tbuckley/cabot-search huggingface dataset:
A phase I/II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 dosed q14d without and with prophylactic G-CSF in non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL)
Authors: J. F. Gerecitano, O. O'Connor, H. Van Deventer, J. Hainsworth, J. Leonard, B. Afanasayev, M. Chen, J. Seroogy, R. Escandon, A. Wolff, M. Conlan
Journal: Journal of Clinical Oncology (2009)

8578 Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. In the first-in-humans (FIH) trial, the MTD was 4 mg/m 2 q21d. Since neutropenia was the major DLT, with recovery by ∼d15, a q14d schedule without (-GCSF) and with prophylactic G-CSF (+GCSF) is being explored. Methods: In phase I of this phase I/II trial, DLT and MTD of SB-921 given on d1 and d15 q28d (-GCSF) and (+GCSF) will be determined. Eligible patients (pts) have relapsed or refractory HL or NHL, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for stem cell transplant. This is a standard 3+3 dose escalation trial design, starting at 2 mg/m 2 and escalating by 1 mg/m 2 . Once DLT (-GCSF) is identified, (+GCSF) dosing starts at the (-GCSF) MTD, escalating until (+GCSF) DLT is identified. Results: 39 pts were treated (-GCSF) at 6 dose levels (2–7 mg/m 2 ). 5 pts had DLT: 1/3 at 4 (grade 3 hepatic enzymes; found retrospectively); 2/10 at 6 (both sepsis with neutropenia), and 2/7 at 7 (both grade 4 neutropenia lasting &gt;5d) mg/m 2 . MTD (-GCSF) was 6 mg/m 2 . 12 pts were treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3), 8 (n=3) and 9 (n=2) mg/m 2 , with 1 DLT of neutropenia at 9 mg/m 2 . Expansion of the 9 mg/m 2 (+GCSF) cohort to n=6 is ongoing. For all 51 pts treated to date, mean age was 52 yr; 53% were male; 39% HL, 33% aNHL, and 28% iNHL; 76% had ≥3 prior CT regimens. The most frequent grade 3/4 toxicity was neutropenia: 58% at ≥MTD (-GCSF) and 42% (+GCSF). Other grade 3/4 events were uncommon. There was no neuropathy or alopecia &gt;grade 1. There were 2 partial responses (PR), both in elderly pts with HL with ≥2 prior CT regimens, 1 at 6 (-GCSF) and 1 at 8 (+GCSF) mg/m 2 , ongoing at Cycle 4+. Conclusions: The MTD of SB-921 (-GCSF) on a q14d schedule was 6 mg/m 2 . This dose density (0.43 mg/m 2 /d) is &gt;2-fold higher than in the FIH trial with a q21d schedule (0.19 mg/m 2 /d). Dose escalation (+GCSF) is continuing. SB-921 is well tolerated with minimal toxicity other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥6 mg/m 2 . [Table: see text]
Ultrasound versus physical exam to screen for secondary thyroid cancer among high-risk childhood cancer survivors.
Authors: Jennifer Hess, Alexandra Maria Walsh, Dorothee Newbern, Kristian Schafernak, Tamara Vern-Gross, Janet Foote
Journal: Journal of Clinical Oncology (2019)

e21528 Background: Thyroid cancer is a common secondary malignancy among childhood cancer survivors who have received radiation to the head, neck and/or upper thorax. The optimal strategy for surveillance for thyroid carcinoma in childhood cancer survivors remains controversial. Current Children’s Oncology Group recommendations are limited to physical exam. The objective of this study was to determine the sensitivity and specificity of thyroid ultrasound versus neck exam by a pediatric endocrinologist in the diagnoses of thyroid cancer in a cohort of high-risk childhood cancer survivors. Methods: Medical records of childhood cancer survivors who received radiotherapy to the head, neck and/or upper thorax were reviewed. These patients were seen in a comprehensive childhood cancer survivorship clinic from 01/01/2010 to 12/31/2017. Patient populations included oncology, bone marrow transplant and brain tumor patients. Results: 226 patients received radiation to the head, neck and/or upper thorax. Of those, 129 patients were male (57%). Sixteen (7.1%) of patients developed a secondary thyroid malignancy including 4 patients previously treated for an oncological malignancy, 9 patients treated with bone marrow transplantation, and 3 patients with a CNS malignancy. Median radiation dose was 1800 cGy (range 400-5940 cGy). Time to thyroid carcinoma diagnosis occurred at a median of 12 years (range 4-19 years) from treatment with radiation. Screening ultrasounds were obtained in 146 (65%) patients while 226 (100%) had a physical exam. Two cases were identified by abnormalities on physical exam. The sensitivity of US was 100% (CI 80.6-100) compared to a sensitivity of 12.5% (CI 3.5-36) using physical exam (P &lt; 0.0001). Screening ultrasound had a specificity of 73% (CI 65.1-80.1) while physical exam yielded a specificity of 100% (CI 98.2-100). Conclusions: Regular screening with ultrasounds provide the greatest sensitivity for detection of secondary thyroid carcinomas after head, neck and upper thorax radiation in childhood cancer survivors. If screening ultrasounds were not routinely utilized in our clinic, 14 of the 16 patients (87.5%) would have had a delay in their diagnosis of a secondary thyroid malignancy. Screening ultrasounds may lead to earlier detection of thyroid carcinomas, with the potential to decrease the need for aggressive surgery, radioiodine therapy and, ultimately, to decrease recurrence risk.
A WHO Reference Reagent for lupus (anti-dsDNA) antibodies: international collaborative study to evaluate a candidate preparation
Authors: Bernard J Fox, Jason Hockley, Peter Rigsby, Carl Dolman, Pier Luigi Meroni, Johan Rönnelid
Journal: Annals of the Rheumatic Diseases (2019)

Introduction Antibodies against double-stranded DNA (anti-dsDNA) are a specific biomarker for systemic lupus erythematosus (SLE). The first WHO International Standard (IS) for anti-dsDNA (established in 1985), which was used to assign units to diagnostic tests, was exhausted over a decade ago. Methods Plasma from a patient with SLE was first evaluated in 42 European laboratories. The plasma was thereafter used by the National Institute for Biological Standards and Control to prepare a candidate WHO reference preparation for lupus (anti-dsDNA) antibodies. That preparation, coded 15/174, was subjected to an international collaborative study, including 36 laboratories from 17 countries. Results The plasma mainly contained anti-dsDNA, other anti-chromatin antibodies and anti-Ku. The international collaborative study showed that the field would benefit from 15/174 as a common reference reagent improving differences in performance between different assays. However, no statistically meaningful overall potency or assay parallelism and commutability could be shown. Conclusion 15/174 cannot be considered equivalent to the first IS for anti-dsDNA (Wo/80) and was established as a WHO Reference Reagent for lupus (oligo-specific) anti-dsDNA antibodies with a nominal value of 100 units/ampoule. This preparation is intended to be used to align test methods quantifying levels of anti-dsDNA antibodies.
OS10.3 Primary therapy and survival in over 70-year-old patients with primary central nervous system lymphoma: a contemporary, nationwide, population-based study in the Netherlands
Authors: M van der Meulen, J E C Bromberg, O Visser, J K Doorduijn, A G Dinmohamed
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Elderly patients with primary central nervous system lymphoma (PCNSL) have a poor prognosis. In this contemporary, nationwide, population-based study, we assessed the contribution of primary therapy on overall survival (OS) among elderly PCNSL patients in the Netherlands. METHODS All patients aged ≥ 70 years with cytologically and/or histologically proven PCNSL diagnosed between 2014–2016 were selected from the nationwide Netherlands Cancer Registry. Univariable analysis of OS was performed with the log-rank test. Multivariable Cox regression was applied to assess factors associated with OS, with adjustment for age (71–74, 75–79 and ≥80 years), sex, prior malignancy, primary therapy (no therapy, radiotherapy [RT] only, chemotherapy [CT]), and rituximab treatment. RESULTS Overall, 109 patients were registered; 39%, 39%, and 22% were aged 71–74, 75–79 and ≥80 years, respectively. Most patients received CT (45%), followed by no therapy (33%) and RT only (22%). With increasing age, the application of CT decreased (60%, 43%, and 24%), and RT only increased (10%, 26%, 26%) in the three age groups. CT consisted of methotrexate (MTX)-based or MTX only regimens in 98%. In patients treated with CT, Rituximab was added in 31%. During follow-up, 89 patients (82%) died. Median OS was 5.3 months (95% confidence interval [CI], 3.3–7.8), no difference was observed in median OS across the three age groups (6.8, 4.4, and 4.6 months, respectively; P=0.348). However, in the groups no therapy, RT only, and CT, median OS (95% CI) was 1.3 (1.0–2.0), 6.5 (4.4–12.5), and 20.3 (8.6–41.4) months (P&lt;0.001), respectively. Moreover, 2 year OS (95%CI) was 49% (34–62) in patients treated with chemotherapy compared with 17% (5–34) in patients treated with RT. Median OS (95% CI) was 20.3 (8.6–41.4) in recipients of MTX-based regimens and 5.0 (2.4-not reached) months in recipients MTX only (P=0.185). In multivariable analysis, treatment with CT or RT was the only factor associated with OS: age group and the addition of Rituximab were not associated with OS. CONCLUSION In this contemporary population-based study, OS remained poor among patients with PCNSL aged over 70 years, irrespective of age group. Clinical condition likely influenced therapy choices but in those judged fit enough to receive CT, almost 50% survived 2 years. Therefore, future prospective intervention studies are warranted to assess which group of elderly patients benefit from CT or less intensive approaches.
Development of new TB regimens: Harmonizing trial design, product registration requirements, and public health guidance
Authors: Christian Lienhardt, Andrew A. Vernon, Marco Cavaleri, Sumati Nambiar, Payam Nahid
Journal: PLoS Medicine (2019)

Regulatory approval of new tuberculosis (TB) drugs can be based on data from trial(s) using a surrogate endpoint of treatment efficacy under an accelerated or conditional procedure.In such circumstances, policy makers and TB programs can be hampered in their ability to make recommendations on the optimal use of the drug(s), and consequently, the uptake by national or international public health institutions of such recommendations can be limited.• Based on the essential need to produce high-quality evidence for policy decisions, this paper reflects on specific methodological issues in clinical trial design that need to be addressed to improve compliance with clinical, regulatory, and public health requirements.• Established mechanisms for communication between drug developers and regulators already exist; however, equal engagement with policy makers is also essential for the optimal selection of trial designs, endpoints, and markers of treatment outcome and for giving consideration to public health and program aspects.• The next generation of TB trials should better reconcile the research agenda with the need for global policies on access to TB medicines.Policy decision-makers should establish formal mechanisms for iterative feedback on regimen-development pathways.In this paper, we provide examples of how the need for interactions between regulators, trialists, and policy decision-makers can be addressed.
Erratum: Toll-like receptors on tumor cells facilitate evasion of immune surveillance (Cancer Research (June 15, 2005) 65 (5009-5014))
Authors: Bo Huang, Jie Zhao, Hongxing Li, Kai Li He, Yibang Chen, Shu Hsia Chen, Lloyd Mayer, Jay C. Unkeless, Huabao Xiong
Journal: Cancer Research (2005)
Cancer overtakes CVD to become leading cause of death in high income countries
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Cancer is now responsible for twice as many deaths as cardiovascular disease (CVD) in high income countries, according to two new papers published in the Lancet .

The studies said that while CVD remains the leading cause of mortality among middle aged adults globally, accounting for 40% of all deaths, this is no longer the case in high income countries.

The researchers estimated that of 55 million deaths that occurred in the world in 2017, approximately 17.7 million were from CVD.

The findings come from the PURE study, a large prospective international cohort study that involves substantial data from a large number of middle, low, and high income countries.

Countries analysed in the two reports include: Argentina, Bangladesh, Brazil, Canada, Chile, China, Colombia, India, Iran, Malaysia, Pakistan, Palestine, Philippines, Poland, Saudi Arabia, South Africa, Sweden, …
NHS leaders are underwhelmed at extra £6.2bn for NHS in next financial year
Authors: Adrian O’Dowd
Journal: BMJ (2019)

The government is to invest an extra £6.2bn (€6.9bn; $7.5bn) in the NHS next year and £1.5bn in social care as part of its spending review announced on 4 September, but health leaders have given it a lukewarm response. The BMA’s Chaand Nagpaul said that all the money had already been promised to the NHS and was not new, calling the announcement “another missed opportunity.”

The chancellor of the exchequer, Sajid Javid, announced his spending review, which is—unusually—just for a one year period, saying that he was setting “the real increase in day-to-day spending” next year at £13.8bn overall.

Speaking to the House of Commons Javid said that there was “no higher priority” than the NHS and pointed to the fact that last year the government had announced it would increase NHS …
Effects of COJEC induction on neuroblastoma patient-derived xenografts (PDX).
Authors: Adriana Manas Nunez, Kristina Aaltonen, Karin Hansson, Katarzyna Radke, Javanshir Esfandyari, David Gisselsson, Daniel Bexell
Journal: Journal of Clinical Oncology (2019)

e21503 Background: Neuroblastoma (NB) is a solid pediatric tumor that causes 15% of childhood cancer deaths. High-risk patients have 50 to 70% mortality after 5 years. Currently, the standard way to treat high risk patients is COJEC induction followed by surgery, chemotherapy with stem cell transplants, irradiation and immunotherapy. This intense treatment has significantly increased overall survival, but mortality is still high, survivors are prone to relapse and treatment resistance is a major clinical problem. COJEC induction consists in the cycled administration of the chemotherapeutics Cisplatin, Vincristine, Etoposide, Cyclophosphamide and Carboplatin. These drugs have been long used in the clinic, but a comprehensive preclinical study combining all of them had not been done. The aim of this project was to establish a PDX model for chemotherapy induction in high-risk NB and investigate tumor characteristics and response upon treatment. Methods: NB cells from previously developed high-risk PDX models were injected subcutaneously in nude mice. When tumors reached an appropriate size, they were treated with either a COJEC-like protocol or single agent induction with high dose cisplatin. After treatment, tumors were analyzed by immunohistochemistry, chromosomal copy number analysis and RNA sequencing. Results: Most mice responded well to COJEC induction and 8/10 tumors were reduced. Within the reduced tumors, 4 were subjected to total resection and relapsed after several weeks, mimicking the clinical situation. Cisplatin treatment alone led to no significant tumor reduction and 6/10 tumors were highly resistant. Thus, as for humans, multidrug induction is more successful in reducing tumor size but presents an uneven response with high relapse rate. The responsive tumors show a higher degree of cellular differentiation when compared to resistant tumors. Cisplatin treated tumors have accumulation of chromosomal aberrations when compared to controls, and subclonal dynamics are enhanced in resistant tumors. Conclusions: We established a PDX model for chemotherapy induction in high-risk NB. The results mimic clinical findings seen in high-risk NB patients. The model is useful to understand the mechanisms of treatment resistance and for the testing of novel therapies against high-risk NB.
Proximal tubule cyclophilin D regulates fatty acid oxidation in cisplatin-induced acute kidney injury
Authors: Hee-Seong Jang, Mi Ra Noh, Eui-Man Jung, Woo-Yang Kim, Siddesh Southekal, Chittibabu Guda, Kirk W. Foster, David Oupicky, Fernando A. Ferrer, Babu J. Padanilam
Journal: Kidney International (2019)
Progress and trends in the utilization and adoption of palliative care in patients with terminal gynecologic cancer in the United States: A study of 4,264 women.
Authors: Anthony Milki, Amandeep Kaur Mann, Daniel Stuart Kapp, John K. Chan
Journal: Journal of Clinical Oncology (2019)

11606 Background: To determine the factors associated with the utilization of palliative care (PC) in patients with metastatic gynecologic cancer who died while hospitalized. Methods: Data were extracted from the National Inpatient Sample (NIS) database for patients with cervical, uterine, and ovarian cancers from 2005 to 2011. Chi-squared and logistic regression models were employed for statistical analyses. Results: Of 4264 women with gynecologic cancer, 983 (23.0%) utilized PC (median age: 66 years). 2633 (61.8%), 1034 (24.3%), and 597 (14.0%) patients had ovarian, uterine, and cervical cancer, respectively. The majority were white (57.9%), and the remainder were black (12.6%), Hispanic (7.8%), and Asian (3.1%). 24.9, 23.9, 23.6, and 25.2% were low, low-middle, middle-high, and high with respect to median income. Medicare, Medicaid, and private insurance was found in 46.7, 10.8, and 37.6% of patients. 36.9, 21.0, 18.0, and 24.1% of patients were treated in hospitals in the South, West, Midwest, and Northeast. 11.3, 23.9, and 64.2% of patients were treated in small, medium, and large hospitals, designated as teaching (53.1%) and nonteaching (46.3%) institutions. The utilization of PC increased from 5.2% in 2005 to 30.4% in 2011. Older age (OR: 1.34; 95% CI: 1.10-1.64; P = 0.01), high SES (OR: 1.37; 95% CI: 1.09-1.72; P = 0.01), privately insured (OR: 1.81; 95% CI: 1.46-2.24; P &lt; 0.001), treatment at Western (OR: 1.94; 95% CI: 1.56-2.41; P &lt; 0.001) and Midwestern hospitals (OR: 1.43; 95% CI: 1.15-1.77; P = 0.001), and depression (OR: 1.34; 95% CI: 1.00-1.80; P = 0.05) were associated with higher PC use. However, race, cancer type, hospital teaching status, and hospital location were not associated with PC use. Conclusions: The use of inpatient palliative care has increased significantly over the study period. The lower utilization of palliative care for terminal illness associated with younger, lower socioeconomic status, Southern and smaller volume hospitals warrants further attention.
Abstract 23: Incidence of Adult In-Hospital Cardiac Arrest in the United States
Authors: Mathias J Holmberg, Catherine Ross, Paul S Chan, Jordan Duval-Arnould, Anne V Grossestreuer, Tuyen Yankama, Michael W Donnino, Lars W Andersen
Journal: Circulation (2018)

Introduction: Current incidence estimates of in-hospital cardiac arrest in the United States are based on data from more than a decade ago, with an estimated 200,000 adult cases per year. The aim of this study was to estimate the contemporary incidence of in-hospital cardiac arrest in adult patients, which may better inform the public health impact of in-hospital cardiac arrest in the United States. Methods: Using the Get With The Guidelines®-Resuscitation (GWTG-R) registry, we developed a negative binomial regression model to estimate the incidence of index in-hospital cardiac arrests in adult patients (&gt;18 years) between 2008 and 2016 based on hospital-level characteristics. The model coefficients were then applied to all United States hospitals, using data from the American Hospital Association Annual Survey, to obtain national incidence estimates. Hospitals only providing care to pediatric patients were excluded from the analysis. Additional analyses were performed including both index and recurrent events. Results: There were 154,421 index cardiac arrests from 388 hospitals registered in the GWTG-R registry. A total of 6,808 hospitals were available in the American Hospital Association database, of which 6,285 hospitals provided care to adult patients. The average annual incidence was estimated to be 283,700 in-hospital cardiac arrests. When including both index and recurrent cardiac arrests, the average annual incidence was estimated to 344,800 cases. Conclusions: Our analysis indicates that there are approximately 280,000 adult patients with in-hospital cardiac arrests per year in the United States. This estimate provides the contemporary annual incidence of the burden from in-hospital cardiac arrest in the United States.
Comparison of the effectiveness of oral morphine versus oral tramadol on early pain control in opioid-naive patients with moderate cancer pain.
Authors: Ramila Shilpakar, Bishnu D. Paudel, Aarati Shah, Soniya Dulal
Journal: Journal of Clinical Oncology (2019)

11581 Background: Adequate pain control, an essential part of cancer care remains a challenge in resource limited countries like Nepal. Early use of morphine for Moderate Cancer Pain (MCP) and not sequential World Health Organization (WHO) analgesic ladder seems reasonable in the setting of limited access to health care. The purpose of this study was to compare efficacy of oral Morphine (MOR) with oral Tramadol (TRM) in control of pain as well as physical wellbeing in patients (pts) with MCP using Edmonton Symptom Assessment Scale (ESAS). Methods: An IRB approved randomized phase II trial was performed in opioid-naive pts with MCP as defined by pain score in Numerical rating score (NRS)of 4-6.Patients were randomized to receive MOR syrup 5 mg 4 hourly or TRM 50 mg four times a day. Titration of dose was done in both groups for 3 days as per standard recommendation for MOR or till maximum recommended daily dose for TRM. MOR was changed to prolonged release form at Day 4.The primary endpoint was number of early responders, defined as pts with at least 20% reduction in pain intensity on NRS on Day 3. Secondary outcome was number of patients with highly meaningful pain reduction, defined as decrease in pain intensity on NRS by ≥ 5 and improvement in physical well-being with ESAS at Day 7. Results: 68 pts consented and were randomized, 34 in each arm. The primary endpoint occurred in 94.1% pts in MOR and 55.9% in TRM (p &lt;0.001). Number of patients with highly meaningful pain reduction was significantly higher in MOR than in TRM (76.5% vs. 32.35%; p&lt;0.001). Improvement in general physical wellbeing as assessed by ESAS was better in morphine group. No difference in adverse effects was noted between the treatment arms. Conclusions: In this study Morphine was superior to Tramadol in the control of pain with statistically significant difference in the primary and secondary endpoints. So, early use of morphine skipping the WHO sequential analgesic ladder for moderate cancer pain seems a higher value option in resource scarce country with limited access to healthcare.