Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies.

In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81-10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9-18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2-14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

Efficacy and safety of frontline systemic therapy for advanced HCC: A network meta-analysis of landmark phase III trials.

Background & Aims: Direct comparisons across first-line regimens for advanced hepatocellular carcinoma are not available. We performed a network metanalysis of phase III of trials to compare first-line systemic treatments for hepatocellular carcinoma in terms of overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate, and incidence of adverse events (AEs). Methods: After performing a literature review from January 2008 to September 2022, we screened 6,329 studies and reviewed 3,009 studies, leading to identification of 15 phase III trials for analysis. We extracted odds ratios for objective response rate and disease control rate, relative risks for AEs, and hazard ratios (HRs) with 95% CIs for OS and PFS, and used a frequentist network metanalysis, with fixed-effect multivariable meta-regression models to estimate the indirect pooled HRs, odds ratios, relative risks, and corresponding 95% CIs, considering sorafenib as reference. Results: Of 10,820 included patients, 10,444 received active treatment and 376 placebo. Sintilimab + IBI350, camrelizumab + rivoceranib, and atezolizumab + bevacizumab provided the greatest reduction in the risk of death compared with sorafenib, with HRs of 0.57 (95% CI 0.43-0.75), 0.62 (95% CI 0.49-0.79), and 0.66 (95% CI 0.52-0.84), respectively. Considering PFS, camrelizumab + rivoceranib and pembrolizumab + lenvatinib were associated with the greatest reduction in the risk of PFS events compared with sorafenib, with HRs of 0.52 (95% CI 0.41-0.65) and 0.52 (95% CI 0.35-0.77), respectively. Immune checkpoint inhibitor (ICI) monotherapies carried the lowest risk for all-grade and grade ≥3 AEs. Conclusions: The combinations of ICI + anti-vascular endothelial growth factor, and double ICIs lead to the greatest OS benefit compared with sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates. Impact and Implications: In the last few years, many different therapies have been studied for patients with primary liver cancer that cannot be treated with surgery. In these cases, anticancer drugs (alone or in combination) are given with the intent to keep the cancer at bay and, ultimately, to prolong survival. Among all the therapies that have been investigated, the combination of immunotherapy (drugs that boost the immune system against the cancer) and anti-angiogenic agents (drugs that act on tumoural vessels) has appeared the best to improve survival. Similarly, the combination of two types of immunotherapies that activate the immune system at different levels has also shown positive results. Systematic Review Registration: PROSPERO CRD42022366330.

Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials.

BACKGROUND: Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking. METHOD: We conducted a literature search in MEDLINE (https://pubmed.ncbi.nlm.nih.gov), the Cochrane library (https://www.cochranelibrary.com) and Embase (www.embase.com) between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489). FINDINGS: Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.

Risk of Severe Infection among Rheumatoid Arthritis Patients on Biological DMARDs: A Population-Based Cohort Study.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) are widely used for the management of rheumatoid arthritis, although their benefits are counterweight by an increased risk of infections. In the present study, we used administrative data to compare the risk of severe infections among different classes of bDMARDs. A retrospective cohort study was conducted using Administrative Health Databases of the Piedmont Region, Italy. Relevant data were obtained from: (1) the inhabitants registry, (2) hospital discharge records, and (3) the co-payment exemption registry and (4) drug claims registry. Fine and Gray competing risk models were fitted to evaluate the association between the use of different types of bDMARDs and occurrence of severe infection accounting for treatment interruption as competing risk. A total of 1780 new users of bDMARDs were identified. Among them, 50 hospitalizations for infection occurred during the study period. The use of Tocilizumab was associated with an increased risk of infection, compared to tumor necrosis factor (TNF) inhibitor drugs (sub-distribution hazard ratios-sHR: 2.510; 95% CI: 1.279-4.926), whereas no difference in the risk of severe infection was found for abatacept (sHR: 0.584; 95% CI: 0.234-1.457). bDMARDs treatment is generally safe in clinical practice with slight but important differences among classes. The increased risk of infection associated with tocilizumab use should be taken into account when balancing the risk and benefits of starting a treatment with this drug.

Heparin versus normal saline locking for prevention of occlusion, catheter-related infections and thrombosis in central venous catheter in adults: Overview of systematic reviews.

Venous access devices are used in health care. To prevent occlusions the evidence confirmed the need for routine catheter flushing before and after infusion as well as at the end of use. To date, the efficacy of heparin has not been demonstrated. The aim of this study was to evaluate the effectiveness of the locking of central venous catheters with heparin versus normal saline in adults to prevent occlusion, catheter-related infections and thrombosis in adults. A literature search using Medline, Embase, Cochrane Library and Cinahl was performed to identify all meta-analyses addressing the effectiveness of heparin versus normal saline in locking central venous catheters in adults. Four reviewers independently selected publications assessed quality and extracted data. Parameter estimates regarding occlusion, catheter- related infections and thrombosis were pooled using an umbrella review. We identified 6356 references. Seven systematic reviews were included in the study. Most of the studies included in the systematic reviews were conducted in oncohaematology departments, intensive care and cardiac surgery units among patients with multiple diseases and chronicity. Most studies report a heparin concentration of 10 to 5000 IU/ml versus normal saline and other solutions. There was no evidence that heparin was more effective than normal saline in reducing complications such as occlusion, catheter-related infections and thrombosis. No statistically significant difference was found between heparin and normal saline in reducing catheter occlusion. Heparin is not superior compared to normal saline.

Time-Trends of Drug-Drug Interactions among Elderly Outpatients in the Piedmont Region (Italy): A Population-Based Study.

Adverse drug reactions (ADRs) are a major health problem in the primary care setting, particularly among the elderly population. While the high frequency of ADRs in the elderly has several causes, a major and common determinant is polypharmacy, which can in turn increase the risk of drug-drug interactions (DDIs). In this paper, we analyzed the drugs prescriptions dispensed to elderly outpatients, to assess changes in the prevalence of selected DDIs in the period 2013−2019. Overall, about 15% of the patients aged >65 years were poly-treated. Among them, a decreasing trend in prevalence was observed for the majority of DDIs during the study period. This trend was particularly noticeable for DDIs involving fluoroquinolones and vitamin K antagonists, where a sharp reduction of over 40% was observed. On the opposite, a small increase in prevalence was observed for the association of antidiabetics and beta-blocking agents and for that of clopidogrel and PPIs. While the occurrence of most of the considered DDIs among poly-treated elderly decreased over time, the prevalence of some of them is still worrying. The complexity of the national drug formularies, as well as the increased number of prescribing actors that are involved, further urges the update of DDI lists to be used to monitor drug appropriateness and reduce avoidable ADRs.

COVID-19 Sequelae and the Host Proinflammatory Response: An Analysis From the OnCovid Registry.

BACKGROUND: Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post-COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae. METHODS: OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided. RESULTS: Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5 mg/L vs 22.2 mg/L, P < .001), lactate dehydrogenase (310 UI/L vs 274 UI/L, P = .03), and the neutrophil to lymphocyte ratio (NLR; 6.0 vs 4.3, P = .001) were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP (AUC = 0.66, 95% confidence interval [CI]: 0.63 to 0.69), followed by the NLR (AUC = 0.58, 95% CI: 0.55 to 0.61) and lactate dehydrogenase (AUC = 0.57, 95% CI: 0.52 to 0.61). Using a fixed categorical multivariable analysis, high CRP (odds ratio [OR] = 2.56, 95% CI: 1.67 to 3.91) and NLR (OR = 1.45, 95% CI: 1.01 to 2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR = 0.57, 95% CI: 0.36 to 0.91), whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found. CONCLUSIONS: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development.

Potentially Inappropriate Prescribing among Elderly Outpatients: Evaluation of Temporal Trends 2012-2018 in Piedmont, Italy.

Pharmacological intervention is one of the cornerstones in the treatment and prevention of disease in modern healthcare. However, a large number of drugs are often prescribed and used inappropriately, especially in elderly patients. We aimed at investigating the annual prevalence of potentially inappropriate prescriptions (PIPs) among older outpatients using administrative healthcare databases of the Piedmont Region (Italy) over a seven-year period (2012-2018). We included all Piedmont outpatients aged 65 years or older with at least one drug prescription per year. Polypharmacy and the prevalence of PIPs according to the ERD list explicit tool were measured on an annual basis. A range between 976,398 (in 2012) and 1,066,389 (in 2018) elderly were evaluated. Among them, the number of subjects with at least one PIP decreased from 418,537 in 2012 to 339,764 in 2018; the prevalence significantly reduced by ~25% over the study period. The stratified analyses by age groups and sex also confirmed the downward trend and identified several differences in the most prevalent inappropriately prescribed drugs. Overall, despite a reduction in PIP prevalence, one out of three older outpatients was still exposed to inappropriateness, highlighting the extensive need for intervention to improve prescribing.

Time-Dependent COVID-19 Mortality in Patients With Cancer: An Updated Analysis of the OnCovid Registry.

Importance: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. Objective: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. Design, Setting, and Participants: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). Results: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P = .001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P < .001) and anti-COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. Conclusions and Relevance: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

Prevalence and impact of COVID-19 sequelae on treatment and survival of patients with cancer who recovered from SARS-CoV-2 infection: evidence from the OnCovid retrospective, multicentre registry study.

BACKGROUND: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. METHODS: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients' death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. FINDINGS: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4-57·8) from cancer diagnosis and 44 days (28-329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113-148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio [HR] 1·80 [95% CI 1·18-2·75]) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 [95% CI 1·45-8·59]), but dose or regimen adjustments were not (0·84 [0·35-2·02]). INTERPRETATION: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients. FUNDING: National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.

Determinants of enhanced vulnerability to coronavirus disease 2019 in UK patients with cancer: a European study.

BACKGROUND: Despite high contagiousness and rapid spread, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to heterogeneous outcomes across affected nations. Within Europe (EU), the United Kingdom (UK) is the most severely affected country, with a death toll in excess of 100,000 as of January 2021. We aimed to compare the national impact of coronavirus disease 2019 (COVID-19) on the risk of death in UK patients with cancer versus those in continental EU. METHODS: We performed a retrospective analysis of the OnCovid study database, a European registry of patients with cancer consecutively diagnosed with COVID-19 in 27 centres from 27th February to 10th September 2020. We analysed case fatality rates and risk of death at 30 days and 6 months stratified by region of origin (UK versus EU). We compared patient characteristics at baseline including oncological and COVID-19-specific therapy across UK and EU cohorts and evaluated the association of these factors with the risk of adverse outcomes in multivariable Cox regression models. FINDINGS: Compared with EU (n = 924), UK patients (n = 468) were characterised by higher case fatality rates (40.38% versus 26.5%, p < 0.0001) and higher risk of death at 30 days (hazard ratio [HR], 1.64 [95% confidence interval {CI}, 1.36-1.99]) and 6 months after COVID-19 diagnosis (47.64% versus 33.33%; p < 0.0001; HR, 1.59 [95% CI, 1.33-1.88]). UK patients were more often men, were of older age and have more comorbidities than EU counterparts (p < 0.01). Receipt of anticancer therapy was lower in UK than in EU patients (p < 0.001). Despite equal proportions of complicated COVID-19, rates of intensive care admission and use of mechanical ventilation, UK patients with cancer were less likely to receive anti-COVID-19 therapies including corticosteroids, antivirals and interleukin-6 antagonists (p < 0.0001). Multivariable analyses adjusted for imbalanced prognostic factors confirmed the UK cohort to be characterised by worse risk of death at 30 days and 6 months, independent of the patient's age, gender, tumour stage and status; number of comorbidities; COVID-19 severity and receipt of anticancer and anti-COVID-19 therapy. Rates of permanent cessation of anticancer therapy after COVID-19 were similar in the UK and EU cohorts. INTERPRETATION: UK patients with cancer have been more severely impacted by the unfolding of the COVID-19 pandemic despite societal risk mitigation factors and rapid deferral of anticancer therapy. The increased frailty of UK patients with cancer highlights high-risk groups that should be prioritised for anti-SARS-CoV-2 vaccination. Continued evaluation of long-term outcomes is warranted.

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score.

BACKGROUND: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. METHODS: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. RESULTS: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). CONCLUSIONS: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.

Presenting Features and Early Mortality from SARS-CoV-2 Infection in Cancer Patients during the Initial Stage of the COVID-19 Pandemic in Europe.

We describe the outcomes in cancer patients during the initial outbreak of the COVID-19 in Europe from the retrospective, multi-center observational OnCovid study. We identified 204 cancer patients from eight centers in the United Kingdom, Italy, and Spain aged > 18 (mean = 69) and diagnosed with COVID-19 between February 26th and April 1st, 2020. A total of 127 (62%) were male, 184 (91%) had a diagnosis of solid malignancy, and 103 (51%) had non-metastatic disease. A total of 161 (79%) had > 1 co-morbidity. A total of 141 (69%) patients had > 1 COVID-19 complication. A total of 36 (19%) were escalated to high-dependency or intensive care. A total of 59 (29%) died, 53 (26%) were discharged, and 92 (45%) were in-hospital survivors. Mortality was higher in patients aged > 65 (36% versus 16%), in those with > 2 co-morbidities (40% versus 18%) and developing > 1 complication from COVID-19 (38% versus 4%, p = 0.004). Multi-variable analyses confirmed age > 65 and > 2 co-morbidities to predict for patient mortality independent of tumor stage, active malignancy, or anticancer therapy. During the early outbreak of SARS-CoV-2 infection in Europe co-morbid burden and advancing age predicted for adverse disease course in cancer patients. The ongoing OnCovid study will allow us to compare risks and outcomes in cancer patients between the initial and later stages of the COVID-19 pandemic.

Comparison between high-field 3 Tesla MRI and computed tomography with and without arthrography for visualization of canine carpal ligaments: A cadaveric study.

OBJECTIVE: To compare the quality of visualization of canine carpal ligaments by using computed tomography (CT), MRI, CT arthrography (CTA), and magnetic resonance arthrography (MRA). STUDY DESIGN: Prospective descriptive study. STUDY POPULATION: Cadavers from dogs weighing more than 20 kg. METHODS: A 16-slice CT scanner and a 3 Tesla MRI were used for the investigation. A dilute contrast medium was injected into the middle carpal and radiocarpal joints under fluoroscopic control, and CTA and MRA images were acquired. To evaluate the difference between imaging modalities, 3 observers graded carpal ligaments of clinical interest using a scale from 0 to 4 for their quality of visualization. Data were analyzed by using a random-effect ordinal logistic regression with Bonferroni adjustment. The interobserver agreement was calculated by using the weighted Cohen's κ. RESULTS: Normal carpal joints (n = 9) were investigated. Magnetic resonance arthrography improved visualization of the majority of carpal ligaments compared with MRI (P < .05) and offered the best visualization overall. Magnetic resonance imaging and MRA offered better visualization compared with both CT and CTA (P < .05). There was no difference between CT and CTA. Interobserver agreement was discrete (0.2 < κ ≤ 0.4) for all observers. CONCLUSION: Arthrography improved the capabilities of MRI but not of CT for visualization of the canine carpal ligaments. Magnetic resonance arthrography was particularly useful for evaluation of the stabilizers of the antebrachiocarpal joint. CLINICAL SIGNIFICANCE: 3 Tesla MRA and MRI allow excellent visualization of the ligamentous morphology and may be helpful in the diagnostic process of carpal sprains in dogs.

Use of proton pump inhibitors and risk of ischemic events in the general population.

BACKGROUND AND AIMS: A potential increased risk of cardiovascular events has been suggested for proton pump inhibitors (PPIs), the most commonly prescribed drugs for the management of upper gastrointestinal disorders. We aimed to estimate the risk of hospitalization for cardio/cerebrovascular (CV) events in a cohort of incident PPI users. METHODS: A nested case-control study was carried out using regional healthcare utilization databases. For each case (hospitalization for non-haemorrhagic CV event), up-to-five controls randomly selected from the cohort were matched by gender, age at cohort entry, and index date. Exposure was estimated as recency of therapy (current, recent and past users) and number of days covered. Adjusted conditional logistic regression was used to estimate the association between exposure and outcome. RESULTS: Among new PPI users, we identified 17,832 cases and 89,160 controls (males 64.9%; mean age 58.9 years). Cases showed a significantly higher prevalence of use of drugs for diabetes, hypertension and hypercholesterolemia than controls. Risk of CV events was significantly higher for current (OR 1.61; 95%CI 1.55-1.68) and recent users (OR 1.15; 95%CI 1.06-1.26) compared to past users. Analogous results were found stratifying for cardiovascular (ORcurrent 1.71; 95%CI 1.63-1.81) and cerebrovascular events (ORcurrent 1.43; 95%CI 1.34-1.54). The increased risk was confirmed in subgroups by antithrombotic, statin use, or exposure duration. The same analysis for H2-antagonists use showed no significant results. CONCLUSIONS: In primary care setting, PPI use was independently associated with increased risk of first-time cardiovascular event, consistent with the evidence that PPIs adversely impact vascular function, underlying the need to promote appropriate prescribing of these drugs.

Prevalence and incidence of psoriatic arthritis: A systematic review and meta-analysis.

BACKGROUND: Psoriatic arthritis (PsA) is a specific form of inflammatory arthritis associated with psoriasis affecting in the same measure men and women but with a consistent geographic variability. Since the burden of PsA frequency has important implications in the definition of the healthcare policies, it is important to measure the frequency of disease in the general population. OBJECTIVE: To quantify the global health burden of PsA summarizing the data provided by the population-based available studies investigating prevalence and incidence of the disease. METHODS: A MEDLINE search was performed to identify all studies reporting the prevalence or incidence of PsA. Fixed- and random-effect models were fitted to estimate the prevalence and incidence pooled estimates. Between-study heterogeneity was evaluated using the Q statistic and the I2 index and Publication bias using Egger's asymmetry test. RESULTS: Twenty-eight studies were included in the meta-analysis, 17 retrieved from the literature search and 11 from the meta-analysis of Alamanos et al. The random effect pooled PsA prevalence and incidence rates are respectively 133 every 100,000 subjects (95% CI, 107-164 every 100,000 subjects) and 83 every 100,000 PY (95% CI, 41-167 every 100,000 PY). High between-study heterogeneity was found for both prevalence and incidence estimates. CONCLUSIONS: This study allowed the estimation of a global average prevalence and incidence rates of PsA and the evaluation of the geographic variability. The high between-study heterogeneity suggests the importance to look not only at the pooled estimates but also at the study-specific estimate.

Drug treatment and adherence of subjects <40 years with diagnosis of heterozygous familial hypercholesterolemia.

BACKGROUND AND AIMS: We aimed at describing the therapeutic approach in young adult patients diagnosed with heterozygous familial hypercholesterolemia (HeFH) and their adherence and persistence to treatment. METHODS: From regional administrative databases, individuals aged ≤40 years, who received exemption for HeFH between January 1, 2003 and December 31, 2011, and concomitantly started statin treatment, were identified. Within the first year of treatment, we evaluated therapeutic changes, adherence as MPR (medication possession ratio), persistence as continuous drug coverage without gaps ≥60 days, and influencing factors using log binomial models. RESULTS: Of 1404 patients, 42.4% were initially treated with a high-efficacy statin. 23.4% of patients showed at least one treatment change. Mean MPR was 68.7% (29.9), and patients showing continued statin use were 47.0%. Therapy modification was significantly associated with a past cardiovascular event (relative risk, RR [95% confidential interval] 2.28 [1.69-3.09]) and at least one lipid test (RR 1.82 [1.31-2.53]). MPR ≥80% was significantly associated with the first statin prescribed (atorvastatin RR 1.28 [1.09-1.51] and rosuvastatin RR 1.21 [1.01-1.44], vs. simvastatin), a past cardiovascular event (RR 1.33 [1.12-1.59]), at least one therapy change (RR 1.28 [1.15-1.43]), at least a lipid test (RR 1.26 [1.07-1.49]). A similar pattern was observed for persistence. CONCLUSIONS: This analysis of young adult HeFH patients showed that therapy change was quite frequent, and probably reflected adjustments according to individual response. Adherence and persistence were inadequate, even in this population at high cardiovascular risk, and they need to be improved through proper patient education and shared treatment decision-making approach.

Statins and primary liver cancer: a meta-analysis of observational studies.

Statins are among the most commonly prescribed drugs used to manage dyslipidemia. Hepatocellular carcinoma is the third leading cause of cancer mortality and its rates have recently been increasing in central and northern Europe and USA. To quantify the association between statin use and risk for HCC, we performed a meta-analysis of published studies. We conducted a MEDLINE search for observational studies reporting the association between exposure to statins and risk for incident liver cancer until March 2012. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Moreover, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Five observational studies (two case-control and three cohort studies) based on 2574 cases of HCC were included. Statin treatment, compared with no treatment, was inversely related to HCC (summary RR=0.58; 95% CI 0.46-0.74). Between-study heterogeneity was significant (P<0.001) and numerically relevant (I=65%). When only longest statin use was considered, the RR was 0.66 (95% CI 0.55-0.80). Influence analysis on the overall estimate showed that heterogeneity was largely because of one study; when omitting it, the I dropped to 27% (P=0.240), whereas the summary RR was only marginally modified (RR=0.52; 95% CI 0.44-0.62). There was no evidence of publication bias. This meta-analysis suggests a favorable effect of statins on HCC, in the absence, however, of a duration-risk relationship.

Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis.

OBJECTIVE: Oral antidiabetic drugs (including metformin and sulfonylurea) may play a role in the relationship between type 2 diabetes and cancer. To quantify the association between metformin and sulfonylurea and the risk of cancer, we performed a meta-analysis of available studies on the issue. MATERIALS AND METHODS: We performed a MEDLINE search for observational studies that investigated the risk of all cancers and specific cancer sites in relation to use of metformin and/or sulfonylurea among patients with type 2 diabetes mellitus. Fixed- and random-effect models were fitted to estimate the summary relative risk (RR). Between-study heterogeneity was tested using χ(2) statistics and measured with the I(2) statistic. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test. RESULTS: Seventeen studies satisfying inclusion criteria and including 37,632 cancers were evaluated after reviewing 401 citations. Use of metformin was associated with significantly decreased RR of all cancers (summary RR 0.61, 95% confidence interval [CI] 0.54-0.70), colorectal cancer (0.64, 95% CI 0.54-0.76), and pancreatic cancer (0.38, 95% CI 0.14-0.91). With the exception of colorectal cancer, significant between-study heterogeneity was observed. Evidence of publication bias for metformin-cancer association was also observed. There was no evidence that metformin affects the risk of breast and prostate cancers, nor that sulfonylurea affects the risk of cancer at any site. CONCLUSIONS: Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk. This has relevant implications in light of the exploding global epidemic of diabetes.

A meta-analysis on alcohol drinking and the risk of Hodgkin lymphoma.

The role of alcohol intake in the risk of Hodgkin lymphoma (HL) is still largely unclear. To summarize the evidence on the issue, we carried out a meta-analysis of the available studies. We identified eight case-control and two cohort studies, including a total of 1488 cases of HL. We derived meta-analytic estimates using random-effects models, taking into account the correlation between estimates, and carried out a dose-risk analysis using nonlinear random-effects metaregression models. Compared with nondrinkers, the relative risk for alcohol consumers was 0.70 [95% confidence interval (CI), 0.60-0.81] overall, 0.66 (95% CI, 0.56-0.78) among case-control, and 0.92 (95% CI, 0.63-1.33) among cohort studies. Compared with nondrinkers, the pooled relative risks were 0.71 (95% CI, 0.57-0.89) for light (i.e. ≤1 drink/day) and 0.73 (95% CI, 0.60-0.87) for moderate-to-heavy (i.e. >1 drink/day) alcohol drinking. This meta-analysis suggests a favourable effect of alcohol on HL, in the absence, however, of a dose-risk relationship. The inverse association was restricted to--or greater in--case-control as compared with cohort studies. This indicates caution in the interpretation of results.