Trends in Venous Thromboembolism and Chemoprophylaxis Utilization in Elective Total Knee Arthroplasty From 2011 to 2020.

BACKGROUND: Venous thromboembolism (VTE) is a feared complication of joint arthroplasty, leading to recent clinical practice guidelines aimed at VTE prevention and prophylaxis. However, limited studies have examined national changes in practice regarding chemoprophylaxis and the resultant changes in VTE rates. The purpose of this study was to identify: (1) the temporal trends in thrombotic complications; and (2) changes in chemoprophylaxis utilization in patients undergoing elective total knee arthroplasty (TKA). METHODS: A retrospective study was conducted using a large all-payer claims dataset. Patients who underwent osteoarthritis-indicated TKA between 2011 and 2020 were identified. Annual rates of VTE, including deep vein thrombosis and pulmonary embolism, within 90 days of TKA were determined. Utilization patterns for postoperative aspirin and anticoagulant medications were observed. Temporal trends were analyzed with linear regression and the calculation of the cumulative annual growth rate. Multivariable logistic regression was conducted to account for the effects of age and comorbidities. RESULTS: A total of 1,263,351 TKA patients were identified between 2011 and 2020. There were significant reductions in VTE rates (2.9% in 2011 to 1.8% in 2020), deep vein thrombosis rates (2.0% in 2011 to 1.3% in 2020), and pulmonary embolism rates (1.1% in 2011 to 0.6% in 2020). Postoperative utilization of aspirin increased from 5.9% in 2011 to 53.2% in 2020, whereas utilization of anticoagulants decreased from 94.1% in 2011 to 46.8% in 2020. Among anticoagulants, direct factor Xa inhibitors had the greatest increase in utilization (4.6 to 69.7%). The average reimbursement associated with VTE after TKA decreased from $18,061 in 2011 to $7,835 in 2020. CONCLUSIONS: The incidence rate and economic burden of VTE after TKA have significantly declined since 2011. There has been a trend toward increased aspirin and direct oral anticoagulant utilization for postoperative chemoprophylaxis. LEVEL OF EVIDENCE: Level III.

Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma.

With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.

Seasonal malaria chemoprevention combined with community case management of malaria in children under 10 years of age, over 5 months, in south-east Senegal: A cluster-randomised trial.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011. METHODS AND FINDINGS: Twenty-four villages, including 2,301 children aged 3-59 months and 2,245 aged 5-9 years, were randomised to receive SMC with community case management (CCM) (SMC villages) or CCM alone (control villages). In all villages, community health workers (CHWs) were trained to treat malaria cases with artemisinin combination therapy after testing with a rapid diagnostic test (RDT). In SMC villages, CHWs administered SMC to children aged 3 months to 9 years once a month for 5 months. The study was conducted from 27 July to 31 December 2011. The primary outcome was malaria (fever or history of fever with a positive RDT). The prevalence of anaemia and parasitaemia was measured in a survey at the end of the transmission season. Molecular markers associated with resistance to SMC drugs were analysed in samples from incident malaria cases and from children with parasitaemia in the survey. SMC was well tolerated with no serious adverse reactions. There were 1,472 RDT-confirmed malaria cases in the control villages and 270 in the SMC villages. Among children under 5 years of age, the rate difference was 110.8/1,000/month (95% CI 64.7, 156.8; p < 0.001) and among children 5-9 years of age, 101.3/1,000/month (95% CI 66.7, 136.0; p < 0.001). The mean haemoglobin concentration at the end of the transmission season was higher in SMC than control villages, by 6.5 g/l (95% CI 2.0, 11; p = 0.007) among children under 5 years of age, and by 5.2 g/l (95% CI 0.4, 9.9; p = 0.035) among children 5-9 years of age. The prevalence of parasitaemia was 18% in children under 5 years of age and 25% in children 5-9 years of age in the control villages, and 5.7% and 5.8%, respectively, in these 2 age groups in the SMC villages, with prevalence differences of 12.5% (95% CI 6.8%, 18.2%; p < 0.001) in children under 5 years of age and 19.3% (95% CI 8.3%, 30.2%; p < 0.001) in children 5-9 years of age. The pfdhps-540E mutation associated with clinical resistance to sulfadoxine-pyrimethamine was found in 0.8% of samples from malaria cases but not in the final survey. Twelve children died in the control group and 14 in the SMC group, a rate difference of 0.096/1,000 child-months (95% CI 0.99, 1.18; p = 0.895). Limitations of this study include that we were not able to obtain blood smears for microscopy for all suspected malaria cases, such that we had to rely on RDTs for confirmation, which may have included false positives. CONCLUSIONS: In this study SMC for children under 10 years of age given over 5 months was feasible, well tolerated, and effective in preventing malaria episodes, and reduced the prevalence of parasitaemia and anaemia. SMC with CCM achieved high coverage and ensured children with malaria were promptly treated with artemether-lumefantrine. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01449045.

Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions.

Although the widespread use of mold-active agents (especially the new generation of triazoles) has resulted in reductions of documented invasive mold infections (IMIs) in patients with hematological malignancies and allogeneic hematopoietic stem cell transplantation (HSCT), a subset of such patients still develop breakthrough IMIs (bIMIs). There are no data from prospective randomized clinical trials to guide therapeutic decisions in the different scenarios of bIMIs. In this viewpoint, we present the current status of our understanding of the clinical, diagnostic, and treatment challenges of bIMIs in high-risk adult patients with hematological cancer and/or HSCT receiving mold-active antifungals and outline common clinical scenarios. As a rule, managing bIMIs demands an individualized treatment plan that takes into account the host, including comorbidities, certainty of diagnosis and site of bIMIs, local epidemiology, considerations for fungal resistance, and antifungal pharmacological properties. Finally, we highlight areas that require future investigation in this complex area of clinical mycology.

Current Perspectives Among U.S. Dermatologists on Chemoprevention of Nonmelanoma Skin Cancer: A Survey-Based Study.

Introduction: Nonmelanoma skin cancer (NMSC) is the most common malignancy in the US Primary prevention of NMSC with physical photoprotective measures are often not sufficient to impact skin cancer incidence in high-risk individuals. Chemoprevention is the use of agents to prevent, suppress, and reverse carcinogenic progression. Many agents have been investigated, but preclinical and clinical studies are often inconsistent.

Methods: A cross-sectional study was designed to assess current practices, perceptions, and general knowledge of U.S. dermatologists pertaining to chemopreventive strategies. This voluntary online survey was distributed to practicing dermatologists via dermatology society electronic mailing lists. Software from SurveyGizmo.com was used for survey implementation and anonymous data collection. Stata 12.0 statistical analysis software (StataCorp, LP) was used to perform nonparametric Spearman correlation tests.

Results: Approximately half of the 156 responding dermatologists reported being in practice 16 years or more (47.3%) and working in urban communities (48.7%). 59.3% reported "frequently" using topical therapies, while only 13.7% reported frequent use of systemic chemopreventive therapies. Dermatologists practicing in urban settings were more likely to indicate they believe knowledge has increased substantially (P=0.047) as compared to colleagues in other communities. Respondents also reported varying degrees of confidence in selecting appropriate chemopreventive regimens: most feel comfortable determining which agents to use in patients, but 29.1% answered "neutral" or "disagree" when asked if they felt comfortable. More experienced dermatologists were more likely to recommend diet modifications such as increased dietary vitamin D (P=0.014), low fat diet (P=0.022), and tea polyphenols (P=0.04) as methods of chemoprevention.

Discussion: Efforts to identify effective, minimally-toxic chemopreventive agents have long been underway, but conflicting reports in the literature make formulation of validated guidelines challenging. Our study suggests differing perceptions, comfort levels, and practice strategies among U.S. dermatologists. This serves to identify areas of research requiring additional contributions from clinical investigators and reveals a need to broaden understanding of available evidence-based techniques.

J Drugs Dermatol. 2017;16(5):449-452.

Estimating Risk of Venous-Thromboembolic Events in Hospitalized Medical Patients: Comparison between 2008 and 2012 Guidelines.

BACKGROUND: Prophylaxis for hospitalized venous-thromboembolic events (VTEs) is frequently underutilized, in part due to lack of a simple risk assessment model (RAM). OBJECTIVES: To compare patient selection and administration of VTE prophylaxis according to the American College of Chest Physicians (ACCP) 2008 guidelines versus the newer 2012 guidelines, and assess the feasibility of developing simpler local RAMs. METHODS: We conducted a prospective assessment of VTE risk among 300 unselected consecutive patients admitted to a medical hospital ward, using the 2008 and 2012 ACCP guidelines. The frequency and relative weight of each risk factor in the 2012 ACCP guidelines were used to develop a local VTE RAM. RESULTS: VTE prophylaxis was indicated by the 2008 and 2012 ACCP guidelines in 40% and 42% of the cohort respectively, and was administered in 28% and 26% of eligible patients, respectively. Contraindication to VTE prophylaxis was found in 29% of patients according to both guidelines. In comparison to the 2008 guidelines, sensitivity and specificity of the 2012 guidelines were 96% and 88%, respectively. A local RAM based on the following concise score, comprising age, malignancy and immobility, correctly identified 99% of at-risk patients based on the 2012 guidelines, with a sensitivity and specificity of 98% and 95%, respectively. CONCLUSIONS: Both guidelines performed to a similar degree and were poorly implemented in daily practice. A simplified RAM accurately identified the vast majority of these eligible patients. The development of local RAMs is feasible and may result in higher utilization rates.

[Latest international guidelines for screening, prevention and treatment of familial breast cancer - implications for the relevant practice in Hungary]. / Az örökletes emlorák szurésének, megelozésének és kezelésének új nemzetközi irányvonalai - hazai vonatkozásokkal.

INTRODUCTION: Screening, prevention and treatment of familial breast cancer require a multidisciplinary approach. New guidelines were published in the United Kingdom for the management of familial breast cancer. AIM: The authors summarise these new guidelines and analyse the relevant practice in Hungary. METHOD: Relevant guidelines of the National Institute for Health and Care Excellence and Familial Breast Cancer Report (NHS Scotland) are described. RESULTS: New guidelines will increase the number of genetic tests as well as genetic counselling. An increase in the number of breast magnetic resonance imaging is expected, too. Chemoprevention can be offered for individuals with medium risk and above. Promising trials are underway with platinum based chemotherapy and polyADP-ribose polimerase inhibitors for the systemic treatment of familial breast cancer. The increase in the number of genetic tests, counselling, and breast magnetic resonance imaging may have a significant impact on health care budget. CONCLUSIONS: These guidelines will change some aspects of the current management of familial breast cancer. Orv. Hetil., 2016, 157(28), 1117-1125.

Vitamin D in cancer chemoprevention.

CONTEXT: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. OBJECTIVE: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. METHODS: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. RESULTS AND CONCLUSION: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

Prostate cancer prevention: agent development strategies.

Despite advances in surgery, radiation, and medical therapy over the past decade and the widespread adoption of PSA screening, prostate cancer continues to be the second leading cause of cancer death in men in the United States. Invasive cancer is the end result of carcinogenesis, a chronic process occurring over many years driven by genetic and epigenetic alterations. The protracted nature of this transformation to the malignant phenotype provides an opportunity to intervene pharmacologically to prevent, reverse, or delay carcinogenesis, i.e. chemoprevention. Herein, we describe the unique features of cancer prevention, as opposed to cancer treatment, agent development clinical trials, and provide a summary of the ongoing research in this field being supported by the National Cancer Institute.

[Optimization of prophylaxis of hypercoagulation complications in oncological surgery].

The authors investigate the results of prophylaxis of venous thromboembolic complications (VTC) during 24 years in onco- logical surgery. The multicentric study shows that common frequency of occurrence of such VTC was reduced due to period of routine prophylaxis of VTC to 3.4%. The strategy of active revision and escalation of preventive measures in the third period of study in comparison with the second period resulted in the decrease of VTC. Patients with moderate risk degree had the results from 3.2% to 1%, patients with high risk degree moved from 4.1% to 13%. The fatal thromboembolism of the lung artery was 0.1%.

Chemoprevention of Head and Neck Cancer: A Review of Current Approaches and Future Perspectives.

Head and neck squamous cell carcinoma (HNSCC) is a spectrum of heterogeneous malignancies. A variety of genetic, environmental, and lifestyle factors contribute to the development of HNSCC. Carcinogenesis is a multistep process in which cell proliferation-associated oncogenes and cell-cycle regulation-associated tumor suppressor genes are dysregulated, resulting in premalignant lesions. Immune evasion is a critical step in the progression of benign lesions to advanced cancer. This review discusses the advances that have been made in chemoprevention strategies for HNSCC. The rationale for the use of chemopreventive agents to inhibit head and neck cancer development is highlighted by the positive outcomes of several clinical trials. We discuss the potential of some of the commonly studied agents including vitamin A analogs, EGFR inhibitors, COX-2 inhibitors, metabolic modulators, and natural compounds such as green tea, as well as immunotherapy and photodynamic therapy to prevent HNSCC. Our review provides insight into the potential benefits of these agents and the gaps that remain to be addressed. The published results reaffirm the promise of chemoprevention in head and neck cancer and suggest that continued exploration is needed to overcome the limitations. Because the current focus on chemopreventive agents is limited, major efforts in precision oncology approaches and substantial increase in funding will promote research into chemoprevention, which will eventually decrease the incidence of HNSCC.

Reassessing the role of phytochemicals in cancer chemoprevention.

In this comprehensive review we tried to reassess the role of phytochemicals in cancer chemoprevention. The exploration of the "synergistic effect" concept, advocating combined chemopreventive agents, faces challenges like low bioavailability. The review incorporates personal, occasionally controversial, viewpoints on natural compounds' cancer preventive capabilities, delving into mechanisms. Prioritizing significant contributions within the vast research domain, we aim stimulating discussion to provide a comprehensive insight into the evolving role of phytochemicals in cancer prevention. While early years downplayed the role of phytochemicals, the late nineties witnessed a shift, with leaders exploring their potential alongside synthetic compounds. Challenges faced by chemoprevention, such as limited pharmaceutical interest and cost-effectiveness issues, persist despite successful drugs. Recent studies, including the EPIC study, provide nuanced insights, indicating a modest risk reduction for increased fruit and vegetable intake. Phytochemicals, once attributed to antioxidant effects, face scrutiny due to low bioavailability and conflicting evidence. The Nrf2-EpRE signaling pathway and microbiota-mediated metabolism emerge as potential mechanisms, highlighting the complexity of understanding phytochemical mechanisms in cancer chemoprevention.

Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update.

Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer.

Organizing patient-centred anticoagulant therapy.

The advent of new oral anticoagulants (NOACs) is transforming the care of patients in need of anticoagulant therapy. NOACs offer the opportunity to provide patients with more effective, safer and more convenient anticoagulant therapy but there are still pitfalls and hurdles.

Oral premalignant lesions: any progress with systemic therapies?

PURPOSE OF REVIEW: To discuss the recent advances in oral cancer risk prediction, as well as agents that have been or are currently being tested in clinical trials, to treat oral premalignant lesions (OPLs) and prevent oral cancers. RECENT FINDINGS: Multiple predictive markers of OPL malignant transformation have been identified in retrospective or correlative studies involving patients enrolled in chemoprevention clinical trials, including chromosomal allelic imbalances, polysomy, p53, overexpression of podoplanin, p63 or epidermal growth factor receptor (EGFR), increased EGFR gene copy number, cyclin D1 polymorphisms, specific gene expression profiles, and specific DNA methylation profiles. Of these, loss of heterozygosity at specific chromosomal sites stands out as the most consistent and extensively characterized molecular marker of oral cancer risk described to date. This biomarker is now being prospectively integrated in chemoprevention clinical trials. Agents that have been or are currently being tested in patients with OPLs include retinoids, epidermal growth factor receptor inhibitors, cyclooxygenase-2 inhibitors, green tea extract, and peroxisome proliferator activated receptor-γ agonists. SUMMARY: Despite extensive clinical investigations, a standard systemic therapy for patients with OPLs is yet to be developed. Integration of biomarkers of cancer risk into clinical trials using novel agents will hopefully streamline head and neck cancer chemoprevention research.

A comprehensive review of DOACs for cancer associated VTE prophylaxis or treatment.

Cancer is a leading cause of venous thromboembolism (VTE), which contributes to significant morbidity and mortality in these patients. Increased thrombotic risk in cancer patients is modified by tumor-specific biology, disease-directed interventions, and individual comorbidities. Risk stratification for prophylaxis and treatment requires regular reevaluation of these factors, which can be facilitated by validated prediction tools. This review also discusses large clinical trial data (SELECT-D, HOKUSAI-VTE, ADAM VTE, CARAVAGGIO) demonstrating that direct oral anticoagulants (DOACs) are effective in the treatment of cancer-associated VTE, with comparable efficacy to the traditional choice of low molecular weight heparin. In the prophylactic setting derived from patients with cancer with increased VTE risk, DOACs also reduced the incidence of VTE with only modest increases in bleeding risk. The ease of DOAC administration and acceptable risk profile in the carefully selected patient make them an appealing choice for anticoagulation. In instances where the risk of gastrointestinal bleeding is of concern, apixaban, in particular, may still be a suitable option in place of LMWH. These improvements in our anticoagulation approach to cancer-associated VTE are well-timed to accompany the recent advances in disease-directed therapies that are enabling patients to live longer with cancer and therefore at increased risk of complications such as VTE.

Systemic Photoprotection in Skin Cancer Prevention: Knowledge among Dermatologists.

BACKGROUND: Systemic photoprotection (i.e., administration of substances such as nicotinamide, carotenoids, and vitamin D) may be important to reduce photocarcinogenesis or to support long-term protection against UV irradiation. Clinical trials showed that oral nicotinamide is effective in reducing the onset of new nonmelanoma skin cancers (NMSCs), while other oral photoprotectors failed to achieve the reduction of new melanoma or NMSC formation in humans. The aim of this study was to summarize the current state of knowledge of systemic photoprotection and to evaluate the knowledge and attitude of dermatologists regarding these treatments. METHODS: The survey was conducted on a sample of dermatologists recruited according to a snowball sampling procedure. The questionnaire consisted of a first part asking for characteristics of the participant and a second part with 12 specific questions on their knowledge about systemic photoprotection, particularly their knowledge of astaxanthin, ß-carotene, nicotinamide, and vitamin D3. RESULTS: One hundred eight dermatologists answered the survey. Most of them (85.2%) stated that oral photoprotectors have a role in the prevention of skin cancer, and responses mainly mentioned nicotinamide. More than half of them (54.6%) had prescribed all the considered oral photoprotectors, but the majority of them had prescribed nicotinamide, mainly for 2 to 3 months during summer, almost invariably (n = 106) associated with topical photoprotectors. Most dermatologists (>80%) were aware of scientific publications demonstrating an effect of systemic photoprotectors on NMSC. CONCLUSIONS: Most Italian dermatologists have positive views on oral photoprotection in skin cancer and are aware of the demonstrated potential of nicotinamide in the prevention of NMSCs.

Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis.

Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.