Late visual and auditory toxicity of radiotherapy for nasopharyngeal carcinoma

AIMS AND BACKGROUND: Classical irradiation of carcinoma of the nasopharynx involves large fields and high doses; therefore, significant late toxicity and late side effects are to be expected. Given the fact that nasopharyngeal carcinoma (NPC) is a relatively radiosensitive disease and a significant proportion of patients are long-term survivors, late visual and auditory complications of treatment are of utmost concern for patients and radiation oncologists. The aim of this study was to evaluate the long-term visual and auditory toxicity in patients treated with radiotherapy for NPC. METHODS AND STUDY DESIGN: Forty-three long-term survivors (including 11 children), following definitive radiotherapy for NPC, underwent a thorough visual and auditory evaluation 2-22 years after their treatment. Ophthalmological examination consisted of anamnesis of dry eye syndrome and visual acuity, visual acuity testing, slit-lamp examination, Schirmer test, fundus examination, and intraocular pressure measurement, as well as fluorescein angiography in patients with pathological vascular findings in the fundus examination. Audiological evaluation included anamnesis of hearing loss, tinnitus or vertigo, examination of the ears and nasopharynx, audiogram, and tympanogram. RESULTS: Radiation retinopathy was found in 16% of patients by fundus examination, with one patient (2.3%) developing blindness. Severe dry eye syndrome was present in 26%. Fifty-six percent had some degree of hearing impairment, with 74% showing severe sensorineural hearing loss. Fifty-eight percent of patients reported tinnitus and 26% reported suffering from dizziness. Radiation retinopathy as well as all manifestations of auditory toxicity were found to bear a direct correlation with dose per fraction. CONCLUSIONS: Unless there is tumor involvement, the orbital contents should be completely excluded from the target volume. Auditory toxicity is significant when treating NPC with two-dimensional techniques.     

A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma

AIMS: Interferon-gamma (IFN-gamma) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-gamma gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma. METHODS: Patients were enrolled at four successive dose levels: 10(7) infectious units (iu) (n=3), 10(8) iu (n=3), 10(9) iu (n=3), and 10(10) iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated. RESULTS: A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity. CONCLUSION: Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.     

Rickettsia africae, a tick-borne pathogen in travelers to sub-Saharan Africa

BACKGROUND: African tick-bite fever occurs after contact with ticks that carry Rickettsia africae and that parasitize cattle and game. Sporadic reports suggest that this infection has specific clinical and epidemiologic features. METHODS: We studied patients who were tested for a rickettsial disease after returning from a visit to Africa or Guadeloupe. To assess the value of the microimmunofluorescence assay, Western blotting, and cross-adsorption assays, we compared the results of these tests in 39 patients in whom African tick-bite fever had been confirmed by the polymerase-chain reaction assay, cell culture, or both; 50 patients with documented R. conorii infection; and 50 blood donors. These diagnostic criteria were then applied to 376 additional patients who had returned from southern Africa and 2 who had returned from Guadeloupe and whose serum was being tested for rickettsial disease. RESULTS: In the 39 patients with direct evidence of R. africae infection, the combination of microimmunofluorescence assay, Western blotting, and cross-adsorption assays showing antibodies specific for R. africae had a sensitivity of 0.56; however, each test had a positive predictive value and a specificity of 1.0. An additional 80 patients were found to have an R. africae infection on the basis of these serologic criteria. Infections with R. africae were acquired by visitors to 11 African countries and Guadeloupe. The illness was generally mild and was characterized by a rash in 46 percent of the patients; the rash was usually maculopapular or vesicular and rarely purpuric. Ninety-five percent of patients had an inoculation eschar or eschars, and 54 percent of these patients had multiple eschars, a finding that is unusual in patients with rickettsial infection. CONCLUSIONS: In this series, R. africae was the cause of nearly all cases of tick-bite rickettsiosis in patients who became ill after a trip to sub-Saharan Africa.     

Predictors of neuropathological severity in 100 patients with Huntington's disease

Subjects were followed in the Longitudinal Core Study of the Baltimore Huntington's Disease Center and given annual neurological, cognitive, and psychiatric examinations. Postmortem neuropathological grade was assigned using the system of Vonsattel and colleagues. We examined the correlations between the neuropathological grade and scores on the Quantified Neurological Examination (QNE) and its chorea and motor impairment subscales, the Mini-Mental State Examination (MMSE), the HD Activities of Daily Living (ADL) Scale, and a number of demographic variables (CAG number, age of onset, age at death, disease duration) in 100 subjects who had been examined within 1,000 days of death. All measures showed significant correlation with Vonsattel score except for chorea. The strongest effect was that of motor impairment score (r(2) = 0.351, p < 0.0001). In a stepwise correlation of clinical variables, motor impairment remained significant. The largest effect for a demographic variable was for age of onset (r(2) = 0.226, p < 0.0001) A partial correlation was significant between CAG number and Vonsattel grade, controlling for age at death or disease duration. Motor impairment appears to be a good clinical measure of neuronal cell loss, at least late in the course of HD and therefore may prove useful in observational and treatment studies.     

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.     

Patient satisfaction with laparoscopic Burch retropubic urethropexy

OBJECTIVE: To assess six-month and three- to four-year patient-oriented outcomes after laparoscopic Burch retropubic urethropexy. STUDY DESIGN: Twenty-two women with urodynamically proven genuine stress incontinence with urethral hypermobility underwent laparoscopic Burch retropubic urethropexy. Preoperatively, all 22 women completed a questionnaire concerning their incontinence. Postoperative measures of symptoms of incontinence, impact of incontinence on daily activities and patient satisfaction were assessed at six months and three to four years postoperatively. In those women who were followed, the questionnaire data at the three-time points (preoperative, six months and three to four years) were compared. RESULTS: Thirteen women (59%) completed postoperative questionnaires at six months and three to four years. When compared to preoperative data, there was a significant improvement in symptoms of stress incontinence at six months (P = .0005) and at three to four years (P = .002). There was also a significant reduction in limitations on daily activities at six months (P = .0005) and at three to four years (P = .0005) as compared to preoperative data. Twelve of the 13 women considered their surgery successful at six months and at three to four years. CONCLUSION: After laparoscopic Burch retropubic urethropexy, there was a significant improvement in patient-oriented outcomes, including complaints of incontinence and functional status.     

Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period.

This set of experiments investigated the appetitive or motivational processes underlying the performance of maternal behavior. The place preference paradigm was adapted to simultaneously investigate the reinforcing properties of cocaine and pups for maternal, lactating dams. These modifications allowed the authors to assess which stimulus, either a 10 mg/kg s.c. injection of cocaine or 3 pups, had the strongest reinforcing value. At Postpartum Days 10 and 16, the dams preferred the cocaine cue-associated chamber, whereas the dams tested at Postpartum Day 8 preferred the pup cue-associated chamber. Overall, the data revealed an interaction between the postpartum period at testing and the exhibited preference for cocaine or pups. Further testing will investigate the neural circuitry underlying the appetitive processes of each stimulus.