Risks of spontaneous injury and extraction of an active fixation pacemaker lead: report of the Accufix Multicenter Clinical Study and Worldwide Registry.

BACKGROUND: The Telectronics Accufix pacing leads were recalled in November 1994 after 2 deaths and 2 nonfatal injuries were reported. This multicenter clinical study (MCS) of patients with Accufix leads was designed to determine the rate of spontaneous injury related to the J retention wire and results of lead extraction. METHODS AND RESULTS: The MCS included 2589 patients with Accufix atrial pacing leads that were implanted at or who were followed up at 12 medical centers. Patients underwent cinefluoroscopic imaging of their lead every 6 months. The risk of J retention wire fracture was approximately 5.6%/y at 5 years and 4.7%/y at 10 years after implantation. The annual risk of protrusion was 1.5%. A total of 40 spontaneous injuries were reported to a worldwide registry (WWR) that included data from 34 672 patients (34 892 Accufix leads), including pericardial tamponade (n=19), pericardial effusion (n=5), atrial perforation (n=3), J retention wire embolization (n=4), and death (n=6). The risk of injury was 0.02%/y (95% CI, 0.0025 to 0. 072) in the MCS and 0.048%/y (95% CI, 0.035 to 0.067) in the WWR. A total of 5299 leads (13%) have been extracted worldwide. After recall in the WWR, fatal extraction complications occurred in 0.4% of intravascular procedures (16 of 4023), with life-threatening complications in 0.5% (n=21). Extraction complications increased with implant duration, female sex, and J retention wire protrusion. CONCLUSIONS: Accufix pacing leads pose a low, ongoing risk of injury. Extraction is associated with substantially higher risks, and a conservative management approach is indicated for most patients.

Radiation therapy for rhabdomyosarcoma: local failure risk for Clinical Group III patients on Intergroup Rhabdomyosarcoma Study II.

PURPOSE: A subset of 362 pediatric patients with rhabdomyosarcoma was selected from a total of 532 eligible IRS-II patients in Clinical Group III to assess the local and regional failure rates following radiotherapy and to determine patient, tumor, and treatment factors contributing to the risk for local and regional failure. METHODS AND MATERIALS: The study population was selected from all eligible IRS-II Clinical Group III patients. Excluded patients were those with "special pelvic" primary sites whose protocol management restricted radiotherapy (n = 123), and those who were removed from the study before radiotherapy was to begin, or because it was omitted (n = 47). A binary recursive partitioning model was used to identify subgroups of the remaining 362 patients at risk of local or regional failure. RESULTS: The local (only) failure rate was 17% (95% confidence interval, 13-21%), and the local (all) failure rate was 20% (95% confidence interval, 16-24%). The 5-year actuarial risk of local (all) failure was 22% (95% confidence interval, 18-27%). The risk of regional (nodal) failure was between 2% and 23%. Increasing tumor size predicted an increased local failure risk. Primary tumors located above the clavicle had a reduced risk of local failure. The binary recursive partitioning model identified a subset of patients at high risk of local failure. Those patients had primary tumors in the chest, pelvic region, extremity, or trunk, or tumors > 10 cm in diameter. Their local failure rate was 35% (compared to 15% for the remaining patients). The subset of patients at high risk for regional (nodal) failure had node involvement at diagnosis and a primary tumor originating at a site other than orbit, parameningeal, or trunk. Compliance with radiation treatment guidelines approached but did not achieve statistical significance as a predictive factor for local failure. By univariate analysis, factors not influencing local failure risk were age, race, gender, adenopathy, and histology. CONCLUSION: Radiation therapy and chemotherapy administered to Clinical Group III patients entered into the IRS-II protocol produced sustained local control in most cases. Knowledge of the factors which predict an increased risk of local or regional failure will facilitate the design of new treatment strategies.

Microdilution antifungal susceptibility testing of Candida albicans and Cryptococcus neoformans with and without agitation: an eight-center collaborative study.

The growth patterns observed in the trailing wells when fluconazole is being tested may give rise to readings that suggest resistance or increased MICs for known susceptible strains. We conducted a multicenter study to evaluate the intralaboratory and interlaboratory reproducibilities of a method that uses agitation to disperse these types of growth. Ten strains of Candida albicans and five strains of Cryptococcus neoformans were tested against fluconazole, flucytosine, and amphotericin B by using a microdilution adaptation of the proposed reference method of the National Committee for Clinical Laboratory Standards for yeasts (M27-T). The endpoint criterion used before agitation was consistent with the M27-T recommendation, while a criterion of 50% or more reduction of growth compared with the control was used after agitation. The results of this study showed that use of agitation and the modified endpoint criterion both improved intralaboratory and inter-laboratory agreement and increased the frequency of interpretable MICs. The MICs obtained by this method were comparable to those obtained by the broth macrodilution M27-T method. Like M27-T, this method was not able to definitely distinguish amphotericin B-susceptible from -resistant strains, although the MICs for the resistant strains were consistently higher than those for the susceptible ones. The findings imply that agitation should be seriously considered when antifungal agents, particularly fluconazole, are tested in a microdilution format.

Renal toxicity of ifosfamide in pilot regimens of the intergroup rhabdomyosarcoma study for patients with gross residual tumor.

PURPOSE: The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma. PATIENTS AND METHODS: From 1987 to 1991, 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1-2 years. Ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate, or 9 g/m2 of ifosfamide per course. The three-drug regimen was repeated every 3-4 weeks. RESULTS: Twenty-eight patients (14%) developed renal toxicity: 19 had renal tubular dysfunction (RTD) characterized by low serum phosphate (< or = 3 mg/dl) or bicarbonate (< 20 or = mEq/L) levels, five had decreased glomerular function (DGF), and four had both RTD and DGF. When nine or more courses of ifosfamide (> 72 g/m2) were given, children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age (34% versus 6%; p < 0.001). A similar age difference was observed even when eight or fewer courses (< or = 72 g/m2) were given (p = 0.03). A matched case-control comparison showed that renal abnormalities at diagnosis, chiefly hydronephrosis, also increased the risk of renal tubular injury by ifosfamide by a factor of 13 (p < 0.001). Patients with DGF tended to be older than those with RTD, and all but one received > 72 g/m2 of ifosfamide. CONCLUSIONS: Patients who are < 3 years of age who receive more than eight courses (> 72 g/m2) of ifosfamide and who have a preexisting renal abnormality have an increased risk of RTD and DGF. The renal function of patients being considered for ifosfamide treatment must be carefully monitored. Ifosfamide should be avoided in patients with renal abnormalities at diagnosis unless the potential benefit clearly exceeds the risk of further renal impairment.

An optimal three-stage design for phase II clinical trials.

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H0: p < or = p0 versus H1: p > or = p1, where p1 and p0 are response rates such that E does or does not merit further testing at given levels of statistical significance (alpha) and power (1--beta). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H1 at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H1 is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p0, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H0; and the total sample size and criteria for rejection of H1 at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.

Interphase cytogenetics in paraffin-embedded sections from renal cortical neoplasms. Correlation with cytogenetic and flow cytometric DNA ploidy analyses.

Nonisotopic in situ hybridization (ISH) was performed on archival tissue sections from six renal cortical neoplasms and corresponding normal kidney tissue using pericentrometric (alpha-satellite) probes to chromosomes 1, 3, 7, 8, 10, 11, 12, 16, and 17. The results were correlated with classic cytogenetic analyses and flow cytometric DNA ploidy findings of these neoplasms. Our study shows that intratissue and intertissue ISH spot counts were generally homogeneous in normal kidney tissue and markedly heterogenous in tumor specimens. In all cases the correlation between the DNA Index and the ISH spot numbers was statistically significant. A correlation between modal and numerical chromosomal findings by cytogenetic analysis and ISH spot counts was found in three cases and was discordant in three cases. Our results also show that chromosomes 1, 3, 7, and 17 appear to manifest more propensity for aneuploidy than chromosomes 8, 10, 11, 12, and 16. We conclude that 1) numerical chromosomal aberrations by interphase in-situ hybridization correlate with DNA ploidy analysis in these tumors; 2) certain chromosomes may be more prone to aneuploidy than others; 3) determination of monosomy by ISH is less reliable on paraffin-embedded sections; and 4) the ISH technique complements conventional cytogenetic analysis in providing more information for the determination of cytogenetic aberrations and clonal heterogeneity in solid neoplasms.

Surgical management and prognostic factors in patients with subungual melanoma.

OBJECTIVE: Forty-six cases of subungual melanoma were reviewed to identify significant clinicopathologic prognostic factors, determine the role of DNA content analysis in the biologic assessment of these tumors, and evaluate the effectiveness of amputation level, lymph node dissection (LND), and regional limb perfusion on the survival of these patients. BACKGROUND: Subungual melanoma is a unique and rare subtype of melanoma, constituting only 1% to 3% of cases. Thus, little is known about prognostic factors and optimal management of patients with this disease. Moreover, the appropriate level of amputation and LND and limb perfusion in the management of subungual melanoma remain controversial. METHODS: Forty-six patients underwent amputation alone or in combination with LND and/or regional limb perfusion for primary subungual melanoma. The effects of these treatment modalities and the prognostic significance of patient and tumor-related variables, including DNA flow cytometric data, on overall survival were assessed. RESULTS: Univariate statistical analysis identified six factors that significantly affected patient survival. They were stage at diagnosis (p = 0.0001), percentage of aneuploid cells (p = 0.01), presence of ulceration (p = 0.02) or bone invasion (p = 0.02), thickness of the primary lesion (p = 0.03), and percentage of cells in S-phase (p = 0.03). Multivariate analyses identified tumor stage and S-phase fraction as independent prognostic factors in these patients. Survival did not differ among patients who received amputation alone or those who underwent amputation in combination with LND or perfusion (p = 0.90); however, the use of limb perfusion reduced the incidence of locally recurrent disease. The level of amputation did not affect patient survival (p = 0.74) or the incidence of local recurrence. CONCLUSIONS: The study identified several significant prognostic factors, including DNA flow cytometric parameters, in patients with subungual melanoma. In addition, it showed that conservative amputation of the affected digit at the level of the proximal interphalangeal or metacarpophalangeal/metatarsophalangeal joint appears to be safe, provided that clear margins are obtained. Although isolated limb perfusion may reduce the incidence of local recurrence, LND, or limb perfusion in the routine management of subungual melanoma remains controversial.

Acute myeloid leukemia in patients treated for rhabdomyosarcoma with cyclophosphamide and low-dose etoposide on Intergroup Rhabdomyosarcoma Study III: an interim report.

The early occurrence of five cases of acute myeloid leukemia (AML) in children treated for primary rhabdomyosarcoma on the Intergroup Rhabdomyosarcoma Study III (IRS III) has prompted this report. These patients received cyclophosphamide and four received etoposide in addition to other agents. There were 1,062 eligible patients entered on IRS III between 1984 and 1991. Following surgery, treatment consisted of multiagent chemotherapy and radiotherapy in select clinical groups. Median follow-up time is 3.7 years (range 0-7.4 years). Incidence densities and odds ratios for AML were calculated for various treatment groups. Five cases of secondary AML have been reported through August 1992. A single case of osteogenic sarcoma was reported in the same period and a patient with myelodysplastic syndrome has occurred since that time. Median time to development of AML was 39 months. Incidence density of AML for patients receiving neither cyclophosphamide nor etoposide was 0, for those receiving cyclophosphamide but no etoposide it was 7.6, and when both agents were given, it was 51.6. The odds ratios of AML for the latter two groups indicated a risk of AML which was seven times higher in the patients who received both agents. A history of breast cancer was present in all five families of patients with AML and several other cancers had occurred in three families. Preliminary analysis suggests a possible causal role for low-dose etoposide in addition to that assumed for cyclophosphamide in the early development of AML among pediatric patients treated for rhabdomyosarcoma.

Two-site comparison of broth microdilution and semisolid agar dilution methods for susceptibility testing of Cryptococcus neoformans in three media.

This study evaluated the inter- and intralaboratory agreement between results of the semisolid agar dilution and broth microdilution methods of antifungal susceptibility testing of Cryptococcus neoformans. Three media were tested in two laboratories. The drugs tested were amphotericin B, flucytosine, itraconazole, fluconazole, and Schering 39304. Analysis by kappa statistics revealed good agreement between the laboratories for the two methods. The highest level of inter- and intralaboratory agreement was observed in RPMI 1640 with L-glutamine followed by Eagle's minimum essential medium and yeast nitrogen broth. The broth microdilution method appears more suitable than the semisolid agar dilution method for testing cryptococci because of its ease in performance, cost, and simplicity.

Papillary renal cell carcinoma: clinical implication of DNA content analysis.

Papillary renal cell carcinoma is considered a less-aggressive histomorphologic variant of renal cell carcinoma. We investigated the clinicopathologic features and the DNA ploidy pattern in 22 papillary renal cell carcinoma cases and correlated the findings to the patients' length of survival. In this study the demographic data were similar to those of previously published series. Histologically, two neoplasms were Fuhrman's nuclear grade 1, eight were nuclear grade 2, 11 were nuclear grade 3, and one was nuclear grade 4. Six tumors were stage I, three were stage II, five were stage III, and eight were stage IV. With a mean follow-up period of 42 months, eight patients died of disease and 14 were alive and well. DNA aneuploidy was found in 50% of the neoplasms and was frequently associated with high tumor nuclear grade, high tumor stage, and poor prognosis. Conversely, DNA diploidy was preponderantly noted in neoplasms with low tumor nuclear grade and stage, and none of the patients died of their disease. A statistically significant difference between DNA ploidy/tumor stage and patient outcome was obtained. No significant correlation between DNA ploidy and nuclear grade was observed. Our results suggest that DNA content measurements may assist in evaluating the clinical outcome of this neoplasm. Moreover, they indicate that papillary renal cell carcinomas manifest clinicopathologic, DNA content, and biologic characteristics akin to those of nonpapillary variants.

Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee.

PURPOSE: This study was performed to determine the incidence and risk factors involved in the development of a second malignant neoplasm (SMN) after treatment of primary rhabdomyosarcoma (RMS) in patients enrolled onto Intergroup Rhabdomyosarcoma Studies I and II (IRS I and II). PATIENTS AND METHODS: There were 1,770 patients with primary RMS entered onto IRS I and II between 1972 and 1984. They were treated with chemotherapy and, in most instances, radiotherapy according to randomized or assigned regimens based on clinical grouping. Median follow-up time for these patients was 8.4 years. Incidence density (ID) was calculated for each study and for treatment and age groups. The 10-year cumulative incidence was estimated for each study. RESULTS: Twenty-two SMNs have been reported through 1991. The most common tumor type was a bone sarcoma followed by acute nonlymphoblastic leukemia (ANLL). The median time to the development of an SMN was 7 years (range, 1 11/12 to 15 9/12 years). The 10-year cumulative incidence rate was 1.7% for both studies. ID and cumulative incidence estimates were highest for patients who received both an alkylating agent and radiotherapy. The majority of patients for whom family histories were available had either neurofibromatosis themselves or a family history that suggested the Li-Fraumeni syndrome (LFS). CONCLUSION: The results of this study suggest that genetic abnormalities play a prominent role in the development of an SMN after therapy for a primary RMS. Chemotherapy with an alkylating agent and radiotherapy play significant roles in the development of an SMN compared with patients who received only one of these therapeutic modalities.

Collaborative investigation of broth microdilution and semisolid agar dilution for in vitro susceptibility testing of Candida albicans.

A study was performed in two laboratories to evaluate the effect of growth medium and test methodology on inter- and intralaboratory variations in the MICs of amphotericin B (AMB), flucytosine (5FC), fluconazole (FLU), itraconazole (ITRA), and the triazole Sch 39304 (SCH) against 14 isolates of Candida albicans. Testing was performed by broth microdilution and semisolid agar dilution with the following media, buffered to pH 7.0 with morpholinepropanesulfonic acid (MOPS): buffered yeast nitrogen base (BYNB), Eagle's minimal essential medium (EMEM), RPMI 1640 medium (RPMI), and synthetic amino acid medium for fungi (SAAMF). Inocula were standardized spectrophotometrically, and endpoints were defined by the complete absence of growth for AMB and by no more than 25% of the growth in the drug-free control for all other agents. Comparative analyses of median MICs, as determined by each test method, were made for all drug-medium combinations. Both methods yielded similar (+/- 1 twofold dilution) median MICs for AMB in EMEM and RPMI, 5FC in all media, and FLU in EMEM, RPMI, and SAAMF. In contrast, substantial between-method variations in median MICs were seen for AMB in BYNB and SAAMF, FLU In BYNB, and ITRA and SCH in all media. Interlaboratory concordance of median MICs was good for AMB, 5FC, and FLU but poor for ITRA and SCH in all media. Endpoint determinations were analyzed by use of kappa statistical analyses for evaluating the strength of observer agreement. Moderate to almost perfect interlaboratory agreement occurred with AMB and 5FC in all media and with FLU in EMEM, RPMI, and SAAMF, irrespective of the test method. Slight to almost perfect interlaboratory agreement occurred with ITRA and SCH in EMEM, RPMI, and SAAMF when tested by semisolid agar dilution but not broth microdilution. Kappa values assessing intralaboratory agreement between methods were high for 5FC in all media, for AMB in BYNB, ENEM, and RPMI, and for FLU in EMEM, RPMI, and SAAMF. One laboratory, but not the other, reported substantial to almost perfect agreement between methods for ITRA, and SCH in EMEM, RPMI, and SAAMF. Both laboratories reported poor agreement between methods for the azoles in BYNB. Discrepancies noted in azole-BYNB combinations were largely due to the greater inhibitory effect of these agents in BYNB than in other media. These results indicate that the semisolid agar dilution and broth microdilution methods with EMEM or RPMI yield equivalent and reproducible MICs for AMB, 5FC, and FLU but not ITRA and SCH.