Sex-based survival differences in IDH-wildtype glioblastoma: Results from a retrospective cohort study.

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival.

BACKGROUND: Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. PATIENTS AND METHODS: We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. RESULTS: A total of 214 patients were included in the study of whom 68% belonged to the SVZpos group. Median tumor volume was significantly larger in the SVZpos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZpos group (61.4% vs 44.9%; p = .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZpos patient group but 16.9 months and 10.3 months for the SVZneg group (log-rank p = .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. CONCLUSIONS: This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZpos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZneg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZpos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study.

INTRODUCTION: Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a "grey zone" of diagnostic uncertainty has been described. METHODS: We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample. RESULTS: In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival. CONCLUSION: Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.

Extraskeletal osteosarcoma of the orbit: A clinicopathologic case report and review of literature.

Primary extraskeletal osteosarcoma (EOS) is an extremely rare malignancy. In this report, the clinical course of a 32-year-old man presenting with proptoses is described. Medical history included Hirschsprung disease (HD), horseshoe kidney, azoospermia, and vertebral anomalies. Imaging of the orbit showed an oval, well-defined heterogeneous mass adjacent to the lateral wall of the orbit. The patient underwent a lateral orbitotomy and complete excision of the mass. The mass was not attached to the bone. Histopathologic and immunohistochemical examination confirmed the diagnosis of an EOS. The patient received chemotherapy and radiotherapy and is free of the disease 3 years after the diagnosis. Genetic screening showed no mutations for both the RET proto-oncogene for HD and the p53 tumor suppressor gene for osteosarcoma.

A Rare Presternal Soft Tissue Tumor: Ectopic Hamartomatous Thymoma (Branchial Anlage Mixed Tumor).

Ectopic hamartomatous thymoma is a rare benign tumor in adults, mostly located in the lower neck region. It was first reported in 1982 by Smith and McClure. Histopathologically these tumors are typically well marginated and composed of a mixture of spindle cells, mature adipose tissue, and epithelial cells, including both glandular and squamous elements. The histogenesis of this tumor is controversial. Recently, an origin from a remnant of the cervical sinus of His was proposed. Ectopic hamartomatous thymoma needs to be differentiated from malignant lesions such as synovial sarcomas or malignant peripheral nerve sheath tumors. These tumors can have similar clinical features and radiologic images. Recognition of this tumor is important because it follows a benign clinical course and conservative surgical excision is the treatment of choice. To our knowledge, 61 cases have previously been reported. We present the case of a 45-year-old women with an uncomplicated presternal located ectopic hamartomatous thymoma. The morphological and immunohistochemical findings are discussed and a review of literature is made.

Bifocal optic and facial nerve t-cell lymphoma.

PURPOSE: Optic nerve and optic nerve sheath infiltration by a systemic lymphoma is uncommon, but is exceedingly rare when caused by a T-cell lymphoma. This then generally occurs in association with central nervous system (CNS) involvement. We report on a rare case of optic and facial nerve T-cell lymphoma infiltration, without CNS involvement. METHODS: A 63-year old female with systemic T-cell lymphoma in clinical remission presented with painful loss of vision in the left eye. She was initially treated for presumed recurrent optic neuritis. A thorough clinical work-up was performed, followed by an optic nerve biopsy with histopathology. RESULTS: There was no perception of light in the left eye, with a marked relative afferent pupillary defect. Fundoscopy showed significant optic disc oedema and a large peripapillary subretinal infiltration. Subsequently, she developed a 7th cranial nerve paresis. Cranial MRI showed thickening and contrast enhancement of the left optic nerve and right facial nerve. Optic nerve biopsy showed infiltration of CD3- and CD5- positive lymphocytes. A complete systemic workup revealed no evidence of disease elsewhere. The patient was thus considered to have bifocal cranial recurrence of T-cell lymphoma, for which radiotherapy was started. CONCLUSIONS: Optic nerve infiltration from systemic lymphoma is rare and generally occurs with CNS involvement. A bifocal pattern of recurrence from systemic T-cell lymphoma involving the right facial nerve and left optic nerve was seen in this patient. A review of the literature highlights the highly atypical nature of this presentation.

Chordoid meningioma in an adult patient presenting with chronic fatigue and systemic inflammation.

We report a 27-year-old woman presenting with chronic fatigue and depressive symptoms. Aspecific neurologic symptoms and biochemical indices of inflammation and anaemia triggered an MRI, revealing a tumor with compression of the medulla oblongata. After neurosurgical resection, anatomopathologic examination showed a chordoid meningioma. All complaints disappeared and inflammatory parameters normalized, suggesting an association with Castleman syndrome. This case demonstrates the importance of a systematic diagnostic approach in patients presenting with unexplained chronic fatigue.

Influence of an increased intracranial pressure on cerebral and systemic haemodynamics during endoscopic neurosurgery: an animal model.

BACKGROUND: During endoscopic neurosurgery, direct mechanical stimulation of the brain by the endoscope and increased intracranial pressure (ICP) caused by the continuous rinsing can induce potentially lethal haemodynamic reflexes, brain ischaemia, and excessive fluid resorption. METHODS: In a newly presented rat model of endoscopic neurosurgery, stereotactic access to the cerebrospinal fluid was secured and the ICP was increased by controlled infusion until complete suppression of the cerebral perfusion pressure (CPP). The haematocrit (Hct) level was determined before and after the procedure. During the whole procedure, invasive arterial pressure, ICP, and heart rate were continuously recorded and evaluated in a subsequent offline analysis. After the procedure, the animals were allowed to recover and 7 days later they were killed for histological examination. RESULTS: Suppression of the CPP resulted in a severe hypertension combined with tachycardia or mild bradycardia. The Hct decreased from 41 to 35 over the minutes of CPP suppression. After cessation of the infusion, the ICP decreased to 37% of the plateau pressure within 2.5 s. In the first few minutes after restoration of normal ICP, five animals died because of pulmonary oedema. CONCLUSIONS: Upon complete suppression of the CPP, an obvious hypertension developed, often together with tachycardia, but no severe bradycardia. At high ICP levels, we observed an important translocation of irrigation fluid to the vascular space. Fatality was not caused by ischaemia or arrhythmia but due to pulmonary oedema.

Ocular presentation of Wegener granulomatosis.

A 55-year-old woman presented with swelling of the right upper and lower eyelid, diplopia and proptosis. The clinical findings combined with imaging, pathology and full internal work-up allowed to make a diagnosis of limited Wegener granulomatosis. Treatment with systemic corticosteroids and cyclophosphamide markedly decreased the orbital swelling and diplopia.

Cryptococcoma unresponsive to antifungal treatment in a 63-year-old non-HIV-infected male.

Cryptococcosis is an invasive fungal infection mainly due to Cryptococcus neoformans which has become increasingly prevalent in immunocompromised patients. The majority of patients with disseminated infection are immunocompromised due to AIDS, prolonged treatment with corticosteroids, organ transplantation, or malignancy. Invasive cryptococcal infection is rare in healthy immunocompetent individuals. We present a case of cerebral cryptococcoma in a previously healthy individual with development of meningitis and multiple intracerebral lesions in spite of persistently negative cultures and refractory to conventional antifungal therapy. The diagnosis was confirmed by two independent anatomopathological examinations.

Delay in diagnosis and outcome of Acanthamoeba keratitis.

PURPOSE: To evaluate the outcome of Acanthamoeba keratitis with respect to the delay in diagnosis. METHODS: A retrospective review of the records of 14 patients treated for Acanthamoeba keratitis was carried out. Delay in diagnosis was correlated with risk factors, clinical presentation, method of diagnosis, final visual acuity and need for penetrating keratoplasty. RESULTS: Based on the time interval between the first symptoms and the diagnosis of Acanthamoeba keratitis, it appeared that patients could be divided into two groups: an early treatment group (group I), consisting of six patients treated within 18 days of onset of symptoms, and a late treatment group (group II), composed of eight patients treated beyond that time. There were no statistically significant differences between the two groups as far as risk factors, clinical presentation, accuracy of diagnosis and method of diagnosis were concerned, although more extensive and deeper corneal involvement was noted in group II. Improvement in visual acuity following medical therapy was seen in all six patients in the early group and in three (37%) of the eight patients in the late group. One patient in group I needed urgent penetrating keratoplasty for corneal necrosis. In group II, two patients underwent penetrating keratoplasty à chaud to prevent corneal perforation and three patients needed penetrating keratoplasty to restore functional visual acuity. CONCLUSION: A diagnostic delay of less than 18 days between onset of symptoms and start of anti-amoebic treatment results in a better final VA after medical treatment and obviates the need for urgent and elective penetrating keratoplasty.

Influence of neo-adjuvant chemotherapy with 5-fluorouracil on colonic anastomotic healing: experimental study in rats.

PURPOSE: We studied the effect of neo-adjuvant chemotherapy on the operative outcome and colonic anastomotic healing in a rat model. METHODS: Firstly, we determined the maximum tolerated dose (MTD) of intraperitoneal 5-flurorouracil (5-FU) in Wistar rats. Secondly, animals were randomly divided into 3 groups: group CT-H received the MTD of 5-FU, group CT-L received 50% of the MTD and a control group received an equivalent volume of 0.9% saline, intraperitoneally. Colonic anastomosis was performed 4 days after chemotherapy. Animals were sacrificed 10 days after surgery. Evaluations were made of: weight evolution, surgical complications, anastomotic bursting pressure (BP) and histological analysis of the anastomotic site. RESULTS: A dose of 20 mg/kg 5-FU, intraperitoneally, for 5 consecutive days was found to be the MTD. A significant weight loss occurred in group CT-H in comparison to the control group either during chemotherapy (p < 0.01) or after surgery (p = 0.01). Postoperative complications were seen only in group CT-H (30% versus 0% in CT-L and control groups). More intense adhesion formation was observed in group CT-H in comparison to the control group (p < 0.01). Intraperitoneal 5-FU induced more inflammation and fibrosis in the submucosa, either with the low or the high-dose, compared to the control animals (p < 0.05) and more pronounced vascular sclerosis was noticed with a dose of 20 mg/kg (p = 0.03). No significant differences in BP were found between the chemotherapy groups and the control group. CONCLUSION: Neoadjuvant chemotherapy with 5-FU does not alter the strength of colon anastomosis in this rat model. A dose of 20 mg/kg induces significantly more intra-abdominal adhesions and histological alterations at the anastomotic site.

Psammomatoid ossifying fibroma of the ethmoid.

We present a 16 year-old girl who suffered since one year of a painless slow growing mass on the left medial orbital rim causing globe displacement. CT-scan and MRI of the orbit with T1 and T2 weighted images showed the presence of a large mucocoele in the frontal sinus. This occurred secondary to the obstruction of the sinonasal tract by a bony tumour. Histopathology showed a lesion consisting of fibrous tissue and ossicles or psammomatoid bodies. The diagnosis of a psammomatoid ossifying fibroma (POF) was made.

Healing of experimental colonic anastomoses: effects of combined preoperative high-dose radiotherapy and intraperitoneal 5-fluorouracil.

To study the effects of preoperative radiochemotherapy (RCT) on the healing of colonic anastomosis, the rectosigmoid colon in male Wistar rats was irradiated up to an end dose of 41.6 Gy (RT) or sham-irradiated (SR). During the last 5 days of the irradiation schedule, 5-fluorouracil (5-FU) was administered intraperitoneally in either a high dose (20 mg/kg, chemotherapy-high dose [CH]) or a low dose (10 mg/kg, chemotherapy-low dose [CL]). Animals were randomly arranged into six groups: group I, control (SR + saline intraperitoneally); group II, RT only; group III, SR + CL; group IV, RT + CL; group V, SR + CH; group VI, RT + CH. Four days after RCT, a side-to-side anastomosis was constructed between the irradiated rectosigmoid and the nonirradiated caecum. Animals were killed 10 days postoperatively. No significant differences were found in the anastomotic bursting pressure or the bursting wall tension. In group VI, mitoses were less (P < 0.01) and mucosal ulceration was more (P = 0.03) pronounced compared to group I. Sclerotic arteries were seen in all irradiated groups and in animals that received high-dose 5-FU alone. 5-FU administration in high or low dose, with or without RT, induced more inflammation in the submucosa compared to controls (P < 0.05). Conclusively, RCT has no detrimental effect on the mechanical strength of colonic anastomosis in this rat model. However, RCT with high-dose 5-FU induces more histological alterations at the anastomotic site.

The effect of duration and timing of systemic cyclosporine therapy on corneal allograft survival in a rat model.

BACKGROUND: Systemic cyclosporine A (CsA) remains a valuable treatment option in the prevention of corneal graft rejection, but the question of timing and duration of this systemic therapy remains unresolved. The effect of a pre- and postoperative dosing schedule, related to the expected moment of rejection, was examined in a rat model. METHODS: All AO (strain) recipients of PVG grafts were assigned to the following treatment groups: Group 1 (controls), groups 2-5 (a postoperative treatment regimen of CsA for 5, 10, 15 and 30 days respectively) and groups 6 and 7 (CsA preoperatively for 5 days and postoperatively for another 5 or 10 days respectively). Corneal allografts were clinically evaluated and blood CsA levels were measured at various time points. RESULTS: Untreated controls rejected their allografts after 13 days. Regression analysis showed a strongly significant positive correlation between graft survival time and duration of cyclosporine therapy. There was no difference in graft survival between groups 3 (CsA 10 days) and 4 (CsA 15 days). A pre-operative dosing schedule of CsA followed by postoperative treatment had no advantage over a solely postoperative treatment regimen. The moment of rejection was characterized by a low to undetectable CsA concentration. CONCLUSION: The present study demonstrates a significant influence of the duration of systemic CsA administration on allograft survival time. However, preoperative administration of CsA does not seem to have an additional influence on graft survival, which is in line with the biological evidence of the mechanism of action of CsA on the efferent arm of graft rejection.

Polypoidal choroidal vasculopathy pattern in age-related macular degeneration: a clinicopathologic correlation.

PURPOSE: To report the histopathologic features of surgically removed submacular tissue from an elderly patient with a pattern of polypoidal choroidal vasculopathy on indocyanine green angiography. METHODS: Clinical examination including fluorescein and indocyanine green angiography and light microscopy of surgical specimen. RESULTS: A thick yellow proteinaceous subretinal fluid was seen in the right macula of an 81-year-old white man. Fluorescein angiography indicated progressive leakage from undetermined source apart from a few focal hyperfluorescent points. Indocyanine green angiography showed several polyps as well as dilated choroidal vessels in the macula and along the superior temporal arcade. A large plaque was visualized in the late phase. Microscopically, the specimen consisted of a thick fibrovascular membrane located on the choroidal side of the retinal pigment epithelium (RPE). The RPE layer was discontinuous whereas on its choroidal side an almost intact layer of diffuse drusen was observed. A group of dilated thin-walled vessels were found that appeared to be saccular on serial sections. Some of these were located almost immediately under the diffuse drusen. CONCLUSION: Histologic examination of submacular tissue removed from an eye with polypoidal choroidal vasculopathy showed several aneurysmal dilatations located directly under diffuse drusen within a sub-RPE, intra-Bruch's fibrovascular membrane.

An undescribed coexistence of a subserosal exophytic gastric leiomyoma with a serous microcystic pancreatic adenoma.

We present the case of a 66-year-old woman with complaints of odynophagia but normal gastro-oesophagoscopic findings. On computed tomographic examination, a presumptive diagnosis of a cystic liver tumor and a microcystic pancreatic adenoma was made. Histopathological examination of the hepatic mass, however, revealed a subserosal exophytic gastric leiomyoma. Considerations to avoid the potential pitfall of diagnosing an exogastric leiomyoma as a liver tumor are emphasized. Moreover, the unique association of an exogastric leiomyoma and a serous microcystic pancreatic adenoma is discussed.