John Kittelson

OTAGO GLAUCOMA SURGERY OUTCOME STUDY: LONG-TERM RESULTS OF TRABECULECTOMY: 1976 TO 1995

OBJECTIVE To provide data on the long-term results of trabeculectomy performed in the province of Otago, New Zealand. DESIGN Retrospective noncomparative case series. PARTICIPANTS A total of 289 eyes of 193 patients (excluding 4 eyes lost to follow-up soon after operation); all trabeculectomies performed for the first time on cases of primary glaucoma from 1976 through 1995. INTERVENTION Standard Cairns trabeculectomy. MAIN OUTCOME MEASURES Intraocular pressure, visual acuity, visual field damage. RESULTS Trabeculectomy was effective in controlling intraocular pressure at a level of 21 mmHg or less, with probabilities of 0.93 (95% confidence interval [CI], 0.90-0.97), 0.87 (95% CI, 0.82-0.93), and 0.85 (95% CI, 0.77-0.92) at 5, 10, and 15 years, respectively, after surgery. The mean visual acuity improved from 20/60 to 20/40 immediately after trabeculectomy but then declined steadily over the postoperative years. The decline in visual acuity led to blindness in 47 eyes. The Kaplan-Meier estimated probability of retaining useful vision (visual acuity > 20/400 and visual field > 5 degrees radius) in the overall group was 0.87 (95% CI, 0.79-0.91), 0.72 (95% CI, 0.60-0.79), and 0.6 (95% CI, 0.43-0.69) at 5, 10, and 15 years, respectively, after surgery. Those eyes that had good preoperative visual acuity (visual acuity > or = 20/30) had a significantly better chance of retaining useful vision (P = 0.02). CONCLUSIONS The intraocular pressure was well controlled by trabeculectomy, but a steady long-term decline in visual acuity and visual field occurred, decreasing the probability of an eye retaining useful vision up to the time of death to approximately 0.6.

Hemostatic Markers in Acute Ischemic Stroke Association With Stroke Type, Severity, and Outcome

BACKGROUND AND PURPOSE Hemostatic markers can identify activation of the coagulation system in stroke patients. We evaluated whether the levels of these markers at the time of stroke are correlated with stroke severity, type, or mortality. METHODS We measured fibrinopeptide A, cross-linked D-dimer, and beta-thromboglobulin in 70 patients within 1 week of stroke. We examined the association between the level of each of these markers and survival. We adjusted for the possible confounding effect of age, stroke type, or stroke severity using a multivariate Cox proportional hazards model. RESULTS The median follow-up was 1.22 years. Fourteen patients died during follow-up. Univariate survival analysis identified age (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.12), stroke type (hazard ratio, 4.44; 95% CI, 1.29 to 15.23), initial Toronto Stroke Scale score (hazard ratio, 5.05; 95% CI, 2.08 to 12.27), cross-linked D-dimer (hazard ratio, 6.43; 95% CI, 2.83 to 14.62), fibrinopeptide A (hazard ratio, 2.14; 95% CI, 1.26 to 3.63), and beta-thromboglobulin (hazard ratio, 7.63; 95% CI, 2.22 to 26.28) as significantly associated with mortality. In a multivariate model, initial stroke severity and each of the hemostatic markers were independently associated with subsequent mortality. CONCLUSIONS Elevated hemostatic markers after acute ischemic stroke identify patients with increased risk for mortality. This association appears to be independent of stroke severity or stroke type.

Prognostic importance of tumor size for localized conventional (clear cell) renal cell carcinoma: assessment of TNM T1 and T2 tumor categories and comparison with other prognostic parameters.

The T1 and T2 classifications of the International Union Against Cancer TNM classification system for renal cell carcinoma are based on primary tumor size, and in various editions of the classification, the cut points between T1 and T2 have been amended to provide clinical utility. In the current edition, the T1/T2 cut point is less than or equal to and greater than 7 cm. and more recently a subdivision of the T1 classification (less than or equal to and < 4 cm) has been proposed to identify patients suitable for partial nephrectomy. This study investigates the prognostic significance of tumor size in a series of organ‐confined clear cell renal cell carcinomas.

Effects of Testosterone and Progressive Resistance Exercise in Healthy, Highly Functioning Older Men With Low-Normal Testosterone Levels

CONTEXT Aging in men is associated with reduced testosterone (T) levels and physiological changes leading to frailty, but the benefits of T supplementation are inconclusive. OBJECTIVE We studied the effects of T supplementation with and without progressive resistance training (PRT) on functional performance, strength, and body composition. DESIGN, SETTING, AND PARTICIPANTS We recruited 167 generally healthy community-dwelling older men (66 ± 5 years) with low-normal baseline total T levels (200-350 ng/dL). INTERVENTION Subjects were randomized to placebo or transdermal T gel [2 doses targeting either a lower (400-550 ng/dL) or higher (600-1000 ng/dL) T range] and to either PRT or no exercise for 12 months. MAIN OUTCOME MEASURE The primary outcome was functional performance, whereas secondary outcomes were strength and body composition. RESULTS A total of 143 men completed the study. At 12 months, total T was 528 ± 287 ng/dL in subjects receiving any T and 287 ± 65 ng/dL in the placebo group. In the PRT group, function and strength were not different between T- and placebo-treated subjects, despite greater improvements in fat mass (P = .04) and fat-free mass (P = .01) with T. In the non-PRT group, T did not improve function but improved fat mass (P = .005), fat-free mass (P = .03), and upper body strength (P = .03) compared with placebo. There were fewer cardiovascular events in the T-treated groups compared with placebo. CONCLUSIONS T supplementation was well tolerated and improved body composition but had no effect on functional performance. T supplementation improved upper body strength only in nonexercisers compared with placebo.

Oral Iloprost Improves Endobronchial Dysplasia in Former Smokers

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer. Cancer Prev Res; 4(6); 793–802. ©2011 AACR.

Treatment of malignant gliomas with interstitial irradiation and hyperthermia

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.

Pterygium treated with excision and postoperative beta irradiation

A retrospective study was done of 338 patients with pterygia treated between October 1974 and May 1990. These patients resided in the desert of the southwestern United States, where the hot, dry, dusty climate is thought to predispose to pterygium formation and subsequent recurrence. The pterygia were excised, and the administration of beta irradiation was initiated within 24 hr of surgery. Sixteen percent of the pterygia were recurrent. Ninety-five percent of the beta irradiation prescriptions consisted of 3 weekly 800 cGy fractions. For patients with a minimum of 6 months follow-up, the crude local control rate was 225/258 (88%). The Kaplan-Meier estimate of the 5-year local control rate was 84% (95% confidence interval: 79-89%). Ten of 33 recurrences were diagnosed within 6 months, and 32/33 recurrences were diagnosed within 5 years of treatment. Previously untreated pterygia were controlled more easily than were recurrent pterygia (p = 0.005). In 86% of the cases, patients judged the cosmetic results to be satisfactory. No severe complications developed. This study and others, when compared with studies involving excision alone, suggest that postoperative beta irradiation reduces the likelihood for pterygium recurrence. When the beta irradiation is fractionated, satisfactory cosmetic results can be achieved with low morbidity.

Analysis of c-ErbB1/Epidermal Growth Factor Receptor and c-ErbB2/HER-2 Expression in Bronchial Dysplasia: Evaluation of Potential Targets for Chemoprevention of Lung Cancer

Purpose: Lung cancer is preceded by a premalignant phase during which intervention could decrease associated morbidity and mortality. Molecular characterization of factors involved in controlling progression of bronchial dysplasias will provide markers of premalignant change and identify targets for chemoprevention. Experimental Design: Immunohistochemical analysis of epidermal growth factor receptor (EGFR; c-ErbB1/EGFR), HER-2/neu (c-ErbB2/HER-2), Ki-67, and minichromosome maintenance protein 2 (MCM2) expression in bronchial dysplasia was undertaken to characterize molecular alterations associated with the progression of these lesions in 268 bronchoscopically obtained biopsies from 134 subjects. Results: Analysis of biopsies with the most severe diagnosis from each subject showed a linear relationship between increasing marker expression and severity of dysplastic change for EGFR (P < 0.001), Ki-67 (P < 0.001), and MCM2 (P = 0.001) but not HER-2 (P = 0.102). Increased expression of either EGFR or HER-2 was associated with increased levels of Ki-67 and MCM2 expression, and combined overexpression of these receptors was associated with the highest levels of proliferation, suggesting a synergistic effect. Finally, the lack of an associated trend toward increased EGFR expression when comparing the worst and best biopsies within each subject indicated a potential field effect in the induction of EGFR expression. Conclusions: The results suggest a prominent role for EGFR overexpression in the development and progression of bronchial dysplasia and provide rationale for exploring inhibition of EGFR signaling in lung cancer chemoprevention.

Basal cell carcinoma treated with radiation therapy

Between 1974 and 1989, 85 patients with 115 biopsy‐proven basal cell carcinomas were treated with radiation therapy at the University Medical Center in Tucson. Either orthovoltage or megavoltage photons were used to deliver doses ranging from 2000 cGy in a single treatment to 7300 cGy in 35 fractions over 62 days. The median length of follow‐up was 40 months. Kaplan‐Meier estimates of the 5‐year local control rates are presented by American Joint Committee on Cancer stage. The difference between the local control rates for both previously untreated and recurrent Stage I and II carcinomas (95% at 5 years) and Stage III and IV carcinomas (56% at 5 years) was statistically significant (P = 0.0001, by Mantel‐Haensel test). Although recurrent basal cell carcinomas generally have a worse prognosis, the Kaplan‐Meier estimate of the 5‐year local control rate for recurrent Stage I and II carcinomas treated with radiation therapy was 95%. These results, along with a review of the literature, suggest two points: (1) high cure rates can be obtained when Stage I and II basal cell carcinomas are treated with radiation therapy and (2) radiation therapy is a relatively effective method for treating recurrent basal cell carcinomas, with cure rates surpassed only by Mohs micrographic surgery. Cancer 68:2134–2137, 1991.

Interstitial irradiation versus interstitial thermoradiotherapy for supratentorial malignant gliomas: A comparative survival analysis

PURPOSE To compare the survival of two groups of patients with supratentorial malignant gliomas who were treated on two sequential protocols with either interstitial thermoradiotherapy or with interstitial irradiation without hyperthermia. METHODS AND MATERIALS Between 1988-1992, patients with anaplastic astrocytoma or glioblastoma multiforme were treated at the University of Arizona on a Phase I/II protocol of interstitial thermoradiotherapy with ferro-magnetic seeds. The treatment protocol consisted of debulking surgery, a course of external beam radiotherapy and hyperthermia given immediately before and after brachytherapy. The survival of patients so treated was compared with that of a similar group of patients treated with interstitial brachytherapy alone at the Barrows Neurological Institute between 1982-1990. RESULTS Twenty-five patients with primary tumors treated at the time of initial presentation with thermoradiotherapy were compared with a control group of 37 patients treated with interstitial brachytherapy alone. All primary patients were followed for a minimum of 34 months post implant. Multivariate analysis based on proportional hazards models showed that hyperthermia (p = 0.027), patient age (p < or = 0.00001) and histology (anaplastic astrocytoma vs. glioblastoma multiforme, p = 0.0017) were the only factors significantly associated with survival in this data set. From the fitted model, the hazard of dying when treated with hyperthermia was .53 times (95% confidence intervals 0.29-0.94) than that of the control group. In addition, we treated a small group of patients with recurrent tumors (13 with brachytherapy alone, and eight with thermoradiotherapy) and found no survival difference (p = 0.62). CONCLUSION Within the constraints of the selection factors and the different treatment parameters used in these studies, we conclude that an interstitial thermoradiotherapy boost confers a statistically significant survival benefit to patients with primary high grade gliomas when compared to interstitial brachytherapy alone.