Showing papers by "Alexander J. Lazar published in 2009"
TL;DR: MPSNT is a markedly metastatic and aggressive poor prognosis tumor and multiple clinical, pathologic, and molecular markers identified in this study, coupled with findings from previous series, should be considered for an improved MPNST staging system useful for prognostic assessment and management decisions.
Abstract: Objective:Improved staging systems for malignant peripheral nerve sheath tumor (MPNST) prognostication and management are needed. Consequently, we sought to identify clinical, pathologic, and molecular predictors of outcome in patients with/without neurofibromatosis type 1 (NF-1) associated MPNST.Me
246 citations
TL;DR: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases, have implications for the rational development of targeted therapy for this disease.
Abstract: Purpose: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3α/β, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis. Experimental Design: DNA and protein were isolated from dissected frozen melanoma metastases ( n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3α/β, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines ( n = 58) was analyzed for comparison. Results: BRAF-mutant tumors had higher levels of P-AKT-Ser473 ( P = 0.01), P-AKT-Thr308 ( P = 0.002), and P-GSK3α/β ( P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases. Conclusions: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538–46)
229 citations
TL;DR: In this paper, the authors examined the prevalence of all chimeric types and variants to assess the usage of ancillary genetic testing in routine diagnosis in clear cell sarcoma and melanoma.
192 citations
TL;DR: Installing KIT expression in less than 10% of the cells of the invasive component of acral lentiginous/mucosal melanomas appears to be a strong negative predictor of KIT mutation and therefore can potentially be used to triage cases for additional KIT genotyping.
189 citations
TL;DR: In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas.
Abstract: Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma (∼30-40%). In vitro testing demonstrated that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib or sorafenib small molecule KIT inhibitors effective in non-melanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P =0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = -2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor FDG-avidity by PET imaging after dasatinib treatment. This data supports the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acral lentiginous, chronic sun damaged, and mucosal melanomas.
170 citations
TL;DR: Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST and may have implications for future treatment of sarcoma.
Abstract: Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naive historical control. The efficacy of imatinib was assessed by 18fluorodeoxyglucose positron emission tomography (18FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naive cohort (p ≥ 0.1). Most patients responded to preoperative imatinib by 18FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0–33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10–46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy.
161 citations
TL;DR: Current standard-of-care for patients with Ewing’s sarcoma are discussed and the most promising experimental therapies in early-phase clinical trials are highlighted.
Abstract: Ewing sarcoma family tumors (EWS), which include classic Ewing’s sarcoma in addition to primitive neuroectodermal tumor and Askin tumor, are the second most common variety of primary bone cancer to afflict adolescents and young adults. Multi-disciplinary care incorporating advances in diagnosis, surgery, chemotherapy, and radiation has substantially improved the survival rate of patients with localized Ewing sarcoma to nearly 70%. Unfortunately, those advances have not significantly changed the long-term outcome for those with metastatic or recurrent disease; 5-year survival remains less than 25%. This apparent therapeutic plateau exists despite extensive effort during the last four decades to optimize the efficacy of cytotoxic chemotherapy through combination of chemotherapies of mechanistically diverse action, dose-dense scheduling (provided as frequently as every 2 weeks), increased adjuvant treatment duration, and higher dosage per cycle (facilitated with parallel strides in supportive care incorporating growth factors). As has already occurred for malignancies such as breast or colon cancer, the “-omics-based” revolution has enhanced our understanding of the molecular changes responsible for Ewing’s tumor formation and identified a number of potential targets (such as IGF-1R or mTOR) amenable to biological therapy. It has also created both a challenge and an opportunity to develop predictive biomarkers capable of selecting patients most likely to benefit from targeted therapy. In this review, we discuss current standard-of-care for patients with Ewing’s sarcoma and highlight the most promising experimental therapies in early-phase clinical trials.
130 citations
TL;DR: Expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply improved therapeutic approaches for the benefit of afflicted patients, as well as pose the possibility of personalised, targeted therapeutics.
Abstract: Malignant peripheral nerve sheath tumour (MPNST) is a rare malignancy accounting for 3-10% of all soft tissue sarcomas. Most MPNSTs arise in association with peripheral nerves or deep neurofibromas and may originate from neural crest cells, although the specific cell of origin is uncertain. Approximately half of MPNSTs occur in the setting of neurofibromatosis type 1 (NF1), an autosomal dominant disorder with an incidence of approximately one in 3500 persons; the remainder of MPNSTs develop sporadically. In addition to a variety of clinical manifestations, approximately 8-13% of NF1 patients develop MPNSTs, which are the leading cause of NF1-related mortality. Surgical resection is the mainstay of MPNST clinical management. However, because of invasive growth, propensity to metastasise, and limited sensitivity to chemotherapy and radiation, MPNST has a guarded to poor prognosis. Five-year survival rates of only 20-50% indicate an urgent need for improved therapeutic approaches. Recent work in this field has identified several altered intracellular signal transduction cascades and deregulated tyrosine kinase receptors, posing the possibility of personalised, targeted therapeutics. However, expanded knowledge of MPNST molecular pathobiology will be needed to meaningfully apply such approaches for the benefit of afflicted patients.
100 citations
TL;DR: Identification of genetic alterations with specific identification of oncogenes and tumor suppressor genes may lead to additional insights into the tumorigenesis of leiomyosarcoma and the opportunity to confer the benefits of targeted therapy.
96 citations
TL;DR: The results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel therapy for patients harboring MPNST.
Abstract: The mammalian target of rapamycin (mTOR) pathway may constitute a potential target for the treatment of malignant peripheral nerve sheath tumors (MPNST). However, investigations of other cancers suggest that mTOR blockade can paradoxically induce activation of prosurvival, protumorigenic signaling molecules, especially upstream AKT. Consequently, we hypothesized that dual phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR blockade might be applicable for MPNST treatment. Expression of activated mTOR downstream targets (p4EBP1 and pS6RP) and pAKT was evaluated immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign neurofibromas (n = 31). Results were analyzed by Wilcoxon rank-sum tests. mTOR and AKT pathways in human MPNST cell lines, and the effects of rapamycin (mTOR inhibitor), LY294002 (dual PI3K/mTOR inhibitor), and PI-103 (potent dual PI3K/AKT-mTOR inhibitor) on pathway activation were evaluated by Western blot. Effects on cell growth were evaluated via MTS and colony formation assays. Cell cycle progression and apoptosis were assessed by propidium iodide/fluorescence-activated cell sorting staining and Annexin V assays. Acridine orange staining/fluorescence-activated cell sorting analysis, electron microscopy, and Western blot evaluated autophagy induction. p4EBP1, pS6Rp, and pAKT levels were found to be significantly higher in MPNST versus neurofibroma (P < 0.05 for all markers). mTOR and AKT pathways were found to be highly activated in MPNST cell lines. MPNST cells were sensitive to rapamycin; however, rapamycin enhanced pAKT and peIF4E expression. PI-103 abrogated MPNST cell growth and induced G(1) cell cycle arrest potentially through repression of cyclin D1. PI-103 did not elicit apoptosis but significantly induced autophagy in MPNST cells. These results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel therapy for patients harboring MPNST.
85 citations
TL;DR: The results suggest that genomic alterations present in human MFH are conserved in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.
Abstract: Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-KrasG12D; Trp53Flox/Flox mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.
TL;DR: Properly selected elderly patients can safely undergo extensive STS resections and until more effective therapies become available, surgery in the elderly is indicated and remains the best means for STS control.
Abstract: Decreased performance status, comorbidities, and disease natural history may erode enthusiasm for soft tissue sarcoma (STS) resection in elderly patients. Consequently, we evaluated the outcome of elderly patients amenable to complete surgical resection treated at a single institution. Prospectively accrued data were used to identify patients with primary STS age ≥65 years (n = 325) who underwent complete macroscopic resection at our institution (1996–2007). Univariable and multivariable analyses were performed to identify prognostic factors. Median age at presentation was 72 years; 179 patients (55.1%) had associated comorbidities with an ASA score of ≥3. Extremity was the most common site (57.1%; n = 186), undifferentiated pleomorphic sarcoma the most common histology (60.4%; n = 197); 232 (71.2%) were high grade, 222 (68.3%) were >5 cm. Thirty-day postoperative mortality was 0.9% (n = 3); overall complication rate was 30.7% (n = 100), and mean postoperative hospital stay was 9 days (range, 1–84). Estimated median survival was 96 months, 5-year disease-specific survival (DSS) was 63%. Multivariable analysis identified age ≥75 year (HR = 2.03), tumor size: 5–15 vs 15 vs <5 cm (HR = 10.33), and high-grade (HR = 5.53) as significant independent adverse prognostic factors. Compared with patients aged 65–74 years, older patients had more high grade tumors (P = .04), received chemotherapy less often (P < .0001), developed different patterns of recurrence (P < .05), and exhibited a shorter median survival (70 months; P = .05). Properly selected elderly patients can safely undergo extensive STS resections. Until more effective therapies become available, surgery in the elderly is indicated and remains the best means for STS control.
TL;DR: A positive screen of difficult cases with MDM2 IHC would require confirmation by the fluorescence in situ hybridization, as lack ofMDM2 immunoexpression would rule out the possibility of inflammatory well-differentiated liposarcoma.
TL;DR: Locally recurrent AS is often treatable; complete resection can potentially prolong survival and metastatic patients have a grave prognosis; however, patients with isolated lymphatic spread and possibly those treated with taxol-based chemotherapeutic regimens have a favorable outcome.
Abstract: Background
Angiosarcoma (AS) is a rare soft tissue sarcoma with an enhanced propensity for local and systemic failure. The outcome of locally recurrent and metastatic AS treated at a single institution was evaluated.
TL;DR: Assessment and treatment of individual patients in a multidisciplinary setting is critical to achieve the most favorable outcome in this disease and additional study of the molecular determinates of desmoid behavior is needed to guide therapeutic selection.
Abstract: Purpose of reviewDesmoid tumors are associated with a variable and unpredictable clinical course. Surgery is the therapeutic mainstay, but there has been much discussion of late regarding its proper application. Little is known regarding the molecular determinates of desmoid tumor behavior. Some rec
TL;DR: This article focuses on the pathology of GIST, including unusual variants and morphologic changes resulting from treatment, and parameters for risk assessment, potentially helpful new immunohistochemical markers, differential diagnosis, and the application of molecular classification schemes.
Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs harbor a KIT or PDGFRA mutation and express KIT by immunohistochemistry. However, KIT-negative tumors and tumors showing unusual morphologic features can cause major diagnostic problems. The ability to inhibit the active KIT or PDGFRA kinase with tyrosine kinase inhibitors and alternative drugs demands more than ever accurate tumor classification and risk assessment. This article focuses on the pathology of GIST, including unusual variants and morphologic changes resulting from treatment. Parameters for risk assessment, potentially helpful new immunohistochemical markers, differential diagnosis, and the application of molecular classification schemes are discussed.
TL;DR: The data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRf8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in humanSTS therapy.
Abstract: IFN regulatory factor 8 (IRF8) has been shown to suppress tumor development at least partly through regulating apoptosis of tumor cells; however, the molecular mechanisms underlying IRF8 regulation of apoptosis are still not fully understood. Here, we showed that disrupting IRF8 function resulted in inhibition of cytochrome c release, caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase cleavage in soft tissue sarcoma (STS) cells. Inhibition of the mitochondrion-dependent apoptosis signaling cascade is apparently due to blockage of caspase-8 and Bid activation. Analysis of signaling events upstream of caspase-8 revealed that disrupting IRF8 function dramatically increases FLIP mRNA stability, resulting in increased IRF8 protein level. Furthermore, primary myeloid cells isolated from IRF8-null mice also exhibited increased FLIP protein level, suggesting that IRF8 might be a general repressor of FLIP. Nuclear IRF8 protein was absent in 92% (55 of 60) of human STS specimens, and 99% (59 of 60) of human STS specimens exhibited FLIP expression, suggesting that the nuclear IRF8 protein level is inversely correlated with FLIP level in vivo. Silencing FLIP expression significantly increased human sarcoma cells to both FasL-induced and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and ectopic expression of IRF8 also significantly increased the sensitivity of these human sarcoma cells to FasL- and TRAIL-induced apoptosis. Taken together, our data suggest that IRF8 mediates FLIP expression level to regulate apoptosis and targeting IRF8 expression is a potentially effective therapeutic strategy to sensitize apoptosis-resistant human STS to apoptosis, thereby possibly overcoming chemoresistance of STS, currently a major obstacle in human STS therapy.
TL;DR: The molecular signature of alveolar soft part sarcoma is a specific der(17)t(X;17)(p11.2;q25) translocation, resulting in a chimeric transcription factor (ASPSCR1–TFE3) which is expressed in a cohort of ASPS tumour samples.
Abstract: Aims: The molecular signature of alveolar soft part sarcoma (ASPS) is a specific der(17)t(X;17)(p11.2;q25) translocation, resulting in a chimeric transcription factor (ASPSCR1–TFE3). When this disease is no longer amenable to surgical curative intervention, uniformly efficacious therapies are lacking. The aim of this study was to evaluate the expression of potential molecular therapeutic targets in a cohort of ASPS tumour samples.
Methods and results: Immunohistochemical analysis for hepatocyte growth factor, c-Met, phosphorylated c-Met, phosphorylated AKT, phosphorylated MEK, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53 and vimentin was performed on an ASPS tissue microarray, yielding complete data from 26 tumours. Activation of c-Met and its downstream effectors was noted, whereas only limited EGFR expression was seen. VEGF was expressed to varying degrees. Only one sample exhibited strong nuclear p53 expression, while 10 expressed low levels. Vimentin expression was negative in the vast majority of samples (96%).
Conclusions: There is a crucial need for better anti-ASPS therapies. Activated c-Met and the phosphorylation of its downstream effectors validate an intact signalling cascade probably induced by the ASPSCR1–TFE3 chimeric transcription factor. The angiogenic phenotype of these tumours is supported by increased angiogenic factor expression. Combination therapies targeting both tumour cells and angiogenesis merit further investigation.
TL;DR: Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.
Abstract: Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.
TL;DR: The authors compared disease‐specific survival (DSS) in stage‐specific subgroups of patients with clear cell sarcoma, including those with lymph node metastases (N1M0) and those with distant metastased patients (N0M1).
Abstract: BACKGROUND:
The authors compared disease-specific survival (DSS) in stage-specific subgroups of patients with clear cell sarcoma, including those with lymph node metastases (N1M0) and those with distant metastases (N0M1).
METHODS:
Clinical data regarding soft tissue sarcoma patients were obtained from The University of Texas M. D. Anderson Cancer Center (MDACC) (1980-2007) and the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2004). When possible, clear cell sarcoma diagnoses were confirmed using fluorescence in situ hybridization or reverse-transcription polymerase chain reaction. Kaplan-Meier estimates were used to calculate DSS, and Cox multivariate analysis was performed to identify prognostic factors.
RESULTS:
Fifty-two patients at MDACC and 130 SEER patients were diagnosed with clear cell sarcoma. Five-year DSS for the MDACC and SEER cohorts were 67% and 62%, respectively. Patients with N1M0 and N0M1 disease demonstrated significant differences in 5-year DSS: 74% versus 14% at MDACC (P = .014) and 52% versus 0% in SEER (P = .014). After adjustment, the hazards ratio (HR) for dying was 2.79 for N1M0 disease (95% confidence interval [95% CI], 1.32-5.91) and 11.37 (95% CI, 5.19-24.91) for N0M1 disease compared with stage II disease (P < .001). Non-Caucasian ethnicity (HR, 3.99; 95% CI, 2.27-6.99 [P < .001]) and truncal tumor site (HR, 2.41; 95% CI, 1.15-5.05 [P = .02]) were also found to be predictors of decreased DSS.
CONCLUSIONS:
The findings of the current study suggest that patients with N1M0 clear cell sarcoma have 5-year DSS that is more similar to that of patients with stage III than stage IV soft tissue sarcoma. Cancer 2009. © 2009 American Cancer Society.
TL;DR: Compared with breast cancers, STS exhibited lower PT-LVD independent of VEGF-C expression, which may underlie STS lymph node metastasis rarity, and lymphatic vessels appear necessary but not sufficient to sustainSTS lymphatic spread.
Abstract: Purpose: Unlike carcinomas, soft-tissue sarcoma (STS) rarely exhibit lymphatic spread. Consequently, we examined expression and function of vascular endothelial growth factor (VEGF)-C and STS-associated lymphatic vessel density (LVD) components of this process.
Experimental Design: VEGF-C and VEGF-A mRNA and VEGF-C protein expression were evaluated in STS, STS cell lines, and breast cancers (reverse transcription-PCR, quantitative reverse transcription-PCR, and ELISA). STS cell conditioned medium after VEGF-C knockdown was examined for endothelial cell proliferation and migration effects (MTS and migration assays). Paraffin-embedded human lymph node-negative and lymph node-positive STS and lymph node-negative and lymph node-positive breast cancers were examined for VEGF-C, D2-40, and CD31 expression (immunohistochemistry). LVD differences were analyzed by Wilcoxon rank-sum tests.
Results: STS and breast cancer VEGF-C expression was comparable and higher than normal tissue levels. STS cells secreted functional VEGF-C: STS conditioned medium induced lymphatic endothelial cell proliferation and migration, which was abrogated by STS cell VEGF-C knockdown. STS and breast cancer intratumoral LVD was similar. STS peritumoral LVD (PT-LVD) was reduced versus breast cancer PT-LVD ( P < 0.001). Significantly higher PT-LVD was observed in lymph node-positive versus lymph node-negative STS; lymphatic spreading STS subtypes also had higher LVD. STS VEGF-C expression and PT-LVD lacked correlation, and many lymph node-negative STS had high PT-LVD, suggesting complexity in this metastatic process.
Conclusions: Compared with breast cancers, STS exhibited lower PT-LVD independent of VEGF-C expression, which may underlie STS lymph node metastasis rarity. Moreover, lymphatic vessels appear necessary but not sufficient to sustain STS lymphatic spread. Examining STS “nonlymphatic” dissemination may help elucidate mechanisms of lymphatic spread, insights critically important to cancer metastasis control.
TL;DR: The long-term survival of skin allografts applied as a temporary bridge for later skin autografting in three patients too ill to undergo skin autOGrafting is reported, illustrating that selected patients may benefit from allografteding as a potentially final wound closure intervention.
Abstract: Split-thickness skin grafting is a fundamental surgical technique for coverage of large wounds. Skin is harvested at an appropriate depth of dermis to allow the donor site to heal by reepithelialization. However, these open areas may increase morbidity in elderly or debilitated patients with undue pain and slowness in healing. Our efforts to eliminate or minimize the donor site in such individuals have led to the development of alternative temporary skin substitutes. Allografts of human skin have been used since World War II.1,2 The technique simplifies wound care and allows nutritional optimization and emergence from the critical phase of injury. In nonimmunocompromised patients, the allografts fail once the host’s immune response recognizes the foreign tissue. However, allograft survival may be prolonged from 3 to 10 weeks in the severely ill.3,4 We report in this article the long-term survival of skin allografts applied as a temporary bridge for later skin autografting in three patients too ill to undergo skin autografting. These individuals had either chronic comorbidities in addition to acute critical illness or extensive burn injuries. We believe that our reported cases illustrate that selected patients may benefit from allografting as a potentially final wound closure intervention. CASE REPORTS