Biomedical subjects

Samuel Singer

Publications and source records attributed to Samuel Singer.

At least 19 recordsLinked to original sources

PubMed2026

Targeting eIF4A-dependent translation in genetically complex sarcoma.

Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.

Humans↗

PubMed2006

Flavopiridol targets c-KIT transcription and induces apoptosis in gastrointestinal stromal tumor cells.

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations in the c-KIT gene which confers ligand-independent activation of the KIT receptor. Imatinib mesylate has been shown to effectively block constitutively active KIT and delay tumor growth. However, resistance to imatinib mesylate is emerging as a major clinical problem and novel therapies are needed. We report that treatment of GIST cells with the transcriptional inhibitor flavopiridol, initially down-regulates the antiapoptotic proteins bcl-2, mcl-1, and X-linked inhibitor of apoptosis protein which occurs as early as 4 hours after exposure. This is followed at 24 hours by the transcriptional suppression of KIT resulting in poly(ADP-ribose) polymerase cleavage and apoptosis. To separate the apoptotic effect of KIT suppression relative to the down-regulation of antiapoptotic proteins, we used small interfering RNA-directed knockdown of KIT. Results show that focused suppression of KIT alone is sufficient to induce apoptosis in GIST cells, but not to the same extent as flavopiridol. In contrast, imatinib mesylate, which inhibits KIT kinase activity but does not suppress total KIT expression, fails to cause apoptosis. We also show that flavopiridol suppresses KIT mRNA expression through positive transcriptional elongation factor inhibition and decreases KIT promoter activity. This causes a global decrease in the level of functionally mature KIT at the cell surface, resulting in a decrease in autophosphorylation at tyrosine residues 703 and 721, which characterizes activated KIT. Our results indicate that targeting KIT expression and these antiapoptotic proteins with flavopiridol represents a novel means to disrupt GIST cell dependence on KIT signaling and collectively renders these cells sensitive to apoptosis.

Antineoplastic Agents↗

PubMed2006

High-resolution MAS NMR spectroscopy detection of the spin magnetization exchange by cross-relaxation and chemical exchange in intact cell lines and human tissue specimens.

High-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy detects resolved signals from membrane phospholipids and proteins in intact cell and tissue samples. MAS has the additional advantage of quenching spin-diffusion through a mutual "flip-flop" of neighbor spins by time-independent dipolar coupling as long as the dipolar coupling is "inhomogeneous." Under MAS, significant magnetization transfer (MT) was observed between water and each proton site in membrane phospholipid and between water and the NMR-observable protein proton signals. The MT rates between water and membrane phospholipids are lower than those between water and protein proton signals. The interaction of water to other small molecules is selective with the observation of MT from water to creatine, lactate, taurine, and glycine, but not to triglyceride, phosphocholine, choline, or myo-inositol. HR-MAS NMR allows the detection of a complete MT network between water and each proton group of creatine. Two creatine pools (one motion-restricted and one motion-free) were identified in skeletal muscle.

Cell Line↗

PubMed2006

Angiogenic profile of soft tissue sarcomas based on analysis of circulating factors and microarray gene expression.

BACKGROUND: Broader understanding of diverse angiogenic pathways in a particular cancer can lead to better utilization of anti-angiogenic therapies. The aim of this study was to develop profiles of angiogenesis-related gene and protein expression for various histologic subtypes of soft tissue sarcomas (STS) growing in different sites. MATERIALS AND METHODS: Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin 2 (Ang2), and leptin were determined in 108 patients with primary STS. Gene expression patterns were analyzed in 38 STS samples and 13 normal tissues using oligonucleotide microarrays. RESULTS: VEGF and bFGF plasma levels were elevated 10-13 fold in STS patients compared to controls. VEGF levels were broadly elevated while bFGF levels were higher in patients with fibrosarcomas and leiomyosarcomas. Ang2 levels correlated with tumor size and were most elevated for tumors located in the trunk, while leptin levels were highest in patients with liposarcomas. Hierarchical clustering of microarray data based on angiogenesis-related gene expression demonstrated that histologic subtypes of STS often shared similar expression patterns, and these patterns were distinctly different from those of normal tissues. Matrix metalloproteinase 2, platelet-derived growth factor receptor, alpha and Notch 4 were among several genes that were up-regulated at least 7-fold in STS. CONCLUSIONS: STS demonstrate significant heterogeneity in their angiogenic profiles based on size, histologic subtype, and location of tumor growth, which may have implications for anti-angiogenic strategies. Comparison of STS to normal tissues reveals a panel of upregulated genes that may be targets for future therapies.

Angiopoietin-2↗

PubMed2005

Effectiveness of palliative procedures for intra-abdominal sarcomas.

BACKGROUND: Nearly half of patients with intra-abdominal (retroperitoneal, visceral, or pelvic) sarcoma undergo more than one operation. When the objective shifts from cure to palliation, the clinical quandary of doing no harm and maximizing benefit is magnified. Knowledge of the effectiveness of a procedure at achieving its palliative intent, as well as its attendant morbidity and mortality, is therefore paramount during this deliberation. METHODS: A retrospective review was performed of all patients with a diagnosis of intra-abdominal sarcoma who underwent a palliative procedure between 1982 and 2003. A procedure was defined as palliative if it was explicitly performed to relieve symptoms. RESULTS: Ten percent (112 of 1084) of patients with a diagnosis of intra-abdominal sarcoma underwent a total of 156 palliative procedures. The most frequent system for which a palliative procedure was performed was gastrointestinal (68 of 156; 44%). Overall, 71% of patients had improvement of symptoms 30 days after the operation, whereas only 54% of patients remained symptom free after 100 days. Although 54% of gastrointestinal tract obstructive symptoms were successfully relieved at 30 days, only 23% of patients remained symptom free at 100 days. The overall operative morbidity was 29%, and postoperative mortality was 12%. Patients undergoing procedures intended to palliate gastrointestinal obstruction encountered the greatest morbidity (19 of 40; 48%). CONCLUSIONS: Successful palliation of many symptoms associated with advanced intra-abdominal sarcoma may be achieved. However, even in highly selected patients, the progressive and pervasive nature of the disease limits the opportunity to attain sustained relief for gastrointestinal obstructive symptoms.

Abdominal Neoplasms↗

PubMed2005

Influence of site on the therapeutic ratio of adjuvant radiotherapy in soft-tissue sarcoma of the extremity.

PURPOSE: The ultimate goal of adjuvant radiotherapy (RT) in soft-tissue sarcoma of the extremity is to improve the therapeutic ratio by increasing local control while minimizing morbidity. Most efforts in trying to improve this ratio have focused on the sequencing of RT and surgery, with little attention to the potential influence of the tumor site. The purpose of this study was to determine the influence of tumor site on local control and complications in a group of patients with primary high-grade soft-tissue sarcoma of the extremity treated at a single institution with postoperative RT. METHODS AND MATERIALS: Between July 1982 and December 2000, 369 adult patients with primary high-grade soft-tissue sarcoma of the extremity were treated with limb-sparing surgery and postoperative RT. Patients who underwent surgery or RT outside our institution were excluded. The tumor site was the upper extremity (UE) in 103 (28%) and the lower extremity (LE) in 266 (72%). The tumor was < or = 5 cm in 98 patients (27%), and the microscopic margins were positive in 44 (12%). Of the 369 patients, 104 (28%) underwent postoperative external beam RT (EBRT), 233 (63%) postoperative brachytherapy (BRT), and 32 underwent a combination (9%); 325 (88%) received a "conventional" radiation dose, defined as 60-70 Gy for EBRT, 45 Gy for BRT, and 45-50 Gy plus 15-20 Gy for EBRT plus BRT. Complications were assessed in terms of wound complications requiring repeat surgery, fracture, joint stiffness, edema, and Grade 3 or worse peripheral nerve damage. RESULTS: The UE and LE groups were balanced with regard to age, depth, margin status, and type of RT (EBRT vs. BRT +/- EBRT). However, more patients in the UE group had tumors < or = 5 cm and more received a conventional radiation dose (p = 0.01 and P = 0.03, respectively). With a median follow-up of 50 months, the 5-year actuarial rate of local control, distant relapse-free survival, and overall survival for the whole population was 82% (95% confidence interval [CI], 77-86%), 61% (95% CI, 56-66%), and 71% (95% CI, 66-76%), respectively. The 5-year local control rate in patients with UE STS was 70% (95% CI, 60-80%) compared with 86% (95% CI, 81-91%) for LE STS (p = 0.0004). On multivariate analysis, an UE site (p = 0.001; relative risk [RR], 3; 95% CI, 2-5) and positive resection margins (p = 0.02; RR, 2; 95% CI, 1-4) were significant predictors of poor local control. The RT type or radiation dose, age, tumor depth, and size were not significant predictors of local control. The 5-year wound reoperation rate was 1% (95% CI, 0-3) in the UE compared with 11% (95% CI, 7-15) in the LE (p = 0.002). On multivariate analysis, the UE site retained its significance as a predictor of low wound complications (p = 0.001; RR, 0.08; 95% CI, 0.01-0.7). The site did not significantly influence the incidence of fracture (p = 0.7), joint stiffness (p = 0.2), edema (p = 0.5), or Grade 3 or worse peripheral nerve damage (p = 0.3). CONCLUSION: The UE site is associated with a greater rate of local recurrence compared with the LE. This difference was independent of other variables and could not be accounted for by an imbalance between the two groups. With a lower wound complication rate associated with an UE site, it would be of interest to determine whether preoperative RT and/or intensity-modulated RT can increase the local control in UE sarcomas, thus improving the therapeutic ratio.

Adolescent↗

PubMed2005

Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation.

Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies.

Adult↗

PubMed2005

Prognostic factors for survival in patients with locally recurrent extremity soft tissue sarcomas.

BACKGROUND: Factors prognostic for survival in patients with locally recurrent extremity soft tissue sarcomas (STS) are poorly defined, thus making it difficult to identify high-risk patients who may benefit from adjuvant therapy. METHODS: A total of 1421 patients underwent surgical treatment for primary extremity STS at a single institution between 1982 and 2002. Of these, 179 (13%) patients underwent complete surgical resection of an isolated local recurrence and were the subjects of this study. Clinicopathologic factors from both the primary tumor and the local recurrence were analyzed. RESULTS: The median interval to initial local recurrence was 16 months: 65% developed a local recurrence by 2 years and 90% by 4 years. Only four patients who presented with a low-grade primary tumor progressed to a high-grade local recurrence. Independent prognostic factors for disease-specific survival after local recurrence were a high histological grade (hazard ratio, 5.1; P = .0004), a large local recurrence tumor size (hazard ratio, 1.5; P = .0001), and a short local recurrence-free interval (hazard ratio, 1.6; P = .0001). Patients who developed a local recurrence >5 cm in < or =16 months (n = 44; 0 low grade) had a 4-year disease-specific survival of 18%, compared with 81% for patients who developed a local recurrence < or =5 cm in >16 months (n = 46; 11 low grade). CONCLUSIONS: Histological grade, local recurrence size, and local recurrence-free interval are independently predictive of survival in patients with locally recurrent extremity STS. A large local recurrence that develops in a short interval indicates a biologically aggressive tumor with a high tumor-specific mortality. Patients who develop such recurrences are ideal subjects for systemic neoadjuvant therapy trials.

Adolescent↗

PubMed2005

Distant metastasis in retroperitoneal dedifferentiated liposarcoma is rare and rapidly fatal: a clinicopathological study with emphasis on the low-grade myxofibrosarcoma-like pattern as an early sign of dedifferentiation.

The metastatic incidence of retroperitoneal dedifferentiated liposarcoma is comparatively lower than other pleomorphic sarcomas, varying widely from 1 to 18%. Low-grade dedifferentiation resembling low-grade fibrosarcoma has been recently accepted as part of the morphologic spectrum of dedifferentiated liposarcoma and was reported to have similar metastatic and survival rates to its high-grade counterpart. We sought to determine the metastatic incidence of retroperitoneal dedifferentiated liposarcoma, the clinicopathological features related to metastasis, and their postmetastatic behavior. Of all 354 retroperitoneal liposarcoma cases diagnosed at Memorial Sloan-Kettering Cancer Center during 1982-2003, we identified seven patients developing distant metastases, occurring in four females and three males, ranging from 35 to 73 years in age at presentation. They were all de novo dedifferentiated, while none of the well-differentiated liposarcoma or secondary dedifferentiated liposarcoma developed distant metastasis. Primary tumor sizes varied from 7.5 to 25 cm. All seven patients developing metastases contained >or=50% dedifferentiated elements in the primary tumor, with a predominant morphology resembling myxofibrosarcoma in five cases. The metastatic sites included the lung in four patients, somatic soft tissue in two, and liver in one. The median metastasis-free survival was 48 months, with only two patients experiencing local recurrences before developing metastasis. Six patients died of disease at median follow-up of 53 months after diagnosis and only 5 months after their first metastases. In conclusion, retroperitoneal dedifferentiated liposarcoma have a low metastatic rate, which is strongly related to de novo dedifferentiated histology that usually constitutes a prominent component of the primary tumor. Irrespective of the grade dedifferentiated liposarcoma with myxofibrosarcoma-like features should be closely monitored. Once metastases occur, they tend to follow a rapidly fatal course.

Adult↗

PubMed2004

Multiple primary soft tissue sarcomas.

BACKGROUND: The synchronous or metachronous development of multiple primary soft tissue sarcomas (STS) of different histopathology has been reported only in isolated case reports. METHODS: The records of patients who developed multiple primary STS and who were treated at a tertiary cancer center between 1982 and 2003 were reviewed. RESULTS: Nine patients with multiple primary STS were identified, representing 0.2% of all patients who were treated for STS. The median age of patients at the time of initial presentation with sarcoma was 60 years (range, 51-81 years). Most patients in this series (n = 7) had metachronous development of a second primary STS. The incidence of second primary sarcomas in patients who were diagnosed previously with STS (4.0 per 10,000 population per year) was significantly greater than the incidence of primary STS in the general population (3.2 per 100,000 population per year; P < 0.01). CONCLUSIONS: Although it is an uncommon occurrence, patients who have a history of STS are at an increased risk for the development of a second primary STS.

Age of Onset↗

PubMed2004

Validation of the postoperative nomogram for 12-year sarcoma-specific mortality.

BACKGROUND: On the basis of a prospectively followed cohort of adult patients with primary soft tissue sarcoma (STS) who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), a nomogram for predicting sarcoma-specific mortality was developed. Although this nomogram was found to be accurate by internal validation tests, it had not been validated in an external patient cohort, and thus its universal applicability remained unproven. METHODS: Between 1975 and 2002, 1167 adult patients (age > or = 16 years) underwent treatment for primary STS at the University of California-Los Angeles (UCLA; Los Angeles, CA). All patients treated with an ifosfamide-based chemotherapy protocol (n = 238) were excluded from the current analysis. The remaining 929 patients constituted the population on which the validation study was performed. The nomogram validation process comprised two activities. First, the extent of discrimination was quantified using the concordance index. Second, the level of calibration was assessed by grouping patients with respect to their nomogram-predicted mortality probabilities and then comparing group means with observed Kaplan-Meier estimates of disease-specific survival. RESULTS: With median follow-up intervals of 48 months for all patients and 60 months for surviving patients, the 5-year and 10-year disease-specific survival rates were 77% (95% confidence interval [CI], 74-80%) and 71% (95% CI, 67-75%), respectively. Application of the nomogram to the UCLA data set yielded a concordance index of 0.76, and the observed correspondence between predicted and actual outcomes suggested a high level of calibration. CONCLUSIONS: In the current study, the MSKCC Sarcoma Nomogram was found to provide accurate survival predictions when it was applied to an external cohort of patients who were treated at UCLA.

Adolescent↗

PubMed2004

Liposarcoma subtypes: identification with computed tomography and ultrasound-guided percutaneous needle biopsy.

The purpose of the study was to evaluate the feasibility of image-guided percutaneous needle biopsy to enable specific subtype classification of liposarcoma in patients with previously diagnosed disease and compare the yield of fine and large needle techniques for each subtype. We reviewed the medical records and pathology reports of 69 fine (20 g) needle and large (15, 16 g) needle biopsies performed in 44 patients enrolled in a clinical trial evaluating the effect of a novel therapy for advanced liposarcoma in the abdomen and pelvis. Cytopathologists and surgical pathologists identified features that enabled them to classify the tumor into one of four subtypes: well differentiated, myxoid/round cell, pleomorphic and dedifferentiated. The pre-study open surgical biopsy was used as the standard for comparison. The diagnostic yield (proportion of biopsies with correct subtype diagnosis) of percutaneous biopsy for identifying all subtypes of liposarcoma was 81% (64% for fine needles and 73% for large needles alone). There was a significant association between pathologic subtype and the probability of a correct diagnosis (P=0.05). Accurate diagnostic subset classification of liposarcoma by percutaneous biopsy is feasible, although both fine and large needles should be used. Although these data cannot be extrapolated to primary diagnosis of liposarcoma, they are important for screening and subtyping of possible recurrence.

Adult↗

PubMed2004

Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs).

Most gastrointestinal stromal tumors (GISTs) express constitutively activated forms of the KIT receptor tyrosine kinase protein, resulting from oncogenic mutations in the extracellular, juxtamembrane, or kinase domains. KIT oncoproteins are detected early in GIST tumorigenesis, and most GIST patients respond well to treatment with the KIT kinase inhibitor imatinib mesylate (STI571, Gleevec). However, GISTs can develop resistance to imatinib, and additional therapeutic strategies are needed. Little is known about oncogenic KIT signal transduction in GISTs, and whether the type of KIT mutation accounts for selective activation of downstream signaling intermediates. We therefore evaluated KIT downstream signaling profiles in 15 primary GISTs with mutations in KIT exons 9, 11, 13, and 17, and in two human GIST cell lines. All GISTs showed constitutive phosphorylation at KIT tyrosine residues Y703 and Y721. Additionally, most GISTs showed activation of MAPK p42/44, AKT, S6K, STAT1, and STAT3. STAT5 and JNK were not demonstrably activated in any GIST. Using GIST in vitro models, we showed that activation of MAPK p42/44, AKT, and S6K was KIT dependent, whereas STAT1 and STAT3 phosphorylation was only partially dependent on KIT activation. Correlation of activated signaling pathways with the type of KIT mutation revealed low levels of AKT phosphorylation in exon 9 mutant GISTs in contrast to a subset of GISTs with exon 11 mutations. However, additional factors are likely to modify the engagement of signaling pathways in GISTs as suggested by the fact that four GISTs with identical KIT exon 9 mutations had differential activation of MAPK p42/44 and STAT proteins. In summary, in this first report on KIT signal transduction in primary GISTs and GIST cell lines, we identified pathways that are constitutively activated in a KIT-dependent manner and therefore warrant further study as molecular targets in GISTs.

Apoptosis↗

PubMed2004

Evaluation of a clinically applicable post-surgical classification system for primary retroperitoneal soft-tissue sarcoma.

BACKGROUND: The present AJCC/TNM staging system is of limited value for prediction of prognosis for patients with retroperitoneal sarcoma. The objective of the present study was to develop a postsurgical classification system that would enable comparison of outcomes for patients with primary retroperitoneal soft-tissue sarcoma. METHODS: Four classes were defined: I, low-grade/complete resection/no metastasis; II, high-grade/complete resection/no metastasis; III, any-grade/incomplete resection/no metastasis; and IV, any-grade/any resection/distant metastasis. The prognostic value of this classification system was analyzed in a population-based multicenter group(MCG) of patients with primary retroperitoneal soft-tissue sarcoma (n = 124) and in a cohort of patients treated in a single tertiary referral center (SCG; n = 107). RESULTS: Overall 5-year survival rates were 55% in the SCG and 43% in the MCG (P = 0.02). Class III (incomplete resection) was more frequent in the MCG than in the SCG (33% vs. 16%; P = 0.02). In the SCG, stage-specific 5-year survival rates were 89%, 40%, 26%, and 17% for classes I, II, III, and IV, respectively (P < 0.001), in comparison with 68%, 46%, 24%, and 0% in the MCG (P < 0.001). In a comparison of class-specific survival between the groups, only class I patients in the SCG had significantly better survival than class I patients in the MCG (P = 0.048). CONCLUSIONS: Classification based on grade, completeness of resection, and distant metastasis offers a reproducible prognostic tool that can be used to evaluate treatment strategies for primary retroperitoneal soft-tissue sarcoma. The probability of complete resection was significantly higher in the SCG than in the MCG. In patients with low-grade, completely resected sarcoma, there is a significant survival benefit with treatment in a high-volume tertiary center of excellence.

Cohort Studies↗

PubMed2004

Atypical lipomatous tumor/well-differentiated liposarcoma of the extremity and trunk wall: importance of histological subtype with treatment recommendations.

BACKGROUND: This study defines the behavior and classification of atypical lipomatous tumors (ALT) and well-differentiated liposarcomas (WDLS) of the extremity and trunk. METHODS: A total of 91 well-differentiated lipomatous tumors of the extremity and trunk were identified from a soft tissue tumor database between July 1982 and June 2001. A soft tissue pathologist, blinded to prior diagnosis and clinical outcome, reviewed histology. Those composed predominantly of mature adipose tissue with scattered atypical stromal cells and scant lipoblasts or fibrosis were ALTs. Tumors with lipoblasts but <25% fibrosis were termed lipoma-like WDLS, and those with >/=25% fibrosis were identified as sclerosing WDLS. Clinical factors were analyzed to assess effects on local recurrence-free survival (LRFS). RESULTS: Histological review identified 34 ALTs and 57 WDLSs. Of the WDLSs, 29 were lipoma-like and 28 were sclerosing. Five-year and 10-year LRFS were 100% +/- 0% and 78% +/- 9%, respectively. Factors evaluated were age, sex, tumor site, tumor size, histology, presentation status, margin status, and adjuvant radiotherapy. Positive resection margins and sclerosing histology were associated with reduced LRFS. Dedifferentiation was observed in three tumors (3%). CONCLUSIONS: Lipoma-like WDLSs and ALTs share similar histological features and favorable behavior. Margin-positive sclerosing WDLSs have a 10-year LRFS of only 17% and should undergo function-preserving re-excision when possible, or adjuvant radiotherapy.

Adult↗

PubMed2004

Water suppression without signal loss in HR-MAS 1H NMR of cells and tissues.

In cell and tissue samples, water is normally three orders of magnitude more abundant than other metabolites. Thus, water suppression is required in the acquisition of NMR spectra to overcome the dynamic range problem and to recover metabolites that overlap with the broad baseline of the strong water resonance. However, the heterogeneous cellular environment often complicates water suppression and the strong coupling of water to membrane lipids interferes with the NMR detection of membrane associated lipid components. The widely used water suppression techniques including presaturation and double pulsed field gradient selective echo result in more than a 70% reduction in membrane associated lipid components in proton spectra of cells and tissues compared to proton spectra acquired in the absence of water suppression. A water suppression technique based on the combination of selective excitation pulses and pulsed field gradients is proposed to use in the acquisition of high resolution MAS NMR spectra of tissue specimens and cell samples. This pulse sequence methodology enables efficient water suppression for intact cells and tissue samples and eliminates signal loss from cellular metabolites.

Body Water↗

PubMed2004

Reconstruction after soft tissue sarcoma resection in the setting of brachytherapy: a 10-year experience.

Management of recurrent soft tissue sarcomas often involves surgical resection and adjuvant brachytherapy. This study reviews our experience in the management of these patients and proposes a logical approach toward reconstruction. All patients who underwent soft tissue sarcoma resection, adjuvant brachytherapy, and soft tissue flap reconstruction (pedicled or free) during the 10-year period from 1991 to 2000 were included in this study. There were 17 patients (14 male, 3 female) with a mean age of 51 years (range, 16-80 years). Soft tissue sarcomas were distributed in the lower extremity (n = 9), upper extremity (n = 5), and trunk (n = 3). Reconstruction was accomplished by regional transposition flaps (n = 10) and free tissue transfer (n = 7). The average defect size was 143 cm. Patients received 5 to 12 (mean, 8) brachytherapy catheters. The brachytherapy dose delivered ranged from 1600 to 4500 cGy (mean, 3773 cGy). Brachytherapy catheters were loaded with radioactive sources between 5 and 7 days postoperatively. All flaps in this series survived. One patient required return to the operating room for revision of a venous thrombosis with flap salvage. Closed suction drainage tubes were left in place until after the brachytherapy catheters were removed to avoid dislodging the catheters. Two patients developed postradiation partial-thickness skin necrosis with delayed secondary wound healing. This study demonstrates that soft tissue reconstruction in the setting of sarcoma resection and brachytherapy catheter placement is safe and efficacious. Postoperative wound healing complications can be minimized through coordination among the ablative surgeon, reconstructive surgeon, and radiation oncologist. Specifically, placement of microvascular anastomoses well away from the radiation target area is indicated whenever possible. Finally, removal of closed suction drainage tubes should be deferred until after the brachytherapy catheters are removed to minimize complications resulting from catheter dislodgement.

Adolescent↗

PubMed2004

The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma.

OBJECTIVE: To determine if chemotherapy offers a survival benefit to patients with large, high-grade, primary extremity liposarcoma. SUMMARY BACKGROUND DATA: The impact of chemotherapy on the survival of patients with primary extremity soft tissue sarcoma is controversial and its effect on individual histologic subtypes is not defined. PATIENT AND METHODS: Two prospectively collected sarcoma databases were used to identify all patients with >5 cm, high-grade, primary extremity liposarcoma that underwent surgical treatment of cure from 1975 to 2003 (n = 245). Clinical, pathologic and treatment variables were analyzed for disease-specific survival (DSS), distant recurrence-free survival (DRFS) and local recurrence-free survival (LRFS). RESULTS: Sixty-three (26%) patients were treated with ifosfamide based chemotherapy (IF), 83 (34%) with doxorubicin based chemotherapy (DOX) and 99 (40%) received no chemotherapy (NoC). To assess the impact of DOX, a contemporary cohort analysis of patients treated from 1975 to 1990 was performed. The 5 year DSS of the DOX treated patients was 64% (53%-74%) compared with 56% (51%-79%) for the NoC patients (log-rank P value = 0.28). To assess the impact of IF, a contemporary cohort analysis of patients treated from 1990 to 2003 was performed. The 5 year DSS of the IF treated patients was 92% (84%-100%) compared with 65% (51%-79%) for the NoC patients (log-rank P value = 0.0003). Independent prognostic factors for improved DSS were smaller size (HR = 0.7, P = 0.01), myxoid/round cell histologic subtype (HR = 0.3, P = 0.03) and treatment with IF (HR = 0.3, P = 0.01). The five-year DRFS of the IF treated patients was 81% (70%-92%) compared with 63% (50%-76%) for the NoC patients (log-rank P value = 0.02). The 5 year LRFS of the IF treated patients was 86% (76%-96%) compared with 87% (77%-97%) for the NoC patients (log-rank P value = 0.99). CONCLUSIONS: In patients with large, high-grade, primary extremity liposarcoma; DOX is not associated with improved DSS and IF is associated with an improved DSS. Treatment with IF should be considered in patients with high-risk primary extremity liposarcoma.

Adult↗