Activation of Myc triggers a rapid induction of cyclin E/ cdk2 kinase activity and degradation of p27. Overt degradation of p27 is preceded by a speci®c dissociation of p27 from cyclin E/cdk2, but not from cyclin D/cdk4 complexes. We now show that cyclin E/cdk2 phosphorylates p27 at a carboxy-terminal threonine residue (T187) in vitro; mutation of this residue to valine stabilises cyclin E/cdk2 complexes. This reaction is not signi®cantly inhibited by high concentrations of p27, suggesting that cdk2 bound to p27 is catalytically active. In vivo, p27 bound to cyclins E and A, but not to D-type cyclins is phosphorylated. Myc-induced release of p27 from cdk2 requires cdk2 kinase activity and is delayed in a T187V mutant of p27. After induction of Myc, p27 phosphorylated at threonine 187 transiently accumulates in a non cdk2 bound form. Our data suggest a mechanism in which p27 is released from cyclin E/cdk2 upon phosphorylation; in Myc-transformed cells, release is e cient as phosphorylated p27 is transiently bound in a non-cdk2 containing complex and subsequently degraded.

Pelvic bone metastases are a growing concern in the field of orthopedic surgery. Patients with pelvic metastasis are individually different with different needs of treatment in order to attain the best possible quality of life despite the advanced stage of disease. A holistic collaboration among the oncologist, radiation therapist, and orthopedic surgeon is mandatory. Special attention has to be directed to osteolytic lesions in the periacetabular region as they can provoke pathological fractures and subsequent functional impairment. Different reconstruction techniques for the pelvis are available; the choice depends on the patient's prognosis, size of the bone defect, and response of the tumor to adjuvant treatment. If all the conservative treatments are exhausted and the patient is not eligible for surgery, one of the various percutaneous ablation procedures can be considered. We propose a pelvic analogue to the treatment algorithm in long bone metastasis and a scoring system in pelvic metastasis. This algorithm aims to simplify the teamwork and to avoid under- or overtreatment of pelvic bone metastases.

BackgroundThe RANK ligand inhibitor denosumab is being investigated for treatment of giant cell tumor of bone, but the available data in the literature remains sparse and controversial. This study analyzes the results of combining denosumab with surgical treatment and highlights possible changes for the oncologic surgeon in daily practice.MethodsA total of 91 patients were treated surgically for giant cell tumor of bone between 2010 and 2014 in an institution, whereas 25 patients of the total additionally received denosumab and were part of this study. The average age of the patients was 35 years. Eleven patients received denosumab pre- and postoperatively, whereas with 14 patients, the denosumab treatment was applied either before (7 patients) or after (7 patients) the surgery. The average preoperative therapy duration was 3.9 months and the postoperative therapy 6 months by default.ResultsSixteen patients presented a large tumor extension necessitating a resection of the involved bone or joint. In 10 of these patients, the indication for a resection procedure was abandoned due to the preoperative denosumab treatment and a curettage was performed. In the remaining six cases, the surgical indication was not changed despite the denosumab treatment, and two of them needed a joint replacement after the tumor resection. Also with patients treated with curettage, denosumab seems to facilitate the procedure as a new peripheral bone rim around the tumor was built, though a histologic analysis reveals viable tumor cells persisting in the denosumab-induced bone formation.After an average follow-up of 23 months, one histologically proven local recurrence occurred, necessitating a second curettage. A second patient showed a lesion in the postoperative imaging highly suspicious for local relapse which remained stable under further denosumab treatment. No adverse effect of the denosumab medication was observed in this study.ConclusionsDenosumab can be a help to the oncologic surgeon by reconstituting a peripheral rim and switching the stage from aggressive to active or latent disease. But as tumor cells remain in the new-formed bone, the surgical technique of curettage has to be changed from gentle to more aggressive to avoid higher local recurrence rates.

This prospective study showed significantly superior outcomes in all clinical scores between GII and GI. The subanalysis of the high-grade injury type (Rockwood IV/V) revealed that these patients showed significant benefits from the dDBS procedure in the clinical assessments. The cHP procedure resulted in good to excellent clinical outcome data and displayed an alternative procedure for patients needing less restrictive rehabilitation protocols.

Level IV. Case series with no comparison groups.

IV.

BackgroundSarcomas are associated with a relatively high local recurrence rate of around 30 % in the pelvis. Inadequate surgical margins are the most important reason. However, obtaining adequate margins is particularly difficult in this anatomically demanding region. Recently, three-dimensional (3-D) planning, printed models, and patient-specific instruments (PSI) with cutting blocks have been introduced to improve the precision during surgical tumor resection. This case series illustrates these modern 3-D tools in pelvic tumor surgery.MethodsThe first consecutive patients with 3-D-planned tumor resection around the pelvis were included in this retrospective study at a University Hospital in 2015. Detailed information about the clinical presentation, imaging techniques, preoperative planning, intraoperative surgical procedures, and postoperative evaluation is provided for each case. The primary outcome was tumor-free resection margins as assessed by a postoperative computed tomography (CT) scan of the specimen. The secondary outcomes were precision of preoperative planning and complications.ResultsFour patients with pelvic sarcomas were included in this study. The mean follow-up was 7.8 (range, 6.0–9.0) months. The combined use of preoperative planning with 3-D techniques, 3-D-printed models, and PSI for osteotomies led to higher precision (maximal (max) error of 0.4 centimeters (cm)) than conventional 3-D planning and freehand osteotomies (max error of 2.8 cm). Tumor-free margins were obtained where measurable (n = 3; margins were not assessable in a patient with curettage). Two insufficiency fractures were noted postoperatively.ConclusionsThree-dimensional planning as well as the intraoperative use of 3-D-printed models and PSI are valuable for complex sarcoma resection at the pelvis. Three-dimensionally printed models of the patient anatomy may help visualization and precision. PSI with cutting blocks help perform very precise osteotomies for adequate resection margins.

c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two di erent methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53 Vall35 mutant, which adopts a wild-type conformation at 328C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc signi®cantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21 WAF1 , Bax and cytomegalovirus promoters. The impairment of p21 WAF1 transactivation by c-Myc was con®rmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21 WAF1 mRNA protein were signi®cantly reduced by cMyc, while Bax levels were una ected. Consistently, cMyc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.