Real-world outcomes following third or subsequent lines of therapy: A Danish population-based study on 189 patients with relapsed/refractory large B-cell lymphomas.

Outcome data of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have been approved based on single-arm trials, but results need to be contextualized by real-world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline-based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum-based salvage therapy (13%), low-intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2-year OS-/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum-based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0-1 of these risk factors had a 2-year OS estimate of 65%. Only a very small fraction of DLBCL patients received third-line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease.

Circumferential endoscopic submucosal dissection of distal rectal polyp in a patient with portal hypertension complicated by bowel obstruction.

Video 1Circumferential endoscopic submucosal dissection of distal rectal polyp in a patient with portal hypertension complicated by bowel obstruction.

Rare Primary Fallopian Tube Grade 2 Neuroendocrine Tumor: A Case Report With Review of Literature.

Neuroendocrine neoplasms commonly arise from the gastrointestinal tract and lungs. Less commonly, they may occur in the gynecologic tract, typically within the ovary of a mature cystic teratoma. Primary neuroendocrine neoplasms of the fallopian tube are exceptionally rare and only a total of 11 cases have been reported in the literature. We describe the first case to our knowledge of a primary grade 2 neuroendocrine tumor of the fallopian tube in a 47-yr-old female. In this report, we describe the case's unique presentation, review the published literature on primary neuroendocrine neoplasms of the fallopian tube, discuss the treatment options, and speculate on their origin and histogenesis.

Matrix effect in tumor lysates - Does it affect your cytokine ELISA and multiplex analyses?

Quantification of cytokines in cancerous tissue is important for understanding basic tumor biology and for deciphering anti-cancer mechanisms in drug development. Cytokine measurements on protein-level are often done by immunoassays such as enzyme-linked immunosorbent assay (ELISAs) and multiplex assays. However, immunoassays are prone to interference due to the presence of perturbing factors. The sum of these factors is known as the matrix effect, which results in a deviation of the measured cytokine concentration from the actual concentration. In this study, we demonstrated that matrix effects are present in tumor lysates from 11 different syngeneic murine tumors and that it can greatly affect cytokine measurements in ELISAs and multiplex assays. Dilution of tumor lysates and careful selection of lysis buffer components may decrease matrix effects. However, matrix effects are still present, and care should be taken when analyzing cytokine measurements of tumor lysates.

Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy.

BACKGROUND: Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode of action (MoA) is the induction of difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on the immune system are largely unknown. Here, we investigated the immunostimulatory effects of the mesothelin-targeted thorium-227 conjugate (MSLN-TTC) in vitro and in vivo in monotherapy and in combination with an inhibitor of the immune checkpoint programmed death receptor ligand 1 (PD-L1) in immunocompetent mice. METHODS: The murine cell line MC38 was transfected with the human gene encoding for MSLN (hMSLN) to enable binding of the non-cross-reactive MSLN-TTC. The immunostimulatory effects of MSLN-TTC were studied in vitro on human cancer cell lines and MC38-hMSLN cells. The efficacy and MoA of MSLN-TTC were studied in vivo as monotherapy or in combination with anti-PD-L1 in MC38-hMSLN tumor-bearing immunocompetent C57BL/6 mice. Experiments were supported by RNA sequencing, flow cytometry, immunohistochemistry, mesoscale, and TaqMan PCR analyses to study the underlying immunostimulatory effects. In vivo depletion of CD8+ T cells and studies with Rag2/Il2Rg double knockout C57BL/6 mice were conducted to investigate the importance of immune cells to the efficacy of MSLN-TTC. RESULTS: MSLN-TTC treatment induced upregulation of DNA sensing pathway transcripts (IL-6, CCL20, CXCL10, and stimulator of interferon genes (STING)-related genes) in vitro as determined by RNASeq analysis. The results, including phospho-STING activation, were confirmed on the protein level. Danger-associated molecular pattern molecules were upregulated in parallel, leading to dendritic cell (DC) activation in vitro. MSLN-TTC showed strong antitumor activity (T:C 0.38, p<0.05) as a single agent in human MSLN-expressing MC38 tumor-bearing immunocompetent mice. Combining MSLN-TTC with anti-PD-L1 further enhanced the efficacy (T:C 0.08, p<0.001) as evidenced by the increased number of tumor-free surviving animals. MSLN-TTC monotherapy caused migration of CD103+ cDC1 DCs and infiltration of CD8+ T cells into tumors, which was enhanced on combination with anti-PD-L1. Intriguingly, CD8+ T-cell depletion decreased antitumor efficacy. CONCLUSIONS: These in vitro and in vivo data on MSLN-TTC demonstrate that the MoA of TTCs involves activation of the immune system. The findings are of relevance for other targeted radiotherapies and may guide clinical combination strategies.

A Pediatric Hospital Policy for Medical Marijuana Use.

Most US states have now legalized medical marijuana (MMJ) use, giving new hope to families dealing with chronic illness, despite only limited data showing efficacy. Access to MMJ has presented several challenges for patients and families, providers, and pediatric hospitals, including the discrepancy between state and federal law, potential patient safety issues, and drug interaction concerns. Colorado was one of the first states to legalize MMJ and has remained at the forefront in addressing these challenges. Children's Hospital Colorado has created and evolved its MMJ inpatient use policy and has developed a unique consultative service consisting of a clinical pharmacist and social worker. This service supports patients and families and primary clinical services in situations in which MMJ is actively being used or considered by a pediatric patient. The first 50 patients seen by this consultative service are reported. Eighty percent of patients seen had an oncologic diagnosis. Symptoms to be ameliorated by active or potential MMJ use included nausea and vomiting, appetite stimulation, seizures, and pain. In 64% of patients, MMJ use was determined to be potentially unsafe, most often because of potential drug-drug interactions. In 68% of patients, a recommendation was made to either avoid MMJ use or adjust its administration schedule. As pediatric hospitals address the topic of MMJ use in their patients, development of institutional policy and clinical support services with specific expertise in MMJ is a recommended step to support patient and families and hospital team members.

Theranostic Imaging May Vaccinate against the Therapeutic Benefit of Long Circulating PEGylated Liposomes and Change Cargo Pharmacokinetics.

The enhanced permeability and retention (EPR) effect increases tumor accumulation of liposomal chemotherapy and should, in theory, increase anticancer effects and lower toxicity. Unfortunately, liposomal chemotherapy has generally not met the expected potential, perhaps because the EPR effect is not ubiquitous. PET imaging using radiolabeled liposomes can identify cancers positive for the EPR effect. In the current study, we show in clinical canine cancer patients that repeated imaging with radiolabeled liposomes (64Cu-liposome) induces the accelerated blood clearance (ABC) phenomenon. This was observed even with very long intervals between PEGylated liposome injections, which contradict previous reporting in experimental animal models. The induction of ABC may be devastating for the theranostic use of liposomal imaging, as this could vaccinate patients against therapeutic efficacy. To investigate and solve this important problem, an additional study part was designed in which rats were subjected to repeated liposomal administrations, including stealth 64Cu-liposome PET imaging and Caelyx chemotherapy. Most importantly, it was found that, by increasing the lipid dose at the first injection or by supplying a small predose before the second 64Cu-liposome injection, ABC could be prevented. Importantly, signs of liposome tracer breakdown with subsequent renal excretion were observed. These findings highlight the importance of the ABC phenomenon for liposomal predictive imaging in a clinically relevant setting and show that carefully planned application is central to avoid potential detrimental effects on patient benefit.

Unplanned hospitalizations in a racially and ethnically diverse population of women receiving chemotherapy for epithelial ovarian cancer.

OBJECTIVES: Unplanned hospital admission following chemotherapy is a measure of quality cancer care. Large retrospective datasets have shown admission rates of 10-35% for women with ovarian cancer receiving chemotherapy. We sought to evaluate the prevalence and associated risk factors for hospital admission following chemotherapy in our racially diverse urban population. METHODS: After IRB approval, clinicopathologic and treatment data were abstracted from all patients with newly diagnosed epithelial ovarian cancer who received chemotherapy at our institution from 2005 to 2016. Two-sided statistical analyses and Cox regression analysis were performed using Stata. RESULTS: Of 217 evaluable patients, 87 (40%) had unplanned admissions following chemotherapy: adjuvant 64 (74%) and neoadjuvant 23(26%). Thirty (14%) had more than one admission. In total, there were 1314 days of hospitalization. The median readmission duration was 3 days. Body mass index and hypertension were predictive of readmission (p < 0.05). When comparing those readmitted more than once to those admitted once, both race and aspirin use were predictive of readmission (p < 0.05). Of those admitted more than once the self-identified race and ethnicity was 12 (40%) Hispanic, 8 (27%) White, 8 (27%) Black and 2 (7%) other. There was a significant difference in disease free (p = 0.01) and overall survival (p = 0.004) for patients with unplanned admission after chemotherapy as compared to those without admission. CONCLUSIONS: Readmission rates in our racially diverse patient population were higher than previously reported in the literature. Identifying patients at risk of readmission may play a role in chemotherapy decision-making, and resource allocation including patient care navigators.

[A Danish fetal alcohol spectrum disorders definition].

The Danish Paediatric Society presents the first Danish definition of fetal alcohol spectrum disorders (FASD) in a new guideline. FASD is an umbrella term for conditions caused by prenatal alcohol exposure. To varying degrees, fetal alcohol damages manifest as physical defects, characteristic facial features and poor growth, as well as behavioural and cognitive disorders. It requires both somatic and psychological evaluation to identify these damages. Early diagnosis and identification of problems are important for prognosis as professional care has a positive preventive effect on comorbidities.

Early Splenic Flexure Intubation Competency Predicts Early Cecal Intubation Competency in Gastroenterology Fellows.

BACKGROUND: Trainees learn colonoscopy skills at varying speeds. We hypothesized that a fellow's ability to reliably reach the splenic flexure early in training could predict the number of procedures required to achieve competency in intubating the cecum. METHODS: This was a retrospective analysis of prospectively collected data. The most proximal site in the colon reached independently by GI fellows was recorded on consecutive colonoscopies. The number of procedures required to achieve splenic flexure intubation rate (SFIR) ≥ 90 % by cumulative summation learning curve and cecal intubation rate (CIR) ≥ 90 % by rolling average was calculated. Fellows were then dichotomized into "Early" versus "Late" learners based on the median number of procedures required to achieve SFIR ≥ 90 %. The number of procedures required to achieve CIR ≥ 90 % was then compared between the groups. RESULTS: Fellows achieved SFIR ≥ 90 % at a median of 37 colonoscopies. Fellows who achieved SFIR competency early achieved CIR ≥ 90 % at a mean of 208 procedures versus 352 procedures in the fellows who achieved SFIR competency late (p = 0.03). CONCLUSIONS: Data from a single academic medical center show that whether a trainee will learn endoscopy quickly compared to his/her peers can be predicted early in their endoscopy training by tracking SFIR. This knowledge could be used to customize endoscopy curriculum.

Maternal Serum Resistin Is Reduced in First Trimester Preeclampsia Pregnancies and Is a Marker of Clinical Severity.

OBJECTIVE: To examine whether resistin levels in first trimester maternal serum are associated with insulin resistance or preeclampsia (PE). METHODS: A case-control study of maternal serum resistin concentration conducted using 285 normal pregnancies and 123 PE pregnancies matched for gestational age, parity and maternal age. Samples were taken in gestational weeks 10+0-13+6. RESULTS: There was a negative correlation between resistin and clinical severity of PE, but no correlation with IS, TNF-α, body mass index, birth weight and pregnancy length. CONCLUSIONS: Resistin is reduced in first trimester of PE pregnancies, particularly in severe PE. Inflammation and IS cannot explain this phenomenon.

Development of recommendations for dosing of commonly prescribed medications in critically ill obese children.

PURPOSE: The development and use of a decision support tool to help formulate recommendations for dosing of commonly prescribed medications in critically ill obese children are described. METHODS: Medications prescribed in 2010 to critically ill infants and children (younger than 18 years) were identified from the Pediatric Health Information System. The most commonly prescribed and therapeutically monitored medications were extracted. Supportive evidence for obesity dosing was identified through a standardized computerized search involving medical subject heading terminology and age filters using PubMed and Ovid. A usefulness scoring system was developed to rate the strength and applicability of the literature to critically ill obese children. A decision supporttool was then created to aid in the formulation of a dosing weight for each medication based on the usefulness score, published pharmacokinetic properties, clinical studies available in the primary literature, and consideration of clinical consequences of underdosing or overdosing. RESULTS: A total of 113 medications were evaluated, and 122 discrete citations, supporting 66 medications, were reviewed. Seventy-two percent of citations had general obesity dosing information, and 13% had pediatric-specific information. The overall mean usefulness score was 5.1±4.7 (median, 7). The decision support tool was incorporated to make final dosing weight recommendations for obese children. Ultimately, total body weight was recommended for 52 medications, adjusted weight for 43 medications, and ideal body weight for 18 medications. CONCLUSION: The inadequacy of obesity dosing information for most medications commonly ordered for children admitted to a pediatric intensive care unit led to the development of a decision support tool to aid in formulating dosing recommendations.

Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats.

Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures of environmentally relevant EDCs with estrogenic, anti-androgenic or dissimilar modes of action (TotalMix) of 100-, 200- or 450-fold high end human intake estimates. Mammary glands of prepubertal and adult female and male offspring were examined. Oestrogens increased mammary outgrowth in prepubertal females and the mRNA level of matrix metalloproteinase-3, which may be a potential biomarker for increased outgrowth. Mixtures of EDCs gave rise to ductal hyperplasia in adult males. Adult female mammary glands of the TotalMix group showed morphological changes possibly reflecting increased prolactin levels. In conclusion both estrogenic and anti-androgenic chemicals given during foetal life and lactation affected mammary glands in the offspring.

Partial remission definition: validation based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish children with new-onset type 1 diabetes.

OBJECTIVE: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c). SUBJECTS AND METHODS: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset of type 1 diabetes (T1D). Receiver operating characteristic curve (ROC) analysis was used to evaluate the predictive value of IDAA1c and age on partial C-peptide remission (stimulated C-peptide, SCP > 300 pmol/L). RESULTS: PR (IDAA1c ≤ 9) in the Danish and Hvidoere cohorts occurred in 62 vs. 61% (3 months, p = 0.80), 47 vs. 44% (6 months, p = 0.57), 26 vs. 32% (9 months, p = 0.32) and 19 vs. 18% (12 months, p = 0.69). The effect of age on SCP was significantly higher in the Danish cohort compared with the Hvidoere cohort (p < 0.0001), likely due to higher attained Boost SCP, so the sensitivity and specificity of those in PR by IDAA1c ≤ 9, SCP > 300 pmol/L was 0.85 and 0.62 at 6 months and 0.62 vs. 0.38 at 12 months, respectively. IDAA1c with age significantly improved the ROC analyses and the AUC reached 0.89 ± 0.04 (age) vs. 0.94 ± 0.02 (age + IDAA1c) at 6 months (p < 0.0004) and 0.76 ± 0.04 (age) vs. 0.90 ± 0.03 (age + IDAA1c) at 12 months (p < 0.0001). CONCLUSIONS: The diagnostic and prognostic power of the IDAA1c measure is kept but due to the higher Boost stimulation in the Danish cohort, the specificity of the formula is lower with the chosen limits for SCP (300 pmol/L) and IDAA1c ≤9, respectively.

Comparison of 3 body size descriptors in critically ill obese children and adolescents: implications for medication dosing.

OBJECTIVE: To compare 3 methods of weight determination for medication dose calculations in obese children and to discuss feasibility for use in routine care. METHODS: This was a patient safety and quality improvement study evaluating patients (2-19 years old) admitted to the pediatric intensive care unit during a 13-month period (July 2010-July 2011). Patients identified as obese (≥95th percentile body mass index [BMI] for age), including severely obese (≥99th percentile BMI for age), were included in the weight method comparison portion of this study. Lean body mass estimations, using equations derived by the Peters and Foster methods, were compared to ideal body weight estimates by using the BMI method. Absolute differences between values generated by the 3 methods, intraclass correlation (ICC), and Bland-Altman plots were calculated. RESULTS: A total of 1369 patients met initial criteria; 176 met criteria for the dosing weight comparison (age ± SD = 9.28 ± 5 years; actual weight ± SD = 55.5 ± 33.9 kg; 46% female). Sixty were severely obese and 116 were obese. Mean ICC between methods was 0.968 (95% Confidence interval (CI): 0.959, 0.975). The Peters method estimated higher weights than the Foster or BMI method. Bland-Altman plots illustrated good agreement between methods in children with weight below 50 kg, but decreased agreement above 50 kg, which was influenced by sex. CONCLUSIONS: All methods demonstrated strong correlation and acceptable agreement in children below 50 kg. Systematic biases were identified in children above 50 kg where variance was higher. The BMI method was least complex to calculate and the most feasible method for daily use.

Ethical issues related to screening for preeclampsia.

The implementation of new methods of treating and preventing disease raises many question of both technical and moral character. Currently, many studies focus on developing a screening test for preeclampsia (PE), a disease complicating 2-8% of pregnancies, potentially causing severe consequences for pregnant women and their fetuses. The purpose is to develop a test that can identify pregnancies at high risk for developing PE sufficiently early in pregnancy to allow for prophylaxis. However, the question of implementing a screening test for PE does not only involve an evaluation of technical feasibility and clinical efficacy, it also requires an analysis of how the test influences the conditions and choices for those tested. This study evaluates state-of-the-art techniques for preeclampsia screening in an ethical framework, pointing out the central areas of moral relevance within the context of such screening activity. Furthermore, we propose ethical guidelines that a screening programme for PE should meet in order to become an uncontroversial addition to prenatal health care.