Hemostatic Management in an Infant With Neuroblastoma and Severe Hemophilia B With Extended Half-life Recombinant Factor IX Fusion Protein.

In the rare co-occurrence of childhood cancer and severe hemophilia, hemostatic management is of paramount therapeutic importance. We present the case of an 11-month-old boy with severe congenital hemophilia B, who was diagnosed with metastatic high-risk neuroblastoma. He consequently developed paraneoplastic coagulopathy with life-threatening tumor hemorrhage and intracranial hemorrhage, showing central nervous system relapse. Management consisted of factor IX replacement with extended half-life factor IX fusion protein, adjusted to bleeding risk. Additional interventions included factor XIII, fibrinogen, fresh frozen plasma, tranexamic acid, and platelet transfusions. The half-life of factor IX products was markedly reduced requiring close factor IX monitoring and adequate replacement. This intensified treatment allowed chemotherapy, autologous stem cell transplantation, and GD2 antibody immune therapy without bleeding or thrombosis.

Tumour markers and their utility in imaging of abdominal and pelvic malignancies.

The utility of tumour biomarkers has increased considerably in the era of personalised medicine and individualised therapy in oncology. Biomarkers may be prognostic or predictive, and only a handful of markers are currently US Food and Drug Administration (FDA)-approved for clinical use. Tumour markers have a wide array of uses such as screening, establishing a differential diagnosis, assessing risk, prognosis, and treatment response, as well as monitoring disease status. Major overlap exists between biomarkers and their associated pathologies; therefore, despite suggestive imaging features, establishing a differential diagnosis may be challenging for the radiologist. We review common biomarkers that are of interest to radiologists such as carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), prostate-specific antigen (PSA), beta human chorionic gonadotropin (ß-hCG), carbohydrate antigen 19-9 (CA 19-9), alpha fetoprotein (AFP), and carbohydrate or cancer antigen 125 (CA 125), as well as their associated malignant and non-malignant pathologies. We also present relevant case examples from our practice.

Postoperative circulating tumor cells: An early predictor of extrahepatic metastases in patients with hepatocellular carcinoma undergoing curative surgical resection.

BACKGROUND: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. METHODS: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. RESULTS: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P < .001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P < .001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α-fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α-fetoprotein level during postoperative follow-up (all P < .05). The results were confirmed in the validation cohort. CONCLUSIONS: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM.

Extended duration chemoprophylaxis for venous thromboembolism following abdominopelvic oncologic surgery.

Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is the most common cause of 30-day morbidity in oncology patients following surgery due to their hypercoagulable state. To combat this, VTE prophylaxis with anticoagulation extending beyond hospital discharge, termed extended duration chemoprophylaxis (EDCP), has been proposed, with the most recent guidelines recommending 28 post-operative days of EDCP. However, the literature has demonstrated poor compliance to these recommendations. We extended the duration of EDCP to 28 days post hospital discharge, effectively creating a standard discharge prescription for all surgical oncology patients. Our aim is to assess our EDCP protocol on patient compliance and VTE rate following major oncologic resection. We performed a retrospective, single institution, cohort study that involved chart review and telephone survey on patients who underwent major open abdominopelvic oncologic resection. A total of 130 patients were included; 60 received EDCP and 68 did not. VTE rate for the EDCP cohort was 0% and 7.4% for the non-EDCP cohort (p = 0.04). 85% of patients were fully compliant with EDCP. No bleeding related complications with EDCP were identified. Our data is consistent with prior literature in demonstrating a lower VTE rate with EDCP without an increase in bleeding related complications and we have demonstrated that it is possible to achieve a high rate of patient compliance with EDCP.

Ultrasound-Guided 125I Seed Implantation in Treatment of Abdominal Wall Metastases.

Background: The treatment of abdominal wall metastasis presents a challenge, because resection can be followed by poor healing and external radiotherapy is associated with serious adverse events. This study aimed to evaluate the efficacy and safety of interstitial 125I seed implantation under ultrasound (US) guidance for treating abdominal wall metastasis. Materials and Methods: The cases of 21 patients with 28 abdominal wall metastases who received brachytherapy with 125I seeds at the department from August 2010 to March 2015 were retrospectively reviewed. 125I seeds were implanted in the abdominal wall lesions under US guidance and with the help of a treatment planning system. Follow-up was performed using computed tomography at 1 d and at 3, 6, and 12 months after implantation. The lymphocyte count before the surgery was compared with the 3-month postoperative count. The main indicators observed were changes in tumor size, side effects, and complications. Results: All 21 patients were successfully treated with 125I seed implantation under US guidance. The median follow-up since 125I seed implantation was 15 months (range 6-23 months). The response rates and local tumor control after 3, 6, and 12 months were 78.6% and 89.3%, 64.3% and 85.7%, and 52.4% and 71.4%, respectively. The mean preoperative lymphocyte count was 0.262 ± 0.117 × 109/L, which did not differ significantly from the postoperative count, which was 0.259 ± 0.094 × 109/L (p = 0.122). Procedure-related complications included fever, bleeding, and pain, but all these were Grade 1-2. No severe side effects or complications were noted. Conclusions: Percutaneous interstitial implantation of 125I seeds under US guidance is safe and feasible for abdominal wall metastases. However, its long-term efficacy requires further investigation.

Abilities of Pre- and Postoperative High-Sensitivity C-Reactive Protein Levels to Predict 90-Day Mortality After Surgery for Abdominal and Thoracic Cancers.

BACKGROUND: Elevated high-sensitivity C-reactive protein (hsCRP) levels are known to be associated with a poor prognosis for cancer patients, but inadequate data exist regarding whether pre- or postoperative hsCRP levels have better predictive value after oncologic surgery. This study evaluated the associations between pre- and postoperative hsCRP levels and 90-day postoperative mortality among patients who underwent surgery for abdominal or thoracic cancers. METHODS: This retrospective cohort study included 7933 patients who underwent elective surgery between January 2010 and December 2016. Cox regression analysis and receiver operative characteristic curve analyses were used to evaluate the prognostic values of preoperative hsCRP (< 1 month before surgery) and postoperative hsCRP (< 3 days after surgery). RESULTS: For predicting 90-day mortality, the area under the receiver operating characteristic curve was significantly larger for preoperative hsCRP than for postoperative hsCRP [0.76; 95% confidence interval (CI) 0.71-0.81 vs 0.65 95% CI 0.57-0.72; P < 0.001]. The optimal cutoff values were 0.5 mg/dL for preoperative hsCRP and 9.7 mg/dL for postoperative hsCRP. Based on these cutoff values, increased risks of 90-day mortality were significantly associated with preoperative hsCRP levels higher than 0.5 mg/dL [hazard ratio (HR) 7.60; 95% CI 4.43-13.03; P < 0.001] and postoperative hsCRP levels higher than > 9.7 mg/dL (HR 1.83; 95% CI 1.12-2.98; P = 0.016). CONCLUSION: Both elevated pre- and postoperative hsCRP levels were associated with increased risks of 90-day mortality after surgery for thoracic and abdominal cancer. However, preoperative hsCRP had better prognostic value than postoperative hsCRP.

Cushing syndrome in a child due to pro-opiomelanocortin (POMC) secretion from a yolk sac tumor.

CONTEXT: Pituitary microadenomas and adrenal tumours are the most common causes for endogenous Cushing syndrome (CS) in children. CASE DESCRIPTION: We describe a two-year old girl with Cushing syndrome due to ectopic pro-opiomelanocortin (POMC) production from an abdominal yolk sac tumor. Cortisol concentrations were elevated but adrenocorticotropic hormone (ACTH) concentrations were equivocal. The use of antibodies specifically detecting ACTH precursors revealed that plasma ACTH precursors were elevated. Additionally, an ACTH assay with a low cross-reactivity for precursors showed low concentrations of ACTH. Immunohistochemistry suggested POMC but not ACTH production by the tumour. CONCLUSION: We describe a yolk sac tumour as a novel source of ectopic POMC production leading to CS in a young girl.

Inconspicuous Presentation of Metastatic Neuroblastoma.

Neuroblastoma is a malignant tumor arising from nerve tissue that accounts for approximately 15 percent of pediatric cancer fatalities. Primary tumors most commonly arise in sympathetic nervous tissue of the abdomen and metastasize to the bone marrow, liver, and lymph nodes. This case report depicts a 3-year-old girl who presented with a recurring fever, runny nose, and a positive test for rhinovirus suggesting a simple case of the common cold. Further investigation, however, revealed stage 4 neuroblastoma. This patient experience emphasizes the importance of having a high level of suspicion to rule out more serious underlying pathology in a seemingly unremarkable patient presentation.

The Role of Matrix Metalloproteinase-9 (MMP-9) as a Prognostic Factor in Epithelial and Lymphatic Neoplasia.

Matrix metalloproteinase 9 is a zinc-dependent extracellular matrix remodeling endopeptidase directly involved in the local invasion mechanisms and in metastasis. The current review aims to evaluate the expression of MMP-9 and its prognostic value in the most common epithelial and lymphatic neoplasia of the pelvic-abdominal region. We included 19 studies published between January 1st, 1995 and July 31st 2015, involving a total of 1523 patients. The analysis indicate that MMP-9 is valid marker of poor survival in epithelial and lymphatic neoplasia.

Direct Lipido-Metabolomics of Single Floating Cells for Analysis of Circulating Tumor Cells by Live Single-cell Mass Spectrometry.

Direct trapping of a single floating cell, i.e. a white blood cell from a drop of blood, within a nanospray tip was followed by super-sonication after the addition of ionization solvent. Molecular detection of an increased number of peaks with a higher intensity and a wider m/z range, which extends from metabolites to lipids, was acquired than of that without sonication. This method was applied to a few separated circulating tumor cells (CTC) from a neuroblastoma patient's blood to obtain their lipido-metabolomic molecular profile at the single cell level. In addition to vital molecules such as amino acids, catechol amine metabolites, which are specific to neuroblastoma, and drugs included in the patient's course of therapy were detected. This established "direct single-cell lipido-metabolomic method" seems to be useful for direct and wide range molecular detection not only for many live single-cells, but also for rare cells, such as CTCs, for future molecular diagnosis.

Effect of fasting on the size of lymphangioleiomyomas in patients with lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomas occur in 38% of patients with sporadic lymphangioleiomyomatosis (LAM) and may cause pain and increased abdominal girth, mimicking the presence of a malignancy. Lymphatic involvement in LAM is closely associated with elevated serum levels of vascular endothelium growth factor-D (VEGF-D). Because lymphangioleiomyomas undergo diurnal variation in volume, we hypothesized that daytime ingestion of food, by increasing chyle formation and lymphatic flow, is the cause of an increase in lymphangioleiomyoma volume. METHODS: Subjects had abdominopelvic sonograms and blood drawn for measurement of serum VEGF-D levels under nonfasting (day 1) and fasting (day 2) conditions. The size of the lymphangioleiomyomas was determined by a radiologist who was blinded to the subjects' status. The Wilcoxon signed rank test was used to determine whether the nonfasting tumor size was different from the fasting tumor size. RESULTS: Thirty-five women were studied (aged 45.2 ± 8.5 years; FEV1, 82% ± 25%; diffusing capacity of the lung for carbon monoxide, 64% ± 25% predicted). Images suitable for volume measurements were obtained in 30 subjects. Fasting decreased the tumor size by 20.7 ± 39.3 cm3 (24% ± 40%, P < .001). Fasting VEGF-D levels (10,650 ± 900 pg/mL) were not significantly different from nonfasting values (12,100 ± 800 pg/mL, P = .56). CONCLUSIONS: Lymphangioleiomyoma volume decreased during the fasting state. Conversely, a combination of food intake and decreased chyle flow through lymphatics partially obstructed by LAM cells may account for increases in lymphangioleiomyoma size. Imaging studies performed under fasting conditions may help in determining whether an abdominal tumor is a result of LAM or malignancy.

Relationship between deep venous thrombosis and inflammatory cytokines in postoperative patients with malignant abdominal tumors

Deep venous thrombosis (DVT) is a common surgical complication in cancer patients and evidence that inflammation plays a role in the occurrence of DVT is increasing. We studied a population of cancer patients with abdominal malignancies with the aim of investigating whether the levels of circulating inflammatory cytokines were associated with postoperative DVT, and to determine the levels in DVT diagnoses. The serum levels of C-reactive protein (CRP), interleukins (IL)-6 and IL-10, nuclear transcription factor-κB (NF-κB) and E-selectin (E-Sel) were determined in 120 individuals, who were divided into 3 groups: healthy controls, patients with and patients without DVT after surgery for an abdominal malignancy. Data were analyzed by ANOVA, Dunnet's T3 test, chi-square test, and univariate and multivariate logistic regression as needed. The CRP, IL-6, NF-κB, and E-Sel levels in patients with DVT were significantly higher than those in the other groups (P<0.05). The IL-10 level was higher in patients with DVT than in controls but lower than in patients without DVT. Univariate analysis revealed that CRP, IL-6, NF-κB, and E-Sel were statistically associated with the risk of DVT (OR=1.98, P=0.002; OR=1.17, P=0.000; OR=1.03, P=0.042; and OR=1.38, P=0.003; respectively), whereas IL-10 had a protective effect (OR=0.94, P=0.011). Multivariate analysis showed that E-Sel was an independent risk factor (OR=1.41, P=0.000). Thus, this study indicated that an increased serum level of E-Sel was associated with increased DVT risk in postoperative patients with abdominal malignancy, indicating that E-Sel may be a useful predictor of diagnosis of DVT.

Relationship between deep venous thrombosis and inflammatory cytokines in postoperative patients with malignant abdominal tumors.

Deep venous thrombosis (DVT) is a common surgical complication in cancer patients and evidence that inflammation plays a role in the occurrence of DVT is increasing. We studied a population of cancer patients with abdominal malignancies with the aim of investigating whether the levels of circulating inflammatory cytokines were associated with postoperative DVT, and to determine the levels in DVT diagnoses. The serum levels of C-reactive protein (CRP), interleukins (IL)-6 and IL-10, nuclear transcription factor-κB (NF-κB) and E-selectin (E-Sel) were determined in 120 individuals, who were divided into 3 groups: healthy controls, patients with and patients without DVT after surgery for an abdominal malignancy. Data were analyzed by ANOVA, Dunnet's T3 test, chi-square test, and univariate and multivariate logistic regression as needed. The CRP, IL-6, NF-κB, and E-Sel levels in patients with DVT were significantly higher than those in the other groups (P<0.05). The IL-10 level was higher in patients with DVT than in controls but lower than in patients without DVT. Univariate analysis revealed that CRP, IL-6, NF-κB, and E-Sel were statistically associated with the risk of DVT (OR=1.98, P=0.002; OR=1.17, P=0.000; OR=1.03, P=0.042; and OR=1.38, P=0.003; respectively), whereas IL-10 had a protective effect (OR=0.94, P=0.011). Multivariate analysis showed that E-Sel was an independent risk factor (OR=1.41, P=0.000). Thus, this study indicated that an increased serum level of E-Sel was associated with increased DVT risk in postoperative patients with abdominal malignancy, indicating that E-Sel may be a useful predictor of diagnosis of DVT.

Elevated serum CA 19-9 at screening tests: underlying conditions and role of abdominopelvic CT.

OBJECTIVES: To investigate underlying conditions of patients with elevated CA 19-9 at screening tests and to evaluate diagnostic performance of abdominopelvic CT. METHODS: One hundred and thirteen patients with elevated CA 19-9 (>37 U/ml) who underwent abdominopelvic CT in a screening program were selected. Underlying conditions were determined by reviewing all available data and follow-up records. Patients were categorized into malignancy, benign, and normal/non-related disease groups. Their mean CA 19-9 and percent of patients with CA 19-9 ≥ 100 U/ml were compared. Diagnostic sensitivity of CT for detecting underlying conditions of elevated CA 19-9 was analysed. RESULTS: Seventeen patients (17/113, 15 %) had 17 elevated CA 19-9-related malignancies, and 55 patients (55/113, 48.7 %) had 70 benign diseases. Mean CA 19-9 and percent of patients with CA 19-9 ≥ 100 U/ml in the malignancy group were significantly higher than in the two other groups. CT detected all except one malignant lesion with a detection sensitivity of 94.1 % (16/17). Of 70 CA 19-9-related benign diseases, CT detected 34 benign diseases (48.6 %) providing an alternative diagnosis for elevated CA 19-9. CONCLUSION: Abdominopelvic CT is not only useful in detecting malignancies, but can also diagnose alternative benign causes of elevated CA 19-9 in asymptomatic screening tests. KEY POINTS: • Fifteen percent of asymptomatic patients with elevated CA19-9 may have intra-abdominal malignancies. • Mean value of CA19-9 is different among malignant, benign, and non-related groups. • CT shows excellent sensitivity for intra-abdominal malignancies as causatives of elevated CA19-9. • CT provides alternative benign diagnoses as causatives of elevated CA19-9. • Detection of causatives of elevated CA19-9 using CT alleviates concerns and uncertainty.

[Experience of application of multimodal combined spinal-epidural anesthesia during operative interventions for abdominal cavity tumors in children].

The investigations were conducted in 44 children, operated on for abdominal cavity tumors and tumors of ovaries. In patients of the first group a combined spinal-epidural analgesia and a continuous intravenous phentanyl infusion were applied; while in the second group--the intravenous continuous infusion of phentanyl. Conduction of a multimodal analgesia have had reduced significantly a negative outcomes of insufficient analgesia in children and secured an effective analgesia after traumatic operations.

Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing.

CONTEXT: Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL. OBJECTIVES: The aim of this study was to identify novel disease causing genes in PCC and PGL tumors. DESIGN, SETTING, AND PARTICIPANTS: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions. RESULTS: Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007). CONCLUSIONS: We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.

Sunitinib for the treatment of metastatic paraganglioma and vasoactive intestinal polypeptide-producing tumor (VIPoma).

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (NETs) are rare tumors of the endocrine and nervous systems. Whereas early surgical resection can significantly reduce tumor mass, there are few data available concerning the control of hormonal secretion and associated symptoms. Studies have shown that the tyrosine kinase inhibitor sunitinib significantly prolongs progression-free survival in patients with pancreatic NETs. Here, we present 2 case reports of sunitinib in patients with different types of NETs. METHODS: The patients were a 12-year-old boy with metastatic vasoactive intestinal polypeptide-producing tumor (VIPoma) and a 70-year-old woman with metastatic paraganglioma/NET. Both were treated in an outpatient clinical setting. Sunitinib was titrated to 37.5 mg on a continuous daily dosing schedule in the patient with VIPoma, and the dose was 50 mg/d (4 weeks on, 2 weeks off) in the patient with the paraganglioma/NET. RESULTS: The patient with the paraganglioma/NET had a confirmed complete radiographic response and the patient with VIPoma had a confirmed partial response (Response Evaluation Criteria in Solid Tumors). In both patients, improvements were observed in biochemical tumor markers, clinical responses, and quality of life. CONCLUSIONS: In these patients, sunitinib reduced biochemical markers and stabilized or reduced tumor bulk and may therefore be a potential therapeutic option for these tumor types.

Advanced extragonadal yolk sac tumor serially followed up with (18)F-fluorodexyglucose-positoron emission tomography and computerized tomography and serum alpha-fetoprotein.

Although yolk sac tumors (YSTs) are the second most common malignant germ cell tumor of the ovary, those arising from the omentum or pelvic peritoneum are extremely rare and have no established treatment guidelines. We report a case of a primary YST disseminated throughout the abdomen and associated with a high serum alpha-fetoprotein (AFP) elevation (441 611 ng/ml). Optimal cytoreduction was not achieved in order to preserve the patient's fertility and avoid adjacent organ injury. Residual tumor responded to adjuvant chemotherapy with a sharp decline in AFP levels, and confirmed remission was documented by serial (18)F-fluorodexyglucose-positoron emission tomography and computerized tomography (FDG-PET/CT). In cases of advanced YST with unresectable residual disease, AFP levels combined with FDG-PET/CT scans may be a helpful way to monitor treatment response and assist in treatment planning for a disease that primarily affects young women who may desire to preserve fertility.