Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST.

BACKGROUND: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition. METHODS: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure. RESULTS: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST. CONCLUSIONS: These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Composite grading algorithm for the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

BACKGROUND: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested. METHODS: A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443). RESULTS: In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation. CONCLUSION: A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting.

What happened to the US cancer cooperative groups? A status update ten years after the Institute of Medicine report.

The US cancer cooperative groups (cooperative groups) were founded in the 1950s to establish a standing infrastructure to conduct multi-institutional cancer clinical trials. Initially funded almost entirely by the US National Cancer Institute (NCI), over the years, the research conducted by the Cooperative Groups has evolved to meet the demands of cancer clinical research, with a scope now encompassing trials to advance cancer treatment, cancer control, biomarker development and validation, and health services research, with a corresponding broadening of their funding sources. The cooperative groups are also a critical mechanism for educating the next generation of cancer clinical trialists from many different disciplines. This review outlines the overall mission, structure, and funding of the cooperative groups, beginning in 1955 when they were first established by the NCI, and describes the considerable progress against cancer achieved over the past decade.

The electronic health record as a clinical trials tool: Opportunities and challenges.

Clinical trials provide evidence essential for progress in health care, and as the complexity of medical care has increased, the demand for such data has dramatically expanded. Conducting clinical trials has also become more complicated, evolving to meet increasing challenges in delivering clinical care and meeting regulatory requirements. Despite this, the general approach to data collection remains the same, requiring that researchers submit clinical data in response to study treatment protocols, using precisely defined data structures made available in study-specific case report forms. Currently, research data management is not integrated within the patient's clinical care record, creating added burden for clinical staff and opportunities for error. During the past decade, the electronic health record has become standard across the US healthcare system and is increasingly used to collect and analyze data reporting quality metrics for clinical care delivery. Recently, electronic health record data have also been used to address clinical research questions; however, this approach has significant drawbacks due to the unstructured and incomplete nature of current electronic health record data. This report describes steps necessary to use the electronic health record as a tool for conducting high-quality clinical research.

Sorafenib inhibits proliferation and invasion in desmoid-derived cells by targeting Ras/MEK/ERK and PI3K/Akt/mTOR pathways.

Desmoid tumors (DTs) are unusual neoplasms of mesenchymal origin that exhibit locally invasive behavior. Surgical resection is the initial treatment of choice for DTs. For patients with recurrent or unresectable disease, however, medical options are limited. Sorafenib is a multikinase inhibitor with known antitumor activity in various cancers via suppression of the PI3K/Akt/mTOR pathway. Here, we examined the effects of sorafenib on patient-derived DT cell lines, with the aim of characterizing the efficacy and molecular mechanism of action. Early passage DT-derived cells were treated with increasing doses of sorafenib (0-10 µM) and demonstrated up to 90% decrease in proliferation and invasion relative to controls. Signaling arrays identified multiple potential targets of sorafenib in the Ras/MEK/ERK and PI3K/Akt/mTOR signaling cascades. Immunoblot analysis revealed that sorafenib inhibited Akt, MEK and ERK phosphorylation, and this effect correlated with inhibition of total Akt and total MEK, while total ERK levels remained unchanged. Sorafenib also inhibited 4E-BP1 phosphorylation, and this effect correlated with decrease of p-eIF4E and total eIF4E. Finally, in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus, sorafenib decreased phosphorylation of the ribosomal protein and mTOR effector S6K in an additive manner. Taken together, our results suggest that sorafenib suppresses DT proliferation and invasion via inhibition of Ras/MEK/ERK and PI3K/Akt/mTOR signaling pathways with additional effects on translation. Sorafenib may be a promising therapeutic option in the treatment of DTs. Additional studies in DT patients are warranted to examine the efficacy of combination therapy using sorafenib.

Cytoreductive Surgery for Metastatic Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors: A 2-institutional Analysis.

OBJECTIVE: To refine treatment recommendations for patients with metastatic gastrointestinal stromal tumors (GISTs) treated with tyrosine kinase inhibitors (TKIs) and surgery. BACKGROUND: Early reports suggested that patients with metastatic GIST responding to TKIs treated with surgery may have favorable outcomes. However, identification of prognostic factors was limited by small cohorts. METHODS: Progression-free survival (PFS) and overall survival (OS) from time of surgery and from start of initial TKI was determined. Multivariate analysis was conducted on all patients undergoing GIST metastasectomy between 2001 and 2014 at 2 institutions. RESULTS: We performed 400 operations on 323 patients with metastatic GIST on TKIs. Radiographic response at time of surgery was classified as responsive disease (RD, n = 64, 16%), stable disease (SD, n = 100, 25%), unifocal progressive disease (UPD, n = 132, 33%), and multifocal progressive disease (MPD, n = 104, 26%). For patients on imatinib before surgery, radiographic response was predictive of PFS from time of surgery (RD 36 months, SD 30 months, UPD 11 months, MPD 6 months; P < 0.001) and from imatinib initiation (RD 71 months, SD 51 months, UPD 47 months, MPD 33 months; P < 0.001). Radiographic response was predictive of OS from time of surgery (RD not reached, SD 110 months, UPD 59 months, MPD 24 months; P < 0.001), and from imatinib initiation (RD not reached, SD 144 months, UPD 105 months, MPD 66 months; P = 0.005). Radiographic response was not predictive of PFS/OS for patients on sunitinib. Metastatic mitotic index ≥5/50 HPF, MPD, and R2 resection were prognostic of worse PFS/OS; primary mutation was not. CONCLUSIONS: Surgery in metastatic GIST patients in the absence of MPD on imatinib is associated with outcomes at least comparable with second-line sunitinib and may be considered in select patients.

Amputation for Extremity Sarcoma: Contemporary Indications and Outcomes.

INTRODUCTION: Amputation for localized extremity sarcoma (ES), once the primary therapy, is now rarely performed. We reviewed our experience to determine why patients with sarcoma still undergo immediate or delayed amputation, identify differences based on amputation timing, and evaluate outcomes. METHODS: Records of patients with primary, nonmetastatic ES who underwent amputation at our institution from 2001 to 2011 were reviewed. Univariate analysis was performed, and survival outcomes were calculated. RESULTS: We categorized 54 patients into three cohorts: primary amputation (A1, n = 18, 33%), secondary amputation after prior limb-sparing surgery (A2, n = 22, 41%), and hand and foot sarcomas (HF, n = 14, 26%). Median age at amputation was 54 years (range 18-88 years). Common indications for amputation (> 40%) were loss of function, bone involvement, multiple compartment involvement, and large tumor size (A1); proximal location, joint involvement, neurovascular compromise, multiple compartment involvement, multifocal or fungating tumor, loss of function, and large tumor size (A2); and joint involvement and prior unplanned surgery (HF). There was no difference in disease-specific survival (DSS) (p = 0.19) or metastasis-free survival (MFS) (p = 0.31) between early (A1) and delayed (A2) amputation. Compared with cohorts A1/A2, HF patients had longer overall survival (OS) (p = 0.04). CONCLUSIONS: Indications for amputation for extremity sarcoma vary between those who undergo primary amputation, delayed amputation, and amputation for hand or foot sarcoma. Amputations chosen judiciously are associated with excellent disease control and survival. For patients who ultimately need amputation, timing (early vs. delayed) does not affect survival.

Surgical Management of Primary Retroperitoneal Sarcomas: Rationale for Selective Organ Resection.

BACKGROUND: Recently, some have argued for routine resection of adjacent but uninvolved organs in patients with retroperitoneal sarcoma (RPS) without stipulating the rationale for such organ resection (beyond the need to achieve a macroscopically complete resection) or examining histopathologic organ invasion (HOI). This study reviewed the authors' experience with primary RPS to investigate the rate and rationale for individual organ resection and the rate of HOI. METHODS: Operative and pathology reports for patients with primary RPS who underwent resection at our institution were retrospectively reviewed. Histopathologic organ invasion was confirmed by a dedicated sarcoma pathologist. RESULTS: From 2002 through 2011, 118 patients underwent resection of a primary RPS, and 99 of these patients (84%) had at least one organ resected. Kidney (n = 57), colon (n = 51), and adrenal (n = 41) were the most commonly resected organs. For the 302 organs removed, the perioperative clinical rationale for the resection was suspected invasion or tumor origin (n = 52, 17%), involved end-organ vasculature (n = 39, 13%), organ encasement (n = 42, 14%), tumor adherence (n = 127, 42%), resection required for R0/R1 resection (n = 25, 8%), or other (n = 17, 6%). The presence of HOI was found in 77 (25%) of the 302 organs resected. In the reviewed studies, HOI was identified in 34 (65%) of 52 organs suspected of invasion or tumor origin, in 19% of organs resected due to tumor encasement, and in 26% of organs with adherent tumor, even when not suspected intraoperatively, but was never identified in organs resected purely as part of a liberal en bloc resection of adjacent organs. When invasion was suspected intraoperatively, HOI was confirmed in 50, 78, and 100% of resected organs respectively for well-dedifferentiated liposarcoma, dedifferentiated liposarcoma (DDLPS), and leiomyosarcoma (LMS). CONCLUSIONS: Histologic organ invasion was observed more commonly in organs resected with suspicion of invasion than in organs resected simply to achieve a negative margin, although this reflects a degree of subjectivity and selection bias. In more than one-fourth of adherent organs, HOI was present even when not suspected intraoperatively. Histologic subtype may predict HOI because DDLPS and LMS are associated with high rates of HOI when invasion is suspected intraoperatively. Development of a data-driven, histology-specific rationale for adjacent organ resection is critical.

Cutaneous Radiation-associated Breast Angiosarcoma: Radicality of Surgery Impacts Survival.

OBJECTIVE: Cutaneous radiation therapy (RT)-associated breast angiosarcoma (AS) is a rare consequence of breast RT associated with poor outcomes. Previous small case series have documented high recurrence rates and poor survival. We reviewed our experience and focused on the impact of conservative versus radical resections. METHODS: Data for patients with RT-associated breast AS evaluated at our institution from 1993 to 2015 who underwent surgery were reviewed. RESULTS: Seventy-six women were diagnosed with RT-associated breast AS at a median 85 months from surgery for invasive breast carcinoma or ductal carcinoma in situ. Thirty-eight underwent mastectomy/wide excision with partial skin resection ("conservative") and 38 underwent resection of all or nearly all previously irradiated skin plus mastectomy ("radical"). The radical group (vs the conservative group) more often had multifocal disease (80% vs 56%, P = 0.04), chemotherapy for AS (58% vs 22%, P < 0.01), margin-negative resection (100% vs 73%, P < 0.01), reconstructive surgery (100% vs 13%, P < 0.01), and re-operation (16% vs 3%, P = 0.04). Five-year crude cumulative incidences of local recurrence and distant metastasis for radical versus conservative groups were 23% versus 76% (P < 0.01) and 18% versus 47% (P = 0.02), respectively. Five-year disease-specific survival (DSS) for radical versus conservative groups was 86% versus 46% (P < 0.01), respectively. On multivariable analysis, age, radicality of surgery, and margin were predictive of DSS. CONCLUSIONS: For patients with RT-associated breast AS, radical resection was associated with reduced recurrence rates and improved DSS. Although margin was predictive of DSS, multifocality calls into question the reliability of negative margin assessment.

A Study of Thymidylate Synthase Expression as a Biomarker for Resectable Colon Cancer: Alliance (Cancer and Leukemia Group B) 9581 and 89803.

PURPOSE: Tumor levels of thymidylate synthase (TS), a target of 5-fluorouracil (5-FU)-based chemotherapy for colorectal cancer, have been studied as a predictive or prognostic biomarker with mixed results. PATIENTS AND METHODS: Tumor TS levels were prospectively evaluated in two adjuvant therapy trials for patients with resected stage II or III colon cancer. TS expression was determined by standard immunohistochemistry and by automated quantitative analysis. Tumor mismatch repair deficiency (MMR-D) and BRAF c.1799T > A (p.V600E) mutation status were also examined. Relationships between tumor TS, MMR-D, and BRAF mutation status, overall survival (OS), and disease-free survival (DFS) were investigated in the subset of stage III patients. RESULTS: Patients whose tumors demonstrated high TS expression experienced better treatment outcomes, with DFS hazard ratio (HR) = 0.67, 95% confidence interval (CI) = 0.53, 0.84; and OS HR = 0.68, 95% CI = 0.53, 0.88, for high versus low TS expression, respectively. No significant interaction between TS expression and stage was observed (DFS: interaction HR = 0.94; OS: interaction HR = 0.94). Tumors with high TS expression were more likely to demonstrate MMR-D (22.2% vs. 12.8%; p = .0003). Patients whose tumors demonstrated both high TS and MMR-D had a 7-year DFS of 77%, compared with 58% for those whose tumors had low TS and were non-MMR-D (log-rank p = .0006). Tumor TS expression did not predict benefit of a particular therapeutic regimen. CONCLUSION: This large prospective analysis showed that high tumor TS levels were associated with improved DFS and OS following adjuvant therapy for colon cancer, although tumor TS expression did not predict benefit of 5-FU-based chemotherapy. The Oncologist 2017;22:107-114Implications for Practice: This study finds that measurement of tumor levels of thymidylate synthase is not helpful in assigning specific adjuvant treatment for colorectal cancer. It also highlights the importance of using prospective analyses within treatment clinical trials as the optimal method of determining biomarker utility.

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.

Antitumor effects of hyaluronan inhibition in desmoid tumors.

Desmoid tumors (DTs) are rare, mesenchymal tumors that exhibit features of an abundant wound healing process. Previously, we showed that mesenchymal stem cells (MSCs) are constituents of DTs and may contribute to desmoid tumorigenesis via activities associated with wound healing. Hyaluronan (HA) is a long-charged chain of repeating glucuronate and N-acetylglucosamine disaccharides that is synthesized by HA synthases (HAS) and degraded by hyaluronidases (HYAL). HA is secreted into the extracellular matrix by injured stroma and is important for normal tissue repair and neoplastic progression. Here, we investigated the presence of HA in DTs and the antitumor effects of the HA inhibitor, 4-methylumbelliferone (4-MU), on DT-derived mesenchymal cells. By immunohistochemistry and enzyme-linked immunosorbent assay, we found abundant expression of HA in 29/30 DTs as well as >5-fold increased HA levels in DT-derived cell lines relative to controls. Immunohistochemistry also demonstrated high expression of HAS2 in DTs, and quantitative PCR analysis showed increased HAS2 upregulation in frozen DTs and DT-derived cells. 4-MU treatment of DT-derived cells significantly decreased proliferation as well as HA and HAS2 levels. Fluorescent immunohistochemistry showed that MSCs in DTs coexpressed HA, HAS2, HYAL2, as well as the major HA receptor CD44 and HA coreceptor TLR4. Taken together, our results suggest that paracrine regulation of HA signaling in DTs may contribute to MSC recruitment and tumor proliferation. Future studies investigating the role of HA in tumor-stroma crosstalk and inhibition of HA-MSC interactions as a novel therapeutic target in DTs and other solid tumors are warranted.

CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer.

BACKGROUND & AIMS: The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL). METHODS: We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated. RESULTS: Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses. CONCLUSIONS: Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Comparison of gastric cancer survival between Caucasian and Asian patients treated in the United States: results from the Surveillance Epidemiology and End Results (SEER) database.

BACKGROUND: The prognosis for gastric cancer is better for Asian than for Caucasian patients. The primary driver of this difference is unknown. This study determined whether the survival advantage of Asian ethnicity continued to hold after control was used for other well-known prognostic factors. METHODS: In this study, 12,773 patients who underwent gastrectomy for treatment of adenocarcinoma of the stomach were identified from the Surveillance, Epidemiology, and End Results cancer registry. Patients with cardia tumor were excluded from the study. The independent prognostic effect of ethnicity was evaluated by adjusting for other known factors. RESULTS: The Asian patients tended to have a diagnosis at an earlier age (66.8 vs. 68.5 years), more lymph nodes examined (16 vs. 13), and more positive lymph nodes (5.1 vs. 4.8). Survival was better for the Asian patients than for the Caucasian patients, with a 12 % 5-year survival difference. Among the patients with IB, IIA, and IIB disease, the Asian patients had 37, 72, and 13 months longer median survival time than the corresponding Caucasian patients. The multivariate Cox model showed persistence of this result after adjustment for imbalances of age, gender, tumor grade, and number of examined and positive lymph nodes. The largest risk reduction was observed for the stage IA patients (31 %) and the smallest for the stage IIIC patients (9 %). CONCLUSION: After excluding proximal gastric cancers, controlling for the imbalance of known prognostic factors, and decreasing in the influence of D2 lymphadenectomy, stage migration, and chemo/radiation therapy by including only patients treated in the United States, this study found that the survival advantage of Asian ethnicity continued to be present.

Safety and efficacy of radiation dose delivered via iodine-125 brachytherapy mesh implantation for deep cavity sarcomas.

BACKGROUND: Radiation delivered as brachytherapy (BRT) via catheters placed during extremity soft tissue sarcoma (STS) resection results in acceptable local control rates; however, there are limitations in deep cavities. (125)I seeds embedded in mesh provide a flexible BRT platform that may be contoured to irregular deep cavities surfaces, but the risks and benefits are unknown. METHODS: Patients with thoracic, abdominal, pelvic, retroperitoneal, and deep truncal STS undergoing resection and implantation of permanent (125)I mesh BRT at our institution were reviewed. Local recurrence rates within the tumor bed covered by mesh (in field) and postoperative complications were analyzed. RESULTS: Between 2000 and 2010, a total of 46 patients were treated for primary (n = 8, 17 %) or recurrent (n = 38, 83 %) deep cavity STS (median follow-up 34.8 months); 74 % received external-beam radiotherapy for this or a prior presentation. In-field recurrences were observed in 9 patients (19.5 %). Crude cumulative incidences of in-field, regional, and distant recurrences at 5 years were 26.3, 54.2, and 54.1 %, respectively. 5-year overall survival rate was 47.2 %; median survival was 44.0 months. Twenty-two patients (48 %) experienced complications, half of whom (24 %) developed grade III/IV complications requiring percutaneous intervention (n = 6) or reoperation (n = 5) at a median of 35.5 days. There were no postoperative deaths. CONCLUSIONS: To our knowledge, this is the first study to report safety and efficacy for permanent (125)I mesh BRT implantation after resection of deep cavity STS. Local in-field recurrence rates were relatively low in this high-risk population. However, 24 % developed complications requiring intervention. (125)I mesh BRT appears effective, but it should be used with caution.

Celecoxib inhibits early cutaneous wound healing.

BACKGROUND: Cyclooxygenase-2 (COX-2) is an inducible enzyme that is rapidly upregulated in response to injury, resulting in the production of prostaglandin E2 (PGE2), a primary mediator of inflammation and wound healing. The selective COX-2 inhibitor, celecoxib, is was used to treat pain and inflammation. When used to treat injuries, we postulated that loss of PGE2 activity by COX-2 inhibition would have detrimental effects on wound healing. Our objective was to study the effect of selective COX-2 inhibition with celecoxib on cutaneous wound healing. MATERIALS AND METHODS: C57BL/6J mice with uniform full-thickness wounds (1 cm(2)) to their dorsum were fed diet with or without celecoxib (1500 ppm). Wound closure analysis measured wound contraction, reepithelialization, and open wound as a percentage of the initial wound area, and was quantified by planimetry. Wounds were excised en bloc at day 7 to examine cellular proliferation, angiogenesis, cytokine production, and extracellular matrix (ECM) formation. RESULTS: Celecoxib-induced reduction in wound PGE2 levels was documented by enzyme-linked immunosorbent assay on day 7 after wounding. Wound contraction and reepithelialization were significantly reduced by celecoxib treatment, resulting in a 20% greater open wound area at day 7 (P < 0.05). In response to celecoxib treatment, immunohistochemistry analysis showed epithelial cell proliferation, angiogenesis, and ECM components including collagen and myofibroblasts were significantly decreased. CONCLUSIONS: Wound healing is significantly delayed by celecoxib treatment. These data indicate that COX-2 and its downstream product PGE2 modulate the activity of multiple essential functions of the inflammatory stroma, including epithelial proliferation, angiogenesis, and ECM production. As a result, reepithelialization and wound closure are delayed by celecoxib treatment. These findings have potential clinical implications in postoperative wound management.