Urinary metabolomics reveals unique metabolic signatures in infants with cystic fibrosis.

BACKGROUND: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF. METHODS: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (n = 22); CF (n = 63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, n = 22), low length (CF LL, n = 23), and low weight (CF LW, n = 15). RESULTS: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins. CONCLUSIONS: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).

Joint spatial time-series epidemiological analysis of malaria and cutaneous leishmaniasis infection.

Malaria and leishmaniasis are among the two most important health problems of many developing countries especially in the Middle East and North Africa. It is common for vector-borne infectious diseases to have similar hotspots which may be attributed to the overlapping ecological distribution of the vector. Hotspot analyses were conducted to simultaneously detect the location of local hotspots and test their statistical significance. Spatial scan statistics were used to detect and test hotspots of malaria and cutaneous leishmaniasis (CL) in Afghanistan in 2009. A multivariate negative binomial model was used to simultaneously assess the effects of environmental variables on malaria and CL. In addition to the dependency between malaria and CL disease counts, spatial and temporal information were also incorporated in the model. Results indicated that malaria and CL incidence peaked at the same periods. Two hotspots were detected for malaria and three for CL. The findings in the current study show an association between the incidence of malaria and CL in the studied areas of Afghanistan. The incidence of CL disease in a given month is linked with the incidence of malaria in the previous month. Co-existence of malaria and CL within the same geographical area was supported by this study, highlighting the presence and effects of environmental variables such as temperature and precipitation. People living in areas with malaria are at increased risk for leishmaniasis infection. Local healthcare authorities should consider the co-infection problem by recommending systematic malaria screening for all CL patients.

High prevalence of hepatitis B nonimmunity in vaccinated pediatric liver transplant recipients.

Durable protection from hepatitis B virus (HBV) and other vaccine-preventable diseases assumes great importance due to improved long-term patient and graft survival rates in pediatric liver transplantation. Vaccine immunogenicity data in transplanted children is limited. This was a cross-sectional, single-center, point-prevalence study evaluating HBV immunity in 160 pediatric liver transplant recipients. Patients with hepatitis B surface antibody levels <10 IU/L were considered nonimmune. Predictor variables for nonimmunity identified in univariate analyses were later analyzed within a logistic regression model. All subjects received the full HBV vaccination series prior to transplant. The majority (67%) of previously immunized pediatric liver transplant patients were nonimmune. Older children (p < 0.001) and children who were further out from transplant (p < 0.001) were more likely to be nonimmune in univariate analyses, but only time from transplant was a significant predictor of nonimmunity in a logistic regression model (odds ratio 1.3, p < 0.001 at 1 year). The mean time since transplant was 5.6 years ± 4.6. Markers of nutrition, immunosuppression, white blood cell parameters and type/severity of disease did not correlate with HBV immunity. Information on the anamnestic response to boosting or revaccination is needed to adequately address this vulnerable group.

Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases.

PURPOSE: A specific TLS-CHOP fusion gene resulting from the t(12;16) is present in at least 95% of myxoid liposarcomas (MLS). Three common forms of the TLS-CHOP fusion have been described, differing by the presence or absence of TLS exons 6-8 in the fusion product. Type 5-2 (also known as type II) consists of TLS exons 1-5 fused to CHOP exon 2; type 7-2 (also known as type I) also includes TLS exons 6 and 7 in the fusion, whereas type 8-2 (also known as type III) fuses TLS exons 1-8 to CHOP exon 2. We sought to determine the impact of TLS-CHOP fusion transcript structure on clinical outcome in a group of well-characterized MLS cases. We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations. METHODS: We analyzed TLS-CHOP fusion transcripts by reverse-transcription PCR using RNA extracted from frozen tissue in 82 MLS confirmed previously to harbor a CHOP rearrangement either by Southern blotting or by cytogenetic detection of the t(12;16). Parameters analyzed included age, location, size, percentage of round cell (RC) component, areas of increased cellularity, necrosis, and surgical margins. In 71 (87%) cases, adequate tumor tissue was available for immunohistochemical analysis of P53 status, using DO7 antibody. The Kaplan-Meier method, log-rank, and Cox regression tests were used for survival analyses. RESULTS: Most MLS were >10 cm (73%), arising in the thigh (70%), and localized at presentation (89%). RC component was <5% in 47 (57%) cases and > or =5% in 35 (43%). The TLS-CHOP fusion transcript was type 5-2 in 55 (67%), type 7-2 in 16 cases (20%), and type 8-2 in 8 (10%). One tumor had a unique variant fusion, between exon 6 TLS and exon 2 CHOP. Two other cases (2%) showed an EWS-CHOP fusion transcript. Overexpression of P53 (defined as > or =10% nuclear staining) was detected in 12 (17%) cases. High histological grade (defined as > or =5% RC; P < 0.01), presence of necrosis (> or =5% of tumor mass; P < 0.05), and overexpression of P53 (P < 0.001) correlated with reduced metastatic disease-free survival in localized tumors. The presence of negative surgical margins (P < 0.01) and extremity location (P = 0.02) were found to be significant in predicting local recurrence in the entire group as well as localized cases by univariate and multivariate analysis. Although there was no significant correlation between TLS-CHOP transcript type and histological grade or disease-specific survival, an association was found between the P53 status and type 5-2 fusion (P < 0.01). CONCLUSION: In contrast to some other translocation-associated sarcomas, the molecular variability of TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in MLS. Instead, high histological grade (> or =5% RC), presence of necrosis, and P53 overexpression are predictors of unfavorable outcome in localized MLS.

Is there a role for incomplete resection in the management of retroperitoneal liposarcomas?

Complete surgical resection is the most effective modality for the treatment of retroperitoneal sarcomas. Previous studies of all types of retroperitoneal sarcomas have not shown a survival benefit of incomplete resection over no resection. Because death often occurs as a result of local progression in retroperitoneal liposarcomas (RPLS), it is possible that incomplete resection may be beneficial in this histologic type. In this study we have sought to determine the clinical outcomes in patients with incompletely resected and unresected RPLS with the aim of defining patients who may benefit from palliative resection. From a prospective clinical database 55 patients with incompletely resected (n = 43) or unresected (n = 12) RPLS were identified between 1982 and 1999. Statistical analyses were performed using the log-rank test and Kaplan-Meier estimates with disease-specific survival as the primary end point. Variables studied included age, gender, recurrent versus primary disease, tumor grade, and tumor size. The patient population consisted of 34 men and 21 women with a mean age of 61 +/- 14 (SD) years. The median time to death was 10 months (range 1 to 83 months) with a median followup of 12 months (range 1 to 60 months) for survivors. Partial resection was an independent factor for increased survival as compared with exploration or biopsy only (median survival 26 versus 4 months, p < 0.0001). Of patients who received incomplete resections, locally recurrent presentation (n = 19) versus primary disease (n = 24) was a negative prognostic variable (median survival 17 versus 46 months, p = 0.009). Successful palliation of symptoms was achieved in 24 of 32 patients (75%) with preoperative symptoms. In select patients with unresectable RPLS, incomplete surgical resection can provide prolongation in survival and successful symptom palliation. Most likely to benefit are those patients presenting with primary tumors, suggesting that surgical resection should be attempted in the majority of patients.

Soft tissue sarcomas of the groin: diagnosis, management, and prognosis.

BACKGROUND: Sott tissue sarcomas (STS) of the groin may present a difficult problem because or misdiagnosis as groin hernia and proximity to major neurovascular structures. We evaluated our management and survival in a large cohort of patients. STUDY DESIGN: Patients treated between July 1, 1982 and July 1, 1998 with primary or recurrent STS of the groin were included. Groin sarcomas were defined as those tumors within 5 cm of the inguinal crease. Patient, tumor, clinical, and survival data were analyzed using a log rank test and Cox regression. RESULTS: We treated and followed 88 patients with STS of the groin. The median age was 52 years (range 16 to 86 years) and 55 patients (63%) were male. Disease-specific survival was 72% at 5 years. Tumors tended to be larger than 5 cm (52%), deep (72%), and high-grade (60%). Unfavorable prognostic factors for disease-specific survival were high grade (p < 0.001), neurovascular invasion (p < 0.001), positive margin (p < 0.01), deep depth (p < 0.01), and selection for adjuvant therapy (p < 0.005). Multivariate analysis indicated age greater than 50 years (p < 0.05), high grade (p < 0.001), neurovascular invasion (p < 0.001), and positive microscopic margins (p < 0.001). Fourteen patients (16%) were diagnosed with STS at hernia operation then went on to a definitive operation with no impact on survival. Seventeen patients (19%) had involvement of a major vessel or nerve, and 5 of these ultimately required amputations, 3 for local recurrence. CONCLUSIONS: High grade, neurovascular invasion, and positive microscopic margins are associated with poor outcomes. The biology of these tumors is similar to other extremity STS, and similar principles of management apply. Even with neurovascular involvement, most patients with primary groin STS do not require amputation.

Amputation for recurrent soft tissue sarcoma of the extremity: indications and outcome.

BACKGROUND: Limb salvage after primary site failure of extremity soft tissue sarcoma is a challenging problem. Amputation may be the most effective treatment option in selected patients with local recurrence. We compared the outcome of patients treated with amputation versus limb-sparing surgery (LSS) for locally recurrent extremity sarcoma. METHODS: From 1982 to 2000, 1178 patients with localized primary extremity sarcoma underwent LSS. Of these, 204 (17%) developed local recurrence. Eighteen (9%) required major amputation and the remainder underwent LSS, of which 34 were selected for matched-pair analysis according to established prognostic variables. Rates of recurrence or death were estimated by the Kaplan-Meier method. Following adjustment for prognostic variables, a Mantel-Haenszel test was used to compare the outcome between the two treatment groups. RESULTS: Patients in each group were well matched. All patients had high-grade tumors deep to the fascia. Median time to local recurrence was similar for both groups. Median follow-up was 95 months. Amputation was associated with a significant improvement in local control of disease (94% vs. 74%; P = .04). We observed no difference in disease-free (P = .48), disease-specific (P = .74), or overall survival (P = .93) between the two groups. Median postrecurrence survival was 20 months and 5-year OS was 36% for the entire study group. CONCLUSIONS: Limb-sparing treatment achieves local control in the majority of recurrent extremity sarcomas for which amputation is infrequently indicated. Amputation improves local disease control but not survival under these circumstances.

Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors.

Tissue microarrays allow high-throughput molecular profiling of cancer specimens by immunohistochemistry. Phenotype information of sections from arrayed biopsies on a multitissue block needs to be representative of full sections, as protein expression varies throughout the entire tumor specimen. To validate the use of tissue microarrays for immunophenotyping, we studied a group of 59 fibroblastic tumors with variable protein expression patterns by immunohistochemistry for Ki-67, p53, and the retinoblastoma protein (pRB). Data on full tissue sections were compared to the results of one, two, and three 0.6-mm core biopsies per tumor on a tissue array. Ki-67 and p53 staining was read as two categories (positive or negative). Concordance for this staining between tissue arrays with triplicate cores per tumor and full sections were 96 and 98%, respectively. For pRB staining was read as three categories (high, moderate, or negative), where concordance was 91%. The use of three cores per tumor resulted in lower numbers of lost cases and lower nonconcordance with standard full sections as compared to one or two cores per tumor. Correlations between phenotypes and clinical outcome were not significantly different between full section and array-based analysis. Triplicate 0.6-mm core biopsies sampled on tissue arrays provide a reliable system for high-throughput expression profiling by immunohistochemistry when compared to standard full sections. Triplicate cores offer a higher rate of assessable cases and a lower rate of nonconcordant readings than one or two cores. Concordance of triplicate cores is high (96 to 98%) for two category distinction and decreases with the complexity of the phenotypes being analyzed (91%).

Isotonic designs for phase I trials.

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this paper, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs. Control Clin Trials 2001;22:126-138

Optimal designs for evaluating a series of treatments.

Several articles in this journal have studied optimal designs for testing a series of treatments to identify promising ones for further study. These designs formulate testing as an ongoing process until a promising treatment is identified. This formulation is considered to be more realistic but substantially increases the computational complexity. In this article, we show that these new designs, which control the error rates for a series of treatments, can be reformulated as conventional designs that control the error rates for each individual treatment. This reformulation leads to a more meaningful interpretation of the error rates and hence easier specification of the error rates in practice. The reformulation also allows us to use conventional designs from published tables or standard computer programs to design trials for a series of treatments. We illustrate these using a study in soft tissue sarcoma.

A Bayesian decision approach for sample size determination in phase II trials.

Stallard (1998, Biometrics 54, 279-294) recently used Bayesian decision theory for sample-size determination in phase II trials. His design maximizes the expected financial gains in the development of a new treatment. However, it results in a very high probability (0.65) of recommending an ineffective treatment for phase III testing. On the other hand, the expected gain using his design is more than 10 times that of a design that tightly controls the false positive error (Thall and Simon, 1994, Biometrics 50, 337-349). Stallard's design maximizes the expected gain per phase II trial, but it does not maximize the rate of gain or total gain for a fixed length of time because the rate of gain depends on the proportion of treatments forwarding to the phase III study. We suggest maximizing the rate of gain, and the resulting optimal one-stage design becomes twice as efficient as Stallard's one-stage design. Furthermore, the new design has a probability of only 0.12 of passing an ineffective treatment to phase III study.

Correlation of peripheral venous pressure and central venous pressure in surgical patients.

OBJECTIVE: To determine the degree of agreement between central venous pressure (CVP) and peripheral venous pressure (PVP) in surgical patients. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Patients without cardiac dysfunction undergoing major elective noncardiac surgery (n = 150). MEASUREMENTS AND MAIN RESULTS: Simultaneous CVP and PVP measurements were obtained at random points in mechanically ventilated patients during surgery (n = 100) and in spontaneously ventilating patients in the postanesthesia care unit (n = 50). In a subset of 10 intraoperative patients, measurements were made before and after a 2-L fluid challenge. During surgery, PVP correlated highly to CVP (r = 0.86), and the bias (mean difference between CVP and PVP) was -1.6 +/- 1.7 mmHg (mean +/- SD). In the postanesthesia care unit, PVP also correlated highly to CVP (r = 0.88), and the bias was -2.2 +/- 1.9 (mean +/- SD). When adjusted by the average bias of -2, PVP predicted the observed CVP to within +/-3 mmHg in both populations of patients with 95% probability. In patients receiving a fluid challenge, PVP and CVP increased similarly from 6 +/- 2 to 11 +/- 2 mmHg and 4 +/- 2 to 9 +/- 2 mmHg. CONCLUSION: Under the conditions of this study, PVP showed a consistent and high degree of agreement with CVP in the perioperative period in patients without significant cardiac dysfunction. PVP -2 was useful in predicting CVP over common clinical ranges of CVP. PVP is a rapid noninvasive tool to estimate volume status in surgical patients.

Clinicopathologic analysis of patients with adult rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS) in adults (age > or = 16 years) is rare, accounting for less than 3% of adult soft tissue sarcomas. There is little information describing the disease biology or clinicopathologic factors that influence survival in adults with RMS. The objective of this study was to define the factors in patients with adult RMS that predict outcome, disease progression, and survival. METHODS: Eighty-four adult patients with a pathologic diagnosis of RMS that was confirmed by immunohistochemistry were identified by a prospective inpatient data base during the period 1982--1999 and were analyzed for disease specific survival and metastasis free survival using the Kaplan-Meier actuarial method. Statistical significance was evaluated using the log-rank test for univariate influence and a Cox regression model for multivariate influence. RESULTS: The median disease specific survival was 22 months. Patient age, extent of disease, tumor size at the time of diagnosis, and margin status after resection were significant predictors of disease specific survival. Patients who underwent a complete resection had a significantly longer median survival (105 months) compared with any other subgroup of patients. The histologic subtype did not predict patient survival but did vary with patient age. Most notably, the proportion of the pleomorphic subtype increased with advancing age, accounting for 42% of RMS in patients over the age of 40 years. CONCLUSIONS: The most important predictors of outcome in patients with adult RMS are patient age, tumor size, extent of disease, and margin status after resection. In contrast to patients with pediatric RMS, no association was noted between survival and histologic subtype in this group of patients with adult RMS. All histologic subtypes of RMS are aggressive malignancies with poor disease specific survival despite aggressive multimodality management.

Soft tissue tumors of the abdominal wall: analysis of disease patterns and treatment.

HYPOTHESIS: Abdominal wall tumors, though clinically similar, have varying degrees of biological behavior. DESIGN: Retrospective review of prospective databases. SETTING: Memorial Sloan-Kettering Cancer Center. PATIENTS: Eighty-five patients with abdominal wall soft tissue tumors. MAIN OUTCOME MEASURES: Primary endpoints included time to first local recurrence, distant metastases, and disease-related mortality. Survival analysis was performed by Kaplan-Meier method, and comparisons were made by log-rank analysis. RESULTS: Thirty-nine desmoids, 32 soft tissue sarcomas (STS), and 14 dermatofibrosarcoma protuberans (DFSP) underwent surgery directed at achieving margin-negative resection. Unlike DFSP, most STS (77%) and desmoids(87%) were deep lesions requiring full-thickness abdominal wall resection and mesh reconstruction. Median follow-up time was 53 months, 101 months, and 31 months, with 5-year local recurrence-free survival rates of 97%, 100%, and 75%, for desmoids, DFSP, and STS, respectively. Desmoid tumors resected with positive microscopic margins had higher local failure rates (68% [positive margin] vs 100% [negative margin] 5-yr local recurrence-free survival, P<.05). For STS, high grade, deep location, and size at or above 5 cm were adverse prognostic factors for disease-specific and distant recurrence-free survival (P<.05); patients experiencing local recurrence was associated with decreased 5-year relapse-free survival rates (87% [primary] vs 50% [local recurrence], P<.05). Characteristically, no DFSP or desmoid developed distant metastases. Soft tissue sarcomas had significantly lower relapse-free survival rates than DFSP or desmoids (P<.05). CONCLUSION: Abdominal wall tumors demonstrate a broad spectrum of biological behavior. Desmoids and DFSP are a local problem. High grade, size at or above 5 cm, and deep location predict distant failure and tumor-related mortality for patients with STS. Complete surgical resection is the recommended treatment approach to achieve local control. Stratification by prognostic factors will facilitate selection of patients with STS for adjuvant systemic therapies.

Effects of diltiazem prophylaxis on the incidence and clinical outcome of atrial arrhythmias after thoracic surgery.

OBJECTIVES: We sought to determine whether early prophylaxis with an L -type calcium channel blocker reduces the incidence and morbidity associated with atrial fibrillation/flutter and supraventricular tachyarrhythmia after major thoracic operations. METHODS: In this randomized, double-blind, placebo-controlled study, 330 patients were given either intravenous diltiazem (n = 167) or placebo (n = 163) immediately after lobectomy (> or =60 years) or pneumonectomy (> or =18 years) and orally thereafter for 14 days. The primary end point with respect to efficacy was a sustained (> or =15 minutes) or clinically significant atrial arrhythmia during treatment. RESULTS: Postoperative atrial arrhythmias (atrial fibrillation/flutter = 60; supraventricular tachyarrhythmias = 5) occurred in 25 (15%) of the 167 patients in the diltiazem group and 40 (25%) of the 163 patients in the placebo group (P = .03). When compared with placebo, diltiazem nearly halved the incidence of clinically significant arrhythmias (17/167 [10%] vs. 31/163 [19%], P = .02). The 2 groups did not differ in the incidence of other major postoperative complications or overall duration or costs of hospitalization. No serious adverse effects caused by diltiazem were seen. CONCLUSIONS: After major thoracic operations, prophylactic diltiazem reduced the incidence of clinically significant atrial arrhythmias in patients considered at high risk for this complication.

Repeat resection of pulmonary metastases in patients with soft-tissue sarcoma.

BACKGROUND: Even after an apparent complete resection of sarcomatous pulmonary metastases, 40% to 80% of patients will re-recur in the lung. The benefit of subsequent re-resection is poorly defined. This study examines patient survival after repeat pulmonary exploration for re-recurrent metastatic sarcoma at a single institution. STUDY DESIGN: Between July 1982 and December 1997, data on 3,149 adult in-patients with soft tissue sarcoma were prospectively gathered. Of these, pulmonary metastases were present or developed in 719 patients and 248 underwent at least one resection. Of the patients relapsing in the lung after an apparently complete resection, 86 underwent reexploration. Disease-specific survival (DSS) after re-resection was the end point of the study. Time to death was modeled using the method of Kaplan and Meier. The association of factors to time-to-event end points was analyzed using the log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis. Clinicopathologic factors were analyzed with the Pearson chi-square or Fisher's exact test when appropriate. RESULTS: The median DSS after re-resection for all patients undergoing at least two pulmonary resections was 42.8 months with an estimated 5-year survival of 36%. The median DSS in patients with complete reresection was 51 months (n = 68) compared with 6 months in patients with an incomplete re-resection (n = 16, p<0.0001). Patients with one or two nodules at re-resection (n = 39) had a median DSS of 51 months compared with 20 months in patients with three or more nodules (n = 40, p = 0.003). Patients in whom the largest metastasis re-resected was less than or equal to 2 cm (n = 33) had a median DSS of 44 months compared with 20 months in patients with metastasis greater than 2 cm (n = 43, p = 0.033). Patients with primary tumor high-grade histology (n = 75) had a median DSS of 32 months and patients with low-grade histology (n = 11) had a median DSS that was not reached (p = 0.041). Three independent prognostic factors associated with poor outcomes may be determined preoperatively: > or =3 nodules, largest metastases > 2 cm, and high-grade primary tumor histology. Patients with either zero or one poor prognostic factor had a median DSS > 65 months and patients with three poor prognostic factors had a median DSS of 10 months. CONCLUSIONS: Reexploration for recurrent sarcomatous pulmonary metastases appears beneficial for patients who can be completely re-resected. Outcomes are described by factors that may be determined preoperatively, including metastasis size, metastasis number, and primary tumor histologic grade. Patients who cannot be completely re-resected or those with numerous, large metastasis and high-grade primary tumor pathology have poor outcomes and should be considered for investigational therapy.

Dermatofibrosarcoma protuberans: A clinicopathologic analysis of patients treated and followed at a single institution.

BACKGROUND: Despite optimal surgical therapy for patients with dermatofibrosarcoma protuberans (DFSP), some patients still continue to develop local recurrence. The authors' objective was to identify and analyze clinicopathologic factors for disease free survival in a large group of patients who were followed prospectively at a single institution. METHODS: Prospectively collected data and pathology slides were available for review from 159 patients with primary or recurrent DFSP who underwent treatment between July 1950 and July 1998. The study group was comprised of patients with either the "classic" form of DFSP or the fibrosarcomatous "high grade" variant of DFSP (FS-DFSP). Patient, tumor, pathologic, and treatment factors were analyzed using the log rank test for univariate influence and Cox regression analysis for multivariate influence. Local recurrence free survival was determined by the Kaplan-Meier actuarial method. RESULTS: Of the 159 patients who comprised the current study group, 134 (84%) had the classic form of DFSP. The FS-DFSP variant was found in the remaining 25 patients (16%). The overall 5-year local recurrence free survival rate was 75%, with a median follow-up of 4. 75 years. The 5-year recurrence free survival rate for each group was 81% and 28%, respectively. On univariate analysis, age > 50 years, very close (< 1 mm) to positive microscopic margins, FS-DFSP variant, high mitotic rate, and increased cellularity were unfavorable prognostic factors. Multivariate analysis determined very close (< 1 mm) to positive microscopic margins and FS-DFSP variant to be independent adverse prognostic factors. For the 34 patients who developed a recurrence after surgical resection (21%), the median time to local recurrence was 32 months. Of the patients in this group, two died from metastatic disease. CONCLUSIONS: The prognosis after surgical resection with negative and sometimes positive microscopic margins for patients with DFSP is very good. However, increased age, high mitotic index, and increased cellularity are predictors of poor clinical outcome. The FS-DFSP variant represents a much more aggressive tumor with metastatic potential. Patients who are treated with curative intent for FS-DFSP should undergo aggressive attempts at complete surgical resection. Patients with recurrent classic DFSP without evidence of adverse prognostic features may benefit from conservative management, especially in the setting of potentially unresectable disease.