Haemophilia of the third age

Editoria

Haemophilia and ageing

Advances in the development of effective and safe treatments for haemophilia over the last 50 years have resulted in a significant increase in the life expectancy of persons with haemophilia (PWH). The management of this new cohort of middle‐aged and elderly PWH is challenging because of the opposing risks of haemophilia and age‐related cardiovascular disease and malignancy. Furthermore, this cohort of ageing PWH has the additional comorbidities of human immunodeficiency virus/hepatitis C and chronic haemophilic arthropathy. This article reviews the prevalence, underlying mechanisms and treatment strategies for managing these comorbidities. International collaboration is essential for registry data and further prospective trials to inform optimal evidence‐based management for this rare disorder in the future

Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy

Purpose: Neoadjuvant chemotherapy and pelvic surgery are significant risk factors for thromboembolic events. Our study objectives were to investigate the timing, incidence and characteristics of thromboembolic events during and after neoadjuvant chemotherapy and subsequent radical cystectomy in patients with muscle invasive bladder cancer. Materials and Methods: We performed a multi-institutional retrospective analysis of 761 patients who underwent neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer from 2002 to 2014. Median followup from diagnosis was 21.4 months (range 3 to 272). Patient characteristics included the Khorana score, and the incidence and timing of thromboembolic events (before vs after radical cystectomy). Survival was calculated using the Kaplan-Meier method. The log rank test and multivariable Cox proportional hazards regression were used to compare survival between patients with vs without thromboembolic events. Results: The Khorana score indicated an intermediate thromboembolic event risk in 88% of patients. The overall incidence of thromboembolic events in patients undergoing neoadjuvant chemotherapy was 14% with a wide variation of 5% to 32% among institutions. Patients with thromboembolic events were older (67.6 vs 64.6 years, p = 0.02) and received a longer neoadjuvant chemotherapy course (10.9 vs 9.7 weeks, p = 0.01) compared to patients without a thromboembolic event. Of the thromboembolic events 58% developed preoperatively and 72% were symptomatic. On multivariable regression analysis the development of a thromboembolic event was not significantly associated with decreased overall survival. However, pathological stage and a high Khorana score were adverse risk factors for overall survival. Conclusions: Thromboembolic events are common in patients with muscle invasive bladder cancer who undergo neoadjuvant chemotherapy before and after radical cystectomy. Our results suggest that a prospective trial of thromboembolic event prophylaxis during neoadjuvant chemotherapy is warranted.Peer reviewe

Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study

<p>Abstract</p> <p>Background</p> <p>This multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).</p> <p>Methods</p> <p>Patients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.</p> <p>Results</p> <p>A total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.</p> <p>Conclusions</p> <p>This study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00649545">NCT00649545</a>.</p

Choosing and using non-steroidal anti-inflammatory drugs in haemophilia

The management of pain and inflammation in haemophilic arthropathy is challenging due to the lack of anti-inflammatory analgesic agents perfectly suitable for this population. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of arthritis due to their analgesic and anti-inflammatory effects. Their use in persons with haemophilia (PWH), however, is limited due to increased risk of bleeding mainly from the upper gastrointestinal (UGI) tract. Cyclooxygenase-2 (COX-2) selective NSAIDs which have comparable analgesic effect to traditional NSAIDs (tNSAIDs) but with less UGI bleeding have been considered to be a suitable option for treatment of haemophilic arthropathy. COX-2 inhibitors, however, have an increased in the risk of cardiovascular (CV) disease. Although the atherosclerotic burden in PWH is similar to that in the general population, the risk of CV-related deaths is lower. PWH have a higher risk of GI bleeding and lower risk of thrombotic disease compared to general population. Therefore, when PWH require anti-inflammatory/analgesic agents, it seems reasonable to use lowest dose of COX-2 inhibitors for the shortest period together with a proton pump inhibitor. Helicobacter pylori infection should be tested for and eradicated prior to starting NSAID treatment in PWH. Furthermore, regular blood pressure and renal function test monitoring is required during COX-2 inhibitor treatment

Correction to: Putting genome-wide sequencing in neonates into perspective

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article

Co-morbidity in adult haemophilia patients

Haemophilia is an X-linked inherited bleeding disorder, caused by a deficiency of clotting factor VIII or IX. Due to the availability of treatment with clotting factor concentrates, life expectancy of haemophilia patients is now approaching that of the general population. Haemophilia patients are therefore increasingly confronted with age-related types of co-morbidity, such as cardiovascular disease (CVD) and malignancies. In two retrospective evaluations we performed in large cohorts of haemophilia patients, however, the cumulative incidence of acute ischemic cardiovascular events appeared to be lower in patients with severe haemophilia than in the general age-matched male population, while the occurrence of angina pectoris was similar. This suggests that (very) low clotting factor levels might have a protective effect against acute thrombotic arterial occlusion, but not against atherosclerosis development. Baseline data of a prospective study on CVD occurrence and risk factors in over 700 haemophilia patients showed that the prevalence of hypertension was significantly increased in haemophilia patients compared with the general population. Moreover, haemophilia patients had more unfavourable overall CVD risk profiles. The prospective follow-up of these patients will have to determine whether the occurrence of cardiovascular events is indeed lower than in the general population, despite the more unfavourable risk profiles. In our retrospective analyses, the occurrence of malignancies (other than hepatocellular carcinoma) was similar in haemophilia patients and the general population. Unfortunately, in the past, many patients with inherited bleeding disorders were infected with hepatitis C (HCV) and/or HIV due to the use of contaminated clotting factor concentrates. HCV can be ‘silently’ present in the liver for several decades, but can eventually lead to liver fibrosis, liver cirrhosis and hepatocellular carcinoma. The aim of antiviral treatment is to eradicate HCV and stop progression of liver damage. In a large cohort of HCV infected patients with inherited bleeding disorders with over 30 years of follow-up, we found that a significant proportion of patients had developed end-stage liver disease (ESLD) and that hepatocellular carcinoma appeared to be an increasing problem. After successful antiviral treatment, however, hardly any cases of ESLD occurred. Antiviral treatment must be administered for 24-48 weeks and has many side-effects, of which depression seems to be underestimated. Fortunately, these side-effects are mostly transient. Liver stiffness measurements (LSM) using Fibroscan® is a relatively new, non-invasive method to determine the extent of liver damage and help guide treatment decisions and determine prognosis. When used longitudinally, LSM appears to behave similarly to serial liver biopsies in patients with chronic HCV infection, but interpretation of the results can be difficult in individual patients. In patients who underwent successful antiviral treatment, LSM showed that this treatment has a large and lasting beneficial effect on the extent of liver damage. The impact of HIV infection has decreased significantly after the introduction of highly-activated antiretroviral treatment (HAART) in the 1990s. Before this time, many HIV infected haemophilia patients died of AIDS. HAART can, however, have serious side-effects, such as diabetes mellitus and possibly an increased risk of spontaneous intracranial bleeding

Prognosis and treatment of invasive bladder cancer

This thesis focuses on prognosis and treatment of invasive bladder cancer (BC). The concept “invasive BC” comprises two entities: muscle-invasive BC (MIBC) and T1 bladder cancer, which invades the lamina propria and not the muscularis propria. T1 bladder cancer T1 bladder cancer can either be treated with transurethral resection and intravesical instillations or with radical cystectomy. Treatment depends on the risk of progression to MIBC and/or metastases. We performed two multicenter studies aimed at identifying prognostic factors for T1 bladder cancer as these are currently lacking. We found that the “old” WHO1973 grade classification was prognostic for progression and cancer-specific mortality, while the “new” WHO2004 classification was not. This contradicts with current recommendations by the American Urological Association. We also explored the prognostic value of two substage classifications for T1 bladder cancer and found that Metric substage, based on the diameter of the invasive tumour component, was highly prognostic for progression and cancer-specific mortality. Combined with WHO1973 grade, this substage classification could aid in treatment decision making for T1 bladder cancer. Muscle-invasive bladder cancer: Systemic treatment For MIBC, standard treatment consists of radical cystectomy (RC) following neoadjuvant chemotherapy (NAC). A complete pathologic tumour response to NAC significantly improves survival. The second part of this thesis aimed at predicting pathologic MIBC response by means of response imaging and by means of genomic tumour marker analysis prior to NAC. We found that 18F-FDG-PET/CT imaging could be used to distinguish responders from non-responders. However, 18F-FDG-PET/CT could not be used to accurately identify complete pathologic response. Results on genomic tumour markers were more promising. We found that ERBB2 (HER2) missense mutations were highly predictive for a complete pathologic BC response to chemotherapy. If these findings are confirmed by future studies, they will ultimately aid in patient selection for NAC. Muscle-invasive bladder cancer: locoregional treatment RC comprises surgical resection of the bladder, prostate or uterus / anterior vaginal wall / ovaries, and pelvic lymph node dissection. It is associated with high morbidity, a long period for recovery and lasting functional impairment. The third part of this thesis included a study on organ-preserving therapy for a selected group of MIBC patients. Treatment comprised NAC, pelvic lymph node dissection and combined external beam radiation with panitumumab (an EGFR inhibitor) administration. Toxicity was non-inferior to the commonly used cisplatin/radiotherapy combination and response rates were promising. Prostate-sparing cystectomy (PSC) is an option for a selected group of patients who wish to preserve sexual function. PSC is debated for fear of incomplete resection and incidental prostate carcinoma. Our two-centre study in this thesis confirms that PSC oncologic outcomes are acceptable, provided that extensive work-up including preoperative prostatic urethral biopsies or per-operative frozen section analysis is performed. Future research should validate the patient’s perception of functional advantages by means of quality of life questionnaires. Conclusion The work presented in this thesis may aid in risk stratification, therapy selection and ultimately survival of bladder cancer patients. Organ-preserving therapies and critical appraisal of surgical boundaries should reduce morbidity and functional loss

Prognosis and treatment of invasive bladder cancer

This thesis focuses on prognosis and treatment of invasive bladder cancer (BC). The concept “invasive BC” comprises two entities: muscle-invasive BC (MIBC) and T1 bladder cancer, which invades the lamina propria and not the muscularis propria. T1 bladder cancer T1 bladder cancer can either be treated with transurethral resection and intravesical instillations or with radical cystectomy. Treatment depends on the risk of progression to MIBC and/or metastases. We performed two multicenter studies aimed at identifying prognostic factors for T1 bladder cancer as these are currently lacking. We found that the “old” WHO1973 grade classification was prognostic for progression and cancer-specific mortality, while the “new” WHO2004 classification was not. This contradicts with current recommendations by the American Urological Association. We also explored the prognostic value of two substage classifications for T1 bladder cancer and found that Metric substage, based on the diameter of the invasive tumour component, was highly prognostic for progression and cancer-specific mortality. Combined with WHO1973 grade, this substage classification could aid in treatment decision making for T1 bladder cancer. Muscle-invasive bladder cancer: Systemic treatment For MIBC, standard treatment consists of radical cystectomy (RC) following neoadjuvant chemotherapy (NAC). A complete pathologic tumour response to NAC significantly improves survival. The second part of this thesis aimed at predicting pathologic MIBC response by means of response imaging and by means of genomic tumour marker analysis prior to NAC. We found that 18F-FDG-PET/CT imaging could be used to distinguish responders from non-responders. However, 18F-FDG-PET/CT could not be used to accurately identify complete pathologic response. Results on genomic tumour markers were more promising. We found that ERBB2 (HER2) missense mutations were highly predictive for a complete pathologic BC response to chemotherapy. If these findings are confirmed by future studies, they will ultimately aid in patient selection for NAC. Muscle-invasive bladder cancer: locoregional treatment RC comprises surgical resection of the bladder, prostate or uterus / anterior vaginal wall / ovaries, and pelvic lymph node dissection. It is associated with high morbidity, a long period for recovery and lasting functional impairment. The third part of this thesis included a study on organ-preserving therapy for a selected group of MIBC patients. Treatment comprised NAC, pelvic lymph node dissection and combined external beam radiation with panitumumab (an EGFR inhibitor) administration. Toxicity was non-inferior to the commonly used cisplatin/radiotherapy combination and response rates were promising. Prostate-sparing cystectomy (PSC) is an option for a selected group of patients who wish to preserve sexual function. PSC is debated for fear of incomplete resection and incidental prostate carcinoma. Our two-centre study in this thesis confirms that PSC oncologic outcomes are acceptable, provided that extensive work-up including preoperative prostatic urethral biopsies or per-operative frozen section analysis is performed. Future research should validate the patient’s perception of functional advantages by means of quality of life questionnaires. Conclusion The work presented in this thesis may aid in risk stratification, therapy selection and ultimately survival of bladder cancer patients. Organ-preserving therapies and critical appraisal of surgical boundaries should reduce morbidity and functional loss