Laparoscopic intervention for late-onset perforating peritonitis due to a ventriculoperitoneal shunt: a case report and literature review.

BACKGROUND: Ventriculoperitoneal (VP) shunt placement is commonly performed to treat hydrocephalus and complications are not uncommon. We report here a case of generalized peritonitis caused by migration of the abdominal end of a VP shunt catheter into the bowel after multiple VP shunt revisions over 30 years. Laparoscopic surgery was successfully performed for the peritonitis and the VP shunt system subsequently reconstructed without complications. CASE PRESENTATION: The patient was a 49-year-old woman who had a VP shunt placed for obstructive hydrocephalus at the age of 13 years. The shunt system required seven revisions because of various malfunctions, including two occasions where a nonfunctioning shunt catheter was left inside the abdomen for safety reasons. Approximately 1 year after the seventh revision, she developed abdominal pain and fever. Abdominal computed tomography suggested that the shunt catheter had migrated into the small intestine and caused an intra-abdominal abscess. We performed emergency exploratory laparoscopy, which revealed perforation of the small intestine by the tip of a nonfunctioning shunt catheter. A growing abscess was found around the perforated intestinal wall, causing bacterial ascites. After the functioning shunt catheter was pulled out from the abdomen, the nonfunctioning catheter that had perforated the intestinal wall was removed. The functioning shunt catheter was then connected to the cerebrospinal fluid drainage system to manage her severe hydrocephalus. Finally, the contaminated abdominal cavity was copiously irrigated with saline solution and a peritoneal drain placed. Twenty-five days later, she underwent another VP shunt surgery in which a VP shunt catheter was placed. She was discharged 45 days after the surgery for peritonitis without complications. CONCLUSION: In cases of peritonitis with a history of VP shunt placement, perforation by a VP shunt catheter is possible, though rare. A delay in treatment could lead to a potentially fatal complication, such as septic shock. Laparoscopic surgery enabled a faster, more hygienic, and minimally invasive operation for managing this rare but serious complication of VP shunt placement.

Cranial Reconstruction with Titanium Mesh for Open Depressed Skull Fracture in Children: Reports of Two Cases with Long-term Observation.

In the treatment of open depressed skull fracture in pediatric cases, it is preferable to use the patient's own bone material rather than artificial material. However, there are occasions when self-material reconstruction may be impossible. In such cases the safe option is to leave the defect until future replacement of the skull becomes possible, however this often causes such children to experience severe limitations to school life. We present two thought-provoking cases in which we solved such issues by early stage cranioplasty using a titanium mesh. The first case involved a 9-year-old boy who sustained a depressed fracture in the right temporal region after falling down a riverbank. Although he underwent surgical repair, bacterial infection forced removal of the bone flap postoperatively. His school life was severely restricted and sports activities were prohibited due to the residual regional bone defect. Cranial reconstruction with a titanium mesh made it possible for him to enjoy a more active lifestyle. The second case involved a 7-year-old boy who sustained a right frontal depressed fracture in a traffic accident. The fractured skull was promptly replaced by a titanium mesh at the initial surgery due to the extreme degree of bone fragmentation. Both boys returned to school life enjoying normal activities and without any complications for up to 8 years now. The cases presented here indicate that early cranioplasty even using artificial material is not only safe but enables school age patients to participate in physical activities. From the standpoint of physical and psychological development, early stage cranioplasty with titanium mesh may be a valuable treatment option for pediatric open depressed skull fracture.

Interval between endoscopic surgery and decreased intracranial pressure related to putaminal hemorrhage prognosis.

BACKGROUND: Endoscopic evacuation of a putaminal hemorrhage is effective and minimally invasive; however, it may not result in sufficient brain decompression. While monitoring postoperative intracranial pressure (ICP) is likely useful, specific ICP data in patients with a putaminal hemorrhage are limited. The aim of this study was to determine the association between postoperative ICP and the prognosis of patients with putaminal hemorrhage after endoscopic surgery. METHODS: We retrospectively analyzed 24 consecutive patients with a putaminal hemorrhage in whom ICP monitoring after endoscopic surgery was performed. Clinical data regarding hematoma volume, evacuation rate, onset-to-treatment time, operation time, ICP max, ICP peak out time (T peak out), and neurological outcomes on discharge were investigated. RESULTS: From August 2011 to October 2015, 24 patients with a putaminal hemorrhage were analyzed. Consciousness on admission and hemorrhage volume were associated with poor outcomes after endoscopic surgery for putaminal hemorrhage. The hematoma volume, operation time, and evacuation rate of hemorrhage were correlated to early peak out of ICP. Furthermore, a T peak out ≤24 h was significantly associated with good neurological outcomes on discharge. CONCLUSIONS: Our data suggest that early peak out (≤24 h) of ICP after endoscopic surgery is predictive of a good prognosis following putaminal hemorrhage. Operation time and evacuation rate of hemorrhage could hasten peak out of ICP and improve outcomes in patients with a putaminal hemorrhage after endoscopic surgery.

Histological analysis of infiltrating macrophages in the cerebral aneurysm walls.

A series of recent evidences suggested activated macrophages have broadly two distinct forms that possess opposite functions for the process of inflammation: classically activated macrophages (M1/kill macrophages) and alternatively activated macrophages (M2/repair macrophages) according to their functions and expression markers. To elucidate what roles those two phenotypes of macrophages play in the evolution of cerebral aneurysm, the presence of macrophages inside the aneurysm walls was assessed with an immunohistochemical approach. The portions of the aneurysm domes deflated after neck clipping were utilized for the further histological examinations, including immunostainings with five antibodies to identify macrophage subpopulations. In this study, contrary to the previous reports, the following various ratios of subtypes were observed in the aneurysm walls: M1 > M2 (2 cases), M1 < M2 (2 cases), M1 = M2 (3 cases). While M1-like macrophages have been typically regarded as a main driver of the degenerating process, these surprisingly richer presences of M2-like macrophages in the aneurysm walls suggests that an unrecognized biological process might be in play in aneurysm development.

Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas.

Despite abundant evidence implicating receptor tyrosine kinases (RTK), including the platelet-derived growth factor receptor (PDGFR), in the pathogenesis of glioblastoma (GBM), the clinical use of RTK inhibitors in this disease has been greatly compromised by the rapid emergence of therapeutic resistance. To study the resistance of proneural gliomas that are driven by a PDGFR-regulated pathway to targeted tyrosine kinase inhibitors, we utilized a mouse model of proneural glioma in which mice develop tumors that become resistant to PDGFR inhibition. We found that tumors resistant to PDGFR inhibition required the expression and activation of the insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) for tumor cell proliferation and survival. Cotargeting IR/IGF1R and PDGFR decreased the emergence of resistant clones in vitro Our findings characterize a novel model of glioma recurrence that implicates the IR/IGF1R signaling axis in mediating the development of resistance to PDGFR inhibition and provide evidence that IR/IGF1R signaling is important in the recurrence of the proneural subtype of glioma in which PDGF/PDGFR is most commonly expressed at a high level. Mol Cancer Ther; 16(4); 705-16. ©2017 AACR.

Palliative lumboperitoneal shunt for leptomeningeal metastasis-related hydrocephalus: A case series.

BACKGROUND: Leptomeningeal metastasis-related hydrocephalus causes distress to patients with end-stage cancer through headache and other symptoms by elevating intracranial pressure, thus reducing quality of life. Ventriculoperitoneal shunt has been used as a treatment option in palliative care. We review four cases of patients who underwent lumboperitoneal shunt for leptomeningeal metastasis-related hydrocephalus. CASES: All patients suffered from severe headache and nausea. The primary lesion was histologically diagnosed as lung adenocarcinoma in each case. The duration from diagnosis to onset of hydrocephalus symptoms ranged from 0 to 52 (mean 26) months. Cerebrospinal fluid pressure in every case was above the normal range due to high intracranial pressure. Case management: Conventional procedures for lumboperitoneal shunt were employed for all patients. Adjustable pressure valves were retrofitted into the shunt system. Case outcome: Three patients demonstrated significant improvement of clinical symptoms and quality of life after placement of lumboperitoneal shunts. In two cases, not only did performance status improve to independent daily activity but also comparatively long-term survival was achieved due to subsequent chemotherapies after surgery. No symptoms of peritoneal dissemination by floating cancer cells in cerebrospinal fluid were seen in any patients. CONCLUSION: Lumboperitoneal shunt appears to improve quality of life if the patient is suffering from symptoms of leptomeningeal metastasis-related hydrocephalus. Compared to ventriculoperitoneal shunt, lumboperitoneal shunt is less invasive and simpler, providing a suitable option for frail patients with end-stage cancer. Adjustable pressure shunt valves can cope with varying symptoms and ventricle sizes.

PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells.

Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1 Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling. Cancer Res; 76(10); 2964-76. ©2016 AACR.

Effectiveness of Endoscopic Surgery for Comatose Patients with Large Supratentorial Intracerebral Hemorrhages.

To evaluate the effectiveness of endoscopic surgery for life-threatening large brain hemorrhage, we reviewed our empirical cases of comatose patients with large supratentorial intracerebral hemorrhage. Among 35 patients with putaminal or subcortical hemorrhage that was evacuated endoscopically, 14 cases (40%) presented both findings of neurological grade IV for severity and hematoma volume exceeding 70 mL in the recent 3 years (endoscope group), whereas 8 cases with the same conditions were treated by conventional craniotomy for the preceding 3-year period (craniotomy group). Between these two groups, mean age was higher and duration of surgery was shorter in the endoscope group, but no significant differences in hematoma size or evacuation rate were recognized. In the 10 cases that presented with signs of cerebral herniation (neurological grade IVb) and required emergent decompression, the preparation time for surgery tended to be shorter in the endoscope group, although the difference was not significant. Additional ventricular drainage was performed in 7 cases and showed a supplemental effect of reducing intracranial pressure (ICP). Consequently, all patients in the endoscope group were rescued without decompressive large craniectomy, even with symptoms of cerebral herniation. In conclusion, endoscopic surgery has the potential to offer an effective therapeutic option for comatose patients with large supratentorial intracerebral hemorrhages, matching conventional craniotomy for emergent treatment in terms of mortality and management of ICP.

Id2 mediates oligodendrocyte precursor cell maturation arrest and is tumorigenic in a PDGF-rich microenvironment.

Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation. Constitutive expression of Id2 in differentiating NSCs resulted in maturation-resistant oligodendroglial precursor cells (OPC), a cell population implicated in the initiation of glioma. Mechanistically, Id2 overexpression was associated with inhibition of the Notch effector Hey1, a bHLH transcription factor that we here characterize as a direct transcriptional repressor of the oligodendroglial lineage determinant Olig2. Orthotopic inoculation of NSCs with enhanced Id2 expression into brains of mice engineered to express platelet-derived growth factor in the central nervous system resulted in glioma. These data implicate a mechanism of altered NSC differentiation in glioma development and characterize a novel mouse model that reflects key characteristics of the recently described proneural subtype of glioblastoma multiforme. Such findings support the emerging concept that the cellular and molecular characteristics of tumor cells are linked to the transformation of distinct subsets of adult tissue progenitors.

Proliferation-independent control of tumor glycolysis by PDGFR-mediated AKT activation.

The differences in glucose metabolism that distinguish most malignant and normal tissues have called attention to the importance of understanding the molecular mechanisms by which tumor energy metabolism is regulated. Receptor tyrosine kinase (RTK) pathways that are implicated in proliferation and transformation have been linked to several aspects of tumor glucose metabolism. However, the regulation of glycolysis has invariably been examined under conditions in which proliferation is concomitantly altered. To determine whether RTKs directly regulate glycolysis without prerequisite growth modulation, we first identified a specific RTK signaling pathway, platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) that regulates glycolysis in glioma-derived tumor stem-like cells from a novel mouse model. We determined that PDGF-regulated glycolysis occurs independent of PDGF-regulated proliferation but requires the activation of AKT, a known metabolic regulator in tumor. Our findings identifying a key characteristic of brain tumors, aerobic glycolysis, mediated by a pathway with multiple therapeutic targets suggests the possibility of inhibiting tumor energy metabolism while also treating with agents that target other pathways of pathologic significance.

Spinal glioma: platelet-derived growth factor B-mediated oncogenesis in the spinal cord.

Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracycline-responsive element (TRE/hPDGFB). These TRE/hPDGFB mice were mated with transgenic mice expressing the tetracycline transcriptional activator (tet-off), tTA, regulated by the human glial fibrillary acidic protein (GFAP) promoter and exhibiting uniquely strong promoter activity in the spinal cord. These transgenic mice (GFAP/tTA:TRE/hPDGFB) expressed hPDGFB in GFAP-expressing glia in a manner responsive to doxycycline administration. Without doxycycline, almost all GFAP/tTA:TRE/hPDGFB mice developed spinal cord neoplasms resembling human mixed oligoastrocytoma. Tumorigenesis in these animals was suppressed by doxycycline. To further examine the importance of PDGFB in mouse primary intramedullary spinal cord tumors, we also created transgenic mice expressing hPDGFB under the control of the human GFAP promoter (GFAP/hPDGFB). These GFAP/hPDGFB mice also developed spinal oligoastrocytoma. PDGFB can mediate the development of mouse spinal tumors that are histologically and pathologically indistinguishable from primary intramedullary spinal tumors of humans and may provide opportunities for both novel insights into the pathogenesis of these tumors and the development of new therapeutics.

Diffuse encephaloventriculitis and substantial leukoencephalopathy after intraventricular administration of recombinant adenovirus.

OBJECTIVES: The use of recombinant adenovirus as a vehicle for gene transfer into ependymal cells is a potential therapeutic tool for the treatment of various neural disorders. However, gene transfer into the ependymal cells of the ventricular wall is associated with high-level expression of the transferred gene, which declines rapidly. The purpose of this study is to understand the cause of this early decline in gene expression. METHODS: Different doses of adenovirus-expressing beta-galactosidase (Ad-beta-gal) were injected into the lateral brain ventricle of C57BL/6 mice, and the brains were observed histologically and with magnetic resonance (MR) imaging for a month. RESULTS: Inoculation of the lateral ventricle with more than 1 x 10(8) viral particles (2.6 x 10(6) pfu) resulted in a rapid decline of beta -gal expression. MR imaging indicated gradual ventriculomegaly and histological analysis showed the loss of the ependymal cells from the ventricular wall, lymphocytes infiltration near the wall, degeneration of myelinated fibers and apoptosis in the external capsule. Reactive astrocytes proliferated in the external capsule 17 days following inoculation. To avoid this irreversible brain atrophy, the inoculated adenovirus should be reduced to less than 1 x 10(7) particles (2.6 x 10(5) pfu) in mice. DISCUSSION: Our results indicate the presence of a unique and diffuse immune response of the brain; therefore, the clinical use of recombinant virus for intraventricular gene transfer must be carefully evaluated.