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.

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.

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.

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.

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.

Intussusception due to ectopic pancreatic tissue in a nine-month-old child.

Ileo-colic intussusception was diagnosed in a nine-month-old male infant who presented with abdominal distention, irritability, and bilious vomiting. After reduction of the invaginated segment, a mass measuring one cm was palpated at the antimesenteric border of the terminal ileum. Pathological examination of the mass revealed ectopic pancreatic tissue, which most likely caused the intussusception.

Multiple primary malignancy: a report on Langerhans cell histiocytosis associated with Hodgkin's disease.

Since multiple primary malignant tumors are rare in children, their presence can be a diagnostic and therapeutic problem. In this report, we present a six-year-old boy with Langerhans cell histiocytosis and Hodgkin's disease. On admission, the patient had lytic lesions and a periosteal reaction on the left trochanter major from which an open bone marrow biopsy was performed. The biopsy revealed Langerhans cell histiocytosis. Eight months later, the child presented with enlarged left cervical lymph nodes and the biopsy demonstrated Hodgkin's disease. Although there was an eight-month interval between the two histopathological diagnoses, the diffuse pulmonary parenchymal infiltration observed on the first admission, was later confirmed by an open-lung biopsy as Hodgkin's disease. The patient was said to have two concurrent lymphoreticular malignancies. To our knowledge, this is the youngest case reported with this association in the English language literature.

Renal lymphoma. An unusual presentation in a child.

An unusual case of non-Hodgkin's lymphoma with primary renal involvement in a four-year-old boy is presented. The diagnosis was established by renal biopsy. The findings of an exploratory laparotomy and an extensive staging procedure showed no other primary site. The patient has been followed up for 14 months and no evidence of recurrence has been observed.

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.

Combined chemotherapy in 76 children with non-Hodgkin's lymphoma excluding Burkitt's lymphoma.

From January 1983 to December 1986 seventy-six previously untreated children with non-Hodgkin's lymphoma (NHL) were treated by combination chemotherapy. Burkitt's lymphoma patients were ineligible. The treatment regimens include intermittent chemotherapy and for non-localized patients, prophylactic central nervous system chemotherapy. Intrathoracic non-Hodgkin's lymphoma patients also had cranial prophylactic radiotherapy. Sixty-six patients (86.8%) achieved complete remission. Two year failure-free survival rate was 82.1% for localized (stage I and II) NHL and 53.3% for non-localized (stage III and IV) NHL patients. Failure-free survival did not differ significantly for the two major histologic diagnoses, but two year survival rate was lower in diffuse poorly differentiated lymphoblastic than undifferentiated non-Burkitt's lymphoma (50% versus 66.8% respectively). Failure-free survival rate was 53.7% in mediastinal disease and, 73.2% in abdominal disease at 24 months. Relapse rate was higher in mediastinal cases (46.1%) than primary abdominal cases (24.3%) at 24 months. Eleven (13.5%) died of treatment related sepsis. Although the overall survival rate was 72.4% at 2 years we need novel or more intensive programmes for mediastinal and non-localized disease.

Cytotoxic drug-induced fever: a report on procarbazine-induced hyperpyrexia.

A case of hyperpyrexia induced by procarbazine in a child with Hodgkin's disease, neurofibromatosis, and pectus excavatum deformity is presented. After the diagnosis of stage IIIS Hodgkin's disease, combined COPP chemotherapy was initiated. One week later she presented with high fever. After a diagnosis of infection was made, chemotherapy was stopped and antibiotics were given. Nearly the same picture recurred three times after reinstituting chemotherapy. On the fourth occasion, the patient had to be hospitalized because of hyperpyrexia and arrhythmia. There was no obvious reason for fever, and cytotoxic-induced fever was considered. The drugs were given one at a time. When a test dose (10 mg) of procarbazine was given, she developed a high fever with severe nausea and vomiting. The reaction was controlled by antihistaminics and steroids. To our knowledge this is the second report on hyperpyrexia due to procarbazine administration.

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.

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.

Microphthalmos with bilateral colobomatous orbital cyst accompanied by polycystic kidney disease and vacuolization of myeloid progenitor cells.

A case of microphthalmos with bilateral colobomatous orbital cyst accompanied by polycystic kidney disease and vacuolization of myeloid progenitor cells is presented. Association of these three entities has not been described previously in the literature.

Vitamin D-deficiency rickets and myelofibrosis.

This study was aimed at detecting the early appearance of myelofibrosis by bone marrow biopsy examination in children with vitamin D-deficiency rickets. Twelve children, aged 4 to 18 months, were evaluated. Only a minimal increase of the reticulin was shown in rachitic children without anemia in whom no other laboratory evidence of myelofibrosis was present. Early signs of myelofibrosis with increase of reticulin were present in rachitic infants with anemia. In patients of the same age with iron deficiency anemia, the bone marrow reticulin findings were normal. Bone marrow biopsy after successful treatment of rickets could be repeated in one patient with myelofibrosis; results indicated that the myelofibrosis with anemia associated with vitamin D-deficiency rickets is reversible by vitamin D treatment.

Pearson's marrow-pancreas syndrome in 2 Turkish children.

Two unrelated infants, 1 female and 1 male, with Pearson's syndrome are presented. Both patients presented with severe macrocytic refractory anemia starting early in infancy. Investigation of the mitochondrial (mt), DNA showed that one of the patients had a 4,977 bp deletion, and the other had a 4.5 kb mtDNA deletion. It is concluded that Pearson's syndrome should be borne in mind in the differential diagnosis of refractory anemia especially when there are accompanying gastrointestinal disturbances and metabolic acidosis.

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.