Partnership in Cancer Research (PCAR) Program Increases Medical Student Knowledge and Confidence to Perform Cancer Research.

Arkansas has a high cancer burden, and a pressing need exists for more medical students to pursue oncology as a career. The Partnership in Cancer Research (PCAR) program provides a summer research experience at the University of Arkansas for Medical Sciences for 12 medical students who have completed their first year of medical training. A majority of participants spend time pursuing cancer research in basic science, clinical, or community-based research. Students report on their research progress in an interactive "Live from the Lab!" series and assemble a final poster presentation describing their findings. Other activities include participation in a moderated, cancer-patient support group online, lecture series on cancer topics, medical simulations, palliative care clinic visit, "Death Over Dinner" event, and an entrepreneurship competition. Students completed surveys over PCAR's first 2 years in operation to evaluate all aspects of the program. Surveys reveal that students enthusiastically embraced the program in its entirety. This was especially true of the medical simulations which received the highest evaluations. Most significantly, surveys revealed that the program increased cancer knowledge and participant confidence to perform cancer research.

Safe Positioning for Sexual Intercourse After Proximal Femoral Replacement.

Hip arthroplasty is a common procedure used for the treatment of fractures and degenerative processes affecting the hip. Proximal femoral replacement is an uncommon type of hip arthroplasty used for reconstruction after extensive bone loss. Proximal femoral replacement is used most commonly after the resection of the proximal femur for malignancies and for extensive bone loss encountered in revision hip arthroplasty and occasionally for extensive bone loss after fractures. The authors present a case of a female patient who sustained a prosthetic dislocation of her proximal femoral replacement during sexual intercourse. Standard hip arthroplasty itself can pose a risk factor for dislocation associated with certain sexual positions. Proximal femoral replacement surgery likely carries an increased risk for dislocation, given the magnitude of soft tissue loss at the time of resection. The authors believe that routine perioperative conversations for sexually active patients with proximal femur replacements should include this potential risk and discuss appropriate positioning to prevent a potential dislocation. [Orthopedics. 2018; 41(2):e292-e294.].

High Relative Expression of Pannexin 3 (PANX3) in an Axillary Sweat Gland Carcinoma With Osteosarcomatous Transformation.

Primary cutaneous sweat gland carcinomas (SGCs) are rare tumors that commonly involve axillae, have a high local recurrence rate, and rarely show sarcomatoid transformation. A 68-year-old man presented with rapid enlargement of a previously stable, asymptomatic pea-sized nodule in the left axilla. Initial excision (with positive surgical margins) at another institution showed characteristic histologic features of a high-grade osteosarcoma and molecular analysis using a 92-gene real-time quantitative reverse transcription-polymerase chain reaction assay confirmed a diagnosis of osteosarcoma with 96% certainty. Notably, the molecular assay demonstrated consistently high relative expression of pannexin 3 (PANX3), a gene involved in normal osteoblast differentiation which, when highly expressed, strongly predicts osteosarcoma per the assay's algorithm. However, on further histologic review, the tumor also contained focal cystic areas, nests, and ducts composed of malignant epithelial cells reminiscent of SGC; these areas directly transitioned into the osteosarcomatous component and were strongly positive for pancytokeratin, CK7, and p63. Within 2 weeks, the lesion recurred and grew rapidly, prompting complete resection, histologic sections of which showed high-grade osteosarcoma without residual epithelial elements. This is the fifth report, to our knowledge, of osteosarcomatous transformation in a SGC, and the only report to date including molecular data. This case demonstrates that osteosarcoma arising from a SGC has a similar molecular profile to de novo primary osteosarcoma of bone. It also emphasizes the importance of histopathologic findings as the established diagnostic gold standard and the need to interpret molecular results within the clinical context.

Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity.

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01-0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1716-1724, 2016.

Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group.

BACKGROUND: Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear. METHODS: Patients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type. RESULTS: Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups. CONCLUSIONS: In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.

Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans.

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET-derived full length IL-8(1-77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

Cisplatin inhibits bone healing during distraction osteogenesis.

Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP.

Bone metastasis: mechanisms and therapeutic opportunities.

The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy.

The promise of bone cancer proteomics.

Mass spectrometric analysis of the low-molecular-weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments, predicted to be derived from circulating low-abundance proteins. While genomics and proteomics are the primary discovery research tool, recent innovations in high-throughput proteomics are now standard practice for biomarker and target discovery. Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) is the current mainstay for serum or plasma analysis, although other methods are emerging as alternative high-throughput approaches. From a proteomics perspective, the bone cancers, such as myeloma, breast and prostate cancer bony metastases, and osteosarcoma, are likely among the least studied. As recent advances in proteomic technology have thrust the bone cancer field into the era of proteomics, a review of the current status of the proteome as it relates to the skeletal consequences of malignancy seems reasonable.

Gene therapy to enhance allograft incorporation after host tissue irradiation.

Structural bone allografts are used to reconstruct large skeletal defects after tumor surgery. Although allograft-related complications are declining, the use of perioperative radiation therapy is associated with a poorer outcome. Recently, BMP-2 levels in the host bed were reportedly diminished after exposure to radiation doses consistent with those used perioperatively to treat musculoskeletal sarcoma. Reintroduction of this osteogenic protein may circumvent the deleterious effects of preoperative radiation on allograft incorporation. We introduced a novel polymeric BMP-2 gene delivery system into the host-allograft junctions at the time of transplantation in an ovine tibial defect model with or without preoperative exposure to 50 Gy radiation. After 4 months, we noted no radiographic or histologic improvements in allograft incorporation after preoperative radiation and BMP-2 reintroduction; however, 50 Gy radiation was associated with increased porosity in the interface regions and poorer radiographic healing. We identified no BMP2-expressing cells or protein in the interface at the study end point, suggesting the polymeric gene delivery system was unable to promote extended expression of the protein or induce a healing response. Although gene therapy may hold promise as a novel technique to improve allograft incorporation, our data do not support that contention with the current approach.

Partners in research: benefits of a summer research program.

BACKGROUND: The Partners in Research program provides first-hand research experiences for medical, pharmacy, and African-American undergraduate students. METHODS: During ten weeks, students participate in on-going cancer research, weekly educational sessions, two observational clinic sessions, and at least one patient support-community outreach clinic. RESULTS: Over the past six years the program has enrolled 155 students. Surveys indicate that most students give the course high ratings and would recommend the course to their peers. Follow-up shows their continued interest in research. CONCLUSIONS: The program will encourage students to pursue careers in cancer research and provide a solid base of knowledge to future health care professionals.

The effect of host tissue irradiation on large-segment allograft incorporation.

Therapeutic radiation delivered to bone and the adjacent local tissues before allograft limb-salvage surgery has been associated with poor graft incorporation and higher numbers of clinical complications. Our objective was to determine the effect of preoperative radiation therapy on specific histologic, molecular and structural parameters of large-segment, bone allograft incorporation in a canine model. Skeletally mature dogs received a total of 0, 25, or 50 Gy of radiation to the foreleg (radius and ulna) delivered in 2-Gy fractions during a 5-week period before reconstruction of a 3.5-cm defect in the radius. The dogs were sacrificed at postoperative day 150. Nondestructive four-point bending was done on the harvested allograft-host bone immediately after euthanasia and specimens were compared using biomechanical, histomorphometric, immunohistochemical, and in situ reverse transcription polymerase chain reaction techniques. Preoperative irradiation significantly impaired allograft incorporation as determined by radiographic healing scores, histomorphometry, and frequency of nonunions. Biochemical differences included diminished bone morphogenetic protein-2 and bone morphogenetic protein-4 protein levels and messenger ribonucleic acid expression. Vascular endothelial growth factor expression was not altered. These data suggest that bone morphogenetic protein-2 and bone morphogenetic protein-4 signaling at the allograft-host junction is altered after preoperative fractionated radiation and provides a plausible albeit partial mechanistic explanation for radiation-mediated delays in allograft incorporation.

Evidence for telomeric fusions as a mechanism for recurring structural aberrations of chromosome 11 in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a benign but often aggressive tumor with a tendency toward local recurrence. Telomeric associations (tas) or telomeric fusions are common cytogenetic findings that have been implicated in the initiation of chromosome instability and tumorigenesis. We performed cytogenetic studies on 5 cases of GCTB to further characterize chromosome aberrations in these tumors. Four of the 5 cases showed abnormal karyotypes with clonal telomeric fusions involving chromosome 11. In 3 cases, the telomeric fusions of 11pter were apparently the precursor lesions to the progression of sub-clones with structural chromosome aberrations of 11p. Two tumors demonstrated a similar pattern of progression resulting in whole arm losses of 11p, including sub-clones with both whole-arm unbalanced translocations and whole-arm deletions. A third tumor with clonal tas of 11pter showed 2 additional subclones, one with ring chromosome 11 and the other with an extra copy of 1q. To our knowledge, the 2 cases with del(11)(p11) represent the first report of a recurring structural chromosome aberration in GCTB. These findings support the concept that telomeric instability is responsible for a large degree of intratumor heterogeneity and serves as a precursor lesion to subsequent clonal structural aberrations of chromosome 11 in GCTB.

A clonal reciprocal t(2;7)(p13;p13) in plantar fibromatosis.

Cytogenetic reports of plantar fibromatosis are rare, and to our knowledge no clonal reciprocal translocations have been reported in these lesions. Reciprocal chromosome translocations have been identified in a number of solid tumors and in some cases have helped identify genes involved in their pathogenesis. We report a case of plantar fibromatosis with the novel finding of a t(2;7)(p13;p13) balanced reciprocal translocation as the sole cytogenetic abnormality.

A reciprocal t(4;9)(q31;p22) in a solitary neurofibroma.

Cytogenetic reports of solitary neurofibromas are rare and, to our knowledge, no clonal reciprocal translocations have been reported in these tumors. Reciprocal chromosome translocations have been identified in a number of solid tumors and can have both diagnostic and prognostic significance. We report the first case of a solitary circumscribed neurofibroma with a (4;9)(q31;p22) balanced reciprocal translocation as the sole cytogenetic abnormality.