Impact of spleen-preserving total gastrectomy on postoperative infectious complications and 5-year overall survival: systematic review and meta-analysis of contemporary randomized clinical trials.

Background: The role of splenectomy in proximal gastric cancer is still debated. The objective of the present meta-analysis was to provide more-robust evidence about the effect of spleen-preserving total gastrectomy on postoperative infectious complications, overall morbidity, and 5-year overall survival (os). Methods: PubMed, embase, and the Web of Science were consulted. Pooled effect measures were calculated using an inverse-variance weighted or Mantel-Haenszel in random effects meta-analysis. Heterogeneity was evaluated using I2 index and Cochran Q-test. Results: Three randomized controlled trials published between 2000 and 2018 were included. Overall, 451 patients (50.1%) underwent open total gastrectomy with spleen preservation and 448 (49.9%) underwent open total gastrectomy with splenectomy. The patients ranged in age from 24 to 78 years. No differences were found in the number of harvested lymph nodes (p = 0.317), the reoperation rate (p = 0.871), or hospital length of stay (p = 0.347). The estimated pooled risk ratios for infectious complications, overall morbidity, and mortality were 1.53 [95% confidence interval (ci): 1.09 to 2.14; p = 0.016], 1.51 (95% ci: 1.11 to 2.05; p = 0.008), and 1.23 (95% ci: 0.40 to 3.71; p = 0.719) respectively. The estimated pooled hazard ratio for 5-year os was 1.06 (95% ci: 0.78 to 1.45; p = 0.707). Conclusions: Spleen-preserving total gastrectomy should be considered in patients with curable gastric cancer because it is significantly associated with decreased postoperative infectious complications and overall morbidity, with no difference in the 5-year os. Those observations appear worthwhile for establishing better evidence-based treatment for gastric cancer.

Perforated esophageal intervention focus (PERF) study: a multi-center examination of contemporary treatment.

The treatment of esophageal perforation (EP) remains a significant clinical challenge. While a number of investigators have previously documented efficient approaches, these were mostly single-center experiences reported prior to the introduction of newer technologies: specifically endoluminal stents. This study was designed to document contemporary practice in the diagnosis and management of EP at multiple institutions around the world and includes early clinical outcomes. A five-year (2009-2013) multicenter retrospective review of management and outcomes for patients with thoracic or abdominal esophageal perforation was conducted. Demographics, etiology, diagnostic modalities, treatments, subsequent early outcomes as well as morbidity and mortality were captured and analyzed. During the study period, 199 patients from 10 centers in the United States, Canada, and Europe were identified. Mechanisms of perforation included Boerhaave syndrome (60, 30.1%), iatrogenic injury (65, 32.6%), and penetrating trauma (25, 12.6%). Perforation was isolated to the thoracic segment alone in 124 (62.3%), with 62 (31.2%) involving the thoracoabdominal esophagus. Mean perforation length was 2.5 cm. Observation was selected as initial management in 65 (32.7%), with only two failures. Direct operative intervention was initial management in 65 patients (32.6%), while 29 (14.6%) underwent esophageal stent coverage. Compared to operative intervention, esophageal stent patients were significantly more likely to be older (61.3 vs. 48.3 years old, P < 0.001) and have sustained iatrogenic mechanisms of esophageal perforation (48.3% vs.15.4%). Secondary intervention requirement for patients with perforation was 33.7% overall (66). Complications included sepsis (56, 28.1%), pneumonia (34, 17.1%) and multi-organ failure (23, 11.6%). Overall mortality was 15.1% (30). In contemporary practice, diagnostic and management approaches to esophageal perforation vary widely. Despite the introduction of endoluminal strategies, it continues to carry a high risk of mortality, morbidity, and need for secondary intervention. A concerted multi-institutional, prospectively collected database is ideal for further investigation.

The yield of video-EEG telemetry evaluation for non-surgical candidate children.

BACKGROUND: Video EEG (VEEG) is performed for most pediatric patients in order to evaluate unclear paroxysmal events and improve our understanding of difficult to control epileptic patients. PURPOSE: To characterize the video EEG studies on children who are not candidates for surgery in order to identify the parameters that affect results in level of improving the rate of acquisition, as well as improving the ability to expect the likelihood of epilepsy and of gathering new information as a result of the VEEG. METHODS: Retrospective chart analysis of all consecutive patients who underwent VEEG in two VEEG monitoring units. RESULTS: 323 children of a mean age of 7 years (STD 4.73, range 0-17 years) were monitored for a mean duration of 2 days (STD 1.65, range 1-10 days). The main reasons for monitoring were: evaluation of unclear events (n = 234), evaluation of previously diagnosed epilepsy (n = 36) and confirmation of Electrical Status Epilepticus in Sleep (ESES) (n = 34). The main event types for evaluation were: staring episodes (n = 67), myoclonic jerks (n = 35) and abnormal eye movement (n = 22). Suspected events were captured in 70% of the patients. There was a positive correlation between acquisition of suspected events and each of the following: duration of the monitoring, the frequency of investigated events per history, the type of investigated events. A prior interictal epileptic activity on routine EEG was a positive predictor of an event to be epileptic (p = 0.003). Amongst the group of known epileptic patients, VEEG had role in changing diagnosis in 53% of patients. Many of them had focal interictal epileptiform activity in their routine EEG. CONCLUSIONS: Selecting patients with frequent events and longer monitoring periods increase the yield of VEEG. Looking carefully into clinical characteristics of the patient prior to VEEG can clarify diagnosis therefore render the VEEG test superfluous to subgroups of patients. Prior routine epileptic EEG, coexistence of other seizure types, behaviors accompanying the investigated habitual behavior and abnormalities in other investigations (MRI, cognitive function and EEG) are the parameters that can predict diagnosis of epilepsy. Precise diagnosis in known epileptic patients as a result of VEEG is more likely for those with focal interictal epileptiform discharges in routine EEG.

Reduced fibrinolytic resistance in patients with factor XI deficiency. Evidence of a thrombin-independent impairment of the thrombin-activatable fibrinolysis inhibitor pathway.

UNLABELLED: Essentials Plasma of factor XI-deficient patients (FXI-dp) displays enhanced fibrinolysis. We investigated the role of thrombin activatable fibrinolysis inhibitor (TAFI) in 18 FXI-dp. FXI-dp generated less activated TAFI (TAFIa) on clotting challenge and were resistant to TAFIa. TAFI activation and TAFIa resistance correlated with bleeding score and bleeding phenotype. SUMMARY: Background Factor XI (FXI) deficiency, a rare disorder with unpredictable bleeding, has been associated with reduced fibrinolytic resistance as a result of abnormal fibrin density. Objective We investigated the involvement of thrombin-activatable fibrinolysis inhibitor (TAFI) in the increased lysability of FXI-deficient (FXI-def) clots and the role of thrombin. Patients/Methods Eighteen patients with FXI deficiency (1-58%) and 17 matched controls were investigated for fibrinolytic resistance to t-PA, thrombin generation, TAFI activation and response to TAFIa. Results When clotting was induced by 0.5 pm tissue factor (TF), FXI-def plasmas displayed less thrombin and TAFIa generation and shorter lysis time than controls. A 100-fold higher TF concentration (to bypass FXI) abolished the difference in thrombin generation but not in lysis time between patients and controls. Normalization of FXI levels by a FXI concentrate increased thrombin generation but had no effect on the lysis time of FXI-def plasma. Moreover, when clots were induced by purified thrombin and high concentrations of FXa inhibitor, FXI-def plasma still generated less TAFIa and displayed a shorter lysis time than controls. Finally, upon TAFIa addition, the lysis time of FXI-def plasma was prolonged significantly less than that of control plasma, suggesting a TAFIa resistance. TAFIa generation and TAFIa resistance were correlated with the bleeding score, displaying a considerable capacity to discriminate between patients with and without bleeding. Conclusions TAFI pathway impairment, largely caused by a hitherto unknown TAFIa resistance, appears to be one main cause of decreased fibrinolytic resistance in FXI deficiency and might be clinically useful for assessing the bleeding risk of FXI-def patients.

Baseline factor VIII plasma levels and age at first bleeding in patients with severe forms of von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. The age of bleeding onset is highly variable, also in patients with similar degree of severity. AIM: The primary aim of this study was to evaluate whether baseline factor VIII (FVIII) plasma levels correlate with age at first bleeding in patients with extremely low levels of VWF:RCo (<6 IU dL(-1) ). METHODS: One hundred and three patients with VWF:RCo <6 IU dL(-1) (6 VWD1, 73 VWD2 and 24 VWD3) undergoing a medical examination between September 2010 and September 2013 were included. The relationship between baseline FVIII levels and age at first bleeding was tested in a multivariable linear regression model, adjusting for sex. RESULTS: The median age at first bleeding was lower in patients with VWD3 than in those with severe forms of VWD1 or VWD2 (1 year vs. 7 and 8 years, respectively, P < 0.0001). A positive non-linear relationship between FVIII levels and age at first bleeding was found, the latter increasing by 5 years for every 10 IU dL(-1) increase of FVIII (ß = 4.95 [95% CI: 2.02-7.87]) until levels of 30 IU dL(-1) , after which the age increased slowly. This relationship was not found in VWD 2A and 2B. In 65 patients (63%) there was a more than 6-month delay between bleeding onset and VWD diagnosis, with no difference over decades. CONCLUSIONS: Baseline FVIII plasma levels influence the age at bleeding onset in VWD patients with extremely low levels of VWF:RCo, except in those with types 2A and 2B.

Long-term prophylaxis in severe factor VII deficiency.

INTRODUCTION: The spectrum of bleeding problems in FVII deficiency is highly variable and FVII levels and causative genetic mutations correlate poorly with the bleeding risk. Long-term prophylaxis is generally initiated in order to prevent subsequent CNS bleeding after a first event or in patients with other major/ life threatening/ frequent bleeding symptoms as gastrointestinal bleeding or hemarthrosis. However few data are available in the literature regarding FVII prophylaxis and clinical decisions cannot be based on evidence. AIMS: We report the data available in the literature on FVII prophylaxis and our personal experience regarding three patients affected by severe FVII deficiency. METHODS: Specific papers on long-term prophylaxis in severe FVII deficiency were identified using the database, PUBMED. RESULTS: The most frequent indications for long-term prophylaxis were CNS bleeding (58%), hemartrosis (15%) and GI bleeding (9%). Patients were treated with various dosages and frequency. Prophylactic treatment with 10-30U/kg (pdFVII) or 20-30mcg/kg (rFVIIa) twice or three times/weeks was described to be effective. CONCLUSIONS: In the literature and in our experience, prophylaxis can be considered in patients with severe FVII deficiency and severe bleeding phenotype. A dose of 10-30U/kg (pdFVII) or 20-30 microg/kg (rFVIIa) twice or three times/week is usually administrated, but dose and frequency can be tailored based on the clinical follow-up of the patients. Since hemarthrosis is a frequent manifestation, a suggestion to improve the outcomes of patients with severe FVII deficiency is to monitor joint condition in order to identify early arthropathy that could be another indication to start secondary prophylaxis.

Predictors of von Willebrand disease diagnosis in individuals with borderline von Willebrand factor plasma levels.

BACKGROUND: In individuals with borderline von Willebrand factor (VWF) plasma levels, second-level tests are required to confirm or exclude von Willebrand disease (VWD). These tests are time-consuming and expensive. OBJECTIVE: To assess which parameters can predict VWD diagnosis in individuals with borderline VWF levels (30-60 IU dL(-1) ). METHODS: Nine hundred and fifty individuals with bleeding episodes or abnormal coagulation test results were investigated with first-level tests (blood count, prothrombin time, activated partial thromboplastin time, blood clotting factor VIII, VWF ristocetin cofactor activity [VWF:RCo], and VWF antigen), and 93 (62 females and 31 males; median age, 28 years; interquartile range 15-44) had borderline VWF:RCo levels. All underwent second-level investigations to confirm or exclude VWD. A multivariable logistic regression model was fitted with sex, age, bleeding score, family history, VWF:RCo and ABO blood group as predictors, and used to predict VWD diagnosis. RESULTS: Forty-five of the 93 individuals (48%) had VWD (84% type 1). A negative linear relationship between VWF:RCo levels and risk of VWD diagnosis was present, and was particularly evident with blood group non-O [adjusted odds ratio 7.00 (95% confidence interval [CI] 1.48-33.11) for every 5 IU dL(-1) decrease in VWF:RCo]. The other variable clearly associated with VWD diagnosis was female sex (adjusted odds ratio 5.76 [95% CI 1.47-22.53]). The area under the receiver operating characteristic curve of the full logistic model was 0.89 (95% CI 0.82-0.95). CONCLUSIONS: In individuals with borderline VWF, the two strongest predictors of VWD diagnosis are low VWF:RCo levels (particularly in those with blood group non-O) and female sex. This predictive model has a promising discriminative ability to identify patients with borderline VWF levels who are likely to have VWD.

Management of orthopaedic surgery in rare bleeding disorders.

Knowledge regarding the management of orthopaedic surgery in patients with rare bleeding disorders (RBDs) is limited. Retrospective data collection and analysis of 35 orthopaedic procedures (6 minor and 29 major) carried out in 22 patients with RBD between 1982 and 2013. These surgeries were performed using heterogeneous regimens of hemostatic therapy, except for seven procedures performed with no hemostatic treatment in four patients with mild factor deficiency. Of the 28 procedures carried out with hemostatic treatment, nine (32%) were performed using replacement therapy with dosages of concentrates of the deficient factor aimed to achieve perioperative plasma levels judged to be compatible with hemostasis; three (11%) using factor replacement therapy associated with fresh frozen plasma (FFP); four (14%) using recombinant activated factor VII; four (14%) using virus inactivated plasma alone; three (11%) using virus inactivated plasma associated with desmopressin; one (4%) using FFP alone; and four (14%) procedures using tranexamic acid alone. Bleeding complications occurred in 7 of 35 procedures (20%) involving five patients. Prophylaxis of venous thromboembolism was performed only in one case with no excessive bleeding, but two patients not on thromboprophylaxis developed superficial thrombophlebitis. A satisfactory control of hemostasis was achieved in most patients. In some of those characterized by mild factor deficiency (FVII, FXI) hemostatic treatment could be avoided in some instances. The control of hemostasis combined with an adequate surgical technique is needed for the successful outcome of orthopaedic surgery in RBDs that requires the involvement of specialized haemophilia centres.

Orthopaedic surgery in patients with von Willebrand disease.

Patients with von Willebrand disease (VWD) may need orthopaedic surgery because of disabling chronic arthropathy due to recurrent joint bleeding. They may also require this surgery independently of their haemostasis disorder. Knowledge regarding the management of orthopaedic surgery in VWD is limited. Description of management of orthopaedic surgery in patients with VWD, based upon retrospective data collection and analysis of 32 orthopaedic procedures carried out over a period of 33 years in 23 patients was the aim of this study. Of 32 procedures, six were minor (three hand surgery, one foot surgery, two others) and 26 were major (seven joint replacements, nine arthroscopic procedures, two foot surgery, eight others). Twenty-two procedures were performed using replacement therapy with plasma-derived concentrates containing both factor VIII (FVIII) and von Willebrand factor (VWF). Two procedures in patients with acquired von Willebrand syndrome (AWVS) were performed using FVIII-VWF concentrates associated with intravenous immunoglobulins, or desmopressin plus tranexamic acid. Seven procedures were performed using desmopressin alone and one using intravenous immunoglobulins in AVWS. Bleeding complications occurred in seven procedures (22%). In one patient, an anti-VWF antibody was diagnosed after surgery. Anticoagulant prophylaxis of venous thromboembolism was implemented in four cases only and in two instances there was excessive bleeding. In conclusion, control of surgical haemostasis was achieved in most patients with VWD undergoing orthopaedic surgery. The control of haemostasis combined with an adequate surgical technique and early post-operative rehabilitation are warranted for the successful performance of orthopaedic surgery in VWD, which requires the involvement of specialized haemophilia centres.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.

BACKGROUND: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. OBJECTIVES: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. PATIENTS/METHODS: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. RESULTS: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. CONCLUSIONS: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.

Central nervous system bleeding in patients with rare bleeding disorders.

Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2 years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation.

Health-related quality of life and psychological well-being in elderly patients with haemophilia.

Many persons with severe haemophilia reach seniority thanks to effective treatment. There is no information on health-related quality of life (HRQoL) of these patients, who had lived for many years when regular replacement therapy was unavailable. Italian patients with severe haemophilia aged ≥65 years born in the 1940s or earlier were compared with men without bleeding disorders matched for age and geography. HRQoL was assessed via generic and disease-specific questionnaires. Potential associations with concomitant illnesses, orthopaedic status, physical functioning, cognitive status and depression were evaluated. In addition, the newly adapted HRQoL questionnaire specific for elderly persons with haemophilia (Haem-A-QoL(Eldlery)) was psychometrically tested and validated. Thirty-nine patients, aged 65-78 years, were investigated, 33 with haemophilia A and six with haemophilia B, and compared to 43 controls, aged 65-79 years. Chronic blood borne viral infections, hypertension and arthropathy were more frequent in patients, whereas hypercholesterolemia and cardiovascular diseases were more frequent in controls. Psychometric characteristics of Haem-A-QoL(Elderly) showed good to excellent values for reliability and validity. HRQoL was worse in patients at EQ-VAS, WHOQOL-BREF and WHOQOL-Old. The highest impairments were found in patients by means of the haemophilia-specific Haem-A-QoL(Elderly) in such dimensions as 'physical activity & leisure', 'physical health' and 'view'. A poor orthopaedic status was negatively associated with HRQoL. Compared to age-matched controls elderly patients with haemophilia had an impaired HRQoL in association with their health status. The newly developed Haem-A-QoL(Elderly) proved to be a reliable and valid instrument for HRQoL assessment in elderly haemophilia patients.

Dietary interactions and INR variability: retrospective evaluation of patients couples on oral anticoagulant therapy.

AIM: The association between dietary vitamin K intake and International Normalized Ratio (INR) variability in patients on oral anticoagulants treatment (OAT) has been evaluated in several studies. Changes in diet composition are known to lead to INR variability. We evaluated INR over time in married couples on OAT and non-cohabitant couples on OAT, to assess clinical relevance of the diet. METHODS: Among outpatients receiving OAT we selected 31 married couples. Husbands and wives were then matched by demographic and clinical characteristics to 31 men and 31 women on OAT not married nor living together. We analyzed 6,357 INR measurements recorded from February 1998 to November 2009. RESULTS: We found similar average INR values within married couples and also within non-cohabitant couples. Using mixed models we confirmed INR differences between seasons and the slightly lower INR in non-cohabitant couples compared to married couples; although statistically significant, they were of marginal clinical significance. CONCLUSION: Within both married and non-cohabitant couples, we did not find statistically or clinically significant differences between men and women over time. The lack of INR differences over time within non-cohabitant couples indicates that diet is not an important determinant of INR over time. Also seasonal INR variations and differences between married and non-cohabitant couples were of little practical importance.

Non-invasive tool for foetal sex determination in early gestational age.

Free foetal DNA in maternal blood during early pregnancy is an ideal source of foetal genetic material for non-invasive prenatal diagnosis. The aim of this study was to evaluate the use of free foetal DNA analysis at early gestational age as pretest for the detection of specific Y-chromosome sequences in maternal plasma of women who are carriers of X-linked disorders, such as haemophilia. Real-time quantitative PCR analysis of maternal plasma was performed for the detection of the SRY or DYS14 sequence. A group of 208 pregnant women, at different gestational periods from 4 to 12 weeks, were tested to identify the optimal period to obtain an adequate amount of foetal DNA for prenatal diagnosis. Foetal gender was determined in 181 pregnant women sampled throughout pregnancy. Pregnancy outcome and foetal gender were confirmed using karyotyping, ultrasonography or after birth. The sensitivity, which was low between 4th and 7th week (mean 73%), increased significantly after 7+1th weeks of gestation (mean 94%). The latter sensitivity after 7+1th week of gestation is associated to a high specificity (100%), with an overall accuracy of 96% for foetal gender determination. This analysis demonstrates that foetal gender determination in maternal plasma is reliable after the 9th week of gestation and it can be used, in association with ultrasonography, for screening to determine the need for chorionic villus sampling for prenatal diagnosis of X-linked disorders, such as haemophilia.

Gynaecological and obstetrical problems in women with different bleeding disorders.

The aim of this case-control study was to analyse the prevalence of gynaecological, obstetrical and other more general bleeding symptoms in 114 women affected by various inherited bleeding disorders, who were compared with 114 apparently healthy women. Retrospective information were collected by means of two specific questionnaires, one on gynaecological and obstetrical bleeding symptoms, with special focus on the presence of menorrhagia as defined by a pictorial blood loss assessment chart (PBAC); and the other on general bleeding symptoms, whose severity was graded by means of the bleeding score (BS). Compared to normal women, the whole group of women with inherited bleeding disorders had a higher prevalence of excessive bleeding at menarche (25% vs. 5%, P < 0.0001) and menorrhagia (59% vs. 46%, P = 0.06). Affected women also had a higher frequency than controls of general bleeding symptoms that scored as severe by a BS > or = 12 (49% vs. 0%, P < 0.0001). In affected women, the BS increased according to the severity of the haemostasis defect. In conclusions, the BS and the PBAC are simple tools to evaluate the severity of general bleeding symptoms and menorrhagia in women with inherited bleeding disorders. These instruments may help to identify those women for whom a therapeutic intervention is warranted.