Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: IGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. METHODS: Patients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). RESULTS: 61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1-18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8-89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0-3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8-2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. CONCLUSIONS: IGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer.

PURPOSE: Insulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. DESIGN: Patients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. RESULTS: 170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82-1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). CONCLUSION: Addition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Unit responses from commissural fibers of optic lobes of fish.

The paired optic lobes of teleost fish are connected by two commissures. One of these, the tectal commissure, was studied with metal microelectrodes. Fibers are rhythmically active for prolonged periods in the dark and respond to light by a decrease in the rate of discharge. There is a rebound acceleration when the light is turned of. Each fiber is influenced by light in one eye only, and there is no response when light is projected into the opposite eye. This behavior resembles the "off" response recorded from the optic lobes and the optic nerve of fish. Unlike most units from the visual pathways of lower animals, single commissural fibers do not seem to give any recognizable response to patterned input such as small light or dark objects or small light sources stationary or moving anywhere in the visual field, nor do they respond to a vertical black bar moved over a white background.

Measurements of finger doses in x-ray guided surgery, nuclear medicine and research.

The Norwegian Radiation Protection Authority has performed measurements of finger doses to nuclear medicine staff exposed to 99Tc(m), researchers handling 32P, surgeons performing X-ray guided orthopaedic surgery and surgeons and radiologists performing X-ray guided endovascular treatment of abdominal aortic aneurysms (AAA). Calibrations were done with X-ray qualities N-40, N-60 and N-300 and with the beta source 90Sr + 90Y. Annual doses were estimated for the nuclear medicine staff and the orthopaedic surgeons. The mean annual finger dose to nuclear medicine staff exposed to 99Tc(m) was estimated to be 18.8 mSv, and the mean annual finger dose to surgeons performing X-ray guided orthopaedic surgery was 13.7 mSv. The surgeons and radiologists performing X-ray guided endovascular treatment of AAA received a mean finger dose of 0.35 mSv per treatment. The majority of researchers handling 32P received no finger dose at all, and the maximum reading was 1.65 mSv. All occupational groups received finger doses well below the annual finger dose limit of 500 mSv.

Mast cell TNF mRNA expression in nasal mucosa demonstrated by in situ hybridization: a comparison of mast cell detection methods.

We have used 35S-labelled RNA probes to detect TNF cytokine gene expression in nasal mucosa derived from patients with perennial rhinitis. As mast cells comprise a minor component of the total cell population in nasal mucosa, additional methods are needed to determine whether mast cells contribute to the cytokine mRNA detected by in situ hybridization. We have combined in situ hybridization with alternate methods to detect mast cells (tryptase immunostaining or toluidine blue staining) and determined that in situ hybridization coupled with tryptase immunostaining provides optimal methods to detect mast cell cytokine gene expression in tissue sections. Using in situ hybridization and tryptase immunostaining, we demonstrate that mast cells in nasal mucosa can express TNF mRNA. However, the number of tryptase-, TNF+ cells (1.99 +/- 1.59 cells/mm2) exceeded the number of tryptase+, TNF+ mast cells (0.09 +/- cells/mm2). Mast cells thus comprised a subpopulation of the total number of TNF mRNA positive cells in nasal mucosa.

Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck.

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.

Rapid clinical evaluation of anosmia in children: the Alcohol Sniff Test.

Smell impairment affects 1-2% of Americans and leads to frequent physician visits. Olfactory functional testing is available in chemosensory centers, but is frequently omitted in routine cranial nerve examinations. A new smell test, using the standard 70% isopropyl alcohol pad, was developed at the UCSD Nasal Dysfunction Clinic: The Alcohol Sniff Test (AST). The current study examined the reliability of the AST in children, using test-retest measures. A standard 70% isopropyl alcohol pad was moved upward 1 cm per exhalation until the participant reported detection. Test-retest reliability of the AST in children was significant, r = 0.80. The AST predictably classified children as anosmic, hyposmic or normosmic, p < 0.0001. The AST requires only 5 minutes to administer with materials readily available in any physician's office or hospital. The AST is an effective screening tool, even in children, for the average physician who can then refer patients who show less than normal function for further comprehensive testing.

Importance of the columellar-labial junction in rhinoplasty.

Concentration on tip positioning may draw a surgeon's attention away from modifying positions of the nasofrontal angle and of the columellar-labial junction. All three landmarks are, however, vital to the establishment of desirable profiles. This article emphasizes that changes in the positioning of the columellar-labial junction may (1) eliminate certain hazards involved in changing tip position, (2) make it possible to produce aesthetic effects that cannot be achieved with tip positioning alone, and (3) make rhinoplasty safer and more predictable in certain difficult cases. Also presented are techniques that have been found to work most satisfactorily in changing angle and position. A few patients selected from among several thousand rhinoplastic cases are analyzed to underscore the significance of this area in rhinoplastic planning. Follow-up varied from several months to several years.

Anatomy of the superficial temporal artery.

The anatomy of the superficial temporal artery was investigated in radiographic and cadaveric studies. The superficial temporal artery divides into an anterior and posterior branch, and the diameters of these vessels are similar. The anatomy of these two vessels is described, and implications for their use in reconstructive flaps are suggested.

Browplasty as an adjunct to rhinoplasty.

Brow modifications are discussed with respect to their role as aids in achieving certain aesthetic effects when rhinoplasty is being performed. If a deep nasofrontal angle should not be brought forward, reduction of the brow may be indicated. If the nasofrontal angle should not be retrodisplaced to deepen a shallow angle, brow augmentation may prove helpful in separating the nose from the forehead or in making the nose appear shorter in the vertical dimension. Augmentation and reduction browplastic techniques are discussed, and selected methods are illustrated. Some involve additional resection of frontal bone or procerus muscle at the time of nasal-hump removal. Others employ grafts of bone and/or cartilage removed from the nose at the time of septorhinoplasty. The versatile aesthetic surgeon should be capable of changing all structures adjacent to the nose. Certain difficult cosmetic problems are best treated by directing appropriate attention to these structures and to the nose rather than by concentrating on the nose alone. That the brow is one of these important abutting landmarks is demonstrated.

Selective hypnotic amnesia: is it a successful attempt to forget or an unsuccessful attempt to remember?

Subjects in 2 experiments (ns = 72 and 50) learned a 16-item, 4-category word list and were then administered hypnotic suggestions to be amnesic for all the words in 1 of the categories. Even when selective amnesia was completely successful, subjects in both experiments revealed a high level of recall for words not targeted for amnesia; moreover, these words were recalled in a highly organized, category-by-category fashion. Evidently, attention to relevant retrieval (i.e., organizational) cues does not oblige recall of words targeted for amnesia. Forgetting in the presence of such powerful mnemonic cues seems to characterize hypnotic amnesia and some spontaneous forms of forgetting as well. We argue that mnemonic lapses of this kind represent a failed attempt to remember rather than a successful attempt to forget.

Envenomation by the colubrid snake Atractaspis bibronii: a case report.

A reptile caretaker was bitten and envenomated by Atractaspis bibronii while handling a box of "non-venomous" colubrid feeder snakes. The patient was bitten on a finger by a single fang. Pain and swelling were noted within 10 min and dissipated over the ensuing 3 days. This case report adds to the limited number of bites by A. bibronii already found in the literature and reviews what is currently known about the species.

Intraarticular envenomation by Trimeresurus flavomaculatus mcgregori resulting in joint destruction.

This article reports a case of digital intraarticular envenomation from a T. flavomaculatus mcgregori pit viper resulting in severe joint damage. Bites by these snakes are rare in the U.S.A. since this species is only found in collections and zoos. Intraarticular envenomations from crotalids are rare and may result in joint destruction.

Odor sensitivity is impaired in HIV-positive cognitively impaired patients.

An estimated 7-28% of patients infected by the human immunodeficiency virus (HIV) develop dementia and at least 50% develop mild neurocognitive impairment. Past studies have shown odor identification impairments in HIV + neurocognitively impaired patients. It is difficult, however, based on an odor identification test to state with certainty that individuals with cognitive impairment have sensory olfactory deficits, because odor identification tests are known to draw upon cognitive skills. In the present study odor detection sensitivity was evaluated using an ascending, forced-choice, two-alternative, odor threshold test for butanol. Subjects were divided into three groups, HIV seropositive (HIV+) neurocognitively impaired, HIV+ neurocognitively unimpaired, and HIV negative, based on neurological and psychological testing. An analysis of variance revealed significantly poorer odor sensitivity for the HIV+ neurocognitively impaired group than for the two control groups. A significant negative correlation between degree of cognitive impairment and olfactory sensitivity was also found. We suspect that the olfactory deficits found in the HIV+ neurocognitively impaired subjects are primarily due to damage to the central nervous system; however, nasal infection may be a contributing etiology.

Cochlear deoxyglucose uptake: relationship to stimulus intensity.

The relationship between stimulus intensity and the uptake of 2-deoxyglucose (2-DG) in the cochlea of the gerbil was studied using an autoradiographic technique. In silence, incorporation of labeled 2-DG into stria vascularis and the spiral ligament was significantly higher than for other inner ear structures. With increasing intensity of noise exposure, 2-DG uptake in the spiral ganglion and VIIIth nerve increased dramatically when compared to the lateral wall structures. In contrast, relative 2-DG uptake in the organ of Corti was much less affected by noise exposure. Only at 105 dB SPL, the highest intensity tested, was a modest but statistically significant increase observed in the sensory epithelium. The small change in relative 2-DG uptake observed in the organ of Corti during acoustic stimulation is consistent with Davis' (1965: Quant. Biol. 30, 181-190) battery model of the cochlear transduction process. Alternatively, a larger change may have occurred, but been restricted to a small portion of the epithelium, such as one or both populations of hair cells.

Tip suspension suture for superior tip rotation in rhinoplasty.

Superior tip rotation is sometimes necessary to relieve functional obstruction as well as improve the esthetic appearance in the aging nose and the thick skinned heavy tip nose. Conventional techniques including thinning resection, rim strip, lateral crural flap and even external skin excisions are often inadequate to obtain and maintain sufficient superior tip rotation. A technique is described to permanently suture the lower lateral crus to the upper lateral cartilages and to the cartilaginous septum. Long-term follow-up supports this technique's cosmetic and functional effectiveness.

The effect of hemolyzed erythrocytes in the virulence of Escherichia coli and of normal human oral flora in a mouse model.

Hemoglobin enhances the virulence of E. coli in the peritoneum. This study investigates the effect of blood on the virulence of E. coli and human oral anaerobes in the mouse neck. E. coli neck infectivity is significantly enhanced by blood. Oral anaerobic infections are not affected.

Clinical study and literature review of nasal irrigation.

OBJECTIVES/HYPOTHESIS: Nasal disease, including chronic rhinosinusitis and allergic rhinitis, is a significant source of morbidity. Nasal irrigation has been used as an adjunctive treatment of sinonasal disease. However, despite an abundance of anecdotal reports, there has been little statistical evidence to support its efficacy. The objective of this study was to determine the efficacy of the use of pulsatile hypertonic saline nasal irrigation in the treatment of sinonasal disease. STUDY DESIGN: A prospective controlled clinical study. METHODS: Two hundred eleven patients from the University of California, San Diego (San Diego, CA) Nasal Dysfunction Clinic with sinonasal disease (including allergic rhinitis, aging rhinitis, atrophic rhinitis, and postnasal drip) and 20 disease-free control subjects were enrolled. Patients irrigated their nasal cavities using hypertonic saline delivered by a Water Pik device using a commercially available nasal adapter twice daily for 3 to 6 weeks. Patients rated nasal disease-specific symptoms and completed a self-administered quality of well-being questionnaire before intervention and at follow-up. RESULTS: Patients who used nasal irrigation for the treatment of sinonasal disease experienced statistically significant improvements in 23 of the 30 nasal symptoms queried. Improvement was also measured in the global assessment of health status using the Quality of Well-Being scale. CONCLUSIONS: Nasal irrigation is effective in improving symptoms and the health status of patients with sinonasal disease.

MOHS for head and neck mucosal cancer: report on 111 patients.

Microscopically Oriented Histologic Surgery (MOHS) has been applied to primary epidermoid cancers of the mucosal tissues of the head and neck since 1979. In that time we have treated 170 patients and maintained excellent records, losing no patients to follow-up. One hundred three patients have been followed for 2 years. Of this group, only nine patients have developed local recurrences; three were salvaged, six were not. This presentation reviews the concept of MOHS and its application to head and neck mucosal lesions. The results are analyzed, and conclusions are drawn regarding what we have learned about the biologic behavior of head and neck tumors and the role of MOHS in treating these neoplasms.