Cocktail therapy with prednisolone, vincristine and sirolimus for Kasabach­Merritt phenomenon in 10 infants.

Kasabach-Merritt phenomenon (KMP) is a life-threatening condition caused by rare vascular tumors. To reduce drug resistance observed in monotherapy of KMP with prednisone, vincristine (VCR) or sirolimus, the present study evaluated the efficacy and safety of triad therapy in the treatment of KMP. A total of 10 KMP infants managed with prednisolone, VCR and sirolimus in The Second Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China) between April 2017 and August 2021 were retrospectively reviewed. The three female and seven male infants with KMP underwent cocktail therapy with prednisone, VCR and sirolimus. At diagnosis, the infants, aged 49.1±41.0 days, showed laboratory test results with platelet counts 22±15.4x109/l, fibrinogen 81.7±26.9 mg/dl and D-dimer 38649±13443.6 ng/ml. The average maximal diameter of the tumors at diagnosis was 84.5±25.1 mm. KMP risk is increased by large tumors with deep lesions infiltrating the muscle. Platelet counts normalized after a median 10 days (range, 5-69 days) of treatment. With combination therapy maintained for 46.8±24.4 days, ultrasound showed that the thickness of the tumors decreased by 51% from 28.9±12.1 to 13.9±6.2 mm. Neutropenia and gastrointestinal disorders were the most common adverse effects. The present study found that the cocktail therapy with prednisolone, VCR and sirolimus has favorable tolerance and efficacy for life-threatening KMP. Once a stable condition has been achieved, cocktail therapy should be replaced by sirolimus monotherapy to reduce potential side effects.

Laparoscopic surgery of intra-abdominal lymphatic malformation in children.

Lymphatic malformation (LM) in the abdomen is uncommon in children, and the standard treatment is surgical excision. The present study aimed to evaluate the safety and efficacy of laparoscopic surgery of intra-abdominal LM in a pediatric population. The medical records of 10 children with intra-abdominal LM treated by laparoscopic resection from March 2017 to June 2021 in The Second Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China) were retrospectively reviewed. Equal numbers of female and male patients were included and underwent surgery at the median age of 55 months (range, 40 days-94 months). Abdominal pain was the most frequent symptom presenting in eight patients (80%). All children were referral patients, and half of them presented to the emergency department with acute abdominal pain. All 10 of the patients benefited from laparoscopic treatment; three patients underwent extraperitoneal segmental intestinal resection and anastomosis via an enlarged umbilical incision, and two patients were converted to laparotomy because of a large retroperitoneal LM with involvement of the colon. No recurrence or complications occurred in the patients during the follow-up period with mean of 35 months (range, 11-60 months) after surgery. Overall, laparoscopic resection of intra-abdominal LM was an effective, minimally invasive therapy in the pediatric population. Segmental intestinal resection is usually required to achieve the complete removal of lesions to lessen the risk for recurrence.

Sirolimus as initial therapy for kaposiform hemangioendothelioma and tufted angioma.

BACKGROUND: Sirolimus has been used to manage various complex vascular anomalies. Kaposiform hemangioendothelioma and tufted angioma may develop Kasabach-Merritt phenomenon in infancy. METHODS: We retrospectively reviewed the clinical and laboratory data of eight patients with kaposiform hemangioendothelioma and tufted angioma who were initially treated using oral sirolimus in our center, including six with Kasabach-Merritt phenomenon. RESULTS: Five girls and three boys seen between September 2012 and March 2015 were included. Age at initiation of sirolimus ranged from 30 days to 14 weeks (mean±SD 8.6 ± 3.5 weeks). Six of these eight patients had kaposiform hemangioendothelioma, and two had a tufted angioma. Platelet count before start of oral sirolimus ranged from 5 × 109 /L to 189 × 109 /L ((78.8 ± 65.2)×109 /L) and fibrinogen level from 68 to 215 mg/dL (123.1 ± 50.5 mg/dL). All patients received standard doses of sirolimus (0.05 mg/kg orally, twice daily) as initial therapy. All patients with thrombocytopenia or hypofibrinogenemia reached a normal platelet count and a normal fibrinogen level within 3 to 4 weeks after sirolimus treatment. Length of treatment ranged from 12 to 79 weeks (39.9 ± 15.3 weeks). Two patients developed grade 2 oral mucositis during treatment. CONCLUSION: Sirolimus as first-line therapy shows great promise in the treatment of kaposiform hemangioendothelioma and tufted angioma.

Sirolimus for Vincristine-Resistant Kasabach-Merritt Phenomenon: Report of Eight Patients.

BACKGROUND: The use of sirolimus for patients with multidrug-resistant Kasabach-Merritt phenomenon (KMP) has been reported in recent years. We present the experience of a single center in treating vincristine-resistant KMP using sirolimus alone. METHODS: Children with vincristine-resistant KMP who were treated with oral sirolimus alone were eligible for inclusion in the study. We evaluated responses according to graded response criteria and acute toxicities according to the National Cancer Institute Common Toxicity Criteria. RESULTS: Between March 2012 and October 2014, eight patients underwent sirolimus treatment. The response rate of hematologic parameters was 100% (8/8). Three tumors shrank enough to allow excision. The tumors were resected after hematologic parameters normalized. Of the five patients with unresectable vascular lesions, three had complete response, and two had partial response of their tumors at the completion of long-term (39.7 ± 24.4 wks) sirolimus treatment. Grade 3 or 4 adverse events were not documented during treatment or follow-up. No recurrence or progression of the disease was observed during follow-up. CONCLUSION: In this small case series, we found sirolimus to be highly effective, with minimal side effects, for vincristine-resistant KMP. A larger study to compare sirolimus and vincristine for KMP is warranted.

Detection of autophagy in Hirschsprung's disease: implication for its role in aganglionosis.

Hirschsprung's disease (HD) is a common congenital gastrointestinal malformation, characterized by the lack of ganglion cells from the distal rectum to the proximal bowel, but the pathogenesis is not well understood. This paper evaluates the effects of autophagy in HD. Using electron microscopy, the autophagosomes were detected in three segments: narrow segment (NS), transitional segment (TS), and dilated segment (DS). Typical autophagosome structures are found in the Auerbach plexus of both NS and TS. Real-time PCR results showed that Beclin1 (NS vs. TS, P<0.01) and LC3 (NS vs. TS, P<0.05) mRNA were the highest in the NS, but p75 (NS vs. TS, P<0.01) was the highest in the DS. Correlation analysis results showed a positive correlation between Beclin1 and LC3 mRNA levels (R=0.736, P=0.000), whereas inverse correlations were found between p75 and Beclin1/LC3 mRNA levels (p75 vs. Beclin1: R=-0.714, P=0.000; p75 vs. LC3: R=-0.619, P=0.000). Immunohistochemistry analyses indicated a consistent result with mRNA levels, by increased Beclin1-positive and LC3-positive neurons, but reduced p75-positive neurons in the Auerbach plexus of TS compared with DS. These findings indicated that autophagy exists in the bowel of patients with HD. On the basis of the detection of the highest expression of the autophagy genes in NS, autophagy may additionally cause the lack of neurons.

Dramatic Response of Topical Doxycycline in Umbilical Granuloma: Report of 84 Cases.

We previously observed that topical doxycycline powder was effective in the treatment of umbilical granuloma. This study aims to evaluate the efficacy of this agent. The patients were randomly assigned into inpatient group and outpatient group. Doxycycline powder was administered topically once daily for 5 days. The protocol was restarted if no response observed. Eighty-four patients were included in this study. With one course of therapy, the overall cure rate was 82.14% (69/84), and the statistical difference in response rate was not significant between the 2 groups (P > .05). With 2 courses of therapy, the overall cure rate was 94.05% (79/84). No complication was observed during treatment. No recurrence was observed during follow-up. The treatment of umbilical granuloma using topical doxycycline is safe and efficacious. The administration of the agent can be performed conveniently by parents at home. This protocol could be considered to be the first treatment option for this disorder in neonates and infants.

Comparison of surgical stress between laparoscopic and open appendectomy in children.

PURPOSE: The present study aimed to evaluate laparoscopic appendectomy (LA) in comparison with conventional open appendectomy (OA) in children, with special emphasis on the extent of surgical trauma after LA and OA, and to assess whether LA had any clear advantages compared with conventional OA. METHODS: A total of 160 patients with a median age of 7.9 years (range 3-15 years) were studied. Sixty-nine of them underwent LA, and the remaining 91 underwent OA. Serum interleukin (IL) 6 and C-reactive protein (CRP) levels which are thought to play a pivotal role in the pathogenesis of surgical trauma and can also be used to monitor the magnitude of surgical trauma were measured using an enzyme-linked immunosorbent assay before surgery and 12 hours after surgery. In addition, we compared operating time, hospital stay, incidence of wound infection, and incidence of intra-abdominal infection. RESULTS: The operative time of normal and suppurative appendix in the laparoscopic group was significantly shorter than that in the open group, respectively, but the operative time of gangrenous appendix was not different between the laparoscopic group and open group. The hospital stay in the laparoscopic group was also significantly shorter than that in the open group. Postoperatively, 1 patient had port-site infection in the laparoscopic group, whereas 10 had wound infection in the open group; this difference was highly significant (chi2 = 4.19, P < .05). Three patients in the open group and 2 patients in the laparoscopic group had intra-abdominal infection, and the difference had no statistically significant difference (chi2 = 0.10, P < .05). Preoperative IL-6 levels were not different between the 2 groups, but the rise (preoperative vs postoperative) of IL-6 in the laparoscopic group was remarkably less than that in the open group. Similar results were obtained for CRP; serum CRP levels in the basal state were not different between the 2 groups, but the rise (preoperative vs postoperative) of CRP in the laparoscopic group was also substantially less compared with that in the open group. CONCLUSIONS: LA for children was as safe and effective as the open procedure and had significant advantages over OA because of less operating time, less postoperative complications, less surgical trauma, and more rapid postoperative recovery.

Role of urokinase plasminogen activator and its receptor in metastasis and invasion of neuroblastoma.

BACKGROUND/PURPOSE: Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in tumor invasion and metastasis. It binds to a specific membrane receptor, uPA receptor (uPAR), and activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates the activation of uPA from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Because of the high metastatic and invasive potential of neuroblastoma (NB) cells, the authors have analyzed in the current study, the concomitant of uPA and its receptor in NB. METHODS: The expression and distribution of uPA and uPAR were analyzed by immunostaining in 52 neuroblastoma tissues; at the same time we use the reverse transcriptase polymerase chain reaction (RT-PCR) for neuroendocrine protein gene products 9.5 (PGP 9.5) mRNA to detect small numbers of NB cells in the peripheral blood and bone marrow (BM) and study the relationship uPA and uPAR to the ability of invasion and metastasis of NB cells. To identify risk factors for disease progression, the authors performed a retrospective analysis of clinical (age, sex, and risk group) and tumor biologic markers (histology, MYCN, DNA ploidy, chromosome 1 p, PGP9.5, uPA, uPAR, and combined uPA and uPAR) in all patients. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The results of immunohistochemistry showed that uPA and uPAR were localized mainly in the membrane and cytoplasm of tumor cells. The positive rate of uPA in the high-risk group (23 of 25, 92.0%) was remarkably higher than that in intermediate-risk group (8 of 17, 47.1%) and low-risk group (3 of 10, 30.0%), in UH (26 of 29, 89.7%) was higher than in FH (8 of 23, 34.8%), respectively, and statistical significance was remarkable both P < .01). Similar results were obtained for uPAR. The positive rate of uPAR in the high-risk group (22 of 25, 88.0%) was substantially higher compared with that in intermediate-risk group (6 of 17, 35.3%) and low-risk group (2 of 10, 20.0%; P < .01). The positive rate of uPAR in UH (24 of 29, 82.8%) was higher compared with that in FH (6 of 23, 26.1%), and statistical significance was remarkable (P < .01). PGP9.5 mRNA in peripheral blood and BM was detected in 24 of 52 (45.2%) patients. The positive rate of PGP 9.5 mRNA in peripheral blood and BM in the cases positive for uPA (22 of 34, 64.7%) was markedly higher than that in the cases negative for uPA (11.1%, 2 of 18), and statistical significance was remarkable (P < .01). There was significant difference in the positive rate of PGP9.5 mRNA between the group positive for uPAR (66.7%, 20 of 30) and the group negative for uPAR (18.2%, 4 of 22), and a larger difference was found between the group positive for both uPA and uPAR (73.1%, 19 of 26) and the group negative for uPA or uPAR (19.2%, 5 of 26). The overall survival (OS) and event-free survival (EFS) rates at 5 years for all patients were, respectively, 70% +/- 3% and 63% +/- 3% with a median follow-up of 65 months (range 13 to 20). Among all the biologic and clinical features analyzed, multivariate analysis using Cox proportional hazards regression showed that age, MYCN, and combined uPA and uPAR remained significant predictors for both OS and EFS (P < .01, respectively). Both EFS rate and OS rate were significantly better for patients who positively expressed uPA and uPAR than those who negatively expressed uPA or uPAR. CONCLUSIONS: This study showed that uPA and uPAR were overexpressed in high-risk and UH tumor of NB, and that overexpression of both factors was associated with the ability of invasion, metastasis, and prognosis of NB. The presence of high levels of combined uPA and uPAR may be a new prognostic marker that would allow us to identify patients with poorer prognosis who might benefit from more aggressive surgical and adjuvant treatment.