Improved Clinic Flow and Satisfaction After Lean Implementation in a Pediatric Ophthalmology Clinic.

PURPOSE: To report outcomes using Lean concepts (FlowOne Lean Consulting, LLC) and implemented changes in a single academic pediatric ophthalmology practice. METHODS: Lean principles such as patient flow, wasted movement, and non-value added visit time were taught to clinic staff. Spaghetti maps to document patient and staff movement during examinations, patient simulation, and clinic flow exercises were performed prior to implementing clinic changes. Clinic changes included maximizing easily reachable equipment and standardizing equipment in each examination room, physician-controlled doorbells to notify staff for help, and implementing a visual real-time electronic board of patients throughout the entirety of their examination. Patient surveys before and after Lean and staff feedback were obtained. RESULTS: Four years of data were collected of patient examination visits after Lean principles were introduced. Prior to Lean implementation, mean pediatric ophthalmology clinic visit times were 120 minutes. Within 3 months of Lean clinic changes, mean visit times reduced to 75 minutes. Four years later, this was sustained at 69 minutes. Clinic templates were modified and increased by 17%. Patient satisfaction surveys before and after demonstrated improved scores from 6.5 to 9.0. Patient survey comments included satisfaction with shorter patient examination visits, less shuffling between examination rooms, less non-value added time, and perception of happier clinic staff. Staff survey comments included receiving fewer parent complaints, feeling less disorganized, being able to troubleshoot in real time, and leaving at an earlier time at the end of the clinic day. CONCLUSIONS: Lean improved clinic efficiency, reduced patient visit times, and improved patient and staff satisfaction. These improvements were sustained 4 years after Lean principles were implemented. [J Pediatr Ophthalmol Strabismus. 2024;61(1):14-19.].

Can we predict the development of acute gastric dilatation in patients with anorexia nervosa?

BACKGROUND: Acute gastric dilatation can develop in patients with anorexia nervosa who are being refed to achieve weight restoration. If unrecognized, this condition is associated with significant morbidity and mortality. Patients with acute gastric dilatation usually have abdominal pain, nausea, and vomiting. Abdominal imaging confirms the diagnosis. This study aims to identify risk factors associated with the development of acute gastric dilatation in patients with severe restrictive eating disorders in order to hasten diagnosis and guide treatment. This study also aims to define the clinical outcomes of patients with acute gastric dilatation. METHODS: In this retrospective case series, 15 patients with a restrictive eating disorder were studied. Multiple variables were assessed for significant correlation with stomach size. RESULTS: 15 patients with a restrictive eating disorder were identified as being diagnosed with acute gastric dilatation through chart review during the study period. The average dilated stomach size was 20.5 cm. There was no significant correlation of stomach size with any of the following: % ideal body weight on day of admission, % ideal body weight on day of imaging study, rate of weight gain (kg per week), or duration of illness. Serum levels of sodium, potassium, phosphorus, magnesium, calcium, bicarbonate, blood urea nitrogen, glucose, albumin, and hematocrit on the day of imaging, did not correlate with stomach size. All patients were treated with conservative management. None of the patients required surgical intervention or progressed to gastric necrosis or perforation, and there were no recurrences of the acute gastric dilatation. CONCLUSIONS: There are no specific risk factors significantly associated with the development of acute gastric dilatation in patients with severe restrictive eating disorders. Clinicians should maintain a high index of suspicion for this condition when patients are experiencing abdominal pain, nausea, or vomiting. When promptly diagnosed and treated, outcomes are good. If diagnosis is delayed, the outcome can be dire.

The mainstay of treatment of patients with severe restrictive eating disorders is initiation of nutrition to gain weight. One potential complication when patients are started on nutrition is the development of a massively enlarged stomach, also called acute gastric dilatation. If a patient's care provider does not recognize the development of acute gastric dilatation, it can lead to serious problems, including death. Patients with this condition usually have abdominal pain, nausea, and vomiting. These are common symptoms in patients with anorexia nervosa and are often dismissed. Identifying risk factors associated with developing acute gastric dilatation could help providers recognize this condition and promptly start treatment. This study sought to identify risk factors associated with developing acute gastric dilatation in patients with severe restrictive eating disorders. Several variables, including patient age, duration of illness, body mass index, %ideal body weight, laboratory values, medications, type of nutrition, and rate of weight gain were analyzed. This study found that there are no specific risk factors significantly associated with development of acute gastric dilatation in patients with severe restrictive eating disorders being initiated on nutrition. Therefore, providers need to listen to their patients, evaluate symptoms, and have a high index of suspicion for underlying acute gastric dilatation.

Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium.

The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology community. This Commentary describes some of the key topics that were discussed during the 2022 symposium: scientific and career trajectory, leadership, mentoring, collaborations, and publishing. For each of these topics, established investigators discussed the elements that facilitate success in these areas as well as mistakes that can hinder progress. Herein, we outline the critical points raised in these discussions for establishing a successful independent research career. These points are highly relevant for the broader scientific community.

Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies.

Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability. Consequently, the overall benefit of monotherapies remains limited. Cutting-edge technologies now allow for extensive tumor profiling, which can be used to define tumor cell intrinsic and extrinsic pathways of primary and/or acquired immune resistance, herein referred to as features or feature sets of immune resistance to current therapies. We propose that cancers can be characterized by immune resistance archetypes, comprised of five feature sets encompassing known immune resistance mechanisms. Archetypes of resistance may inform new therapeutic strategies that concurrently address multiple cell axes and/or suppressive mechanisms, and clinicians may consequently be able to prioritize targeted therapy combinations for individual patients to improve overall efficacy and outcomes.

Abnormal response to chronic social defeat stress and fear extinction in a mouse model of cholinergic dysregulation.

Cholinergic signaling is critical for an individual to react appropriately and adaptably to salient stimuli while navigating a complex environment. The cholinergic neurotransmitter system drives attention to salient stimuli, such as stressors, and aids in orchestrating the proper neural and behavioral response. Fine-tuned regulation of the cholinergic system has been linked to appropriate stress responses and subsequent mood regulation while dysregulation has been implicated in mood disorders. Among the multiple layers of regulation are cholinergic protein modulators. Here, we use validated models of experiential-based affective disorders to investigate differences in responses to stress in a genetic mouse model of cholinergic dysregulation based on the loss of protein modulator. The lynx2 nicotinic receptor modulatory protein provides negative cholinergic regulation within the amygdala, medial prefrontal cortex, and other brain regions. We discovered here that lynx2 knockout (KO) mice demonstrate an inability to update behavior with an inability to extinguish learned fear during a fear extinction test. We also observed, under an increased stress load following exposure to chronic social defeat stress (CSDS) paradigm, there was a unified resilience phenotype in lynx2KO mice, as opposed to the wild-type cohort which was split between resilience and susceptible phenotypes. Furthermore, we provide evidence for the functional role of α7 nicotinic receptor subtypes by phenotypic rescue with MLA or crossing with an α7 null mutant mouse (e.g. lynx2/α7 double KO mice). We demonstrate a direct physical interaction between lynx2 and α7 nAChR by co-immunoprecipitation of complexes from mouse BLA extracts. The genetic predisposition to heightened basal anxiety-like behavior and altered cholinergic signaling impairs individual behavior responses stressors. Together, these data indicate that the effects of social stress can be influenced by baseline genetic factors involved in anxiety regulation.

Emergency room presentations of people with anorexia nervosa.

People with anorexia nervosa (AN) tend to shy away from engaging in typical primary care provider relationships in order to avoid detection. Therefore, they may seek care for their medical concerns through a local emergency department (ED). Inherently, AN is associated with a litany of medical complications, which become more prevalent as the severity of their eating disorder increases. Notwithstanding the typical young age at the onset of AN, no body system is immune to these medical complications. Thus, ED providers may need to pursue a medical diagnosis in order to explain presenting symptoms in people with AN. In addition to the medical issues, AN is also a serious mental illness with high mortality rates, including deaths by suicide. Therefore, ED providers also need to be familiar with relevant mental health issues for these people.

People with anorexia nervosa frequent emergency departments to obtain their medical care. It is thus important for emergency department personnel to be familiar with this increasingly common and serious disorder. As opposed to most other mental illnesses, anorexia nervosa is associated with many dangerous medical complications, which become more problematic as the malnutrition and weight loss become more severe. All body systems are adversely affected. The mortality rate of anorexia nervosa is the second highest of all mental disorders, with medical complications and suicide being the top two causes of death. Mandated medical care may occasionally be required to obtain ongoing treatment for people with anorexia nervosa when they present to the emergency department with severe malnutrition and other emergent complications.

Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.

Vacuolar-type H+-ATPase (V-ATPase) is a multimeric complex present in a variety of cellular membranes that acts as an ATP-dependent proton pump and plays a key role in pH homeostasis and intracellular signalling pathways. In humans, 22 autosomal genes encode for a redundant set of subunits allowing the composition of diverse V-ATPase complexes with specific properties and expression. Sixteen subunits have been linked to human disease. Here we describe 26 patients harbouring 20 distinct pathogenic de novo missense ATP6V1A variants, mainly clustering within the ATP synthase α/ß family-nucleotide-binding domain. At a mean age of 7 years (extremes: 6 weeks, youngest deceased patient to 22 years, oldest patient) clinical pictures included early lethal encephalopathies with rapidly progressive massive brain atrophy, severe developmental epileptic encephalopathies and static intellectual disability with epilepsy. The first clinical manifestation was early hypotonia, in 70%; 81% developed epilepsy, manifested as developmental epileptic encephalopathies in 58% of the cohort and with infantile spasms in 62%; 63% of developmental epileptic encephalopathies failed to achieve any developmental, communicative or motor skills. Less severe outcomes were observed in 23% of patients who, at a mean age of 10 years and 6 months, exhibited moderate intellectual disability, with independent walking and variable epilepsy. None of the patients developed communicative language. Microcephaly (38%) and amelogenesis imperfecta/enamel dysplasia (42%) were additional clinical features. Brain MRI demonstrated hypomyelination and generalized atrophy in 68%. Atrophy was progressive in all eight individuals undergoing repeated MRIs. Fibroblasts of two patients with developmental epileptic encephalopathies showed decreased LAMP1 expression, Lysotracker staining and increased organelle pH, consistent with lysosomal impairment and loss of V-ATPase function. Fibroblasts of two patients with milder disease, exhibited a different phenotype with increased Lysotracker staining, decreased organelle pH and no significant modification in LAMP1 expression. Quantification of substrates for lysosomal enzymes in cellular extracts from four patients revealed discrete accumulation. Transmission electron microscopy of fibroblasts of four patients with variable severity and of induced pluripotent stem cell-derived neurons from two patients with developmental epileptic encephalopathies showed electron-dense inclusions, lipid droplets, osmiophilic material and lamellated membrane structures resembling phospholipids. Quantitative assessment in induced pluripotent stem cell-derived neurons identified significantly smaller lysosomes. ATP6V1A-related encephalopathy represents a new paradigm among lysosomal disorders. It results from a dysfunctional endo-lysosomal membrane protein causing altered pH homeostasis. Its pathophysiology implies intracellular accumulation of substrates whose composition remains unclear, and a combination of developmental brain abnormalities and neurodegenerative changes established during prenatal and early postanal development, whose severity is variably determined by specific pathogenic variants.

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown HMG-CoA is a reactive metabolite that can non-enzymatically modify proteins and impact their activity. Therefore, we predicted that inhibition of HMGCR by statins might increase HMG-CoA levels and protein modifications. Upon statin treatment, we observe a strong increase in HMG-CoA levels and modification of only a single protein. Mass spectrometry identifies this protein as fatty acid synthase (FAS), which is modified on active site residues and, importantly, on non-lysine side-chains. The dynamic modifications occur only on a sub-pool of FAS that is located near HMGCR and alters cellular signaling around the ER and Golgi. These results uncover communication between cholesterol and lipid biosynthesis by the substrate of one pathway inhibiting another in a rapid and reversible manner.

Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in ovarian cancer enhances therapeutic efficacy.

BACKGROUND: In the USA, more than 50% of patients with ovarian cancer die within 5 years of diagnosis, highlighting the need for therapeutic innovations. Mesothelin (MSLN) is a candidate immunotherapy target; it is overexpressed by ovarian tumors and contributes to malignant/invasive phenotypes, making tumor antigen loss disadvantageous. We previously showed that MSLN-specific T cell receptor (TCR)-engineered T cells preferentially accumulate within established tumors, delay tumor growth, and significantly prolong survival in the ID8VEGF mouse model that replicates many aspects of human disease. However, T cell persistence and antitumor activity were not sustained. We therefore focused on Fas/FasL signaling that can induce activation-induced cell death, an apoptotic mechanism that regulates T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature has been detected in the tumor microenvironment (TME) of human and murine ovarian cancers, can induce apoptosis in infiltrating, Fas (CD95) receptor-expressing lymphocytes, and can protect ovarian cancers from tumor-infiltrating lymphocytes. METHODS: To overcome potential FasL-mediated immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. Murine T cells were engineered to express an MSLN-specific TCR (TCR1045), alone or with the IFP, transferred into ID8VEGF tumor-bearing mice and evaluated for persistence, proliferation, cytokine production and efficacy. Human T cells were similarly engineered to express an MSLN-specific TCR (TCR530) alone or with a truncated Fas receptor or a Fas-4-1BB IFP and evaluated for cytokine production and tumor lysis. RESULTS: Relative to murine T cells expressing only TCR1045, T cells expressing both TCR1045 and a Fas-4-1BB IFP preferentially persisted in the TME of tumor-bearing mice, with improved T cell proliferation and survival. Moreover, TCR1045/IFP+ T cells significantly prolonged survival in tumor-bearing mice, compared with TCR1045-only T cells. Human T cells expressing TCR530 and a Fas-4-1BB IFP exhibit enhanced functional activity and viability compared with cells with only TCR530. CONCLUSIONS: As many ovarian tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may be used to enhance engineered adoptive T cell therapy for patients.

Deglutarylation of glutaryl-CoA dehydrogenase by deacylating enzyme SIRT5 promotes lysine oxidation in mice.

A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme sirtuin 5 (SIRT5). Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal that glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We also demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic analyses indicate an expanded role for SIRT5 in regulating amino acid metabolism. Together, these data support a feedback loop model within the lysine/tryptophan oxidation pathway in which glutaryl-CoA is produced, in turn inhibiting GCDH function via glutaryl modification of GCDH lysine residues and can be relieved by SIRT5 deacylation activity.

Multiple early factors anticipate post-acute COVID-19 sequelae.

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.

Examining the Relationship between the Lethality Assessment/Domestic Violence High-risk Team Monitoring (LAP/DVHRT) Program and Prosecution Outcomes.

Lethality assessment (LAP) and team monitoring of high-risk offenders (DVHRT) are recent U.S. policy innovations designed to identify domestic violence offenders who are at high risk for perpetrating serious or lethal violence against their intimate partners. One goal of LAP/DVHRT is to increase offenders' accountability for domestic violence within the legal system. This study examines associations between LAP/DVHRT and prosecution and sentencing outcomes using data on domestic violence offenses (n = 88) involving 37 offenders monitored by a DVHRT and 51 nonmonitored comparison offenders who were identified as high risk on the LAP. We use logistic and OLS regression to estimate models of six prosecution and sentencing outcomes for the full sample and for a sample matched using the coarsened exact matching technique (n = 73). Multivariate results indicate that when the treatment and comparison samples are matched and control variables are included in regression models, the LAP/DVHRT program is not associated with prosecution or conviction rates, number of charges, or bail amount. DVHRT monitoring is positively associated with sentence length in multivariate analysis and in models using the matched sample. Findings suggest that the LAP/DVHRT program increases offender accountability in the form of incapacitation at the sentencing stages.

Biophysical characterization of lynx-nicotinic receptor interactions using atomic force microscopy.

Nicotinic acetylcholine receptors (nAChRs) are broadly expressed in the central and peripheral nervous systems, playing essential roles in cholinergic neurotransmission. The lynx family proteins, a subset of the Ly6/uPAR superfamily expressed in multiple brain regions, have been shown to bind to nAChRs and modulate their function via allosteric regulation. The binding interactions between lynx and nAChRs, however, have not been systematically quantified and compared. In this work, we characterized the interactions between lynx1 or lynx2 and α3ß4- or α7-nAChRs using single-molecule atomic force microscopy (AFM). The AFM technique allows the quantification of the off-rate of lynx-nAChR binding and of the energetic barrier width between the bound state and transition state, providing a biophysical means to compare the selectivity of lynx proteins for nAChR subtypes. Results indicate that lynx1 has a marginal preference for α7- over α3ß4-nAChRs. Strikingly, lynx2 exhibits a two order of magnitude stronger affinity for α3ß4- compared to α7-nAChRs. Together, the AFM assay serves as a valuable tool for the biophysical characterization of lynx-nAChR binding affinities. Revealing the differential affinities of lynx proteins for nAChR subtypes will help elucidate how lynx regulates nAChR-dependent functions in the brain, including nicotine addiction and other critical pathways.

Considerations for treatment duration in responders to immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Associations between intake of calcium, magnesium and phosphorus and risk of pancreatic cancer: a population-based, case-control study in Minnesota.

Experimental studies suggest that abnormal levels of Ca, Mg and phosphorus are implicated in pancreatic carcinogenesis. We investigated the associations between intakes of these minerals and the risk of pancreatic cancer in a case-control study conducted in 1994-1998. Cases of pancreatic cancer (n 150) were recruited from all hospitals in the metropolitan area of the Twin Cities and Mayo Clinic, Minnesota. Controls (n 459) were randomly selected from the general population and frequency matched to cases by age, sex and race. All dietary variables were adjusted for energy intake using the residual method prior to data analysis. Logistic regression was performed to evaluate the associations between intake of three nutrients examined and the risk of pancreatic cancer. Total intake of Ca (936 v. 1026 mg/d) and dietary intake of Mg (315 v. 331 mg/d) and phosphorus (1350 v. 1402 mg/d) were significantly lower in cases than in controls. After adjustment for confounders, there were not significant associations of total and dietary intakes of Ca, Mg and phosphorus with the risk of pancreatic cancer. In addition, no significant interactions exist between intakes of these minerals and total fat on pancreatic cancer risk. In conclusion, the present study does not suggest that intakes of Ca, Mg and phosphorus were significantly associated with the risk of pancreatic cancer.

Highlights from the Era of Open Source Web-Based Tools.

High digital connectivity and a focus on reproducibility are contributing to an open science revolution in neuroscience. Repositories and platforms have emerged across the whole spectrum of subdisciplines, paving the way for a paradigm shift in the way we share, analyze, and reuse vast amounts of data collected across many laboratories. Here, we describe how open access web-based tools are changing the landscape and culture of neuroscience, highlighting six free resources that span subdisciplines from behavior to whole-brain mapping, circuits, neurons, and gene variants.

Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women.

Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.

Diabetes and kidney cancer risk among post-menopausal women: The Iowa women's health study.

BACKGROUND: Many studies have reported a positive association between diabetes and kidney cancer. However, it is unclear whether diabetes is a risk factor for kidney cancer independent of other risk factors, such as obesity and hypertension. We comprehensively examined the association of diabetes and its duration with incident kidney cancer in the prospective cohort Iowa Women's Health Study (1986-2011). METHODS: Diabetes status was self-reported at baseline (1986) and on five follow-up questionnaires. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of baseline and time-dependent diabetes with the risk of incident kidney cancer. RESULTS: During the 25 years of follow-up, 245 cases of kidney cancer occurred among 36,975 post-menopausal women. In an age-adjusted model, there was a significant association between time-dependent diabetes and the risk of kidney cancer [HR (95% CI) = 1.76 (1.26, 1.45)]; the association was attenuated after multivariable adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), hypertension, physical activity, diuretic use, pack-years of smoking, alcohol intake, and total caloric intake [HR = 1.35 (0.94, 1.94)]. However, among non-obese women or women with a waist circumference less than 34.6 in., diabetes was significantly associated with kidney cancer risk: for time-dependent diabetes, HRs (95% CIs) were 1.82 (1.10, 3.00) among those with BMI < 30 kg/m2 and 2.18 (1.08, 4.38) among those with a waist circumference <34.6 in.. CONCLUSIONS: Our results suggest that diabetes is associated with kidney cancer risk among non-obese post-menopausal women.

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.