A phase I dose escalation study of Ad GV.EGR.TNF.11D (TNFerade™ Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation.

BACKGROUND: AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS: TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 10(9) to 4 × 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS: TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 10(10) PU. Monitoring for thrombotic events is indicated.

A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers.

INTRODUCTION: We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC). PATIENTS AND METHODS: Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m(2)/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy. RESULTS: Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen. CONCLUSIONS: Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.

Phase II trial of pemetrexed-based induction chemotherapy followed by concomitant chemoradiotherapy in previously irradiated patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. PATIENTS AND METHODS: Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. RESULTS: Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2-54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6-8.3) and 9.5 months (95% CI 7.2-15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. CONCLUSIONS: The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.

Functional organ preservation with definitive chemoradiotherapy for T4 laryngeal squamous cell carcinoma.

BACKGROUND: Randomized trials established chemoradiotherapy as standard treatment for advanced laryngeal cancer. Patients with large-volume T4 disease (LVT4) were excluded from these trials. The purpose of this study was to report T4 laryngeal cancer patient outcome, including those with LVT4 disease, treated with chemoradiotherapy. PATIENTS AND METHODS: This study is a retrospective subset analysis of 32 patients with T4 laryngeal carcinoma including LVT4 tumors treated on three consecutive protocols investigating paclitaxel (Taxol), 5-fluorouracil, hydroxyurea, and 1.5-Gy twice daily (BID) radiotherapy (TFHX). RESULTS: Median follow-up is 43 months. Four-year locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and laryngectomy-free survival (LFS) was 71%, 67%, 53%, and 86%, respectively. Four patients required laryngectomy for recurrent or persistent disease. Of disease-free patients with >or=1 year follow-up, 90% demonstrated normal or understandable speech. None required laryngectomy for complications. Among LVT4 patients, 4-year LRC, DFS, OS, and LFS was 71%, 65%, 56%, and 81%, respectively. Induction chemotherapy improved 4-year LRC (90% versus 46%, P = 0.03) and DFS (84% versus 42%, P = 0.03). CONCLUSIONS: Promising control and functional outcomes are achieved with TFHX for T4 laryngeal patients. LVT4 disease had outcomes similar to patients with less advanced disease treated on Radiation Therapy Oncology Group 91-11. Induction chemotherapy improved outcomes, warranting further investigation.

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels.

BACKGROUND: We hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity. PATIENTS AND METHODS: Stages III-IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy. RESULTS: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027). CONCLUSIONS: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

[Intracranial localization revealing Hodgkin's disease]. / Lésion intracrânienne révélatrice d'une maladie de Hodgkin.

The central nervous system's (CNS) involvement is uncommon in Hodgkin's disease (HD) and usually occurs in patients with relapsing disease many years after the initial diagnosis. An isolated involvement of the CNS is extremely rare and therefore, difficult to diagnosis. We report the case of a 27-year-old woman with seizure and a left cerebrodural mass on the cerebral imaging; secondarily, she developed cervical lymph node swelling; histological examination of the node revealed HD of the nodular sclerosis type. The dural lesion resolved after chemotherapy for HD.

[Listeria monocytogenes encephalitis revealed by left progressive hemiparesis]. / Hémiparésie d'installation progressive révélant une encéphalite à listéria monocytogènes.

INTRODUCTION: Central nervous system listeriosis is a diagnostic and therapeutic challenge for the clinician. CASE REPORT: We report the case of a 66-year-old woman who was admitted for a left progressive hemiparesis associated with headaches. She was treated for one year by immunosuppressive drugs for vulgaris pemphigus. At the time of admission, examination revealed left hemiparesis without fever, and a computed tomography brain scan demonstrated a focal lesion in the right frontal lobe. Blood analyses were normal. Two days after, she suddenly developed fever (40 degrees C), and aggravation of her motor deficit followed by partial motor seizures. The cerebrospinal fluid was normal. Treatment with amoxicillin (3g IV q6h), cefotaxim, gentamycin (120mg IV q12h) and aciclovir was started empirically. The brain MRI without gadolinium displayed infiltrative lesions in the right hemisphere and in the mildbrain. The blood culture grew Listeria monocytogenes. The antimicrobial regimen was changed to amoxicillin for seven weeks and gentamicin for the first ten days. Four days after beginning the antimicrobial regimen, the brain MRI with gadolinium displayed several abscesses measuring less than one cm diameter. The clinical and imaging outcome excellent. CONCLUSION: Meningitis is by far the most central nervous system listeriosis. In our patient, the diagnosis of listeria monocytogenes encephalitis was established on the basis of positive blood cultures, as such patients do not have sterile cerebrospinal fluid.

Improving Catheter Associated Urinary Tract Infection Rates in the Medical Units.

Sheikh Khalifa Medical City (SKMC) in Abu Dhabi is the main tertiary care referral hospital in the United Arab Emirates (UAE) with 560 bed capacity with a high occupancy rate. SKMC senior management has made a commitment to make quality and patient safety a top priority. Preventing health care associated infections, including Catheter Associated Urinary Tract Infection (CAUTI), is a high priority for our hospital. In order to improve CAUTI rates a multidisciplinary task force team was formed and led this performance improvement project. The purpose of this publication is to indicate the quality improvement interventions implemented to reduce CAUTI rates and the outcome of those interventions. We chose to conduct the pilot study in General Medicine as it is the busiest department in the hospital, with an average of 390 patients admitted per month during the study period. The study period was from March 2015 till April 2016. Our aim was to reduce CAUTI rates per 1000 device days in the medical units. Implemented interventions resulted in a reduction of CAUTI from 6.8 per 1000 device days in March 2015 to zero CAUTI in February through April 2016.

Improving venous thromboembolism risk assessment compliance using the electronic tool in admitted medical patients.

Sheikh Khalifa Medical City (SKMC) in Abu Dhabi is the main tertiary care referral hospital in the United Arab Emirates (UAE) with 560 bed capacity that is fully occupied most of the time. SKMC senior management has made a commitment to make quality and patient safety a top priority. Venous thromboembolism (VTE) risk assessment has been identified as a critical patient safety measure and key performance indicator. The electronic VTE risk assessment form a computerized decision support tool was introduced to improve adherence with deep venous thrombosis (DVT) prophylaxis recommendations. A multidisciplinary task force team was formed and led this quality improvement project. The purpose of this publication is to indicate the quality improvement interventions implemented to enhance compliance with VTE risk assessment and the outcomes of those interventions. We chose to conduct the pilot study in General Medicine as it is the busiest department in the hospital. The study period was from April 2014 till August 2015.The lessons learned were disseminated throughout the hospital. Our aim was to improve VTE risk assessment compliance by using the electronic form in order to ensure patient safety and reduce preventable harm. VTE risk assessment compliance improved in general medicine from 4% to 98%, and overall SKMC compliance from 21% to above 90%.

Cerebral amyloid angiopathy and granulomatous angiitis: immunohistochemical study using antibodies to the Alzheimer A4 peptide.

Neuropathologic study of an 82-year-old male who died from massive cerebral hemorrhage showed extensive amyloid angiopathy, with morphologic and immunohistochemical characteristics similar to those observed in Alzheimer's disease, associated with granulomatous angiitis, including the presence of numerous giant cells. Some of the giant cells contained, in their cytoplasm, congophilic material immunoreactive for the Alzheimer A4 peptide, supporting the hypothesis that the granulomatous angiitis may, in part, represent a foreign body reaction to A4 amyloid deposition.

Anti-galectin-1 autoantibodies in serum of patients with neurological diseases.

The presence of autoantibodies to human brain galectin-1 was investigated in serum from patients with multiple sclerosis, patients with or without evidence of other neurological disorders, and healthy controls, using an ELISA on purified brain galectin-1. Levels of autoantibodies to galectin-1 were significantly higher in patients than in healthy controls. Comparison of levels of anti-galectin-1 and anti-idiotypic antibodies mimicking human brain galectin-1 (L-IgG) showed that the highest levels of autoantibodies were present in patients with low levels of L-IgG. This finding can be explained by hypothesizing that the concentration of autoantibodies to galectin-1 is possibly associated with impairment of the regulation of the immune system.

Tuberculoma of the cavernous sinus: case report.

OBJECTIVE AND IMPORTANCE: The cavernous sinus is an exceptional location for intracranial tuberculomas. A rapid diagnosis, based on pathological findings, improves the prognosis. CLINICAL PRESENTATION: A case of left cavernous sinus tuberculoma, revealed by frontal headaches and ipsilateral palsies of Cranial Nerves III and V, in a 48-year-old patient is reported. The lesion mimicked an aggressive meningioma in radiological examinations. INTERVENTION: The lesion was excised through a subtemporal approach. The diagnosis was based on the pathological examination of the mass. Postoperative antituberculous chemotherapy completed the treatment. Neurological symptoms regressed rapidly. CONCLUSION: Although the incidence of intracranial tuberculomas is decreasing in developed countries, a high index of suspicion must be maintained for the diagnosis of intracranial masses in the presence of risk factors for tuberculosis.

Post-anoxic delayed encephalopathy with leukoencephalopathy and non-hemorrhagic cerebral amyloid angiopathy.

A 74 year-old woman with an early-stage senile dementia developed severe hypertonia and akinetic mutism two weeks after exposure to methane. A CT scan showed a diffuse area of decreased density extending symmetrically into the white matter of both cerebral hemispheres. Neuropathology revealed a senile dementia, Alzheimer's type, with severe non-hemorrhagic cerebral amyloid angiopathy and a diffuse spotty demyelination of the cerebral hemispheres sparing the U fibers, corpus callosum and internal capsules. The close resemblance between Grinker's myelinopathy, secondary to CO exposure or to other non-CO anoxic causes, and the leukoencephalopathy associated with cerebral amyloid angiopathy is emphasized.

The morphology of the femur in developmental dysplasia of the hip.

We studied the morphometry of 35 femora from 31 female patients with developmental dysplasia of the hip (DDH) and another 15 from 15 age- and sex-matched control patients using CT and three-dimensional computer reconstruction models. According to the classification of Crowe et al 15 of the dysplastic hips were graded as class I (less than 50% subluxation), ten as class I/III (50% to 100% subluxation) and ten as class IV (more than 100% subluxation). The femora with DDH had 10 to 14 degrees more anteversion than the control group independent of the degree of subluxation of the hip. In even the most mildly dysplastic joints, the femur had a smaller and more anteverted canal than the normal control. With increased subluxation, additional abnormalities were observed in the size and position of the femoral head. Femora from dislocated joints had a short, anteverted neck associated with a smaller, narrower, and straighter canal than femora of classes I and II/III or the normal control group. We suggest that when total hip replacement is performed in the patient with DDH, the femoral prosthesis should be chosen on the basis of the severity of the subluxation and the degree of anteversion of each individual femur.

[An ischemic syndrome of the oculumotor nucleus: associated clinical and anatomical variations on a theme]. / Syndrome nucléaire du nerf oculo-moteur commun (III) d'étiologie ischémique: variations cliniques et anatomiques associées.

Nuclear syndrome of the oculomotor nerve was first described in 1981, it is characterized by the association of an ipsilateral third nerve palsy with a paresis of elevation in the contralateral eye. This syndrome can be caused by vascular or tumoral lesions in the upper midbrain. It is rarely due to ischemic unilateral mesencephalic lesions, because ischemic lesions of the midbrain are usually integrated in a diffuse involvement of the brainstem and the thalamo-sub-thalamic region. In case of nuclear syndrome of the third nerve due to isolated upper midbrain infarct in the paramedian territory, dependent on branches of the basilar artery, oculomotor symptoms are frequently isolated. On the contrary, in fascicular syndromes of the third nerve, resulting from stroke in more lateral territories upon branches of the posterior cerebral artery, many neurological symptoms are associated with the oculomotor signs. We describe 3 patients presenting with a characteristic nuclear syndrome of the third nerve, resulting from a unilateral paramedian ischemic stroke in the upper midbrain, confirmed by cerebral CT scan or MRI examination. Clinical presentation differed in each case, and marked contralateral hemiparesia, cerebellar syndrome and focal asterixis were associated in various ways with the stereotyped oculomotor disorders. In the 3 cases, the nuclear syndrome of the third nerve was associated with fascicular involvement of the nerve, in an unusual clinical picture. The theoretical distinction between nuclear and fascicular syndromes is supported by the anatomical description of the arterial segmentation in the upper midbrain, which remains debated since the first description. According to the variability of clinical presentations, it seems that the arterial territories may be more variable than initially described. Therefore, ischemic lesions of the upper midbrain may involve some vascular borderzones with a high inter-individual variability. Upper midbrain strokes may thus lead to variable clinical pictures.

[Hemiballismus and metastasis to the Luys' body. An anatomo-clinical case]. / Hémiballisme et métastase du corps de Luys. Un cas anatomo-clinique.

A 55 year-old man complained of headaches, dizziness and vomiting. Neurological examination only showed a cerebellar syndrome. CT scan revealed two hyperdense round areas in the right frontal lobe and cerebellar vermis consistent with metastases and a lung carcinoma was diagnosed. Two months later he presented with typical right hemichorea. A second CT scan showed another hypodense lesion with slight contrast enhancement in the left subthalamic region. He died 6 months after clinical onset. Post mortem examination showed an adenocarcinoma of the right lung with liver metastases. Neuropathological examination revealed four intraparenchymatous metastases one of which involved the left subthalamic nucleus. Hemichorea secondary to metastatic neoplasm of the corpus Luysii is uncommon; only 6 cases have been reported previously; five of them had a post mortem examination of the brain. In three cases a CT scan was available and had demonstrated the site and nature of the lesion.

[Study of auditive evoked potentials in multiple sclerosis (author's transl)]. / Etude des potentiels évoqués auditifs au cours de la sclérose en plaques.

The Brain stem evoked response audiometry have been studied in 34 cases of multiple sclerosis. The Brainstem in 8 cases were normal and abnormal on one or both sides in the remaining 26 cases (73.5 p. 100). A Brainstem is considered suspicious of multiple sclerosis when the first wave (N1) is normal as far as the time period is concerned, although there is a loss of synchronisation of the recording particularly as far as the higher part of the brain stem (N4 and N5). In 24 cases of multiple sclerosis of definite diagnosis (according to Mac Alpine criteria) 19 cases had abnormal recordings (79.2 p. 100). In 31 cases that had a neurological test showing a lesion of the brain stem, 23 cases of evoked potentials were abnormal (74.2 p. 100). In 3 cases that clinicaly had no lesion of the brain stem, the evoked potentials were abnormal in 2 of them, suggesting the eventuality of a lesion clinicaly non-reactive which can then be of help to confirm the diagnosis.

[Cerebral lymphoma associated with lesions of multiple sclerosis]. / Lymphome cérébral associé a des lésions de sclérose en plaques.

A 24 year-old man experienced a left retrobulbar neuritis which improved completely after 2 months of non-steroid antiinflammatory therapy. One month after the end of the treatment he developed a Korsakoff-like amnestic syndrome. Three months later he complained of horizontal diplopia. A CT Scan showed a diffuse enhancement of the periventricular areas, corpus callosum and fornix. Diplopia and CT scan abnormalities disappeared after the administration of tetracosactide. Subsequently a progressive worsening of the neurological condition developed, including a 1 1/2 syndrome of Fisher. In C.S.F. proteins ranged from 35 to 66 mg/dl, gammaglobulins from 4 to 5 per cent, cells from 2.2 to 6.8 per mm3 without abnormal cells. Rounded areas of enhancement were observed on CT scan in pons and right occipital lobe. Usual biological tests, abdominal echography and lymphography were normal. Death occurred 15 months after the onset of symptoms. Neuropathological examination showed: 1) a cerebral lymphoma of probable B origin with distinct masses in right occipital lobe and pontine tegmentum and a more diffuse perivascular infiltration on the left side in the amygdaloid nucleus, fourth temporal gyrus, sublenticular area, hypothalamus and in the right internal capsule; 2) multiple small clear-cut foci of demyelination with myelin-axonal dissociation bilaterally in the optic pathways, periventricular regions, corona radiata, cerebral and cerebellar white matter, sublenticular areas, temporal lobes, splenium of the corpus callosum and fornices with secondary atrophy of the mamillary bodies. Both recent and old plaques were observed. Inflammatory perivascular cuffing, when present, consisted of small nontumoral lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

[Gerstmann-Sträussler-Scheinker disease. Pathologal and genetic study]. / Maladie de Gerstmann-Sträussler-Scheinker. Etude pathologique et généalogique.

Gerstmann-Sträussler-Scheinker's disease is a familial spongiform encephalopathy whose pathological hallmark is the existence--especially in the cerebellum--of numerous amyloid plaques. We report here the third clinicopathological case in a French family. Brain tissue from one of its members--initially described as familial Creutzfeldt-Jakob's disease--has been reported as successfully inoculated to monkeys. We present the currently accumulating data favouring the hypothesis of a common etiology for familial Creutzfeldt-Jakob's disease and Gerstmann-Sträussler-Scheinker's disease. The familial characteristics, resulting in different durations of incubation and evolution, could lead to different clinical and histological expressions.