N064A (Alliance): Phase II Study of Panitumumab,Chemotherapy, and External Beam Radiation in Patients with Locally Advanced Pancreatic Adenocarcinoma

BackgroundThis North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer.MethodsThe treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued.ResultsFifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%.ConclusionThe combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial’s goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT00601627","term_id":"NCT00601627"}}NCT00601627).     

Connecting aging biology and inflammation in the omics era

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

Aging has been conceptualized as a continuous duel between damage accumulation — due to a combination of environmental and endogenous processes — and resilience mechanisms that cope with such stressors and resolve damage (1). With aging, resilience mechanisms become less effective at repairing or removing damage and preventing its deleterious effects on health (2). Persistent molecular and cellular damage due to exhausted resilience is ultimately expressed as phenotypes of aging, including inflammaging, susceptibility to chronic diseases, physical and cognitive impairments, and, ultimately, frailty and death.Atop the hierarchy of resilience is the immune system, the aggregate of cells, mediators, and signaling pathways that continuously patrol for pathogens or structural perturbations revealed as “unusual” molecular motifs. The immune system reacts to a variety of threats, such as symbiotic commensal and pathogenic microorganisms, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs) from endogenous and exogenous sources, and orchestrates defense responses aimed at eliminating the specific threat while minimizing damage to the host. While inflammation is important for tissue repair and regeneration, when abnormally intense or persistent, it can drive degeneration and chronic diseases.The immune system undergoes numerous and profound changes with aging, which are extensively reviewed elsewhere (3–5). Hallmarks of immune aging are (a) a state of proinflammatory activation characterized by high circulating levels of proinflammatory cytokines — such as IL-6 and TNF-α — and localized tissue inflammation, and (b) an aberrant response to antigens and pathogens that could either be blunted, such as in flu vaccination, or excessive, such as in response to SARS-CoV-2 (6).Considerable research in both animal models and humans has examined the causes and consequences of inflammaging (4). Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty. Inflammation’s causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated (7).Mechanisms identified as hallmarks of aging biology and immune cell dysfunction have all been hypothesized as causes of inflammation (8). Aging researchers now recognize that measuring a few cytokines in circulation fails to capture the complexity and potential ramifications of inflammaging. Immune cells in tissues, particularly lymphocytes and resident macrophages, show tissue-specific age-related changes likely connected to specific pathological processes (9). By measuring hundreds or thousands of molecules in a few drops of blood, scientists are attempting to identify (a) signatures of accelerated aging that are both informative of the complexity and diversity of the response and predictive of health outcomes and (b) key molecules and molecular mechanisms that can be targeted for intervention (10).Given the extreme complexity of inflammaging, we focus herein on a few topics that have attracted considerable attention and controversy in the field. First, we discuss cellular senescence as a source of local and systemic inflammation. We highlight evidence that mitochondrial dysfunction is a nexus that binds impaired mitophagy with DNA damage and cellular senescence to ultimately foster a chronic inflammatory state. We then summarize efforts to identify circulating signatures of inflammation through “omics.” Finally, we review emerging data indicating that inflammation is involved in brain aging and dementia. Our intent is to discuss the causes and consequences of inflammaging and to enrich the research agenda toward the development of new therapeutic strategies.     

Pregnancy and arterial compliance

OBJECTIVE: To examine the hypothesis that pregnancy is associated with vascular remodeling, leading to an increased vascular compliance that can be observed in subsequent pregnancies. STUDY DESIGN: Chart review of41 multiparous deliveries at our institution from a 2-month period in 2004. Charts examined were from patients with uncomplicated, singleton pregnancies who were nulliparous during their prior delivery. Patients with blood pressure recordings in all 3 trimesters during both pregnancies were included. The mean arterial pressure (MAP) in the index and prior pregnancy was compared. RESULTS: There were no significant MAP differences noted, other than in the late third trimester (MAP, 85.05 vs. 80.15, p < 0.001). When we plotted the difference in >34 weeks MAP against the time between pregnancies, we did not see any statistically significant correlation (Pearson Correlation -0.147, p = 0.35). We examined the mean pulse pressure at >34 weeks. We found no statistically significant differences between the first and second pregnancies (mean pulse pressure, 42.27 vs. 43.55, p = 0.5). CONCLUSION: Our data does not support the hypothesis that pregnancy is associated with vascular remodeling, leading to an increased vascular compliance that can be observed in subsequent pregnancies. This could be due to demographic differences between our population and previously studied populations.     

Ultrasound-diagnosed puerperal osteopenia in young primiparas

OBJECTIVE: To study whether osteopenia occurs following pregnancy and to evaluate its severity in young primiparas. STUDY DESIGN: A prospective case control study. Sixty-one young primigravidae early after birth and 59 nulligravidae matched for age and BMI participated in the study. Bone status was examined using ultrasonic bone transmission velocity over the tibia; Z-score and T-score for bone density were calculated. Serum bone alkaline phosphatase, osteocalcin and urinary N-telopeptide crosslinks were evaluated as bone remodeling biochemical markers. RESULTS: Ultrasonic parameters of bone status following delivery were significantly lower in the puerperal group as compared to the nulligravida group. Serum mean bone alkaline phosphatase levels and urinary N-telopeptide crosslinks secretion were higher by 50% in the puerperal group, while serum osteocalcin levels were significantly lower (by 25%) than in the nulligravida controls. A positive correlation between ultrasonic measurements and biochemical markers was demonstrated in the postpartum group, whereas the control group showed a negative correlation. CONCLUSION: Women at their early puerperium demonstrate a significant cortical bone mass reduction as measured by ultrasonograph and markers of bone turnover. It appears that pregnancy is a state of unbalanced accelerated bone turnover that may be associated with reduced osteoblastic activity.     

Cervical cerclage: a review of the evidence

Cervical insufficiency is a difficult and confusing diagnosis. Its diagnostic criteria, etiology, and treatment are all debated. Cervical cerclage has been a common practice in obstetrics since it was first described by Shirodker and then McDonald in the 1950s. Cerclages have been placed because of a patient's obstetrical history, physical examination, ultrasound, or a combination of the above. However, the data supporting cerclage placement is limited. There has never been a prospective, randomized, controlled trial of cerclage versus no cerclage in patients with a classic history of cervical insufficiency (multiple painless second trimester losses occurring at progressively earlier gestational ages). This article attempts to review the relevant studies regarding cerclage placement for the treatment of cervical insufficiency. Based on the current literature, there is evidence supporting cervical cerclage in the following limited circumstances: a history of 3 or more spontaneous preterm births or second trimester losses; a high-risk patient with a singleton pregnancy who has a short cervix in the second trimester. Because the majority of patients with risk factors for preterm birth and second trimester loss (poor obstetric history, short cervix) will still deliver at term or near-term, studies on the effectiveness of cervical cerclage would need many patients to be powered appropriately.     

Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration.     

Negative fetal fibronectin: who is still treating for threatened preterm labor and does it help?

OBJECTIVE: Fetal fibronectin (fFN) has a high negative predictive value for delivery in the next seven days in patients at risk for preterm birth. Providers sometimes disregard a negative result and manage the patient for threatened preterm labor. Our objective was to identify the rate at which patients with a negative fFN were managed for threatened preterm labor and if delivery outcomes were improved with such management. STUDY DESIGN: Retrospective chart review of 111 patients at a single institution evaluated in the obstetrical triage unit for symptoms of threatened preterm labor with negative fFN results over a 19-month period between November 2004 and June 2006. Charts were reviewed for baseline patient characteristics such as gestational age at presentation to triage and fFN testing, prior obstetrical history, cervical examination and contraction frequency. Gestational age at delivery was documented. Rates of admission to the hospital and treatments for threatened preterm labor in this cohort were reviewed. RESULTS: Thirty-seven of patients (33%) with a negative fFN result were managed for threatened preterm labor (admitted to the hospital, given tocolytics, steroids, or intravenous antibiotics) by their provider. Patients undergoing these interventions were more likely to have cervical dilatation, effacement and were contracting more frequently. Only one of the patients delivered within 7 or 14 days of fFN testing. There was no advantage seen to management of threatened preterm labor in the setting of a negative fFN in terms of pregnancy prolongation, even when analyzing the patients with meaningful clinical findings (dilated 2 cm, effaced >or=80%, or contracting >or=12 times/h). CONCLUSION: Patients with meaningful clinical findings suspicious for preterm labor are more likely to undergo interventions by their physicians in the face of a negative fFN. This management does not improve length of gestation.