The role of medications in successful aging.

Successful aging includes good health and low levels of disability. To that end, primary prevention is far better than managing subsequent organ damage. When medication is needed to prevent or manage disease, the preferred choice should be associated with the greatest benefits and fewest adverse effects. Cardiovascular diseases are the leading cause of morbidity and mortality in postmenopausal women worldwide. Considering disease-adjusted life years, other leading causes are chronic obstructive pulmonary disease, diabetes mellitus, dementias, hearing loss, cancers of the breast, lung and bowel, osteoporosis, fractures and falls, depression, osteoarthritis, refractive errors of the eye and non-diabetic chronic kidney disease. This review explores the global prevalence of these diseases in women aged 50 years and older, and medications commonly used for them, and contrasts the effects of menopausal hormone therapy (MHT) with others. When initiated early, there is good evidence for MHT benefit in all-cause mortality and primary prevention of cardiovascular disease, diabetes and osteoporosis; fair evidence for benefit in dementias, depression and osteoarthritis; limited evidence for benefit in chronic obstructive pulmonary disease, hearing loss, non-diabetic chronic kidney disease and colorectal cancer; null effects on lung cancer and refractive errors; and varied effects on breast cancer and stroke. Relative benefits and adverse effects of other medications warrant consideration.

Hormone replacement therapy - where are we now?

Hormone replacement therapy (HRT) was the standard of care for menopause management until 2002, when perceptions changed following release of the initial results from the Women's Health Initiative (WHI) trial. Fears of breast cancer and heart attacks engendered by that report were not supported by the data, especially for recently menopausal women. Clinically, HRT is usually initiated near menopause. The WHI tested something different - the effects of HRT started a decade or more after menopause. As it turned out, age at starting HRT is critical in determining benefit/risk. HRT use plummeted following the WHI in 2002 and has remained low, prompting strong interest in alternative treatments. None provide the range of benefits across multiple organ systems offered by estrogen. Most have concerning adverse effects in their own right. HRT can provide effective relief for a wide range of health conditions, potentially avoiding the need for multiple treatments for separate problems. Unfortunately, among many women and clinicians, the perception of HRT benefit/risk is distorted, and its use avoided, leading to unnecessary distress. Following the WHI, many clinicians have not received adequate training to feel comfortable prescribing HRT. When initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementias.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

The evidence base for HRT: what can we believe?

Prior to the unexpected early termination of the Women's Health Initiative (WHI) trial of continuous conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), the prevailing view was that hormone replacement therapy (HRT) was a low-risk intervention with immediate value for symptom relief in recently menopausal women, and that it probably conferred long-term protection against the major chronic diseases that affect women after menopause. Rather than replicating prior studies, the WHI was designed to test whether the beneficial associations consistently seen in women starting HRT near menopause would be found in women well beyond menopause. Views of the benefits and risks of HRT changed dramatically in 2002 with the unexpected early termination of the CEE + MPA trial and the alarming initial WHI report. HRT use plummeted world-wide, driven by fear of breast cancer and skepticism about cardiovascular benefits. Stunningly, the contrasting findings of the WHI trial of CEE alone reported 2 years later - suggesting prevention of coronary heart disease in women who began HRT at age <60 years, and a reduction in breast cancer overall - were largely ignored. Key lessons from the WHI are that the effects of HRT on most organ systems vary by age and time since last physiologic exposure to hormones and that there are differences between regimens. In the years since the first WHI report, we have learned much about the characteristics of women who are likely to benefit from HRT. The range of HRT regimens has also increased. Not all women have indications for HRT, but for those who do and who initiate within 10 years of menopause, benefits are both short-term (vasomotor, dyspareunia), and long-term (bone health, coronary risk reduction). Critically, the 'facts' that most women and clinicians consider in making the decision to use, or not use, HRT are frequently wrong or incorrectly applied.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

The cardiovascular safety aspects of calcium supplementations: where does the truth lie? A personal perspective.

Clinical guidelines may change with time, as more information from topline studies emerges. Calcium plus vitamin D supplementation became routine decades ago, especially in the older population, based on the assumption that it may promote bone health and prevent fractures, and perhaps induce additional favorable health outcomes. During the past years, an ongoing debate defies this paradigm, mainly because of a potential cardiovascular risk on the one hand, and uncertainty in regard to the extent of the beneficial bone effects on the other hand. The following article summarizes the main recent developments, trying to put some order into the controversial information and opinions which have been published in the medical literature. We conclude that the best current evidence supports a primary strategy of obtaining recommended intakes of calcium and vitamin D from dietary sources. But, since most western diets are inadequate in that regard, and since there is no clear evidence of harm from modest supplementation (up to 1000 mg of elemental calcium and 400 IU of vitamin D3), supplementation is appropriate when dietary intake is inadequate.

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade.

BACKGROUND: Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS: To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS: The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS: Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.

Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas.

BACKGROUND: Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors. METHODS: In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed. RESULTS: Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors. CONCLUSIONS: Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.

Lack of host gut microbiota alters immune responses and intestinal granuloma formation during schistosomiasis.

Fatalities from schistosome infections arise due to granulomatous, immune-mediated responses to eggs that become trapped in host tissues. Schistosome-specific immune responses are characterized by initial T helper type 1 (Th1) responses and our previous studies demonstrated that myeloid differentiation primary response gene 88 (Myd88)-deficient mice failed to initiate such responses in vivo. Paradoxically, schistosomal antigens fail to stimulate innate cells to release proinflammatory cytokines in vitro. Since Schistosoma mansoni infection is an intestinal disease, we hypothesized that commensal bacteria could act as bystander activators of the intestinal innate immune system to instigate Th1 responses. Using a broad spectrum of orally administered antibiotics and anti-mycotics we analysed schistosome-infected mice that were simultaneously depleted of gut bacteria. After depletion there was significantly less inflammation in the intestine, which was accompanied by decreased intestinal granuloma development. In contrast, liver pathology remained unaltered. In addition, schistosome-specific immune responses were skewed and faecal egg excretion was diminished. This study demonstrates that host microbiota can act as a third partner in instigating helminth-specific immune responses.

Neurogenic appendicopathy: A rare differential diagnosis of acute appendicitis.

AIM OF THE STUDY: In histologically non-inflamed but clinically suspect appendices, changes described as neurogenic appendicopathy with fibrous or fibrolipomatous obliterations can be observed. The purpose of this study was to analyse the incidence of these entities of the appendix in a longitudinal patient cohort. PATIENTS AND METHODS: This is a retrospective single-centre study of 457 patients undergoing laparoscopic appendectomy from 2017 to 2020 due to suspected acute appendicitis. RESULTS: In 72 patients (15.8%) with clinically suspected acute appendicitis, the appendix showed no distinct signs of acute inflammation during the procedure. In 43 patients, histological analysis revealed neurogenic appendicopathy or fibrous and fibrolipomatous obliteration. Female gender (P=0.088), younger age (P<0.0001), longer pain duration (P<0.0001) and repetitive pain episodes were more frequent in these patients than in those with acute appendicitis. Inflammation markers were also decreased in the group of patients with neurogenic appendicopathy (leukocytes 9.8±3.5 vs. 13.0±4.5 G/L and C-reactive protein 38.7±60.7 vs. 59.4±70.5mg/L). CONCLUSION: Neurogenic appendicopathy with fibrous/fibrolipomatous obliteration is a differential diagnosis of acute appendicitis that can only be confirmed by pathology. Female gender, young age, prolonged duration with repetitive episodes of pain, and relatively low inflammatory markers are evocative of this diagnosis.

A specific expression profile of heat-shock proteins and glucose-regulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas.

BACKGROUND: Oesophageal adenocarcinomas often show resistances to chemotherapy (CTX), therefore, it would be of high interest to better understand the mechanisms of resistance. We examined the expression of heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) in pretherapeutic biopsies of oesophageal adenocarcinomas to assess their potential role in CTX response. METHODS: Ninety biopsies of locally advanced adenocarcinomas before platin/5-fluorouracil (FU)-based CTX were investigated by reverse phase protein arrays (RPPAs), immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS: CTX response strongly correlated with survival (P=0.001). Two groups of tumours with specific protein expression patterns were identified by RPPA: Group A was characterised by low expression of HSP90, HSP27 and p-HSP27((Ser15, Ser78, Ser82)) and high expression of GRP78, GRP94, HSP70 and HSP60; Group B exhibited the inverse pattern. Tumours of Group A were more likely to respond to CTX, resulting in histopathological tumour regression (P=0.041) and post-therapeutic down-categorisation from cT3 to ypT0-T2 (P=0.040). High HSP60 protein (IHC) and mRNA expression were also associated with tumour down-categorisation (P=0.016 and P=0.004). CONCLUSION: Our findings may enhance the understanding of CTX response mechanisms, might be helpful to predict CTX response and might have translational relevance as they highlight the role of potentially targetable cellular stress proteins in the context of CTX response.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Have we come full circle - or moved forward? The Women's Health Initiative 10 years on.

In mid-summer 2002, the announcement that the Women's Health Initiative (WHI) trial of combination hormone therapy (HRT) had stopped jolted the field of women's health. It set off a cascade that first stunned, then meaningfully changed the future for millions of women, their partners, and tens of thousands of clinicians and scientists. With 10 years' hindsight, we can begin to put the lessons learned from the WHI HRT trials into perspective. These trials were primarily designed to test whether women considerably past menopause, and mostly asymptomatic, experienced treatment benefits from HRT expected from studies of generally symptomatic women who started near menopause. The definitive answer was 'no'. Unfortunately, the findings were generalized to all postmenopausal women regardless of age. Data accumulated from the WHI and other studies over the past decade have shown that, in women with symptoms or other indications, initiating HRT near menopause - the classic pattern of use - will probably provide a favorable benefit : risk ratio. Spurred by the WHI, many hypotheses and some insights about potential mechanisms for HRT effects on diverse organ systems have emerged, along with new perspectives on regimens, compounds, and routes of administration. This overview provides an historical perspective on the WHI design and the evolution of its message; summarizes current perspectives and insights contributed by eminent colleagues; reviews the state of the art; and looks to the future. We have come full circle in some ways, with mounting evidence supporting benefit for HRT started near menopause and with hard lessons learned about pathophysiology, publicity and interpreting data. Now we move on.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Electro-thermally induced structural failure actuator (ETISFA) for implantable controlled drug delivery devices based on micro-electro-mechanical-systems.

A new electro-thermally induced structural failure actuator (ETISFA) is introduced as an activation mechanism for on demand controlled drug delivery from a Micro-Electro-Mechanical-System (MEMS). The device architecture is based on a reservoir that is sealed by a silicon nitride membrane. The release mechanism consists of an electrical fuse constructed on the membrane. Activation causes thermal shock of the suspended membrane allowing the drugs inside of the reservoir to diffuse out into the region of interest. The effects of fuse width and thickness were explored by observing the extent to which the membrane was ruptured and the required energy input. Device design and optimization simulations of the opening mechanism are presented, as well as experimental data showing optimal energy consumption per fuse geometry. In vitro release experiments demonstrated repeatable release curves of mannitol-C(14) that precisely follow ideal first order release kinetics. Thermally induced structural failure was demonstrated as a feasible activation mechanism that holds great promise for controlled release in biomedical microdevices.

Lipid-based nanotherapeutics for siRNA delivery.

RNA interference (RNAi) is a specific gene-silencing mechanism triggered by small interfering RNA (siRNA). The application of RNAi in the clinic requires the development of safe and effective delivery systems. Inspired by progress with lipid-based systems in drug delivery, efforts have been dedicated to the development of liposomal siRNA delivery systems. Many of the lipid-based delivery vehicles self-assemble with siRNA through electrostatic interactions with charged amines, generating multi-lamellar lipoplexes with positively charged lipid bilayers separated from one another by sheets of negatively charged siRNA strands. Internalization of lipid-based siRNA delivery systems into cells typically occurs through endocytosis; accordingly, delivery requires materials that can facilitate endosomal escape. The size of the carrier is important as carriers <100 nm in diameter have been reported to have higher accumulation levels in tumours, hepatocytes and inflamed tissue, whereas larger particles tend to be taken up by Kupffer cells or other components of the reticuloendothelial system (RES). To reduce RES uptake and increase circulation time, carriers have been modified on the surface with hydrophilic materials, such as polyethyleneglycol. Herein, we review the molecular and structural parameters of lipid-based siRNA delivery systems.

On the need to clarify and disseminate contemporary knowledge of hormone therapy initiated near menopause.

The dramatic change in opinion on postmenopausal hormone therapy (HT) following initial reports from the Women's Health Initiative (WHI) came about as the 'baby boom' generation of women created the largest population of newly menopausal women in history. That trial of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) focused on outcomes in women starting HT a decade or more after menopause. Yet clinical practice has focused on initiation near menopause. Recent findings in the limited numbers of younger menopausal women in the WHI CEE + MPA trial, and findings in the CEE-only trial, suggest that age at initiating HT strongly influences outcomes, and that benefits greatly exceed risk for most women who start within 10 years of menopause. Findings in other cohorts support this view. Benefits are both short (vasomotor, dyspareunia) and long term (bone health, possible coronary risk reduction). Not all postmenopausal women have indications for HT, but, even if the fraction is one-third, the numbers affected are staggering. Low-dose and non-oral regimens, and other compounds, were introduced in the wake of the WHI. Emerging evidence suggests that these may further reduce risk in some population subgroups. The demonizing of HT may already have caused a burden of chronic disease that could have been mitigated or delayed. It is time for action to re-establish appropriate clinical context based on this emerging evidence, to reverse the inappropriate broad generalization of the WHI findings to younger menopausal women, and to support outcomes studies of current regimens in younger menopausal women.