Updated meta-analysis of randomized controlled trials on primary outpatient thromboprophylaxis in patients with gastric and gastroesophageal junction cancers receiving chemotherapy.

Advanced gastric cancer is a highly thrombogenic cancer per Khorana score. Recent clinical practice guidelines suggest primary outpatient thromboprophylaxis (POTP) for patients with a Khorana score ≥2. We performed an updated meta-analysis to evaluate the benefit of POTP in patients with gastric cancer and gastroesophageal junction cancers receiving chemotherapy. Randomized controlled trials with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated. A total of 631 patients from subgroups of three randomized controlled trials were included. The VTE incidence was 1.6% and 5.1% in POTP and control groups, respectively (risk ratio 0.31; confidence interval 0.11 to 0.83; P = 0.02), with a number needed to treat of 29 to prevent one VTE event. Even though the recent clinical practice guidelines suggest POTP in patients with gastric cancer and gastroesophageal junction cancers, our meta-analysis findings do not support the routine use of POTP in those patients.

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials.

Acalabrutinib, a second-generation and more selective Bruton's tyrosine kinase inhibitor, was developed to potentiate efficacy while minimizing ibrutinib-associated side effects. We undertook a systematic review and meta-analysis of randomized clinical trials to determine the risks of acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia. Patients on acalabrutinib experienced higher risk of any-grade cardiac events (risk ratio, 1.75; p = 0.01) while there was a considerable trend toward statistical significance in the risk of any-grade atrial fibrillation (risk ratio, 2.56; p = 0.05). There was no significant increase in the risk of hypertension or high-grade cardiac events or atrial fibrillation in the acalabrutinib group.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with ovarian cancer receiving chemotherapy.

Ovarian cancer (OC) is highly associated with venous thromboembolism (VTE). The OC cells stimulate thrombin generation, and chemotherapy potentiates the prothrombotic effect of cancer cells by damaging endothelium and enhancing hypercoagulability. Recently, primary ambulatory thromboprophylaxis (PATP) has been studied as a potential treatment in cancer patients undergoing chemotherapy with an aim of reducing the incidence of VTE and potentially prolonging survival. A meta-analysis was performed of randomized controlled trials of PATP vs control in patients with OC receiving chemotherapy. The primary outcome measure was the incidence of VTE. The secondary outcome measure was the incidence of major bleeding complications. Two articles published between 2012 and 2020 fulfilled selection criteria. The incidence of VTE was 0.9% in the PATP group and 1.8% in the control group. However, the pooled risk ratio was not statistically significant at 0.69 (95% CI: 0.08 to 5.67; P = 0.73). The absolute risk difference was -0.03 (95% CI, -0.17 to 0.11; P = 0.66). There was no statistically significant reduction in VTE by providing PATP to patients with OC receiving chemotherapy. Routine PATP should not be recommended in ambulatory OC patients. Future randomized trials are necessary to define the high-risk subset of OC patients who may benefit from PATP.

Primary ambulatory thromboprophylaxis in patients with pancreatic cancer receiving chemotherapy: hope or hype?

Thrombosis is the second leading cause of death in cancer patients. Patients with pancreatic cancer (PC) have a very high risk of developing venous thromboembolism (VTE). Even though primary ambulatory thromboprophylaxis (PATP) could decrease this risk, there are uncertain issues with regard to the choice and dose of anticoagulants, duration of anticoagulant therapy, and patient selection criteria. In addition, the current practice guidelines on PATP in PC patients are equivocal. This review critically appraises the evidence on the use of PATP in PC patients receiving chemotherapy.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy.

Primary ambulatory thromboprophylaxis (PATP) in patients with solid malignancies is not routinely indicated. We performed a meta-analysis of randomized controlled trials (RCTs) to determine the benefit and risk of PATP in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included. A total of 1932 patients from subgroups of 3 RCTs were eligible. The VTE incidence was 1.26% and 2.55% in PATP and control arms, respectively (risk ratio 0.49; confidence interval 0.25 to 0.96; P = 0.04), with a number needed to treat of 78 to prevent one VTE event. In gastric and gastroesophageal junction cancer patients, the VTE incidence was 1.37% and 3.40% in PATP and control arms, respectively (risk ratio 0.40; confidence interval 0.13 to 1.24; P = 0.11). PATP should not be recommended in patients with nonpancreatic gastrointestinal cancers on chemotherapy.

Pernicious anemia: Pathophysiology and diagnostic difficulties.

Pernicious anemia (PA) is the most common cause of vitamin B12 (cobalamin) deficiency anemia in the world. It is an autoimmune disease, comprising of salient features of autoimmune chronic atrophic gastritis (CAG) and cobalamin deficiency (CD). Although the anemia was first described as pernicious, it may well be controlled with vitamin B12 replacement. The onset and progression of PA is often insidious. Alternatively, patients may have no anemic symptoms since they become acclimatized to the subtle nature of the disease. Oftentimes, there is a possibility that the underlying disease may be missed unless a full blood count (FBC) is investigated, leading to hindrance in the treatment journey. Diagnostic challenges remain tangible for many practicing clinicians, since there is lack of reliable cobalamin assays to diagnose CD as well as clinical mimics, which simulate many other hematological conditions, such as myelodysplastic syndrome, acute leukemia, sideroblastic anemias, bone marrow failure states, thrombotic microangiopathy, and thromboembolism. Moreover, prompt recognition of the symptoms of CD is also vital, because some neurologic sequalae may become irreversible despite replenishing cobalamin. Herein, we discuss a literature review on the pathophysiology, challenging clinical presentations and diagnostic difficulties of PA. Since the cobalamin replacement therapy for PA is straightforward, it will not be discussed in this review.

Systematic review of immunosuppressant guidelines in the COVID-19 pandemic.

AIMS: Individuals taking immunosuppressants are at increased susceptibility to viral infections in general. However, due to the novel nature of the COVID-19, there is a lack of evidence about the specific risks of the disease in this patient group. This systematic review aims to summarize the current international clinical guidelines to highlight areas where research is needed through critical appraisal of the evidence base of these guidelines. METHODS: We conducted a systematic review of clinical practice guidelines about the usage of immunosuppressants during the COVID-19 pandemic. Electronic databases including MEDLINE and the websites of relevant professional bodies were searched for English language guidelines that were published or updated between March 2020 and May 2020 in this area. We assessed the quality and consistency of guidelines. The evidence base underpinning these guidelines was critically appraised using GRADE criteria. RESULTS: Twenty-three guidelines were included. Most guidelines (n = 15, 65.2%) informed and updated evidence based on expert opinion. The methodological quality of the guidelines varied, ranging from 'very low' to 'moderate'. Guidelines consistently recommended that high-risk patients, including those who are taking high doses of steroids for more than a month, or a combination of two or more immunosuppressants, should be shielding during the outbreak. Most guidelines stated that steroids usage should not be stopped abruptly and advised on individualized risk-benefit analysis considering the risk of the effect of COVID-19 infection and the relapse of the autoimmune condition in patients. DISCUSSION: Clinical practice guidelines on taking immunosuppressants during the COVID-19 outbreak vary in quality. The level of evidence informing the available guidelines was generally low. Given the novel nature of COVID-19, the guidelines draw on existing knowledge and data, refer to the use of immunosuppressants and risks of serious infections of other aetiologies and have extrapolated these to form their evidence base.

Venous thromboembolism risk in patients with hormone receptor-positive HER2-negative metastatic breast cancer treated with combined CDK 4/6 inhibitors plus endocrine therapy versus endocrine therapy alone: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR)-positive. Recent studies have shown that CDK4/6 inhibitors (CDKI) improve survival in combination with ET in HR-positive, HER2-negative MBC. The risk of venous thromboembolism (VTE) is 3-4 times higher in patients with breast cancer (BC) than in patients without cancer. The risk is even higher in BC patients receiving ET and chemotherapy. The aim of the study was to determine the VTE risk of CDKIs plus ET versus ET alone in patients with HR-positive, HER2-negative MBC. METHODS: We performed a systematic review and meta-analysis to demonstrate the risk of VTE in patients with HR-positive HER2-negative MBC treated with combined CDKIs and ET versus ET alone. RESULTS: Eight randomized controlled trials (RCT) with a total of 4,557 patients were eligible. The study arms comprised of palbociclib or ribociclib or abemaciclib plus ET while the control arms utilized placebo plus ET. The VTE events were 56 (2%) in the CDKIs plus ET group compared to 10 (0.5%) in the control group. Pooled relative risk (RR) for VTE was 2.62 (95% CI 1.21-5.65; P = 0.01) and the risk difference (RD) was 0.01 (95% CI 0.00-0.03; P = 0.02). Over a median follow-up of up to 36 months, RR was 3.18 (95% CI 1.22-8.24; P = 0.02) and RD was 0.03 (95% CI 0.01-0.06, P = 0.008). CONCLUSIONS: Our meta-analyses demonstrated that the addition of CDKIs to ET in patients with HR-positive HER 2-negative MBC contribute to a higher incidence of VTE. Further trials are required to define the actual relation and definitive incidence of VTE with different CDKIs.

Impact of Primary Ambulatory Thromboprophylaxis (PATP) with Low-Molecular Weight Heparins (LMWHs) on Survival in Patients with Lung Cancer Receiving Chemotherapy.

Lung cancer (LC) is the leading cause of cancer mortality. PATP was provided in experimental trials to decrease the venous thromboembolism (VTE), with ultimate aim to improve overall survival (OS). We undertook an updated systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the impact of PATP with LMWHs on OS and VTE in patients with LC. 5443 patients with LC from nine RCTs were included. The pooled hazard ratio (HR) for OS was 1.02 (95% CI 0.83 to 1.26; P = 0.83) and for progression or metastasis-free survival was 1.03 (95% CI 0.86 to 1.24; P = 0.74). The pooled risk ratio (RR) for VTE was 0.54 (95% CI 0.43 to 0.69; P < 0.00001) and the risk difference (RD) was-0.03 (- 0.05 to - 0.02; P < 0.00001). Our analysis showed no survival advantage with the addition of PATP with LMWHs to standard chemotherapy in patients with LC, regardless of histology or stages of small cell LC.