Tailoring haemophilia A prophylaxis with BAY 81-8973: A case series.

BAY 81-8973 is an unmodified, full-length third generation recombinant factor VIII (rFVIII) which offers a more favorable pharmacokinetic (PK) profile, compared to its predecessor sucrose-formulated rFVIII (rFVIII-FS). We here report on a retrospective case series of nine patients affected by hemophilia A (HA), with variable disease severity, bleeding phenotype and comorbidities, to underline our clinical practice on prophylaxis with a recently introduced standard hall-life recombinant Factor VIII. The current case series highlights how the current clinical management of hemophilia is able to personalize treatment in several specific conditions like concomitant illnesses with thrombotic risk and allergic reactions.

Epithelioid hemangioendothelioma of the spine: results at seven years of average follow-up in a series of 10 cases surgically treated and a review of literature.

PURPOSE: To review a series of ten cases with epithelioid hemangioendothelioma of the spine, that have undergone surgery to describe clinical presentation, results and complications associated with surgical treatment; a review of literature reporting the main characteristics of the cases already published has been reported. METHODS: A review of patients affected by epithelioid hemangioendothelioma surgically treated by the senior author from 1995 to 2012 was carried out. Ten cases were identified and clinical and radiological characteristics, therapy, complications and survival were valued. RESULTS: Wide margin was achieved in two out of ten cases, marginal margin in seven and intralesional margin in one case. Average intraoperative blood loss was about 2,800 ml. Reported complications were one case of cord injury, one of dural tear, two cases of massive blood loss, a case of reconstruction failure, a wound dehiscence with deep infection, a pneumonia episode and a deep vein thrombosis with pulmonary embolism. Average follow-up was 84.4 months. Two local recurrences, after 32 and 37 months and two deaths for metastasis, after 14 and 36 months, were reported. Although several chemotherapy protocols are available for the treatment of EH of soft tissue, they are not relevant for the bone. CONCLUSIONS: Wide surgery is probably associated with a better prognosis. Indeed most deaths and local recurrences reported in literature happened after intralesional surgery or chemotherapy/RT alone. The presenting study suggests that the best approach to achieve long-term local control and a major survival could be wide surgery, nevertheless more cases series are necessary to verify survival rate.

Multilevel en bloc spondylectomy for tumors of the thoracic and lumbar spine is challenging but rewarding.

BACKGROUND: Over the years, en bloc spondylectomy has proven its efficacy in controlling spinal tumors and improving survival rates. However, there are few reports of large series that critically evaluate the results of multilevel en bloc spondylectomies for spinal neoplasms. QUESTIONS/PURPOSES: Using data from a large spine tumor center, we answered the following questions: (1) Does multilevel total en bloc spondylectomy result in acceptable function, survival rates, and local control in spinal neoplasms? (2) Is reconstruction after this procedure feasible? (3) What complications are associated with this procedure? (4) is it possible to achieve adequate surgical margins with this procedure? METHODS: We retrospectively investigated 38 patients undergoing multilevel total en bloc spondylectomy by a single surgeon (AL) from 1994 to 2011. Indications for this procedure were primary spinal sarcomas, solitary metastases, and aggressive primary benign tumors involving multiple segments of the thoracic or lumbar spine. Patients had to be medically fit and have no visceral metastases. Analysis was by chart and radiographic review. Margin quality was classified into intralesional, marginal, and wide. Radiographs, MR images, and CT scans were studied for local recurrence. Graft healing and instrumentation failures at subsequent followup were assessed. Complications were divided into major or minor and further classified as intraoperative and early and late postoperative. We evaluated the oncologic status using cumulative disease-specific and metastases-free survival analysis. Minimum followup was 24 months (mean, 39 months; range, 24-124 months). RESULTS: Of the 38 patients, 34 (89%) were alive and walking without support at final followup. Thirty-one (81%) had no evidence of disease. Two patients died postoperatively and another two died of systemic disease (without local recurrence). Only three patients (8%) had a local recurrence. There were 14 major complications and 22 minor complications in 25 patients (65%). Only one patient required revision of implants secondary to mechanical failure. Two cases of cage subsidence were noted but had no clinical significance. Wide margins were achieved in nine patients (23%), marginal in 25 (66%), and intralesional in four (11%). CONCLUSIONS: In patients with multisegmental spinal tumors, oncologic resections were achieved by multilevel en bloc spondylectomy and led to an acceptable survival rate with reasonable local control. Multilevel en bloc surgery was associated with a high complication rate; however, most patients recovered from their complications. Although the surgical procedure is challenging, our encouraging mid-term results clearly favor and validate this technique. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey.

Despite great advances in haemophilia care in the last 20 years, a number of questions on haemophilia therapy remain unanswered. These debated issues primarily involve the choice of the product type (plasma-derived vs. recombinant) for patients with different characteristics: specifically, if they were infected by blood-borne virus infections, and if they bear high or low risk of inhibitor development. In addition, the most appropriate treatment regimen in non-inhibitor and inhibitor patients compel physicians operating at the haemophilia treatment centres (HTCs) to take important therapeutic decisions, which are often based on their personal clinical experience rather than on evidence-based recommendations from published literature data. To know the opinion on the most controversial aspects in haemophilia care of Italian expert physicians, who are responsible for common clinical practice and therapeutic decisions, we have conducted a survey among the Directors of HTCs affiliated to the Italian Association of Haemophilia Centres (AICE). A questionnaire, consisting of 19 questions covering the most important topics related to haemophilia treatment, was sent to the Directors of all 52 Italian HTCs. Forty Directors out of 52 (76.9%) responded, accounting for the large majority of HTCs affiliated to the AICE throughout Italy. The results of this survey provide for the first time a picture of the attitudes towards clotting factor concentrate use and product selection of clinicians working at Italian HTCs.

Physical activity improved by adherence to prophylaxis in an Italian population of children, adolescents and adults with severe haemophilia A: the SHAPE Study.

BACKGROUND: Physical activity in people with haemophilia (PWH) reduces the development of severe arthropathy, but it must be performed after regular, proper prophylaxis. Strict adherence to treatment is crucial to achieving effectiveness and established outcomes. The primary aim of this study was to collect prospective data on adherence to prophylaxis for over 36 months. A secondary aim was to verify whether adherence correlates with physical activity. MATERIALS AND METHODS: Italian patients with severe haemophilia A treated on prophylaxis with octocog alfa were included in the study. Physical findings were assessed by the Haemophilia and Exercise Project (HEP)-Test-Q and the Early Prophylaxis Immunologic Challenge (EPIC)-Norfolk Physical Activity Questionnaire; orthopaedic status was assessed by the Hemophilia Joint Health Score (HJHS). Adherence was measured as percentage of empty vials returned with respect to the prescribed amount. RESULTS: Forty-two PWH were enrolled: 31% children, 21.4% adolescents, and 47.6% adults. Type, frequency and impact of physical activities differed among the three groups. The HEP-Test-Q showed the highest impairments in the domains "endurance" and "strength/co-ordination". Eight percent of patients were classified as adherent to prophylaxis. Among them, 50% had at least one bleeding episode in the year before enrolment; this percentage dropped during the three years of the study. While remaining stable in the "non-adherent" group, the HJHS score decreased in the "adherent" patients. The mean number of school/work days lost was lower in adherent patients (from 3.4±6.8 to 0.2±0.9) than in non-adherent ones. DISCUSSION: PWH with better orthopaedic scores reported better physical performance. Adherence to long-term prophylaxis proved to be high and correlated with a reduction in bleeds, target joints, school/work days lost, and with a performance improvement in endurance sports activities over time.

Prophylaxis therapy in paediatric patients with haemophilia: a survey of clinical management trends in Italy.

BACKGROUND: Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia. MATERIALS AND METHODS: A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the web-based survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium. RESULTS: A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score". DISCUSSION: This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients.

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study.

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

Four- and five- level en bloc spondylectomy for malignant spinal tumors.

STUDY DESIGN: Retrospective study. OBJECTIVE: To report results of 4- and 5-level en bloc spondylectomy (EBS) in the treatment of malignant spinal tumors. SUMMARY OF BACKGROUND DATA: EBS is widely used to avoid local recurrence in the treatment of spinal malignant tumors. Four- and 5-level EBS are aggressive procedures associated with complications and morbidity. METHODS: We conducted a retrospective study of all patients treated with minimum 4-level EBS. Patient and surgical data were noted. Radiographs, magnetic resonance images, and computed tomographic scans were studied for local recurrence, graft, and instrumentation failures at subsequent follow-up. Type of excision was classified into intralesional, marginal, and wide margins. Complications were divided into major or minor and were further classified as intraoperative, early, and late postoperative. At the last follow-up, the patients were classified as alive with no evidence of local or systemic disease, alive with evidence of local or systemic disease or both, dead with evidence of local disease, or systemic disease or both, and dead without evidence of local and systemic disease. RESULTS: Nine patients were identified who required a minimum 4-level en bloc resection. Five males and 4 females. Average age was 41.66 years (11-66). There were 8 primary malignant tumors: 3 chordomas, 3 osteosarcomas, 1 chondrosarcoma, 1 primary lung tumor and 1 metastatic alveolar soft part sarcoma. Six were operated with 4-level en bloc and 3 with 5 levels. The mean surgical time was 713 minutes and estimated blood loss was 4.5 L. Mean follow-up was 27.7 months (8-84). At the last follow-up, 6 patients were alive with no evidence of local or systemic disease, 1 alive with evidence of systemic disease, 1 dead with evidence of local disease, or systemic disease or both, and 1 DNLS. Only 1 (11%) patient had a local recurrence. Three patients with Frankel D had full neurological recovery. Histopathological assessment showed marginal margins in 7 patients and wide in 2. There were 9 major and 9 minor complications in 7 patients. Five of 7 patients (71%) with complications, had fully recovered from their complications at the last follow-up. CONCLUSION: Multilevel EBS, can be offered to a patient to prevent local recurrence of disease. Even in experienced hands, the risks of intra- and postoperative complications are high (78%). However, most of the patients with complications, recovered completely (71%). Although the surgery itself may prove beneficial, patients should be well informed regarding the morbidity associated with it. LEVEL OF EVIDENCE: 4.

Bone formation and resorption markers as diagnostic tools for bone metastases evaluation.

Bone metastases are a frequent complication of several types of cancers. Since bone metastases are difficult to diagnose with the current available approaches, there is a demand for new methods for assessing bone response. In this context, biochemical markers of bone remodeling may provide useful information on bone turnover that, in turn, may reflect disease activity in bone. In this study we tested a panel of bone remodeling markers (distinguishing between bone formation and bone resorption ones) in different groups of cancer patients, so as to evaluate the potential clinical role of the examined bone remodeling markers in the early diagnosis of metastases formation and progression. Among the bone resorption markers, tartrate resistant acid phosphatase 5b (TRAP5b) resulted the most specific for the metastatic tumor stage. Both the bone formation markers we analyzed displayed a direct correlation (positive for bone-specific alkaline phosphatase [BAP] and negative for osteocalcin [OC]) with tumor disease progression, ranging from healthy controls to primary tumor and, ultimately, to the metastatic stage. Taken together our results suggest that these markers can be valuable tools to be used, in parallel with traditional methods of metastases diagnosis, in order to monitor more in detail the pathological effect of metastases progression in bone tissue.