Cell Cycle Checkpoints p16 and p21-Strong Predictors of Clinicopathologic Outcomes in High-Grade Osteosarcoma.

PURPOSE: In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. METHOD: A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. RESULTS: Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. DISCUSSION: The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.

Periprosthetic Metastatic Lung Carcinoma About a Total Knee Arthroplasty: A Case Report.

CASE: A 64-year-old man presented with unrelenting left knee pain and an unremarkable radiograph 4 months after revision total knee arthroplasty (TKA). Pain persisted, despite conservative management, and repeat imaging demonstrated significant lysis of the left medial tibial condyle. A biopsy demonstrated metastatic squamous cell carcinoma of the lung. Management with excision and curettage of the tibial lesion was followed by palliative radiotherapy and chemotherapy until the patient died 7 months later. CONCLUSION: This case highlights metastasis as an etiology for persistent TKA pain in a patient with significant risk factors.

Massive Osteolysis in a Modern Total Knee Prosthesis.

CASE: An 82-year-old woman underwent right total knee replacement with a sequentially irradiated and annealed highly cross-linked polyethylene insert. At 9 years, she was found to have a massive femoral osteolysis with an impending fracture. CONCLUSION: This case demonstrates a rare occurrence of massive femoral osteolysis, requiring revision surgery, with a sequentially irradiated and annealed highly cross-linked polyethylene.

Generalized infantile myofibromatosis with visceral involvement presenting as diffuse hypopigmented macules at birth.

The initial clinical presentation of infantile myofibromatosis can vary from subtle skin changes to large tumors. Here, we describe a case of congenital generalized infantile myofibromatosis which presented with diffuse hypopigmented macules, some with subtle atrophy and telangiectasia. Further workup revealed visceral involvement which led to treatment with systemic chemotherapy. Awareness of this rare clinical presentation is crucial to expedite workup and treatment given the poor prognosis in infants with visceral involvement.

Eps8 expression is significantly lower in p16+ head and neck squamous cell carcinomas (HNSCCs) compared with p16- HNSCCs.

In vitro head and neck cancer studies have demonstrated that epidermal growth factor receptor kinase substrate 8 (Eps8) overexpression contributes to squamous carcinogenesis. Oral squamous cell carcinoma studies have correlated Eps8 expression with metastatic disease and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) studies comparing its expression by anatomic site or in in vivo regional metastases have not been performed. In this study, we compared Eps8 expression in HNSCCs arising in the oral cavity (OCSCC) and oropharynx (OPSCC) along with their corresponding regional lymph node (LN) metastases. We then correlated our findings with clinicopathologic data including tumor-node-metastasis stage, p16 status, age, sex, and smoking and alcohol history. Eps8 immunohistochemistry was performed on 69 archived OCSCCs and OPSCCs, and 24 paired and 4 unpaired LNs. Expression was scored from 0 to 3. Eps8 expression was detected in 49% of combined OCSCC and OPSCC cases. We found that expression correlated with advanced tumor stage (P = .022) and p16 status (P = .032) but not with anatomic site. Notably, p16+ HNSCCs had significantly lower Eps8 expression than p16- HNSCCs. No significant difference was observed between primary HNSCCs and their corresponding metastatic LNs. Neither p16 status nor anatomic site influenced Eps8 expression in regional LN metastases. In conclusion, our data offer in vivo support that, in HNSCCs, Eps8 is involved in tumor invasion but not necessarily the development of regional LN metastasis. The association between low Eps8 expression and p16+ HNSCCs suggests that alternative signaling pathways may be used for their tumorigenesis.

Bone- and cartilage-forming tumors and ewing sarcoma: an update with a gnathic emphasis.

Over the past decade, there have been remarkable advances in bone tumor pathology. Insights into the genetic basis and pathobiology of many tumor types have impacted diagnosis, classification, and treatment. However, because gnathic lesions may comprise only a small proportion of cases overall for many tumors, clinicopathologic features and management considerations specific to this subset may be overlooked. Here we provide a summary of recent developments in the following tumor types: osteosarcoma (OS), chondrosarcoma (CS), osteoid osteoma (OO), osteoblastoma (OB), and Ewing sarcoma (ES). In particular, we will give special consideration to cases arising in the jaws.

Multi-dye theranostic nanoparticle platform for bioimaging and cancer therapy.

BACKGROUND: Theranostic nanomaterials composed of fluorescent and photothermal agents can both image and provide a method of disease treatment in clinical oncology. For in vivo use, the near-infrared (NIR) window has been the focus of the majority of studies, because of greater light penetration due to lower absorption and scatter of biological components. Therefore, having both fluorescent and photothermal agents with optical properties in the NIR provides the best chance of improved theranostic capabilities utilizing nanotechnology. METHODS: We developed nonplasmonic multi-dye theranostic silica nanoparticles (MDT-NPs), combining NIR fluorescence visualization and photothermal therapy within a single nanoconstruct comprised of molecular components. A modified NIR fluorescent heptamethine cyanine dye was covalently incorporated into a mesoporous silica matrix and a hydrophobic metallo-naphthalocyanine dye with large molar absorptivity was loaded into the pores of these fluorescent particles. The imaging and therapeutic capabilities of these nanoparticles were demonstrated in vivo using a direct tumor injection model. RESULTS: The fluorescent nanoparticles are bright probes (300-fold enhancement in quantum yield versus free dye) that have a large Stokes shift (>110 nm). Incorporation of the naphthalocyanine dye and exposure to NIR laser excitation results in a temperature increase of the surrounding environment of the MDT-NPs. Tumors injected with these NPs are easily visible with NIR imaging and produce significantly elevated levels of tumor necrosis (95%) upon photothermal ablation compared with controls, as evaluated by bioluminescence and histological analysis. CONCLUSION: MDT-NPs are novel, multifunctional nanomaterials that have optical properties dependent upon the unique incorporation of NIR fluorescent and NIR photothermal dyes within a mesoporous silica platform.

Long-term results following postoperative radiotherapy for soft tissue sarcomas of the extremity.

PURPOSE: To review long-term outcomes following postoperative radiotherapy (RT) for extremity soft tissue sarcoma (STS) and identify variables affecting the therapeutic ratio. METHODS AND MATERIALS: Between 1970 and 2008, 173 patients with localized extremity STS were treated with postoperative radiation. No patients received prior irradiation. Sixteen percent of tumors had recurred after initial surgery alone; 89% of tumors were high grade. The median patient age was 57 years (range, 18-86 years). Sixty-one percent underwent >1 surgery before RT in an attempt to achieve wide negative margins. Final margin status was negative in 70% and marginal or microscopically positive in 30%. The median time between final surgery and start of RT was 40 days. The median RT dose was 65 Gy (range, 49-74 Gy). The median follow-up for all patients was 10.4 years and 13.2 years among survivors. RESULTS: At 10 years, local control (LC), cause-specific survival (CSS), and overall survival (OS) rates were 87%, 80%, and 70%, respectively, with 89% of local failures occurring within 3 years after treatment. On multivariate analysis, age >55 years (82% vs 93%, P<.05) and recurrent presentation (67% vs 91%, P<.05) were associated with inferior 10-year LC. The LC according to final margin status was 90% for wide negative margins vs 79% for marginal/microscopically positive margins (P=.08). Age>55 years and local recurrence were associated with inferior CSS and OS on multivariate analysis. Twelve percent of patients experienced grade 3+ toxicity; 12 of these occurred in patients with tumors of the proximal lower extremity, with the most common toxicity of pathologic fracture occurring in 6.3%. CONCLUSIONS: This large single-institution series confirms that postoperative RT for STS of the extremities provides good long-term disease control with acceptable toxicity. Our experience supports recurrent presentation and older age as adverse prognostic factors for LC.

Fractionated photothermal antitumor therapy with multidye nanoparticles.

PURPOSE: Photothermal therapy is an emerging cancer treatment paradigm which involves highly localized heating and killing of tumor cells, due to the presence of nanomaterials that can strongly absorb near-infrared (NIR) light. In addition to having deep penetration depths in tissue, NIR light is innocuous to normal cells. Little is known currently about the fate of nanomaterials post photothermal ablation and the implications thereof. The purpose of this investigation was to define the intratumoral fate of nanoparticles (NPs) after photothermal therapy in vivo and characterize the use of novel multidye theranostic NPs (MDT-NPs) for fractionated photothermal antitumor therapy. METHODS: The photothermal and fluorescent properties of MDT-NPs were first characterized. To investigate the fate of nanomaterials following photothermal ablation in vivo, novel MDT-NPs and a murine mammary tumor model were used. Intratumoral injection of MDT-NPs and real-time fluorescence imaging before and after fractionated photothermal therapy was performed to study the intratumoral fate of MDT-NPs. Gross tumor and histological changes were made comparing MDT-NP treated and control tumor-bearing mice. RESULTS: The dual dye-loaded mesoporous NPs (ie, MDT-NPs; circa 100 nm) retained both their NIR absorbing and NIR fluorescent capabilities after photoactivation. In vivo MDT-NPs remained localized in the intratumoral position after photothermal ablation. With fractionated photothermal therapy, there was significant treatment effect observed macroscopically (P = 0.026) in experimental tumor-bearing mice compared to control treated tumor-bearing mice. CONCLUSION: Fractionated photothermal therapy for cancer represents a new therapeutic paradigm enabled by the application of novel functional nanomaterials. MDT-NPs may advance clinical treatment of cancer by enabling fractionated real-time image guided photothermal therapy.

Fibro-Osseous Lesions.

This article describes the clinical, radiographic, gross, microscopic, and histologic features; differential diagnosis; molecular pathology; treatment; and prognosis of fibrous dysplasia, osteofibrous dysplasia, and adamantinoma of long bones.

External-beam radiotherapy for pediatric and young adult desmoid tumors.

BACKGROUND: To report long-term outcomes following radiotherapy for desmoid tumors in children and young adults and identify variables impacting local-regional control and treatment complications. PROCEDURE: From 1978 to 2008, 30 patients <30 years old were treated with radiotherapy for a pathologically confirmed desmoid tumor. The median age at radiotherapy was 23.7 years old (range, 10.3-29.9). Fifteen patients underwent definitive radiotherapy, 14 received radiotherapy after gross total resection, and 1 received preoperative radiotherapy. Sixteen patients received 1.8 Gy once daily and 14 received 1.2 Gy twice daily. Variables analyzed for prognostic value included gender, age at diagnosis, primary or recurrent presentation, age at radiotherapy, tumor site, tumor size, extent of resection, fractionation schedule, and radiotherapy dose. RESULTS: The actuarial 15-year overall survival and local-regional control rates were 96% and 55%, respectively. Local-regional control in patients <18 years old at the time of radiotherapy was 20% versus 63% in those 18-30 years old (P = 0.08). Local-regional control rates for tumors receiving ≥ 55 Gy and < 55 Gy were 79% and 30%, respectively (P = 0.02). No other factors had a statistically significant association with local-regional control by univariate analysis. Twelve of 30 patients experienced grade 3-4 complications, including pathologic fractures, impaired range of motion, pain, and in-field skin cancers. CONCLUSIONS: The role of radiotherapy in managing young patients with desmoid tumors remains unclear. Younger patient age is associated with inferior local-regional control following RT. In children and young adults, doses ≥55 Gy were associated with improved tumor control, but also lead to increased risk of complications.

Definitive radiotherapy for unresectable pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma.

BACKGROUND: Few published articles describe outcomes following definitive radiation for unresectable pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The purpose of this study is to evaluate the prognostic factors, outcomes, and complications in patients age 30 years or younger with NRSTS treated at the University of Florida from 1973 to 2002. PROCEDURE: Nineteen pediatric and young adult patients with NRSTS were treated with radiotherapy after biopsy. Thirteen patients had high-grade tumors. The median age at radiotherapy was 19.6 years; the median dose was 55.2 Gy. Twelve patients received chemotherapy. Prognostic factors for local recurrence, distant metastases, and survival were analyzed. RESULTS: Median follow-up was 2.6 years. The 5-year local-control rate was 40%. Nine out of 13 local failures occurred in the absence of metastatic disease. All patients with local failures died of their cancer, and 8 patients died without evidence of distant metastases. There was a trend toward improved local control with low/intermediate-grade tumors. Freedom from distant metastases at 5 years was 68%. Fourteen patients died of their disease. The 5-year overall survival was 37%. There was one grade 4 complication based on NCI Common Terminology Criteria for Adverse Events version 3. CONCLUSION: Young patients with unresectable NRSTS have a poor outcome thereby justifying current study efforts focused on treatment intensification. By demonstrating that all patients with local recurrence died of disease and more than half of these deaths occurred in the absence of distant spread, these results suggests that improved means of local control may translate into improvement in survival.

Adjuvant radiotherapy for pediatric and young adult nonrhabdomyosarcoma soft-tissue sarcoma.

PURPOSE: To evaluate the prognostic factors, outcomes, and complications in patients aged ≤30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period. METHODS AND MATERIALS: A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6-30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed. RESULTS: The median follow-up was 7.2 years (range, 0.4-30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor<8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed. CONCLUSION: In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young adult sarcoma patients and have provided a basis for identifying high-risk patients for whom treatment intensification might be justified.

Bacillus cereus necrotizing fasciitis in a patient with end-stage liver disease.

BACKGROUND: Bacillus cereus has been increasingly recognized as a virulent pathogen, particularly in immunocompromised patients. METHODS: Presented is a case report of a 24-year-old man with end-stage liver disease secondary to primary sclerosing cholangitis, who developed necrotizing fasciitis of the right lower leg due to B. cereus. The bacterium isolated from the patient was compared with environmental strains for quantity of secreted proteins as well as hemolytic and cytotoxic activities. RESULT: Despite above-the-knee amputation and aggressive antibiotic therapy, the patient expired on hospital day 13. The patient isolate demonstrated a protein secretion pattern and cytotoxicity similar to those of an environmental strain known to produce exotoxins. However, the isolate did produce a larger ratio of zone of hemolysis to colony size on blood agar plates compared with the environmental strain. CONCLUSION: To the best of our knowledge, this is the only report of B. cereus as the etiology of necrotizing fasciitis in a patient with end-stage liver disease. Because the infecting bacterium correlates with the environmental strain, the severity of the patient's disease is likely related to his immunocompromised state. Therefore, B. cereus should be considered a potential pathogen rather than a contaminant.

Nodular fasciitis: differential considerations and current management strategies.

Nodular fasciitis (NF) typically presents as an enlarging soft tissue mass with imaging characteristics that may be suggestive of soft tissue sarcoma or desmoid tumor. This presentation can make a correct diagnosis and management of patients with NF a challenge. We report our recent experience with two cases of NF that were both referred with a diagnoses of "soft tissue sarcoma." Patient 1 was a 46-year-old woman who had undergone breast augmentation and was referred with a rapidly growing firm mass on the left chest wall beneath the breast implant. Computed tomography of the chest noted the mass to be 8 cm x 11 cm in size displacing the implant laterally with no radiological involvement of the bony structures of the chest. Core biopsy was suggestive of inflammation only. Given the clinical suspicion of malignancy, the patient underwent resection of the mass with implant removal. Final pathology showed NF. Patient 2 was a 65-year-old woman referred with an enlarging tender 3-cm infraclavicular mass and a clinical diagnosis of "soft tissue sarcoma." Preoperative biopsy suggested NF. The patient underwent complete excision, which confirmed the diagnosis. These cases highlight the clinical issues associated with management of patients with NF. Current approaches to evaluation, diagnosis, and treatment of NF are discussed.

Oncogenic human papillomavirus testing in an adolescent population with atypical squamous cells of undetermined significance.

OBJECTIVE: The American Society for Colposcopy and Cervical Pathology 2006 consensus guidelines state that oncogenic human papillomavirus (HPV) DNA testing is unacceptable for patients 20 years and younger with atypical squamous cells of undetermined significance (ASC-US). The objective of this study is to determine the HPV frequency in ASC-US patients 20 years and younger and to investigate subsequent colposcopic diagnoses. MATERIALS AND METHODS: Cytopathology records at the University of Florida/Shands-UF were reviewed from March 2003 to June 2007 to identify patients 20 years and younger with ASC-US on screening Pap tests. Human papillomavirus test results and subsequent colposcopic diagnoses were recorded. RESULTS: A total of 333 patients were identified. Seventy-five were not HPV tested. Of the remaining 258, 127 (49%) were negative(-) for HPV, whereas 131 (51%) were HPV positive(+).In the HPV(-) population (n=127), 3 (2%) patients were referred for colposcopy and had benign findings. In the HPV(+) population (n=131), 48 (37%) patients were referred for colposcopy. Of these 48, 25 had benign colposcopic findings, 12 had cervical intraepithelial neoplasia 1 (CIN 1), and 11 had CIN 2/3. No invasive disease was identified. Nine of the 11 patients with CIN 2/3 were 18 years and older. CONCLUSIONS: In our institution, 51% of ASC-US patients 20 years and younger were HPV(+). Colposcopy with subsequent histological diagnosis, available on 48 patients, demonstrated 11 (23%) of the HPV(+) group to have CIN 2/3. The American Society for Colposcopy and Cervical Pathology guidelines recommend observation (via repeat colposcopy and cytology) for adolescents with CIN 2 and treatment (via excision or ablation) for CIN 3. Human papillomavirus testing ASC-US adolescents in our institution may be "acceptable."