Gérard Mohr

DNA repair protein levels vis-a' -vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program

Nucleotide excision repair (NER) is a multi-enzyme DNA repair pathway in eukaryotes. Several NER genes in this pathway including XPB, XPD, XPA and ERCC-1 have been implicated in anticancer drug resistance in human tumor cells. In this study, we assessed the levels of the above-mentioned proteins in the NCI panel of 60 human tumor cell lines in relation to the cytotoxicity patterns of 170 compounds that constitute the standard agent (SA) database. The database consists of drugs used in the clinic for which a mechanism of action has been at least partially defined. The ERCC-1, XPD and XPB protein expression patterns yielded significant negative Pearson correlations with 13, 32 and 17 out of the 170 compounds, respectively (using p <0.05). XPA produced a random assortment of negative and positive correlations, and did not appear to confer an overall resistance or sensitivity to these drugs. Protein expression was also compared with a pre-defined categorization of the standard agents into six mechanism-of-action groups resulting in an inverse association between XPD and alkylating agent sensitivity. Our present data demonstrate that XPD protein levels correlate with resistance to alkylating agents in human tumor cell lines suggesting that XPD is implicated in the development of this resistance. NER activity, using the in vitro cell-free system repair assay, revealed no correlation between NER activity and the level of XPD protein in four cell lines with widely varying XPD protein levels. This lack of correlation may be due to the contribution of XPD to other functions including interactions with the Rad51 repair pathway.

Mycotic Aneurysm of the Carotid Bifurcation in the Neck: Case Report and Review of the Literature

OBJECTIVE AND IMPORTANCE Mycotic aneurysms of the extracranial carotid artery are rare and difficult to diagnose. A search of the world literature published since 1966 reveals at least six cases of mycotic carotid aneurysms due to a Salmonella septicemia. We present an exceptional case of mycotic pseudoaneurysm of the bifurcation of the carotid artery due to Salmonella septicemia and discuss the pathogenesis as well as various aspects of the diagnosis and surgical management. CLINICAL PRESENTATION A 68-year-old man presented in Poland with Salmonella sepsis; 1 month later, he was admitted to the emergency department of the Sir Mortimer B. Davis-Jewish General Hospital in Montreal with a bulky and pulsatile right cervical mass. An angiogram and a computed tomographic scan revealed a voluminous and partially thrombosed aneurysm the size of a tangerine originating from the posterior aspect of the carotid junction. INTERVENTION Balloon trapping was attempted at the Montreal Neurological Hospital. Subsequently, the patient developed a significant neurological deficit, which was quickly reversed by the administration of hypertensive, hypervolemic, and hemodilution therapy. Thereafter, the pseudoaneurysm was resected surgically, and the internal and external carotid arteries were sacrificed. Pathological examination of the excised specimen of the carotid junction revealed a pseudoaneurysm. Bacterial culture of the lesion showed growth of Salmonella. CONCLUSION The postoperative course was satisfactory except for laryngeal paralysis due to involvement of the vagus nerve. Four months later, a computed tomographic scan showed only small lacunae in both centra semiovale.

Radiosurgery and accelerated radiotherapy for patients with glioblastoma

OBJECTIVE To assess the feasibility, toxicity, and local control of stereotactic radiosurgery followed by accelerated external beam radiotherapy (AEBR) for patients with glioblastoma multiforme. MATERIALS AND METHODS Six males and eight females, with a median age of 67.5 years (range 45-78 years), entered the study. Karnofsky performance status was 90 for five, 80 for six, and 60 for three patients. Following surgery, the patients were left with a residual mass 4 cm. Radiosurgery was delivered with a single dose of 20 Gy to the 90% isodose surface corresponding to the contrast-enhancing edge of the tumour. A total AEBR dose of 60 Gy in 30 fractions was delivered using a concomitant boost technique over four weeks. RESULTS Median survival time was 40 weeks (range 17-80 weeks). Actuarial survivals at 12 and 18 months were 43% and 14%, respectively. The median time to progression was 25 weeks (range 2-77 weeks). One patient developed a seizure on the day of stereotactic radiosurgery. Two patients experienced somnolence at 47 and 67 days post-radiotherapy. Eight patients remained steroid-dependent. Radiological evidence of leukoencephalopathy was observed in one patient, and brain necrosis in two additional patients at 30 and 63 weeks. One of these two patients with brain necrosis developed complete loss of vision in one eye, and decreased vision in the contralateral eye at 63 weeks. CONCLUSION Stereotactic radiosurgery followed by AEBR was feasible but was associated with late complications. The use of such radiosurgical boost for patients with glioblastoma multiforme should be reserved for those patients entering controlled clinical trials.

Mapping of the basal forebrain cholinergic system of the dog: A choline acetyltransferase immunohistochemical study

In an effort to produce a canine model of basal forebrain ischemia with memory deficits, we have shown that dogs possess a medial striate artery that perfuses basal forebrain territory, homologous to the human recurrent artery of Heubner. In the present study, we set out to delineate the precise topography of the cholinergic neurons in the canine forebrain, a neuronal system implicated in cognitive and memory functions. Floating coronal sections, derived from the head of the caudate nucleus to the rostral border of the hippocampus, were stained for choline acetyltransferase using a monoclonal antibody. Representative sections from one dog brain were drawn. These outlines were used for measurement of cell density, cell size, number of processes, and cell roundness. Choline acetyltransferase‐positive neurons constituted four major subdivisions within the basal forebrain. A relatively dense population of cholinergic neurons was present in the medial septal nucleus (Ch1). A continuum of densely packed cells was also delineated within the vertical (Ch2) and horizontal (Ch3) nuclei of the diagonal band of Broca. A fourth group of heterogeneously packed cholinergic neurons represented the nucleus basalis magnocellularis (Ch4). Except for the caudal component of the Ch4 population, the forebrain cholinergic corticopetal system was located within the perfusion territory of the medial striate arteries. The Ch4 cell group in dogs is better defined than that of rodents but is not as sharply demarcated as in human and nonhuman primates. Our findings indicate that the dog may serve as an excellent model for assessing neurological and memory deficits, which, in humans, results from hypoperfusion of the recurrent artery of Heubner.

Distal Mycotic Aneurysm of the AICA Mimicking Intracanalicular Acoustic Neuroma

BACKGROUND Among cases of cerebellopontine angle lesions, vascular lesions involving the internal auditory canal are extremely rare. We report a distal fusiform mycotic pseudoaneurysm of the anterior inferior cerebellar artery (AICA) that simulated an acoustic neuroma on presentation. METHODS A 60-year-old woman was investigated for recent onset of acute dizziness. Laboratory and radiographic investigations are presented, as well as the surgical management of the patient and pathological examination of the aneurysm. CONCLUSIONS An exceptionally rare case of distal mycotic intracanalicular pseudoaneurysm of the AICA with intraluminal thrombus and fusiform anatomy is described. In our review of the literature (1966-present), only five other intracanalicular AICA-aneurysms were encountered, none of which were infectious in etiology. The possible pathophysiologic mechanisms of distal AICA-aneurysms are discussed along with the currently available literature.

Depressed skull fracture and epidural haematoma: an unusual post-operative complication of pin headrest in an adult

SummaryDepressed skull fracture and epidural haematoma caused by pin headrest complicated the post-operative course in an adult, after removal of a parasagittal meningioma. The calvarial thickness was observed to be significantly reduced due to chronic high intracranial pressure. Potentially hazardous complications of pin headrests should not be underestimated in adults.

Ligamentum Flavum Cysts Causing Incapacitating Lumbar Spinal Stenosis

BACKGROUND Cysts of the ligamentum flavum are rare and unusual causes of spinal compression. METHODS We report our experience of four cases of ligamentum flavum cysts occurring in the lumbar spine and discuss some of the possible etiologies and pathophysiologic mechanisms according to the available literature. CONCLUSION This entity is clearly different from the synovial facet-joints or ganglion cysts.

Excision repair cross-complementing rodent repair deficiency gene 2 expression and chloroethylnitrosourea resistance in human glioma cell lines

OBJECTIVE Nitrosoureas are the standard chemotherapeutic agents for malignant brain tumors. However, their anticancer effects are limited because many tumors are resistant to these agents. Nucleotide excision repair can repair bulky deoxyribonucleic acid adducts, including deoxyribonucleic acid damage induced by ultraviolet light and some chemotherapeutic agents, and may be implicated in nitrosoureas resistance. In this study, we compared excision repair cross-complementing rodent repair deficiency Gene 2 (ERCC2), an important component of the nucleotide excision repair system, with 1 ,3-bis-(2-chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea resistance in human glioma cell lines. METHODS ERCC2 expression was evaluated by using established quantitative reverse-transcription polymerase chain reaction. 1,3-Bis-(2-chloroethyl)-1-nitrosourea and (2-chloroethyl)-3-sarcosinamide-1-nitrosourea cytotoxicity were determined by a modification of the sulforhodamine B colorimetric anticancer drug screening assay. RESULTS A significant correlation between ERCC2 expression and 1 ,3-bis-(2-chloroethyl)-1-nitrosourea or (2-chloroethyl)-3-sarcosinamide-1-nitrosourea cytotoxicity was determined (r=0.737, P=0.0226 and r=0.789, P=0.0113, respectively). CONCLUSION Our results suggest that nucleotide excision repair, specifically ERCC2, may play an important role in nitrosoureas drug resistance in human gliomas.

High Dose Tamoxifen and Radiotherapy in Patients with Glioblastoma Multiforme: A Phase IB Study

PURPOSE To assess the feasibility and the toxicity of adjuvant high dose tamoxifen (TAM) and postoperative brain irradiation for patients with newly-diagnosed glioblastoma multiforme (GBM). MATERIAL AND METHODS Twelve patients with histopathologically confirmed GBM entered the study. There were nine males and three females, with median age of 48.8 years (range 30-75 years). Karnofsky performance status (KPS) was 60-70% for four patients and 80-100% for eight patients. Based on the Radiation Therapy Oncology Group recursive partition analysis, there were three class III patients, six class IV, one class V, and two class VI. Eleven patients underwent partial surgical tumor resection and one patient had a near complete resection. Two weeks post surgery, the patients were started on high dose TAM (120 mg/m2 P.O. BID for three months). Two weeks from date of starting TAM, external beam radiotherapy (RT) was given at a dose of 59.4 Gy/33 qd fractions/6.5 weeks. Patients were assessed weekly for toxicity during treatment. Imaging studies were done at the end of two weeks of TAM, then monthly. RESULTS Median follow-up was 40 weeks (range 22-84 weeks). In one patient, TAM was associated with significant vomiting, necessitating the TAM dose to be decreased at three weeks and then stopped at two months. One other patient had bilateral deep venous thrombosis after 52 weeks on TAM, although the relationship to TAM was not firmly established. There were no radiological responses after two weeks of TAM or at the end of RT. The median time to progression was 17.7 weeks (range 5.1-43.8 weeks). Median survival time was 33.4 weeks (range 10-79.7). Actuarial survival at 48 and 74 weeks was 40% and 15%, respectively. CONCLUSION Our study shows that adjuvant high dose TAM is feasible and relatively well-tolerated. Furthermore, the combined use of high dose TAM and RT postoperatively was not associated with any significant increase in radiation-induced neurological toxicity. However, high dose TAM does not appear to improve treatment results.

Pulsation-pressure relationship in experimental aneurysms: Observation of aneurysmal hysteresis

In this study the pulsation-pressure relationship in an experimental model of aneurysms was analyzed. In addition, we have examined pulsatility of the aneurysmal wall reinforced by Guglielmi Detachable Coils (GDC). Bifurcation (BAn), aneurysms (LAn) and bilobar (BiA) aneurysms were produced in 15 mongrel dogs. The aneurysmal dome was constructed from a segment of the external jugular vein which was sutured to the window performed on the apex of bifurcation of the ECA and lingual artery (BAn) or on the ECA (LAn). One set of the GDC (diameter 5 mm, length 20 cm) were inserted into the aneurysm. Intra-aneurysmal pressure, aneurysmal pulsation, ECG and femoral artery pressure were recorded. Results showed that an experimental aneurysm pulsates in synchrony with the intra-aneurysmal pressure and aneurysmal pulsation is proportional to the aneurysmal size. Pulsation profile also depends on the aneurysmal type (BAn, LAn, BiA). The looped pressure-pulsation curve indicates that aneurysms exhibit property of hysteresis. For the same pressure the aneurysm is smaller during the ascending (systolic) portion of the blood pressure wave. Insertion of catheter into the aneurysm and subsequent release of the GDC did not elicit any measurable changes of the intra-aneurysmal pressure. Aneurysm reinforced by GDC showed smaller pulsation and the hysteresis was reduced as well. It was concluded that aneurysmal hysteresis could be an important factor resulting in degeneration of aneurysmal wall since it is known that hysteresis accelerates degeneration of all fibrous elements, predominantly of elastic fibers. GDC seems to buffer the intra-aneurysmal hemodynamic forces and hence they might have a stabilizing effect on the aneurysmal wall.