Comparison of analgesic consumption of hemophilic and non-hemophilic patients in knee arthroplasty.

BACKGROUND: Hemophilia is a rare hereditary bleeding disorder that develops as a result of factor VIII or IX deficiency. Long-term complications of hemophilia such as arthropathy, synovitis, and arthritis can lead to the development of recurrent chronic pain. Pain is therefore a critical aspect of hemophilia. The gold standard treatment for end-stage hemophilic knee arthropathy is total knee arthroplasty (TKA). The hypothesis of this study was that after knee replacement surgeries that cause severe post-operative pain, hemophilia patients with chronic analgesic consumption may experience higher levels of pain than non-hemophilic patients, and use more opioid and non-opioid drugs. METHODS: This retrospective study included 82 patients who were hemophilic and non-hemophilic TKA patients operated under general anesthesia. Seventy-three patients were evaluated and divided into two groups according to the diagnosis of hemophilia: 36 patients were investigated in the hemophilic group and 37 patients in the non-hemophilic group. RESULTS: Post-operative tramadol consumption (p=0.002) and pethidine consumption (p=0.003) were significantly higher in the group hemophilia. The length of stay in the hospital was also significantly longer in the hemophilic group (p=0.0001). CONCLUSION: In the light of these informations, we think that acute post-operative pain management of hemophilia patients should be planned as personalized, multimodal preventive, and pre-emptive analgesia.

Desires vs. conditions: A qualitative study exploring the factors affecting the place of death of child with cancer in Turkey.

OBJECTIVE: The purpose of this study was to describe factors affecting the place of death of children with cancer at the end of life. METHODS: The descriptive phenomenological approach was used. Eighteen mothers who lost their children to cancer participated in in-depth interviews. Data were analysed using MAXQDA software version. Codes and categories were developed inductively from participants' narratives. RESULTS: The factors affecting the place of death of children were categorised into two main themes: (1) desires and (2) conditions. Most of the mothers reported that their deceased children wanted to be with their families at the end of life and they wanted to go home. The conditions related to health services were defined as the barriers to the death of their children in the places of death preferred by the mothers. CONCLUSION: The desire to be close to the child was the main factor affecting the parents' decisions. The findings revealed the prevailing circumstances in the death place decision beyond parental desires. These were the child's health conditions, physical conditions of hospitals, and the lack of home care and paediatric palliative care services, which were factors related to the system, and the lack of other options for parents.

Gene therapy in haemophilia: literature review and regional perspectives for Turkey.

Haemophilia is an X-linked lifelong congenital bleeding disorder that is caused by insufficient levels of factor VIII (FVIII; haemophilia A) or factor IX (FIX; haemophilia B) and characterized by spontaneous and trauma-related bleeding episodes. The cornerstone of the treatment, factor replacement, constitutes several difficulties, including frequent injections due to the short half-life of recombinant factors, intravenous administration and the risk of inhibitor development. While extended half-life factors and subcutaneous novel molecules enhanced the quality of life, initial successes with gene therapy offer a significant hope for cure. Although adeno-associated viral (AAV)-based gene therapy is one of the most emerging approaches for treatment of haemophilia, there are still challenges in vector immunogenicity, potency and efficacy, genotoxicity and persistence. As the approval for the first gene therapy product is coming closer, eligibility criteria for patient selection, multidisciplinary approach for optimal delivery and follow-up and development of new pricing policies and reimbursement models should be concerned. Therefore, this review addresses the unmet needs of current haemophilia treatment and explains the rationale and principles of gene therapy. Limitations and challenges are discussed from a global and national perspective and recommendations are provided to adopt the gene therapies faster and more sufficient for the haemophilia patients in developing countries like Turkey.

A Challenge for Hemophilia Treatment: Hemophilia and Cancer.

BACKGROUND: The risk of developing cancer increases with age and also adverse environmental conditions. The same holds true in the aging people with hemophilia (PwH). Furthermore, cancer is an important challenge for physicians working in multidisciplinary hemophilia care centers. AIM: Here, the authors report 7 hemophiliacs with malignancies diagnosed and managed at our center. STUDY DESIGN: Hemophilia A and B were included. METHOD: Patients with mild, moderate, or severe hemophilia A or B, who were followed-up in our center between January 1999 and December 2018 were included in the study. A total of 470 PwH (391 Hemophilia A and 79 Hemophilia B) were followed in this time period. RESULTS: With a minimum 1 and maximum 20 years (median: 11.5 y) of the following time, 7 of 470 (1.48%) PwH were diagnosed with cancer. The diagnosed cancer types were acute lymphoblastic leukemia, acute myeloid leukemia, thyroid cancer, rectum cancer, malign melanoma, basal cell carcinoma, and gastric cancer. All patients except patients with leukemia had major surgical intervention and the hemostasis control was provided on the basis of institutional protocols. At the end of the study, all of the patients were alive besides the patient with acute myeloid leukemia. CONCLUSIONS: Nowadays, the management of PwH has improved immensely and the life span has progressively become similar to healthy male individuals. For accurate improvement and standardizing care, prospective data collection on the epidemiology of cancer in PwH is an important tool.

Acute Complications and Survival Analysis of Childhood Acute Lymphoblastic Leukemia: A 15-year Experience.

BACKGROUND: We evaluated the acute complications that occurred during the treatment of childhood acute lymphoblastic leukemia (ALL) and documented the survival rates of children with ALL. MATERIALS AND METHODS: We retrospectively evaluated 110 children with a diagnosis of ALL treated with the Children's Oncology Group protocol from 1999 to 2014. The demographic, clinical, and laboratory data of 110 patients and acute complications of eligible and evaluable 105 patients were recorded. RESULTS: Of the 110 patients, 65 were male and 45 were female. The mean age at admission was 8.3 ± 5.2 years. Ninety-seven patients (88.2%) had been diagnosed with pre-B-cell ALL, 11 (10%) with T-cell ALL, 1 (0.9%) with mixed phenotype acute leukemia, and 1 (0.9%) with mature B-cell acute leukemia. Of the 110 patients, 40 (36.3%) were in the standard-risk group and 70 (63.7%) were in high-risk group. Of the 110 patients, 105 had been followed up regularly and evaluated for acute complications. Infection was the most common complication (n = 93; 88.5%), followed by gastrointestinal (n = 29; 27.6%), neurologic (n = 28; 26.6%), metabolic/endocrine (n = 16; 15.2%), drug-related hypersensitivity (n = 16; 15.2%), avascular necrosis (n = 13; 12.3%), thrombotic (n = 11; 10.4%), severe psychiatric (n = 2; 1.9%), and various other (n = 12; 11.4%) complications. Of the 110 patients, 98 were assessed in terms of survival analysis. The 5- and 10-year overall survival rates were both 85.9% (standard error [SE], 3.6%). The relapse-free survival rates at 1, 3, and 5 years were 97.9% (SE, 1.5%), 91.3% (SE, 3%), and 86.3% (SE, 3.7%), respectively. CONCLUSION: Childhood ALL, although categorized as curable malignancy owing to the improvements in treatment strategies in recent years, can cause acute complications affecting various systems. Thus, patients should be treated and followed up by multidisciplinary medical teams with high expertise.

Clinical problems and surgical interventions in inherited factor VII deficiency.

AIM: Factor VII deficiency is one of the hereditary coagulation disorders that has autosomal reccessive inheritance and is observed relatively frequently (1/500 000). It is clinically heterogeneous, and may be asymptomatic or lead to life-threatening bleeding. Thus, there is no correlation between FVII activity and clinical findings. Plasma-derived and recombinant FVII concentrates are currently used for treatment. In countries where access to these products is lacking, fresh frozen plasma and prothrombin complex concentrates are also used, though they contain low amounts of factor FVII. In this study, we present the clinical properties, treatments, and surgical interventions used in patients followed up in our clinic with a diagnosis of factor FVII deficiency. MATERIAL AND METHODS: Patients who were diagnosed as FVII deficiency in Division of Pediatric Hematology and Oncology between July 1997 and July 2018, were included in the study. The patients' demographic characteristics, symptoms at presentation, PT, aPTT, and FVII values, types of bleeding, and treatments and surgical interventions used, were recorded. The bleedings observed in the patients were classified by severity as asymptomatic, minor, and major. RESULTS: A total of 18 patients (7 girls and 11 boys) with a mean age of 9.64±9.63 years were included in the study. The mean follow-up time was found as 78.06±54.4 months. When the bleedings were classified clinically, no bleeding was observed in eight patients (44.4%). The factor FVII level was found as <10% in three of these eight asymptomatic patients and above 20% in the others. Minor bleeding was observed in nine patients (50%) and major bleeding was observed in one patient. When the patients were classified as asymptomatic and symptomatic, there was no significant difference between the two groups in terms of FVII level (p=0.57). A total of 21 surgical interventions were performed in 14 (78%) of 18 patients who were being followed up. CONCLUSION: FVII deficiency has a very wide spectrum both clinically and in terms of approach to surgical interventions. Therefore, patients with factor FVII deficiency should be followed up and treated by comprehensive care centers with close collaboration of multiple disciplines.

Low-dose Immune Tolerance Induction in Hemophilia: A Single-Center Experience.

INTRODUCTION: The development of inhibitors against factors VIII/IX is the most serious complication in hemophilia. The best treatment strategy for inhibitor eradication is immune tolerance induction (ITI). The aim of this study was to evaluate patients treated with low-dose ITI at a single center with limited resources. MATERIALS AND METHODS: In total, 29 (8.05%) of 360 hemophilia A patients exhibited inhibitors. The data from hemophilia patients with inhibitors undergoing ITI between 1999 and 2017 were collected and analyzed. RESULTS: Seventeen ITIs administered to 15 hemophilia A patients with inhibitors were analyzed, and the data from 13 ITIs conducted in 12 patients were evaluated. The median age at ITI onset was 10 years (range: 1.25 to 52 y). The maximum inhibitor titer before ITI was 30 Bethesda Units (BU) (range: 4.48 to 135), and the median inhibitor titer was 1.25 BU (range: 0 to 5.6) at the onset of ITI. The median time interval between the inhibitor development and ITI onset was 60 months (range: 7 to 264 mo). The median inhibitor titer during ITI was 3.4 BU (range: 0 to 158.7). At the end of the treatment, 4 of the 12 patients (33.3%) exhibited a complete response, 4 (33.3%) had partial responses (with continuing ITI), and 4 (33.3%) exhibited ITI failure. CONCLUSIONS: Treatment of hemophilia patients with inhibitors is challenging, and ITI is the best treatment method; however, a high-dose daily ITI regimen cannot be given to every patient in every country due to its high cost. Our results show that low-dose ITI may be a choice for selected patients with inhibitors.

Cutaneous adverse event associated with vemurafenib in a 3-year-old pediatric patient with BRAF mutation-positive metastatic melanoma and factor X deficiency.

Malignant melanoma is very rare in childhood. The approach to diagnosis and treatment in children has been adopted from adult guidelines. Vemurafenib is indicated in adults with BRAF V600 mutation-positive stage IIIc/IV melanoma and causes cutaneous adverse events. We report on a 3-year-old child with recurrent, metastatic (bone) BRAF mutation-positive melanoma. He also had severe factor X deficiency. Four days after vemurafenib treatment, bilateral palpebral edema and violet-colored hyperpigmentation were observed. There was no objective response to vemurafenib; however, bone pain regressed slightly. Our patient is the youngest patient who received vemurafenib for BRAF V600 mutation-positive metastatic melanoma in the literature.

Vincristine, irinotecan, and temozolomide treatment for refractory/relapsed pediatric solid tumors: A single center experience.

BACKGROUND: Although the survival of pediatric cancer has increased dramatically in the last decades, the survival of refractory, relapsed, and metastatic cases is still dismal. The combination of irinotecan and temozolomide has shown activity against refractory/relapsed pediatric solid tumors. METHOD: Thirty-four children with refractory/relapsed solid tumors who had previously been heavily pretreated and who were given vincristine, irinotecan, and temozolomide as third- or further line chemotherapy during 2004-2015 were evaluated. RESULTS: Patients were diagnosed with Ewing sarcoma (n = 15), rhabdomyosarcoma (n = 8), neuroblastoma (n = 8), osteosarcoma (n = 2), and Wilms' tumor (n = 1). Thirty patients presented with disease progression on therapy and the other four presented with relapsing. A total of 141 cycles were administered. Radiotherapy was used in 17 patients and surgery in 4 as local therapy. Among all patients, 6 had complete response, 3 had partial response, 14 had stable disease, and 11 had progressive disease. The objective response was 26.4% (complete response + partial response) and median survival duration was six months. The first and second year overall survival rates were 22.3% and 16.8%. The objective response in Ewing sarcoma patients was 40%. Diarrhea was the most common toxicity and 14 (10%) courses were associated with grade 3-4 diarrhea. CONCLUSIONS: In heavily pretreated patients with refractory/relapsed solid tumors, the vincristine, irinotecan, and temozolomide regimen seemed promising in Ewing sarcoma patients and was well tolerated.

Simultaneous Presentation of Wilms' Tumor and Contralateral Ganglioneuroma in a Child: Case Report and Literature Review.

We demonstrate a 4-year-old girl who presented with progressive, asymmetrical, firm abdominal distention and was diagnosed with synchronous Wilms' tumor and left para-aortic ganglioneuroma (GN). Although synchronous tumors in the pediatric population are commonly associated with malignancy-predisposing syndromes, the patient in question was found to be otherwise healthy and had no clinical evidence nor family history of a syndrome. This case is the second one in the literature diagnosed with synchronous presentation of Wilms' tumor and GN in a previously healthy child. In addition, a GN foci presumed to be a previous metastasis of a neurogenic tumor that subsequently matured to GN was depicted within a left para-aortic lymph node. We aimed to emphasize an extremely rare synchronous occurrence of these embryonal tumors, increase the awareness of physicians, and discuss the radiologic differential diagnosis and management.

Respiratory viral infection`s frequency and clinical outcome in symptomatic children with cancer: A single center experience from a middle-income country.

Büyükkapu-Bay S, Kebudi R, Görgün Ö, Mese S, Zülfikar B, Badur S. Respiratory viral infection`s frequency and clinical outcome in symptomatic children with cancer: A single center experience from a middle-income country. Turk J Pediatr 2018; 60: 653-659. In developing countries, acute respiratory tract infections are a significant cause of morbidity and mortality in children, particularly in pediatric cancer patients. A majority of these illnesses are precipitated by viral infections. In our country, studies were conducted on the single respiratory viral infection in a pediatric hematology-oncology unit; however, the analysis of respiratory viral infections in children with cancer is lacking. The present study aimed to provide analysis of multiple respiratory viral infections and clinical outcome in children with cancer who receive chemotherapy and show signs and symptoms of respiratory tract infections. During January, 2014 and January, 2015 children with cancer under treatment who presented with respiratory tract infections were assessed for viruses by using multiplex real-time reverse transcription polymerase chain reaction (rRT-PCR). Specimens were collected by nasal swabbing at in-patient and out-patient clinics. Overall, 72 samples of respiratory tract infection episodes, collected from children with cancer were evaluated with the simultaneous detection of 20 respiratory viruses. A respiratory viral pathogen was obtained in 56.9% samples. Rhinovirus (24.3%) and co-infection with two viruses (19.5%) were the most frequently isolated pathogens. There were four (9.6%) samples of severe pneumonia. Patients with febrile neutropenic episodes and pneumonia were hospitalized and treated with broad-spectrum antibiotics. Other non-neutropenic and mild respiratory tract infections were treated with supportive care as outpatient procedures. There were no deaths. Because there are no effective antiviral agents for certain respiratory viruses, infection control and early diagnosis are crucial in preventing the spread of infection. Clinical findings and serological results of viral respiratory tract infections help us to accurately determine the treatment approach and avoid the unnecessary use of antibiotics.

Surgery in patients with von Willebrand disease.

Von Willebrand disease (vWD) is the most common inherited bleeding disorder. The biggest challenge in the management of vWD is the difficulty in performing surgical procedures because of bleeding. Treatment guidelines recommend the use of pure von Willebrand factor or von Willebrand factor/factor VIII (vWF/FVIII) concentrate in patients with type 2 or type 3 vWD undergoing surgery, in patients with type 1 vWD undergoing surgery who are unresponsive, and in patients for whom desmopressin acetate is contraindicated. However, there is no consensus on the dosage and optimum levels of these factors to date. The aim of this study was to evaluate the perioperative management of patients with vWD during surgical procedures. Data pertaining to surgical procedures performed at our center from 2003 to 2014 were analyzed retrospectively. All operations, except one appendectomy, were elective, and a plan for the management of hemostasis was prepared for each patient. During this period, 37 surgical procedures (major, minor, and dental) were performed in 23 patients with vWD. Complications occurred in four out of 37 procedures (10.8%). No deaths or life-threatening bleeding occurred during any of the operations and no thromboembolic events were observed. The results from this retrospective study indicate that surgery can be safely performed by providing adequate and timely hemostasis during and after the procedure in patients with vWD. Perioperative and postoperative bleeding complications are rare when patients are closely and carefully monitored.

The Effectiveness of a New Hemostatic Agent (Ankaferd Blood Stopper) for the Control of Bleeding following Tooth Extraction in Hemophilia: A Controlled Clinical Trial.

OBJECTIVE: To assess the hemostatic efficacy of a new local hemostatic agent, Ankaferd Blood Stopper (ABS), for the control of bleeding following tooth extraction in hemophiliacs. MATERIALS AND METHODS: Simple tooth extractions were performed in 27 hemophilia A patients. In the treatment group (n=17) local hemostasis was achieved via application of ABS to the extraction sockets, whereas in the control group (n=10) local hemostasis was achieved via direct packing with gauze. RESULTS: In all, 57 (21 primary and 36 permanent) teeth extractions were performed in 27 hemophilia A patients. There were no significant differences in age or factor VIII level distribution between the 2 groups (p>0.05). The most significant clinical difference between the groups was associated with the use of ABS; those in the treatment group had significantly shorter duration of bleeding (p=0.002). CONCLUSION: This is the first study to evaluate the efficacy of ABS for the control of bleeding following tooth extraction in hemophiliacs. ABS can be considered an alternative local hemostatic agent for reducing clotting factor concentrates in hemophilia patients. CONFLICT OF INTEREST: None declared.

The evaluation of fibrin sealants and tissue adhesives in oral surgery among patients with bleeding disorders.

OBJECTIVE: The aim of this study was to evaluate the efficiency of two local hemostatic agents administered with apreoperative dose of replacement therapy in patients with bleeding disorders undergoing oral surgery. MATERIAL AND METHODS: The study included 21 patients that were randomly divided into 3 groups. Patients in Group1 (n = 7) received preoperative replacement therapy and postoperative fibrin sealant applied to the surgical site. Patientsin Group 2 (n = 7) received preoperative replacement therapy and postoperative tissue adhesive applied to the surgicalsite. Patients in Group 3 (n = 7) were given replacement therapy pre- and postoperatively. RESULTS: Postoperative bleeding was not observed in 17 of the 21 patients, including 5 in Group 1 (71.42%), 6 in Group2 (85.71%), and 6 in Group 3 (85.71%). Hemorrhagic complications occurred in only 4 of the 21 patients. CONCLUSION: The use of fibrin sealant and tissue adhesive was beneficial, as they reduced the level of factor concentratesused for replacement therapy and resulted in rapid hemostasis at the surgical site, facilitating the ability to performserial surgical procedures concurrently.

Metastatic mandibular neuroblastoma: a rare cause of tooth mobility.

Neuroblastoma (NBL), a malignant embryonic tumor derived from neural crest cells, is the most common tumor worldwide among children less than 1 year of age. Metastasis to the mandible is uncommon. This article reports the case of a 15-month-old male diagnosed with NBL with bone metastasis including the mandible which resulted in severe tooth mobility. Dentists or pediatricians should consider the primary or metastatic tumors of the maxillofacial region in the differential diagnosis in children presenting with premature loss of teeth related to tooth mobility.

The genotoxic effects in lymphocyte cultures of children treated with radiosynovectomy by using yttrium-90 citrate colloid.

UNLABELLED: The aim of this study was to investigate the genotoxic effect on the peripheral blood lymphocytes potentially induced by yttrium-90 citrate colloid (Y-90) in children who were undergoing radiosynovectomy for hemophilic synovitis, using chromosomal aberration analysis (CA) and the micronuclei (MN) assay for detecting chromosomal aberrations, as well as the sister chromatid exchanges (SCE) technique for assessed DNA damage. MATERIALS AND METHODS: Cytogenetic analyses were undertaken in 18 boys (mean age, 14.5 +/- 2.1 years) with hemophilic synovitis who underwent radiosynovectomy with Y-90. CA, MN, and SCE were evaluated just prior to, then at 2 and 90 days following radiosynovectomy from the peripheral lymphocytes of the children. An activity of 185 MBq of Y-90 was injected into the 18 knee joints under aseptic conditions. To check the possibility of leakage from the joint and its migration within the body, the patients underwent scanning under a dual-headed gamma camera at the hours 2 and 48 following the procedure. RESULTS: The procedure was well tolerated in all the children, and there was no extra-articular activity owing to extra-articular leakage of radioactive material in whole-body imaging. The mean frequency of CA in lymphocytes determined prior to the onset of therapy (0.31 +/- 0.48/900 cells) was not significantly increased, in comparison to the control values obtained 2 (0.30 +/- 0.48/900 cells) and 90 days (0.15 +/- 0.37/900 cells) after radiosynovectomy (p = 1.0 and 0.625, respectively). We observed that MN frequency was mildly increased in lymphocytes 2 days after therapy (8.30 +/- 1.89 MN/1000 binucleated cells vs. 9.23 +/- 1.79 MN/1000 binucleated cells; p = 0.013). But there was no significant difference between the baseline and the day 90 control levels of MN (p = 0.196). In the analysis of SCE frequency, there were no significant differences between the baseline (8.11 +/- 0.77) and the control analysis performed 2 and 90 days following radiosynovectomy (8.18 +/- 0.77 and 8.07 +/- 0.74; p = 0.710 and 0.662, respectively). CONCLUSIONS: The results of this study indicated that high radiation doses are not obtained by peripheral lymphocytes of children who undergo Y-90 radiosynovectomy and, therefore, they contradict a high cancer risk.

Rhinoplasty and hemophilia A.

Major surgical procedures can be performed safely for hemophiliacs provided the clotting factors are adequate. However, rhinoplasty, an elective facial procedure, has not yet been evaluated in this group of patients. The authors present a hemophilia A patient who underwent rhinoplasty for cosmetic reasons.

Circumcision in hemophilia: a cost-effective method using a novel device.

BACKGROUND/PURPOSE: The authors conducted a prospective clinical study to see whether the need for and the cost of factor substitution after circumcision can be reduced using a novel device for bloodless circumcision in boys with hemophilia. METHODS: Forty-five boys with hemophilia (age range, 1.5 to 25 years; median age, 11; 40 with hemophilia A, 5 with hemophilia B; weight range, 9 to 75 kg; median weight, 30 kg) were circumcised in our department between 1996 and 2001. Severity of the disease was mild in 9 cases, moderate in 11, and severe in 25. After starting systemic prophylaxis including factor substitution and DDAVP (desmopressin acetate) in reduced doses, all patients underwent circumcision under local anesthesia using a modified straight clamp and a battery-operated diathermic knife specially designed for bloodless circumcision. Duration of factor replacement ranged between 7 and 18 days, and the hospitalization period was 2 to 5 days according to severity of the disease. The last 19 patients were given tranexamic acid orally for 7 days after surgery. RESULTS: Transient minimal bleeding was observed in 5 patients and easily responded to factor administration. Moderate edema and hyperemia along the excision line owing to the diathermic effect of the device lasted for 3 to 4 days. Normal cosmetic appearance was regained within 7 to 21 days. Excellent patient and family satisfaction was reported. The average cost of the operation was calculated as 81 dollars, 144 dollars, and 243 dollars per kilogram in mild, moderate, and severe cases, respectively. CONCLUSIONS: Bloodless circumcision with "diathermic knife" is a practical and reliable alternative for boys with hemophilia. Enhancement of local hemostasis using such an alternative device may reduce the need for factor substitution and, accordingly, the cost of circumcision in hemophiliacs, down to 50%.