Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval.

PURPOSE: Tumor responses in early-phase trials are used to determine whether new agents warrant further study. Given that spontaneous regressions are observed in melanoma and renal cell carcinoma, this study assessed whether tumor responses, particularly in these two tumor types, predict for future regulatory drug approval. EXPERIMENTAL DESIGN: The literature was reviewed to assess tumor response rates to cytotoxic agents in phase I and II trials in the following solid tumors: melanoma, renal cell carcinoma, non-small-cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, and other solid tumors. Response rates were categorized and the relationship of these categories to the end point of regulatory drug approval was determined. RESULTS: Fifty-eight drugs were assessed in 100 phase I trials, and 46 of these drugs were also studied in 499 phase II trials. Higher overall response rates in both phase I trials (P = 0.03) and phase II trials (P < 0.0001) were predictive of regulatory approval. However, response in melanoma or renal cell carcinoma was not predictive for either phase I or phase II studies. CONCLUSIONS: For cytotoxic agents, although overall objective response rates reliably predict subsequent marketing approval, isolated responses in melanoma and renal cell carcinoma are not predictive.     

Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study.

PURPOSE: Adjuvant chemotherapy, especially with anthracyclines, is known to cause acute and chronic cardiotoxicity in breast cancer patients. We studied the cardiac effects of chemotherapy in a population-based sample of breast cancer patients aged > or = 65 years with long-term follow-up. PATIENTS AND METHODS: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we analyzed treatments and outcomes among women > or = 65 years of age who were diagnosed with stage I to III breast cancer from January 1, 1992 to December 31, 1999. Propensity scores were used to control for baseline heart disease (HD) and other known predictors of chemotherapy, and Cox proportional hazards models were used to estimate the risk of cardiomyopathy (CM), congestive heart failure (CHF), and HD after chemotherapy. RESULTS: Of 31,748 women with stage I to III breast cancer, 5,575 (18%) received chemotherapy. Chemotherapy was associated with younger age, fewer comorbidities, hormone receptor negativity, multiple primary tumors, and advanced disease. Patients who received chemotherapy were less likely than other patients to have pre-existing HD (45% v 55%, respectively; P < .001). The hazard ratios for CM, CHF, and HD for patients treated with doxorubicin (DOX) compared with patients who received no chemotherapy were 2.48 (95% CI, 2.10 to 2.93), 1.38 (95% CI, 1.25 to 1.52), and 1.35 (95% CI, 1.26 to 1.44), respectively. The relative risk of cardiotoxicity among patients who received DOX compared with untreated patients remained elevated 5 years after diagnosis. CONCLUSION: When baseline HD was taken into account, chemotherapy, especially with anthracyclines, was associated with a substantially increased risk of CM. As the number of long-term survivors grows, identifying and minimizing the late effects of treatment will become increasingly important.     

Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.

PURPOSE: Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. EXPERIMENTAL DESIGN: Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. RESULTS: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. CONCLUSIONS: AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.     

Perforation Rates for Nonsterile Examination Gloves in Routine Dermatologic Procedures

BACKGROUND: Low cost, nonsterile examination gloves are used routinely to perform various dermatologic procedures. OBJECTIVE: To evaluate the perforation rate of nonsterile examination gloves in routine dermatologic procedures. METHODS: Three hundred fifty nonsterile latex examination gloves used to perform shave biopsies were evaluated for perforations using an air inflation/water submersion method. Ninety gloves, which were intentionally perforated with a 30-gauge needle, were used as controls to assess our evaluation method. RESULTS: Eight of the 350 gloves were found to have a perforation, which corresponds to a 2.3% perforation rate. Seven of the eight perforations were found in the web space between the second and third finger sleeves, with one being an obvious manufacturing error. All 90 perforations of the control group were correctly identified. CONCLUSION: There appears to be a very low risk of glove perforation when nonsterile examination gloves are used in routine dermatologic procedures.     

Secondary intraocular lens implantation for pediatric aphakia.

PURPOSE: We sought to report the outcome of secondary intraocular lens (IOL) implantation in children. METHODS: This was a retrospective case review. RESULTS: A total of 77 eyes were identified. An average age at secondary implantation was 7.8 +/- 5.0 years, whereas the average age at primary cataract surgery was 1.5 +/- 2.6 years. Average follow-up was 2.7 +/- 1.9 years. Thirty eyes received a hydrophobic acrylic IOL implantation whereas 47 eyes received a PMMA IOL. The sites of fixation for implanted IOLs were as follows: anterior-chamber (n = 6), sulcus (n = 42), in-the-bag (n = 14), optic-capture (n = 6), piggyback (n = 4), and sutured (n = 5). Complications included clinically significant decentration, 4 (5.2%); visual axis opacification, 4 (5.2%); dislocation of the IOL, 2 (2.6%); and pupillary capture requiring repositioning of IOL, 1 (1.3%). Clinically significant decentration requiring surgical intervention was noted only in eyes with sulcus-fixated foldable IOLs (28.6%; 4/14). None of the 29 eyes with sulcus-fixated PMMA IOL implantation developed decentration. All the decentrations were in an inferior direction and occurred in eyes of male patients (P = 0.03). Eyes with an axial length of >23 mm were 4 times more likely to develop decentration if implanted with a sulcus-fixated foldable IOL when compared with eyes measuring <23 mm (P = 0.03). Postoperative geometric mean visual acuity was significantly better than preoperative visual acuity (P < 0.001). CONCLUSION: Secondary IOL implantation can be safely achieved in pediatric eyes. In-the-bag fixation of foldable IOLs is associated with a low rate of complications. Foldable lenses appear to have a higher rate of decentration than PMMA lenses when placed in the sulcus in eyes of myopic male patients.     

Aggressive therapy of infants with renal failure

Nine infants, who presented with renal failure within the first 3 months of life, were treated with continuous ambulatory peritoneal dialysis (CAPD). Seven infants survived to an age of 12–15 months, when they received transplants. Two patients died while on CAPD. Six infants are alive with a functioning renal allograft, at an average age of 35.5 months and an average of 22 months post-transplant. Neurological development is normal in four of the six infants tested. The mean current height of the six transplant recipients is just below 2 SD from the mean.