tbuckley/cabot-search huggingface dataset:
HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery
Authors: Steven C Katz, Ashley E Moody, Prajna Guha, John C Hardaway, Ethan Prince, Jason LaPorte, Mirela Stancu, Jill E Slansky, Kimberly R Jordan, Richard D Schulick, Robert Knight, Abdul Saied, Vincent Armenio, Richard P Junghans
Journal: Journal for ImmunoTherapy of Cancer (2020)

In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.
Aromatase inhibition in male breast cancer patients: Biological and clinical implications
Authors: J. Doyen, A. Italiano, R. Largillier, J. Ferrero, X. Fontana, A. Thyss
Journal: Journal of Clinical Oncology (2009)

1130 Background: Because male breast cancer (MBC) is rare, treatment recommendations are derived from results of trials in female patients (pts). Although, several studies have shown the superiority of third-generation aromatase inhibitors (AI) over tamoxifen in menopausal women with advanced breast cancer, the role of such molecules remains unknown in male pts. We report here the largest experience about the efficacy of AI in MBC pts with advanced disease and their impact on estradiol (E) levels. Methods: MBC pts were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France) as follows: Metastatic disease with at least one measurable or assessable non-measurable lesion, estrogen receptor (ER) and/or or progesterone receptor (PR) positive, availability of complete clinical and histological data, evidence of progressive disease at initiation of AI, receipt of at least one month of treatment with non steroidal (anastrozole, letrozole) or steroidal (exemestane) AI. Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank. Results: 15 pts entered the study. Median age was 68 (range 39–85). 7 pts received previous lines of hormonal therapy (median = 1) and 3 pts a previous line of chemotherapy before the introduction of AI. The best response was complete response in 2 pts (13%), partial response in 4 pts (27%), stable disease (SD) in 2 pts (13%) and progressive disease (PD) in 7 pts (47%). The median duration of objective response (OR) was 11.6 months (95% confidence interval [CI] 7.6–15.5). At the time of analysis, 8 pts (53%) had died and 7 (47%) were still alive. The median PFS and OS were 4.4 months (95% CI 0.1–8.6) and 33 months (95% CI 18.4–47.6) respectively. The 1-year PFS and OS rates were 20% (95% CI 9.7–30.3) and 84.6% (95% CI 74.6–94.6), respectively. 9 out of 11 pts with available samples had E levels less than the lower limit of the assay during AI treatment. Among the 9 pts with E level decrease, four had OR, one had SD, and four had PD. 1 pt had E levels higher than the upper limit of the assay during AI treatment. This pt showed disease progression. Further data on FSH and testosterone levels will be presented at the meeting. Conclusions: AI are active in MBC pts. This activity is correlated with a significant reduction in E levels. No significant financial relationships to disclose.
Differentiation of a Contractile, Ureter-Like Tissue, from Embryonic Stem Cell–Derived Ureteric Bud and Ex Fetu Mesenchyme
Authors: May Sallam, Anwar A. Palakkan, Christopher G. Mills, Julia Tarnick, Mona Elhendawi, Lorna Marson, Jamie A. Davies
Journal: Journal of the American Society of Nephrology (2020)

There is intense interest in replacing kidneys from stem cells. It is now possible to produce, from embryonic or induced pluripotent stem cells, kidney organoids that represent immature kidneys and display some physiologic functions. However, current techniques have not yet resulted in renal tissue with a ureter, which would be needed for engineered kidneys to be clinically useful.We used a published sequence of growth factors and drugs to induce mouse embryonic stem cells to differentiate into ureteric bud tissue. We characterized isolated engineered ureteric buds differentiated from embryonic stem cells in three-dimensional culture and grafted them into ex fetu mouse kidney rudiments.Engineered ureteric buds branched in three-dimensional culture and expressed Hoxb7, a transcription factor that is part of a developmental regulatory system and a ureteric bud marker. When grafted into the cortex of ex fetu kidney rudiments, engineered ureteric buds branched and induced nephron formation; when grafted into peri-Wolffian mesenchyme, still attached to a kidney rudiment or in isolation, they did not branch but instead differentiated into multilayer ureter-like epithelia displaying robust expression of the urothelial marker uroplakin. This engineered ureteric bud tissue also organized the mesenchyme into smooth muscle that spontaneously contracted, with a period a little slower than that of natural ureteric peristalsis.Mouse embryonic stem cells can be differentiated into ureteric bud cells. Grafting those UB-like structures into peri-Wolffian mesenchyme of cultured kidney rudiments can induce production of urothelium and organize the mesenchyme to produce rhythmically contracting smooth muscle layers. This development may represent a significant step toward the goal of renal regeneration.
Pharmacokinetic and pharmacodynamic results of a 4-hr IV administration phase I study with EPC2407, a novel vascular disrupting agent
Authors: W. L. Read, P. Rosen, P. Lee, S. Anthony, R. Korn, N. Raghunand, B. Tseng, J. Whisnant, D. Von Hoff, R. Tibes
Journal: Journal of Clinical Oncology (2009)

3569 Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m 2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m 2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m 2 over 4 hours, with MTD determined to be 24 mg/m 2 . DLTs at 30 mg/m 2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T 1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m 2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (K trans ) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m 2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed. [Table: see text]
An update on human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) focusing on clinical and laboratory biomarkers
Authors: Junji Yamauchi, Natsumi Araya, Naoko Yagishita, Tomoo Sato, Yoshihisa Yamano
Journal: Pharmacology & Therapeutics (2020)

Human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare inflammatory disease causing unremitting and progressive neurological disorders, such as spastic paraparesis, neurogenic bladder, and sensory disturbance of the lower extremities. Although there is no cure, immune-modulating agents such as corticosteroids are most widely used to slow disease progression. Biomarkers for the clinical assessment of HAM/TSP should be identified because the prediction of functional prognosis and the assessment of treatment efficacy are challenging due to the slowly progressive nature of the disease. The lack of surrogate biomarkers also hampers clinical trials of new drugs. This review summarizes biomarker candidates for the clinical assessment of patients with HAM/TSP. Most of the reported biomarker candidates are associated with viral components or inflammatory mediators because immune dysregulation provoked by HTLV-1 infection is thought to cause chronic inflammation and damage the spinal cord of patients with HAM/TSP. Although information on the diagnostic accuracy of most of the reported biomarkers is insufficient, several molecules, including inflammatory mediators such as CXCL10 and neopterin in the cerebrospinal fluid, have been suggested as potential biomarkers of functional prognosis and treatment response. Several clinical trials for HAM/TSP are currently underway, and we expect that these studies will provide not only evidence pertaining to treatment, but also novel findings regarding the utility of biomarkers in this disease. The establishment of clinical biomarkers will improve patient care and promote the development of therapies for HAM/TSP.
Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications
Authors: Gulab Sher, Nadia Aziz Salman, Abdul Q. Khan, Kirti S. Prabhu, Afsheen Raza, Michal Kulinski, Said Dermime, Mohammad Haris, Kulsoom Junejo, Shahab Uddin
Journal: Seminars in Cancer Biology (2020)

The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
Metabolic Syndrome and COVID-19 Mortality Among Adult Black Patients in New Orleans
Authors: John Xie, Yuanhao Zu, Ala Alkhatib, Thaidan T. Pham, Frances Gill, Albert Jang, Stella Radosta, Gerard Chaaya, Leann Myers, Jerry S. Zifodya, Christine M. Bojanowski, Nassir F. Marrouche, Franck Mauvais-Jarvis, Joshua L. Denson
Journal: Diabetes Care (2020)

Coronavirus disease 2019 (COVID-19) mortality is high in patients with hypertension, obesity, and diabetes. We examined the association between hypertension, obesity, and diabetes, individually and clustered as metabolic syndrome (MetS), and COVID-19 outcomes in patients hospitalized in New Orleans during the peak of the outbreak.
Patient and Visit Characteristics Associated With Use of Direct Scheduling in Primary Care Practices
Authors: Ishani Ganguli, E. John Orav, Claire Lupo, Joshua P. Metlay, Thomas D. Sequist
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Medical practices increasingly allow patients to schedule their own visits through online patient portals, yet little is known about who adopts direct scheduling or how this service is used. <h3>Objective</h3> To determine patient and visit characteristics associated with direct scheduling, visit patterns, and potential implications for access and continuity in the primary care setting. <h3>Design, Setting, and Participants</h3> This cross-sectional study used electronic health record (EHR) data from 17 adult primary care practices in a large academic medical center in the Boston, Massachusetts, area. Participants included patients 18 years or older who were attributed in the EHR to an active primary care physician at 1 of the included primary care practices, were enrolled in the patient portal, and had at least 1 visit to 1 of these practices between March 1, 2018, and March 1, 2019, the period of analysis. Data were analyzed from October 25, 2019, to April 14, 2020. <h3>Main Outcomes and Measures</h3> Adoption of direct scheduling, defined as at least 1 use during the study period. Usual scheduling was defined as scheduling with clinic staff by telephone or in person. <h3>Results</h3> We examined 134 225 completed visits by 62 080 patients (mean [SD] age, 51.1 [16.4] years, 37 793 [60.9%] women) attributed to 140 primary care physicians at 17 primary care practices. A total of 5020 patients (8.1% [95% CI, 7.9%-8.3%]) adopted direct scheduling, with an age range of 18 to 95 years. Compared with nonadopters in the same practices, adopters were younger (adjusted odds ratio [AOR] per additional year, 0.98 [95% CI, 0.98-0.99]) and were more likely to be White (AOR, 1.09 [95% CI, 1.01-1.17]) and commercially insured (AOR vs uninsured, 1.40 [95% CI, 1.11-1.76]) and to have more comorbidities (AOR per additional comorbidity, 1.07 [95% CI, 1.04-1.11]). Compared with usually scheduled visits, directly scheduled visits were more likely to be for general medical examinations (1979 visits [36.7%] vs 26 519 visits [21.9%];<i>P</i> &lt; .001) and with one's own primary care physician (5267 visits [95.2%] vs 94 634 visits [73.5%];<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> These findings suggest that direct scheduling was associated with greater primary care continuity. Early adopters were more likely to be young, White, and commercially insured, and to the extent these differences persist as direct scheduling is used more widely, this service may widen socioeconomic disparities in primary care access.
AB0173 Prevention and treatment of corticosteroid-induced osteoporosis in patients with chronic rheumatic diseases
Authors: K Loddenkemper, G Burmester, F Buttgereit
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Long-term glucocorticoid therapy, a major risk factor for the development of osteoporosis, is often necessary in chronic-rheumatic patients. Generally accepted guidelines for either the prevention of- or the therapy of steroid-induced osteoporosis do not exist to date. <h3>Objectives</h3> In an open prospective study, we examined 99 patients with chronic-rheumatic diseases, who were treated with 5 mg or more equivalent dose of prednisolone/day for at least one year. The study goal was to identify factors which influence the manifestation of osteoporosis besides glucocorticoid therapy. Additionally, the therapeutic efficacy of a) prevention with either calcium 500 mg/day and vitamin D 1000U/day or b) treatment with intermittent cyclical etidronate (400 mg/day for 14 days followed by 500 mg calcium/day for 76 days) was examined prospectively for one year. <h3>Methods</h3> Clinical (e.g. rate of fractures, pain intensity), chemical (values of bone mineral metabolism) as well as radiographic parameters (bone mineral density/BMD (DEXA) were measured. Therefore, the patients were divided in two groups: patients with osteopenia (group 1) and patients with osteoporosis or osteopenia and an increased fracture risk (group 2). Patients in group 1 were given with the above-mentioned "prevention regimen", and those in group 2, the "treatment regimen". <h3>Results</h3> 1. Increasing age was associated with more advanced manifestations of steroid-induced osteoporosis (p &lt; 0.05). Male patients had a risk of steroid-induced osteoporosis, however, this was not statistically significant. Size, weight, daily and cumulative glucocorticoid dose and disease activity showed no significant influence on the degree of osteoporosis. 2. Despite the osteoporosis prevention regime, a significant rise of bone mineral metabolism parameters (pyridinoline, deoxypyridinoline, n-terminal telopeptid, ostase, bone specific alkaline phosphatase) was observed. The BMD was not influenced by therapy. 3. During the etidronate therapy, a significant rise (p &lt; 0.05) in BMD was measured in the lumbar spine, whereas the femoral neck BMD and bone metabolism parameters remained constant. 4. The intensity of back pain was lowered significantly (p &lt; 0.05) in both groups. 5. One year after therapy begin, there were less fractures in group 2 than in group 1. <h3>Conclusion</h3> The early treatment with biphosphonates appears effective in long-term glucocorticoid therapy for early osteoporosis and should be recommended.
<i>PIK3CA</i> Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype
Authors: Valentina Guarneri, Maria Vittoria Dieci, Giancarlo Bisagni, Alba A. Brandes, Antonio Frassoldati, Luigi Cavanna, Antonino Musolino, Francesco Giotta, Anita Rimanti, Ornella Garrone, Elena Bertone, Katia Cagossi, Oriana Nanni, Federico Piacentini, Enrico Orvieto, Gaia Griguolo, Matteo Curtarello, Loredana Urso, Laia Paré, Nuria Chic, Roberto D'Amico, Aleix Prat, Pierfranco Conte
Journal: Clinical Cancer Research (2020)

Abstract Purpose: We explored the prognostic effect of PIK3CA mutation in HER2+ patients enrolled in the ShortHER trial. Patients and Methods: The ShortHER trial randomized 1,253 patients with HER2+ breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. Results: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56–1.27; P = 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n = 232): 5-year DFS 91.8% versus 76.1% (log-rank P = 0.049; HR, 0.46; 95% CI, 0.21–1.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68–0.99; P = 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65–0.99; P = 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53–0.99; P = 0.042 for MYBL2 expression). Conclusions: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes.
Prognostic factors of patients with advanced stage serous borderline tumors of the ovary
Authors: P. Morice, C. Uzan, A. Kane, A. Rey, S. Gouy, P. Pautier, S. Camatte, C. Lhomme, C. Haie-Meder, P. Duvillard
Journal: Journal of Clinical Oncology (2009)

5573 Background: The aim of this study was to determine prognostic factors in a large series of patients with stage II or III serous low malignant potential ovarian tumor (LMPOT) and peritoneal implants. Methods: A retrospective review of patients with a serous LMPOT and peritoneal implants treated or referred in our institution. The slides of ovarian tumors and peritoneal implants were reviewed by the same pathologist. Prognostic factors were studied. Results: From 1969 to 2006, 168 patients were reviewed, 21 of whom had invasive implants. Tumors exhibited a micropapillary pattern in 56 patients. Adjuvant treatment had been administered to 61 patients. The median duration of follow-up was 57 (range, 1–437) months. Forty-four patients had relapsed and 10 patients had died. 5-year overall survival of patients was 98%. Among patients with noninvasive and invasive implants, 8% and 10%, respectively, relapsed at 5 years in the form of invasive disease (p = 0.08). Prognostic factors for recurrence in the univariate analysis were: a laparoscopic approach, conservative treatment and positive second-look surgery. In the multivariate analysis the use of conservative treatment was the only prognostic factors for recurrence. Conclusions: The prognosis of serous LMPOT with peritoneal implants remains good. The strongest prognostic factor in patients with an advanced-stage borderline tumor is the use of conservative surgery. In this series, a micropapillary pattern and implant subtypes (invasive vs. noninvasive) were not prognostic factors. No significant financial relationships to disclose.
Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19
Authors: Eve Garrigues, Paul Janvier, Yousra Kherabi, Audrey Le Bot, Antoine Hamon, Hélène Gouze, Lucile Doucet, Sabryne Berkani, Emma Oliosi, Elise Mallart, Félix Corre, Virginie Zarrouk, Jean-Denis Moyer, Adrien Galy, Vasco Honsel, Bruno Fantin, Yann Nguyen
Journal: Journal of Infection (2020)