tbuckley/cabot-search huggingface dataset:
Multiple primary malignancies among patients with advanced melanoma.
Authors: Matthew Isaiah Ebia, Gino Kim In
Journal: Journal of Clinical Oncology (2021)

e22531 Background: Multiple primary malignancies (MPMs) describe two or more primary tumors arising in a synchronous or metachronous manner in the same individual. Patients with a primary cutaneous melanoma are at high risk of developing MPMs. While melanoma and other tumors are highly immunogenic and may cause immune suppression at the individual level, the molecular underpinnings of immune suppression among patients with MPMs remains to be elucidated. Here, we attempt to describe this rare, but unique group of patients who have both advanced melanoma and at least one other primary malignancy. Methods: Patients with advanced melanoma (stage III-IV disease) and at least one other non-melanoma cancer were identified. Synchronous tumors were defined as those occurring within 6 months of the first primary cancer. Metachronous tumors were defined as those occurring at least 6 months after the first primary cancer. Patients who had melanoma first, before a second cancer, and those who had a prior other cancer first, followed by melanoma were included. Overall survival (OS) describes the time from diagnosis of the first primary cancer to death due to any cause. Two-sample t-tests were used to compare OS among these groups with statistical significance if p &lt; 0.05. Results: Eleven patients with MPMs including advanced melanoma were identified. Advanced melanoma was the first primary tumor in 5 patients and the second primary in 6 patients. A synchronous second primary was observed in 4 patients, whereas a metachronous second primary was observed in 7 patients. The median time between the diagnosis of the first primary cancer to the second primary was 21 months and the median time between the diagnosis of a second primary to a third primary was also 21 months. The median OS for all patients was 73 months. The median OS for synchronous MPMs and metachronous MPMs were 64.5 months and 82 months, respectively (p = 0.013). For patients with melanoma as the first primary cancer, the median OS was 73 months, compared to 87 months when melanoma was the second primary cancer (p = 0.785). Among all 11 patients, two are deceased, while the remaining patients are under surveillance. Among the remaining 9 patients, 100% have no evidence of disease with respect to melanoma. Conclusions: Despite the favorable outcomes from early detection and the advanced treatments available such as immunotherapy, a robust treatment plan should be in place when advanced melanoma is diagnosed as a synchronous tumor or second primary cancer. Further research is warranted since there are no guidelines available for the treatment of MPMs.
Factors influencing the drug release from calcium phosphate cements
Authors: Marco Fosca, Julietta V. Rau, Vuk Uskoković
Journal: Bioactive Materials (2021)

Thanks to their biocompatibility, biodegradability, injectability and self-setting properties, calcium phosphate cements (CPCs) have been the most economical and effective biomaterials of choice for use as bone void fillers. They have also been extensively used as drug delivery carriers owing to their ability to provide for a steady release of various organic molecules aiding the regeneration of defective bone, including primarily antibiotics and growth factors. This review provides a systematic compilation of studies that reported on the controlled release of drugs from CPCs in the last 25 years. The chemical, compositional and microstructural characteristics of these systems through which the control of the release rates and mechanisms could be achieved have been discussed. In doing so, the effects of (i) the chemistry of the matrix, (ii) porosity, (iii) additives, (iv) drug types, (v) drug concentrations, (vi) drug loading methods and (vii) release media have been distinguished and discussed individually. Kinetic specificities of
Participation of older patients with advanced gastroesophageal cancer in clinical trials: A systematic review of age-restrictive inclusion criteria over the last 25 years.
Authors: Maeve Hennessy, Munzir Hamid, Caitriona Goggin, Myo Oo Nay, Marie Carrigan, David Mockler, Anita G. O'Donovan, Anne M. Horgan
Journal: Journal of Clinical Oncology (2021)

e24017 Background: Cancer is a disease of aging, however older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years. We focused on patients with metastatic gastroesophageal cancer. Methods: A search strategy was developed encompassing Embase, Pubmed and The Cochrane Library databases. All completed Phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies for the period 01.01.95 to 18.11.20 were identified. Reference management software (Covidence; Veritas Health Innovation Ltd) was used to screen for inclusion/exclusion. The following details were extracted from trial protocols: country of study, date of publication, patient number, age inclusion and exclusion criteria. The median age of participants and the percentage of older patients enrolled in each study was collected. A linear probability model was used to estimate the change over time in the proportion of studies using an upper age exclusion. Results: 363 phase III studies were identified. 152 studies were eligible for full text review, 86 were excluded, leaving 66 trials for final analysis. 86% (n = 56) included Gastric, 9% (n = 6) Oesophageal and 5% (n = 3) Oesophagogastric malignancies. Asian studies represented 48% (n = 32) of trials, 29% (n = 19) were worldwide and 23% (n = 15) were European. The median age of trial participants was 62, (range 18-94). No clear trend in the ages of study participants over the time period was identified. 32% (n = 21) of studies specified an upper age limit for inclusion and 57% of these were Asian studies. The median age of exclusion was 75 years (range 65-80). All studies starting before 2003 used an upper age exclusion (n = 12); whereas only 9 of the 52 that started in 2003 or later did (17%). Among these later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). 52% (n = 34) of studies specified the proportion of their study population who were over 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%). Our search of currently enrolling trials on clinicaltrials.gov yielded 11 active studies, none of which specified an upper age limit. Conclusions: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.
The Applications of Implementation Science in Water, Sanitation, and Hygiene (WASH) Research and Practice
Authors: Sabrina S. Haque, Matthew C. Freeman
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Delivery of high quality, at-scale, and sustained services is a major challenge in the water, sanitation, and hygiene (WASH) sector, made more challenging by a dearth of evidence-based models for adaption across contexts in low-and middle-income countries.OBJECTIVE: We aim to describe the value of implementation science (IS) for the WASH sector and provide recommendations for its application.METHODS: We review concepts from the growing field of IS-defined as the "scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, and hence, to improve the quality and effectiveness of health services"and we translate their relevance to WASH research, learning, and delivery.DISCUSSION: IS provides a suite of methods and theories to systematically develop, evaluate, and scale evidence-based interventions.Though IS thinking has been applied most notably in health services delivery in high-income countries, there have been applications in low-income settings in fields such as HIV/AIDS and nutrition.Expanding the application of IS to environmental health, specifically WASH interventions, would respond to the complexity of sustainable service delivery.WASH researchers may want to consider applying IS guidelines to their work, including adapting pragmatic research models, using established IS frameworks, and cocreating knowledge with local stakeholders.
Comparison of HBV RNA and Hepatitis B Core Related Antigen With Conventional HBV Markers Among Untreated Adults With Chronic Hepatitis B in North America
Authors: Marc G. Ghany, Wendy C. King, Mauricio Lisker‐Melman, Anna S.F. Lok, Norah Terrault, Harry L.A. Janssen, Mandana Khalili, Raymond T. Chung, William M. Lee, Daryl T.Y. Lau, Gavin A. Cloherty, Richard K. Sterling
Journal: Hepatology (2021)

The clinical utility of two biomarkers, hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), as compared to conventional markers of HBV replication and disease activity, is unclear.Untreated participants in the North American Hepatitis B Research Network Adult Cohort Study were categorized by chronic hepatitis B (CHB) phases based on HBsAg and HBeAg status and HBV DNA and alanine aminotransferase (ALT) levels. HBV RNA and HBcrAg were measured (Abbott HBV pgRNA Research Assay and Fujirebio Lumipulse Immunoassay, respectively), and cross-sectional associations with conventional CHB markers were tested. Among 1,409 participants across all CHB phases, median HBV DNA was 3.8 log10 IU/mL and ALT was 34 U/L. HBV RNA was quantifiable in 99% of HBeAg+ and 58% of HBeAg- participants; HBcrAg was quantifiable in 20% of HBeAg+ (above linear range in the other 80%) and 51% of HBeAg- participants. Both markers differed across CHB phases (P < 0.001), with higher levels in the HBeAg+ and HBeAg- immune active phases. HBV RNA and HBcrAg correlated moderately strongly with HBV DNA in both HBeAg+ and HBeAg- phases (HBV RNA: e+ ρ = 0.84; e- ρ = 0.78; HBcrAg: e+ ρ = 0.66; e- ρ = 0.56; P for all, <0.001), but with HBsAg levels among HBeAg+ phases only (HBV RNA: e+ ρ = 0.71; P < 0.001; e- ρ = 0.18; P = 0.56; HBcrAg: e+ ρ = 0.51; P < 0.001; e- ρ = 0.27; P < 0.001). Associations of higher HBV RNA and HBcrAg levels with higher ALT, APRI, and Fibrosis-4 levels were consistent in HBeAg- , but not HBeAg+ , phases.Despite clear relationships between HBV RNA and HBcrAg levels and CHB phases, these markers have limited additional value in differentiating CHB phases because of their strong association with HBV DNA and, to a lesser extent, with clinical disease indicators.
The importance of maintenance chemotherapy in the first and second lines of treatment of metastatic colorectal cancer.
Authors: Danila Gridnev, Anatoly Popov, Dina Islamova, Vladislav Makarov, Edouard Vozny, Anna Kudryavtseva
Journal: Journal of Clinical Oncology (2021)

e15583 Background: The first and second lines of CT is decisive in the treatment of colorectal cancer. Choosing the right one allows you to increase PFS and improve long-term results. Surgical treatment and maintenance chemotherapy (MT) increase PFS and OS, as they can be prescribed at any stage of treatment. Methods: The analysis included 192 patients diagnosed with metastatic colorectal cancer (mCRC) who received treatment between 2014 and 2019. The average age of the patients was 62 years. At the beginning of treatment, the overall condition of all patients was ECOG1. Primary mCRC had 129 (67%) patients. In 63 (33%) patients, locally advanced disease was first diagnosed, which were included in the study after progression. PFS and OS for all patients were calculated from the start of the 1st line. Localization of the primary tumor in 42 (22%) patients was on the right side of the colon and on the left side in 149 (78%) and 1 patient did not show primary tumor. Among the patients with primary metastatic disease, 100 (52%) had isolated metastases, while the remaining 92 (48%) had 2 or more localizations. Different types of surgical treatment of metastases in the liver occurred in 41 (21%) patients. 119 patients never received MT (with any number of lines) and made a comparison group(A). 73 patients received MT in at least one of the CT lines (B). 12 patients received MT in the 1st and 2nd CT (C). These groups were homogeneous in terms of gender, age, ECOG, accessibility of surgical treatment of distant metastasis, mutational status of the tumor, and accessibility of biotherapy. Evaluation of the effect was performed using RECIST criteria, at intervals of 3 months or the appearance of clinical symptoms of progression. The treatment was carried out before the progression. At the time of analysis, 94 patients are alive and continue to receive treatment. Results: We compared in all three groups: In group A: OS - 12.9 months, PFS 1-line CT - 9.5 months, PFS 2-line CT - 4.5 months In group B: OS - 27.6 months, PFS 1-line CT - 13.6 months, PFS 2-line CT - 9.1 months In group C: OS - 38.3 months, PFS 1-line CT - 14.2 months, PFS 2-line CT - 9.1 months. “Five-year” survival (In those patients who were observed from the start of the study for all 5 years) in group A was 5,8 %, in group B 15 %, and in group C 16 %. Conclusions: Increase of PFS and OS in patients who received MT at least at one of the stages of treatment, and continues to increase in patients receiving MT in the first two lines CT. Thus, MT is a necessary component of the treatment of mCRC.
Preliminary analysis of a phase 1/2 study of NEXI-001 donor-derived multi-antigen-specific CD8<sup>+</sup> T-cells for the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT).
Authors: Monzr Al Malki, Sumithira Vasu, Dipenkumar Modi, Miguel-Angel Perales, Donna Bui, Vineetha Edavana, Sojung Kim, Lauren Suarez, Mathias Oelke, Dan BednÃ¡rik, Robert D. Knight, Juan Carlos Varela
Journal: Journal of Clinical Oncology (2021)

2538 Background: Allogeneic HCT is a potentially curative therapy for many patients with AML that relies on a graft-versus-leukemia (GvL) effect. Patients who relapse after allogeneic HCT have a poor prognosis and few treatment options. Donor lymphocyte infusion (DLI) can achieve a GvL effect in some patients, however, efficacy is frequently associated with the development graft-versus-host disease (GVHD). There is a substantial need for treatment approaches that enhance the benefit of GVL while decoupling toxicities associated with GVHD. Methods: We report ongoing results from a first-in-human study (NCT04284228) of a non-genetically engineered, donor-derived adoptive cellular therapy product, NEXI-001, which contains multiple populations of CD8 + T cells that recognize different HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. NEXI-001 contains T cell memory subtypes that combine anti-tumor potency with long-term persistence. Results: At the time of this analysis, 7 patients with relapsed AML after allogeneic HCT were enrolled. Five Patients were treated with single infusions of NEXI-001 at three different dose levels: 50, 100 and 200 million. Currently, the median follow-up is 5 months. Significantly, GVHD, cytokine release syndrome, neurotoxicity, or NEXI-001-related adverse events were not observed. NEXI-001 treatment resulted in reductions in red blood cell and platelet transfusions and increased donor chimerism. Decreases in myeloblasts in bone marrow and peripheral blood and reduction in the size of an extramedullary myeloid sarcoma were suggestive of an anti-leukemia effect (Table). Correlative studies indicate that NEXI-001 CD8 + cells undergo a rapid proliferation after infusion and are also associated with a robust host lymphocyte recovery that occurs as quickly Day 3 after infusion. NEXI-001 infused CD8 + T cells are detectable by multimer staining in peripheral blood of patients and proliferate over time. TCR sequencing analyses determined that infused NEXI-001 cells contain T cell clones that were undetectable in the peripheral blood of patients at baseline but were detected in blood and bone marrow and persist over time. Conclusions: NEXI-001 has the potential to enhance GvL effect without the associated toxicities of GVHD, cytokine release syndrome, and neurotoxicity. Due to these encouraging results, the trial will proceed with an evaluation of repeated NEXI-001 dosing Clinical trial information: NCT04284228. [Table: see text]
Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia
Authors: Patrícia O. Guimarães, Daniel Quirk, Remo H. Furtado, Lilia N. Maia, José F. Saraiva, Murillo O. Antunes, Roberto Kalil Filho, Vagner M. Junior, Alexandre M. Soeiro, Alexandre P. Tognon, Viviane C. Veiga, Priscilla A. Martins, Diogo D.F. Moia, Bruna S. Sampaio, Silvia R.L. Assis, Ronaldo V.P. Soares, Luciana P.A. Piano, Kleber Castilho, Roberta G.R.A.P. Momesso, Frederico Monfardini, Helio P. Guimarães, Dario Ponce de Leon, Majori Dulcine, Marcia R.T. Pinheiro, Levent M. Gunay, J. Jasper Deuring, Luiz V. Rizzo, Tamas Koncz, Otavio Berwanger
Journal: New England Journal of Medicine (2021)

BackgroundThe efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear.MethodsWe randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.Download a PDF of the Research Summary.ResultsA total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P=0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group.ConclusionsAmong patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.) Quick Take Tofacitinib for Severe Covid-19 Pneumonia 2m 3s
Overall survival in patients with breast cancer treated with a CDK 4/6 inhibitor plus fulvestrant: A U.S. Food and Drug Administration pooled analysis.
Authors: Jennifer J Gao, Joyce Cheng, Tatiana Michelle Prowell, Erik Bloomquist, Shenghui Tang, Suparna B. Wedam, Melanie E Royce, Danielle Krol, Christy Osgood, Gwynn Ison, Rajeshwari Sridhara, Richard Pazdur, Julia A. Beaver, Laleh Amiri-Kordestani
Journal: Journal of Clinical Oncology (2021)

1055 JJG, JC, TMP contributed equally. JAB, LAK contributed equally. Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first or second line treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival of patients in certain clinicopathologic subgroups, and results showed a consistent benefit from the addition of a CDKI to endocrine therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI plus fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of a CDKI plus fulvestrant submitted to the FDA in support of marketing applications. All analyzed patients received at least one dose of a CDKI or placebo, plus fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Results: Results of OS analyses, including all pooled patients, patients treated in the first-line setting, and patients treated in the second line and later settings, are summarized in the table below. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding a CDKI to fulvestrant. In patients age &lt; 40, the estimated OS HR favored fulvestrant alone, but this subgroup had a small sample size (n=89), so this result must be interpreted with caution. All results are considered exploratory and hypothesis-generating. Conclusions: Addition of CDKIs to fulvestrant appears to confer a consistent survival benefit across all pooled patients and within most clinicopathological subgroups of interest.[Table: see text]
Abstract TMIM-070: APELIN PROMOTES OMENTAL METASTASIS OF OVARIAN CANCER CELLS
Authors: Samrita Dogra, Deepika Neelakantan, Maulin Mukeshchandra Patel, Beth Griesel, Ann Olson, Florea Lupu, Sukyung Wool
Journal: Clinical Cancer Research (2019)

Abstract PURPOSE: Ovarian cancer (OvCa) is mainly metastasized to the peritoneal cavity and omentum, an organ primarily composed of adipocytes. Adipocytes produce adipokines including apelin involved in initiating angiogenesis and promote the initial homing of tumor cells to omentum through adipokine secretion. Apelin and its receptor APJ mediates glucose/energy metabolism and angiogenesis. The study objective is to assess the functional role of apelin/APJ pathway in omental metastasis of OvCa and associated benefits from antagonizing this pathway as a novel treatment strategy against OvCa metastasis. METHODS: Mouse adipocyte cell line 3T3-L1 were used to obtain adipocyte-derived conditioned media (adipo-CM). Apelin concentrations in adipo-CM were quantified using Western blot and ELISA. Migration and invasion of human OvCa cell lines (OVCAR-5APJ and OVCAR-8) were determined in vitro in the presence of adipo-CM. In vivo homing and ex vivo adhesion assays were performed to study the role of apelin/APJ pathway in attracting and attaching APJ-overexpressing OvCa cells to the omentum. RESULTS: Apelin expression was 2.5 fold higher in mature adipocytes compared to that in pre-adipocytes. Mature adipocytes secreted 0.8-1 ng/mL of apelin in the CM. In vivo, high APJ expression increased 'homing-in' of OvCa cells by 2.75-fold to the omentum. Adipo-CM increased transwell migration (3-3.5 fold) and invasion (3.5-4 fold) of OvCa cells in vitro. Adhesion of APJ high expression OvCa cells to mice omentum ex vivo increased by 1.5 fold. These apelin-induced pro-metastatic effects were reversed by apelin-specific antagonist (F13A) in a dose-dependent manner. CONCLUSION: We found that apelin/ APJ pathway potentially promotes OvCa metastasis to omentum and F13A effectively inhibited apelin-induced effects. Citation Format: Samrita Dogra, Deepika Neelakantan, Maulin Mukeshchandra Patel, Beth Griesel, Ann Olson, Florea Lupu, and Sukyung Woo1. APELIN PROMOTES OMENTAL METASTASIS OF OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-070.