (6.7, 16.3) .075 *Years (95% CI)
Estrogen receptor (ER) and progesterone receptor (PR) retest rate in breast ductal carcinoma in situ (DCIS) surgical excision specimens.
Authors: Lilit Karapetyan, Jailan Elayoubi, Seda Grigoryan, Gennady Kuzin, Deimante Tamkus
Journal: Journal of Clinical Oncology (2018)

e18524 Background: ER testing in breast DCIS identifies patients who benefit from endocrine manipulation. We hypothesized that ER and PR testing on both biopsy and surgical tumor specimen may increase costs without improving patient outcomes. Methods: We reviewed pathology records of patients diagnosed with DCIS on breast core biopsies that had surgery performed in two community hospitals in Michigan from 2008 to 2016. The association between retesting and categorical variables (testing site, ER/PR expression, grade) was analyzed using a chi-square test. Results: We identified 239 patients who were diagnosed with DCIS on core biopsy and underwent surgery (lumpectomy or mastectomy). Average age of diagnosis was 60.5 years. 37.1% cases had grade 3 DCIS and 15% were ER-/PR-. Only one case had ER-/PR+ DCIS. Repeat ER and PR testing was performed in 39.3% of DCIS cases. The rate of repeat testing varied between the hospitals (80/133 and 14/106 cases, p-value < 0.0001). There was no difference in grade 3 DCIS and ER-/PR- DCIS on biopsies between hospitals (17.4% vs 14.1%, p-value = 0.58; 34.8% vs 39.8%, p-value = 0.49 respectively). Repeat testing was performed in both ER and/or PR+ DCIS (38.6%) and ER-/PR- DCIS (51.3%). In regards to hormone receptor expression, there was no difference in retest patterns between two hospitals. However, pathologists in one hospital more often performed repeat testing if high grade DCIS was identified on biopsy (65.2% vs 14.6%, p-value < 0.0001). 4.1% of patients had invasive disease and 6.2% of patients with DCIS underwent bilateral mastectomy. In such cases, initial reflex ER/PR testing on DCIS core biopsy specimens was not necessary. Only one patient had discordant ER/PR results. Conclusions: Our study reports a wide variation of repeat ER/PR testing in breast DCIS in a community setting and confirms a very low discordance rate of ER/PR between biopsy and surgical excision. ER-/PR+ DCIS is a rare entity and questions the role of PR testing in DCIS. The estimated cost of repeat ER/PR testing is $441.76 per case. Avoiding reflex ER/PR testing in DCIS core biopsies and repeat retesting on the surgical specimen will decrease cost of care without compromising patient outcomes.
The Electronic Health Record and Acquired Physician Autism
Authors: Peter Louis Loper
Journal: JAMA Pediatrics (2018)

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 Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast 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 Pediatrics journal
Incidence, treatment and survival outcomes of small bowel adenocarcinomas: A National Cancer Database (NCDB) analysis.
Authors: Mehmet Akce, Renjian Jiang, Christina Wu, Olatunji B. Alese, Walid Labib Shaib, Madhusmita Behera, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2018)

e16262 Background: Small bowel adenocarcinomas (SBA) are rare tumors. Management of SBA is extrapolated from colorectal cancer treatments. Recent evidence suggests that the biology and molecular features of SBA differ from colorectal cancer. The aim of this study is to evaluate the management and outcome of SBA patients. Methods: In this retrospective analysis of National Cancer Database (NCDB), we aimed to evaluate treatment outcomes including surgery, radiation and systemic therapy and compare them based on SBA location. Results: 7954 SBA patients were identified (58% duodenum (D), 16% jejunum (J), 11% ileum (I), 15% not specified) in NCDB database between 2004 and 2013. 53.6 % male and 76.6 % Caucasian. Median age was 66. Stage I, II, III, IV was 9.0%, 27.1%, 27.5 and 36.4%, respectively. Lymph node positive disease was present in 33.3%. Poorly differentiated/undifferentiated histology was seen in 33%. Surgery, radiation, and chemotherapy were used in 66.2%, 11%, and 47.2%; respectively. Single agent chemotherapy was used in 10.3% and multi-agent in 33.4%. Distributions of primary site locations were different across different stages (p < 0.01). Stage III was seen in 28.4% 27.5% and 30.3% of D, J, and I tumors; respectively. Of patients with stage III disease, 36.1% of D, 53.7% of J, and 50.3% of I received adjuvant chemotherapy (p < 0.01). Median overall survival (OS) was 20.5 months for D, 30 months for J, and 24.4 for I (p < 0.01). Stage IV disease was in 37.6%, 33.8%, and 26.6% of D, J and I tumors, median OS was 4.9, 15.3, and 9 months (p < 0.01), respectively. Conclusions: Majority of patients with SBA present with stage IV disease. Duodenal adenocarcinoma patients had the poorest OS in all stages (p < 0.05). Stage IV jejunal adenocarcinoma patients had the best median OS in stages II to IV (p < 0.05).
Association of early intervention in transfusion independent (TI) patients (Pts) with lower-risk myelodysplastic syndromes (MDS) treated with attenuated doses of hypomethylating agents (HMAs) with high response rates and long duration of response.
Authors: Mahesh Swaminathan, Elias Jabbour, Farhad Ravandi, Tapan M. Kadia, Gautam Borthakur, Nicholas James Short, Sherry Pierce, Jane Waukau, Darla Miller, Jorge E. Cortes, Yesid Alvarado, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2018)

7001 Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that attenuated dose schedules of HMA are safe and active in pts with low risk MDS (Jabbour et al. Blood 2018) but the safety and activity of these therapies is not known in TI pts with low risk MDS. To study this, we performed an analysis of a cohort pts with TI low risk or int-1 risk MDS by IPSS. Methods: Eighty-seven pts with low-risk or int-1 risk MDS treated with HMAs from 2012 to 2017 were analyzed. Pts had been treated in prospective trials of attenuated HMA at a single institution. Therapy could consist of decitabine 20 mg/m2 IV QD x 3 days every 28 days or azacitidine 75 mg/m2 daily x 3 days every 28 days or azacitidine at the same dose and schedule for 5 days. All pts were TI at baseline. Results: The median age was 70 (25-85); 64 pts (74%) were males; 57 pts (66%) were int-1 risk and 30 (34%) were low risk by IPSS. By the MDACC Lower Risk Prognostic Model: 51 pts (59%) were intermediate risk, 23 (26%) high risk and 13 (15%) low-risk. Cytogenetics were good in 59 (68%), intermediate in 22 (25%) and poor in 6 pts (7%). The median time to treatment was 4.13 months and the median number of prior treatments was 0 (0-1). The median total courses of treatment was 14 (1-41). TET2, ASXL1 and RUNX1 mutations occurred in 30%, 9% and 8%, respectively. Of the 87 pts, 80 were evaluable. No deaths were observed during the first 8 weeks of therapy and no severe hematological toxicity. The overall response rate (ORR) was 74% [CR – 40 (50%), mCR with and without HI – 5 (6%), 3 (4%), respectively, HIP – 10 (13%) and HIN – 1 (1%)]. The median OS was not reached and the median event-free survival (EFS) was 35.4 months. Two pts (3%) had progressive disease; 19 (24%) had no response; 6 (8%) progressed to acute myeloid leukemia. Five pts (6%) became transfusion dependent at the time of response evaluation. Conclusions: Early intervention with attenuated doses of HMAs in TI pts with lower risk MDS is safe and active and could potentially alter the natural history of MDS.
Immune cell functions in industrial workers after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: dissociation of antigen-specific T-cell responses in cultures of diluted whole blood and of isolated peripheral blood mononuclear cells.
Authors: M Ernst, D Flesch-Janys, I Morgenstern, A Manz
Journal: Environmental Health Perspectives (1998)

A comparative analysis was performed of the phenotype and function of peripheral blood leukocytes of two age-matched cohorts of industrial workers in chemical plants, one of which was exposed occupationally to high concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Median actual TCDD burdens were 116 ng/kg and 4 ng/kg, respectively. The phenotype analysis of peripheral blood mononuclear cells (PBMC) revealed no significant differences in the proportions of CD3, CD4, or CD8+ T lymphocytes, of CD16+ natural killer cells, and of CD19+ B lymphocytes. However, in PBMC of the TCDD-exposed workers; the proportion of CD8+ memory T cells (CD45R0+) was significantly higher, and that of lymphocytes with naive phenotype (CD45RA+) was significantly lower than in PBMC of the control group. Polyclonal and antigen-specific T-cell activation was assessed in parallel in isolated PBMC as well as in diluted whole blood cultures. In both culture systems the polyclonally stimulated cytokine release did not differ significantly between the two cohorts; however, we found a significantly reduced interferon gamma release in diluted whole blood cultures but not in isolated PBMC cultures of the TCDD-exposed cohort when we performed an antigen-specific T-cell stimulation with tetanus-toxoid. Therefore, we propose that exposure of individuals to high doses of TCDD can partially impair in the