The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases?

Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the disease. At present, there is no specific antiviral drug or vaccine for COVID-19. The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1-S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk-benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.

Bleomycin-induced hyperpigmentation and hypersensitivity reactions to etoposide and vinblastine in a child with endodermal sinus tumor.

We report a pediatric case who developed bleomycin-induced hyperpigmentation and hypersensitivity reactions to both etoposide and vinblastine while receiving chemotherapy for germ cell tumor. Skin hyperpigmentation related to chemotherapeutic agents has been reported only rarely in pediatric patients. This patient developed a characteristic skin hyperpigmentation which was "flagellate" in appearance. Two features of the hyperpigmentation were noteworthy: development at a low cumulative dose of bleomycin and persistence after cessation of chemotherapy. Additive effect of cisplatinum-induced hyperpigmentation was suggested. Although hypersensitivity reactions to etoposide have been previously reported, hypersensitivity reactions to vinblastine are almost unknown. To our knowledge, this is the first report of hypersensitivity reaction to vinblastine in a child in English literature.

High-dose oral methylprednisolone therapy in childhood hemangiomas.

The authors report their experience with high-dose oral methylprednisolone therapy (HDMP) in 15 infants with complicated hemangiomas. The starting dose for methylprednisolone was 30 mg/kg/day for 5 days, then the dose was tapered gradually every 5 days to 20, 10, 5, 2.5, and finally to 1 mg/kg/day. Therapy was then stopped and the patients were followed. An initial response was evident in 12 patients. Nine out of 12 responders showed regrowth signs. After regrowth, 4 cases received prednisolone at doses between 1 to 5 mg/kg/day and 3 patients received a second course with HDMP as additional corticosteroid therapy. Overall, 9 out of 15 cases were responders; very good and good responses were obtained in 5, partial response in 4, and therapy failure in 5 cases. One child was not available for evaluation of response. A very rapid initial response was observed in subglottic and periocular hemangiomas. Side effects were not serious and resolved after discontinuation of treatment. Although the number of patients is small in this study, overall response rate with HDMP regimen seems not to be superior to the regimens that use lower doses (5 mg/kg/day), but it provides a high initial response rate and the duration of therapy is short. Therefore, it may be useful for treating hemangiomas that fail to respond with low doses, especially in centers with limited resources where other treatment modalities cannot be used at the moment.

A rare tumor of craniofacial bones in children: a pediatric chondroblastic osteosarcoma case with diagnostic and therapeutic problems.

Osteosarcoma of the cranial facial region is uncommon and only rarely involves the ethmoid or sphenoid bones. The authors report on an unusual case of a 17-year-old male presenting with chondroblastic osteosarcoma of the maxillary, ethmoid, and sphenoid sinuses who remains well and disease-free at 46 months. He was treated with anterior craniofacial resection followed by postoperative radiotherapy to the sight of the primary tumor. He did not receive chemotherapy because of emerging hepatitis-B infection and vasculitis. The literature on extragnathic craniofacial osteosarcomas is reviewed with particular emphasis on treatment options of this rare tumor.

A case with extraosseous Ewing's sarcoma: a late effect related to bone marrow transplantation for thalassemia or a component of a familial cancer syndrome?

Allogeneic bone marrow transplantation has proved to be a radical form of cure in patients with beta-thalassemia major who have a human leukocyte antigen identical donor. Although malignant neoplasms are serious late complications of bone marrow transplantation, very few reports describing the development of malignant tumors after allografting for thalassemia appeared in the literature. A case is presented here of extraosseous Ewing's sarcoma that developed 8 years after allogeneic bone marrow transplantation performed for beta-thalassemia major. The phenotypic features of the patient's family fulfill the criteria for Li-Fraumeni syndrome. The patient was treated with chemotherapy and radiotherapy and died with recurrent disease. To the authors' knowledge, this is the first case of extraosseous Ewing's sarcoma after bone marrow transplantation for thalassemia. The possible contribution of transplantation procedure and the genetic factors as well as the primary genetic hemoglobinopathy to the development of this malignant tumor are discussed.

Tropisetron in the prevention of chemotherapy-induced acute emesis in pediatric patients.

We evaluated the antiemetic efficacy of tropisetron for control of acute emesis during grade 3 or 4 emetogenic chemotherapy in children. Tropisetron was administered as a single intravenous dose of 0.2 mg/kg on the first day and intravenously or orally with the same dose on subsequent days. A total of 125 courses of highly emetogenic chemotherapy was administered to 22 children with a median age of 14 years (range: 3-18 years). All 22 patients received tropisetron for at least two courses. Overall complete response on day 1 was observed in 80 out of 125 courses (64%). The response rates were consistent over multiple courses; a complete and major response rate on the first day of Course I (n: 22 courses) and Course II (n: 22 courses) was observed in 73 and 77 percent of cases, respectively. When the results were analyzed according to the daily schedules, overall complete response for grade 4, grade 3 and grade 1-2 emetogenic treatment days was 59, 85 and 75 percent, respectively. In this study, cost effectiveness for tropisetron was also determined; the cost per successfully controlled course was 162 USD. No side effects of tropisetron other than mild diarrhea and dry-mouth were documented in this study. In conclusion, the results of this study confirmed that tropisetron is a safe, well tolerated and effective antiemetic drug for the prevention of acute emesis in children and adolescents during highly emetogenic chemotherapy.

Combined central retinal artery and vein occlusion in a child with systemic non-Hodgkin's lymphoma.

PURPOSE: To report on a case of systemic non-Hodgkin's lymphoma and unilateral combined central retinal artery and vein occlusion. METHOD: We examined a 14-year-old boy who experienced a sudden unilateral visual loss five months after the initial diagnosis of systemic non-Hodgkin's lymphoma. RESULT: Visual loss was due to combined central retinal artery and vein occlusion in association with tumoral optic nerve involvement. CONCLUSION: Although very rare systemic non-Hodgkin's lymphoma may present with central retinal artery and vein occlusion prior to overt central nervous system involvement.

Platelet activation in congenital heart diseases.

The research presented here investigated platelet activation in cyanotic and acyanotic congenital heart diseases (CHD). Children with cyanotic CHD are prone to both thrombosis and hemorrhage. However, patients with acyanotic CHD may also have a mild bleeding disorder. The platelet activation in CHD was investigated in support of a hypothesis that platelet activation may play a role in the hemostatic abnormalities reported in these patients. Platelet activation was determined by using flow cytometry with anti-CD62 monoclonal antibody (mAb), which has been shown to be a specific marker of platelet activation. Thirteen children with cyanotic CHD, 33 children with acyanotic CHD and 17 healthy children serving as controls were studied. Platelet activation was significantly higher in the cyanotic group and also in the acyanotic group compared with the healthy children (P = 0.0000 and P = 0.019, respectively). In the cyanotic group, platelet activation showed a direct correlation with arterial O2 saturation (SaO2) (P = 0.014). There was no correlation between platelet activation and erythrocyte related parameters in either group. Platelet activation occurs in CHD, particularly in patients with cyanotic CHD (even in patients with no evidence of clinical thrombosis) and it may play a role in the pathogenesis of thrombotic disorders seen in these patients.

Posterior fossa pseudotumour due to viral encephalitis in a child.

A 14-year-old boy had a 1-month history of diplopia (due to a VI nerve palsy), motor ataxia and dizziness. Brain MRI showed a 1.5-cm mass posterior to the pons. Histopathological examination of a biopsy specimen showed the lesion to be of viral origin. After 3 months, the ataxia and dizziness had resolved and the MRI findings returned to normal. By 5 months the abducens paralysis had also resolved. Viral encephalitis should be considered in the differential diagnosis of posterior fossa tumours.

Hyperglycemia and acute parotitis related to L-asparaginase therapy.

In a boy with non-Hodgkin's lymphoma (NHL), two different complications developed concurrently associated with L-asparaginase (L-ASP) therapy. A non-ketotic hyperglycemic state was observed simultaneously with bilateral acute parotitis after the patient was subjected to L-ASP. The hyperglycemia with normal insulin levels and the absence of plasma and urine ketones was controlled with insulin therapy and no residual impairment of glucose tolerance was demonstrated later. Bilateral acute parotitis, which is a rare complication associated with L-ASP, resolved spontaneously within a week after cessation of L-ASP. The rarely observed toxic effects of L-ASP, such as parotitis, should be recognized as promptly as the better-known complications, e.g., hyperglycemia, to avoid the continuation of this antineoplastic agent.

Long-term pulmonary function in children with Hodgkin's disease.

We studied the long-term pulmonary function of 25 patients who were at least 5 years post-treatment for Hodgkin's disease. The mean age of the patients was 17 years (range 9.5-25 years) at the time of study. Twenty-one of the patients were male. All patients received six courses of COPP chemotherapy and, in addition, 8 of the 25 patients received radiotherapy to the mediastinum in low or moderate doses (20-30 Gy). One patient had symptoms of bronchiectasia. The chest radiographs of nine patients (36%) showed minimal abnormalities. We divided patients into two groups while evaluating their pulmonary function tests according to whether they received mantle irradiation or not. In patients who received mantle irradiation, pulmonary function tests showed a minimal decrease in FEV1. The decrease in FEV1 indicated an obstructive ventilatory defect. We concluded that our treatment protocols for paediatric Hodgkin's disease were curative, well tolerable and might minimize pulmonary functional changes.

Carcinoma of the colon in children.

The symptoms, histology, extent and course of disease in 16 adolescents with colorectal carcinoma who were admitted to Hacettepe University Children's Hospital between 1972 and 1990 are presented. Most patients presented with vague abdominal complaints. Twelve of the 16 patients had mucin-producing adenocarcinoma. Extensive disease at diagnosis and unresponsiveness to medical management were determined. Only one patient survived free of disease four years after diagnosis. Nine of the patients died between one day and one year following the initial surgery. The remaining six patients were very ill when they were discharged from the hospital, after which time no information was received concerning them.

Nonlymphoid gastrointestinal malignancies in Turkish children.

Nonlymphoid gastrointestinal malignancies are not frequently encountered malignant tumors of childhood. From 1972 to 1994, at Hacettepe University Children's Hospital, there were 6,774 malignant tumors encountered in patients from birth to age 17. Thirty-five of them (0.5%) originated from the gastrointestinal tract. There were five carcinoid tumors, four pancreas tumors (two were solid-cystic tumors), four APUD-omas, three leiomyosarcomas, one mesothelioma, two carcinomas of the stomach and duodenum, and 16 colon and rectum carcinomas (12 were mucin-producing). These rare tumors are discussed according to the characteristics of the patients, therapy modalities applied, and outcome of the patients.

Immune thrombocytopenic purpura in a child with Hodgkin's disease.

The occurrence of immune thrombocytopenic purpura (ITP) in Hodgkin's disease is uncommon. This report describes a patient who developed ITP twice before splenectomy, and for the third time several years later, preceding an abdominal relapse of the disease. We suggest that patients with a history of Hodgkin's disease undergo diligent searches for active disease when ITP is diagnosed. ITP may be the only manifestation of active disease and may precede histologic documentation of Hodgkin's disease by months or years.

Hepatitis B vaccination in children with cancer.

Between September 1991 and April 1993 the hepatitis B vaccination with recombinant hepatitis B vaccine was administered in 41 cancer patients following first diagnosis. All patients were under 16 year of age, with negative hepatitis B virus (HBV) serology and normal hepatic function. They received 40 micrograms of vaccine by injection into the deltoid muscle at 0, 1, and 2, months, with a fourth dose planned at the 4th month for nonresponders. At 1 year a booster dose was given. All the patients began vaccination within 1 month following diagnosis, and periodic serologic follow-up was performed immediately after each vaccination and also in the 6th, 9th, and 12th months after vaccination. Patients with production of anti-HBs at a titer equal to or greater than 10 mIU/L were considered seropositive. The seroconversion rates were 12.4%, 21.9%, 41.0%, and 48.7% after the first, second, third, and fourth monthly doses, respectively. Seroconversion rates were 56.0% at 6 months, 67.5% at 9 months, and 70.5% at 12 months. Geometric mean antibody titers were 212 and 373 mI U/L at 9 and 12 months, respectively. No serious side effects were observed. HBV vaccination is recommended for pediatric cancer patients.

Late cardiac effects after treatment for childhood Hodgkin's disease with chemotherapy and low-dose radiotherapy.

Twenty-four patients under 18 years when treated for Hodgkin's disease (20 male, four female) were examined no less than five years after the completion of the treatment. The mean age was 17 years (range 9.5-25.0 years) at the time of study. All patients received six courses of cyclophosphamide-oncovin-procarbazine-prednisolone chemotherapy; in addition, nine patients received low-dose radiotherapy excluding the mediastinum and eight of 24 patients received mediastinal radiotherapy; the dose was between 20-30 Gy. All patients had normal cardiovascular findings on clinical examination. ECG and chest radiography were within normal limits in all patients. Resting left ventricular ejection fraction and fractional shortening were decreased in only one patient (4%), but there was no significant difference between the patient group and a control group for left ventricular systolic function (p > 0.05). In the patient group, early diastolic peak velocity, peak velocity at atrial contraction, left ventricular isovolumic relaxation time, and the rate of decrease of flow velocity in early diastole were significantly different from that of the control group (p < 0.05). In conclusion, the late effects of our treatment protocol for Hodgkin's disease appear to be minimal. These observations support combined modality, low-dose irradiation regimens in children and adolescents and suggest the need for careful cardiac screening of treated patients.