[Quality in Revision Arthroplasty: A Comparison between Claims Data Analysis and External Quality Assurance]. / Ergebnisqualität in der Revisionsendoprothetik: Eine Analyse von Routinedaten mit dem Vergleich zur externen Qualitätssicherung.

BACKGROUND: External quality assurance for revisions of total knee arthroplasty (TKA) and total hip arthroplasty (THA) are carried out through the AQUA institute in Germany. Data are collected by the providers and are analyzed based on predefined quality indicators from the hospital stay in which the revision was performed. The present study explores the possibility to add routine data analysis to the existing external quality assurance (EQS). Differences between methods are displayed. The study aims to quantify the benefit of an additional analysis that allows patients to be followed up beyond the hospitalization itself. MATERIAL AND METHODS: All persons insured in an AOK sickness fund formed the population for analysis. Revisions were identified using the same algorithm as the existing external quality assurance. Adverse events were defined according to the AQUA indicators for the years 2008 to 2011.The hospital stay in which the revision took place and a follow-up of 30 days were included. For re-operation and dislocation we also defined a 365 days interval for additional follow-up. The results were compared to the external quality control reports. RESULTS: Almost all indicators showed higher events in claims data analysis than in external quality control. Major differences are seen for dislocation (EQS SD: 1.87 vs. claims data [cd] SD: 2.06 %, cd+30 d: 2.91 %, cd+365 d: 7.27 %) and reoperation (hip revision: EQS SD: 5.88 % vs. claims data SD: 8.79 % cd+30 d: 9.82 %, cd+365 d: 15.0 %/knee revision: EQS SD: 3.21 % vs. claims data SD: 4.07 %, cd+30 d: 4.6 %, cd+365 d: 15.43 %). Claims data could show additional adverse events for all indicators after the initial hospital stay, rising to 77 % of all events. CONCLUSIONS: The number of adverse events differs between the existing external quality control and our claims data analysis. Claims data give the opportunity to complement existing methods of quality control though a longer follow-up, when many complications become evident.

Pelvic reconstruction with compound osteosynthesis following hemipelvectomy: A clinical study.

To date, all surgical techniques used for reconstruction of the pelvic ring following supra-acetabular tumour resection produce high complication rates. We evaluated the clinical, oncological and functional outcomes of a cohort of 35 patients (15 men and 20 women), including 21 Ewing's sarcomas, six chondrosarcomas, three sarcomas not otherwise specified, one osteosarcoma, two osseous malignant fibrous histiocytomas, one synovial cell sarcoma and one metastasis. The mean age of the patients was 31 years (8 to 79) and the latest follow-up was carried out at a mean of 46 months (1.9 to 139.5) post-operatively. We undertook a functional reconstruction of the pelvic ring using polyaxial screws and titanium rods. In 31 patients (89%) the construct was encased in antibiotic-impregnated polymethylmethacrylate. Preservation of the extremities was possible for all patients. The survival rate at three years was 93.9% (95% confidence interval (CI) 77.9 to 98.4), at five years it was 82.4% (95% CI 57.6 to 93.4). For the 21 patients with Ewing's sarcoma it was 95.2% (95% CI 70.7 to 99.3) and 81.5% (95% CI 52.0 to 93.8), respectively. Wound healing problems were observed in eight patients, deep infection in five and clinically asymptomatic breakage of the screws in six. The five-year implant survival was 93.3% (95% CI 57.8 to 95.7). Patients were mobilised at a mean of 3.5 weeks (1 to 7) post-operatively. A post-operative neurological defect occurred in 12 patients. The mean Musculoskeletal Tumor Society score at last available follow-up was 21.2 (10 to 27). This reconstruction technique is characterised by simple and oncologically appropriate applicability, achieving high primary stability that allows early mobilisation, good functional results and relatively low complication rates.

Endoprosthetic replacement after extra-articular resection of bone and soft-tissue tumours around the knee.

We evaluated the clinical results and complications after extra-articular resection of the distal femur and/or proximal tibia and reconstruction with a tumour endoprosthesis (MUTARS) in 59 patients (mean age 33 years (11 to 74)) with malignant bone or soft-tissue tumours. According to a Kaplan-Meier analysis, limb survival was 76% (95% confidence interval (CI) 64.1 to 88.5) after a mean follow-up of 4.7 years (one month to 17 years). Peri-prosthetic infection was the most common indication for subsequent amputation (eight patients). Survival of the prosthesis without revision was 48% (95% CI 34.8 to 62.0) at two years and 25% (95% CI 11.1 to 39.9) at five years post-operatively. Failure of the prosthesis was due to deep infection in 22 patients (37%), aseptic loosening in ten patients (17%), and peri-prosthetic fracture in six patients (10%). Wear of the bearings made a minor revision necessary in 12 patients (20%). The mean Musculoskeletal Tumor Society score was 23 (10 to 29). An extensor lag > 10° was noted in ten patients (17%). These results suggest that limb salvage after extra-articular resection with a tumour prosthesis can achieve good functional results in most patients, although the rates of complications and subsequent amputation are higher than in patients treated with intra-articular resection.

Expression of beta-catenin and p53 are prognostic factors in deep aggressive fibromatosis.

AIMS: To determine the prognostic significance of beta-catenin in aggressive fibromatosis and to identify potential molecular markers for new targeted therapies. METHODS AND RESULTS: A tissue microarray of 37 cases of deep aggressive fibromatosis was constructed and subjected to immunohistochemical analysis for beta-catenin, p53, smooth muscle actin (SMA), desmin, Ki67, c-erbB2, epidermal growth factor receptor (EGFR), c-kit, CD34 and S100. Complete clinical follow-up was available for 23 patients. Nuclear beta-catenin expression was associated with an increased rate of local tumour recurrence (60.0% 1-year and 0% 5-year event-free survival; P < 0.05). Furthermore, p53 expression was associated with an increased risk of tumour recurrence (50% 1-year event-free survival rate and 0% 5-years event-free survival rate, P < 0.05). The coexpression of p53 and beta-catenin was significantly correlated (P < 0.05). No statistically significant association was seen between MIB1 and p53 or beta-catenin expression, respectively. No expression of EGFR, c-erbB2 or c-kit was seen. CONCLUSIONS: The overexpression of beta-catenin and p53 is associated with a decreased event-free survival in deep aggressive fibromatosis. Further studies are required to establish whether these findings can lead to an improvement in the treatment of this rare neoplasm.

The effect of rotationplasty on the ankle joint: long-term results.

In patients with rotationplasty the biomechanical conditions in the ankle joint are altered dramatically. By displacement and reduction of the weight-bearing area of the joint, the stress affecting its cartilage is increased. The use of an exoprothesis results in skin and soft tissue irritation. Due to these biomechanical changes, a prearthrotic deformity or skin problems could be expected. The current study examines changes in 21 patients treated with rotationplasty (mean follow-up 13.5 years) because of a malignant bone tumour or a femoral segmental defect. Local tenderness, skin and soft tissue changes, problems with exoprostheses, and pain was assessed by clinical examination and documented. Osseous changes were evaluated by plain X-ray. A MRI-scan was also obtained in five patients. Hardened skin and blisters were located at the main loading areas of the rotated foot. These changes could be reduced by optimizing the exoprosthetic fit. Radiographically, a slight asymptomatic attenuation of the articular space was observed in four patients and a slight coexistent subchondral sclerosis with small osteophytes in one patient. No degenerative changes were observed on X-ray and no cartilaginous changes were observed on MRI. The results suggest that the foot is able to adapt to the load changes after this procedure and that rotationplasty does not cause an inevitable arthrosis in the ankle joint.

Free vascularized fibular grafting for reconstruction after tumor resection in the upper extremity.

BACKGROUND: Limb salvage is viable in the majority of patients with malignant bone tumors, but especially in case of extensive tumors and bad soft tissue conditions, it is challenging in upper extremity. OBJECTIVES/METHOD: The clinical and radiological results of 21 patients, who had free vascularized fibular grafts (VFG), for diaphyseal (14), and epipyseal (7) defect reconstruction of the upper extremity, are presented. The indications for VFG were resection after osteosarcoma (9 cases), Ewings sarcoma (9 cases), chondrosarcoma (1 case), rhabdomyosarcoma (1 case), and 1 case of fibrous dysplasia. The 20 malignant tumors were staged as follows: 2a (1), 2b (18), 3 (1). The mean follow-up was 43.6 months (min 6.0-max 131.9). Functional results were described and graded quantitatively according to the MSTS-score. RESULTS: Results were satisfactory with regard to pain, emotional acceptance, manual dexterity, and function. Lifting ability was decreased in two patients. Hypertrophy index was 31% (min 13%-max 71%). Main complications were fracture (5), pseudoarthrosis (4), prolonged wound healing (4), temporary nerve irritation (2), and deep infection (1). Re-operation was required in eight patients (12 operations). CONCLUSION: VFG offers a good possibility for biological reconstruction of large skeletal defects, with an acceptable complication and re-operation rate. When conservative treatment of complications was not successful, further surgery led to recovery in the majority of cases.

[Cartilage tumours of the bone. Diagnosis and therapy]. / Knorpelbildende Knochentumore. Diagnose und Therapie.

Primary malignant bone tumours are rare. The annual incidence of these tumours is 10 per 1 million. Nearly 30% of the primary malignant bone tumours are malignant cartilage tumours. The frequency of benign cartilage tumours cannot be definitely estimated because these tumours are normally clinically inapparent and therefore often diagnosed as an incidental finding. The cartilage tumours appear as benign lesions (e.g. chondroma), as borderline tumours (proliferative chondroma vs grade I chondrosarcoma) or as highly malignant chondrosarcoma (e.g. dedifferentiated chondrosarcoma). Commensurate with the different clinical and oncological manifestations of the cartilage tumours, there are wide differences in the treatment and clinical course of the individual tumour. This article discusses the problems in the diagnosis and treatment of cartilage tumours from an orthopaedic point of view.

Characteristics and outcome of infections associated with tumor endoprostheses.

INTRODUCTION: Infection associated with prosthesis used after tumor resection is a common and serious complication. The purpose of the current retrospective study was to describe the course of infection in patients with a tumor endoprosthesis and the determination of risk factors associated with failed limb salvage. MATERIAL AND METHODS: 30 patients with an infection associated with a tumor endoprosthesis were investigated with regard to treatment strategies, number and type of revision operations, duration of hospital stay, determination of risk factors associated with failed limb salvage and final outcome. RESULTS: Limb salvage related to the complication infection was achieved in 19 patients (63.3%). Two-stage reimplantation of an endoprosthesis was successful in 14 patients but subsequently failed in one patient. Out of 11 patients where limb salvage failed, an amputation was performed in 6 patients, a rotationplasty in 4, and stump lengthening procedure in 1 patient. A poor soft tissue condition was a significant (P<0.05) risk factor for failed limb salvage. No patient receiving chemotherapy with a poor soft tissue condition had limb salvage surgery. The mean number of revision operations per patients was 2.6. The mean duration of hospital stay was 68 days. CONCLUSION: Infection associated with prosthesis is a serious complication and is involved with long hospitalization. Limb salvage failed mostly in the case of a poor soft tissue condition. In these cases repeated revision surgery should be avoided and ablative surgery recommended at an early stage. Rotationplasty is an alternative to amputation in the case of an infection of the proximal or distal part of the femur.

Functional results and quality of life after treatment of pelvic sarcomas involving the acetabulum.

BACKGROUND: Limb salvage after resection of a pelvic sarcoma that involves the acetabulum represents a surgical challenge. The ideal method of reconstruction after acetabular resection remains a subject of controversy, and the outcome in terms of the impact of therapy is still unknown. The purpose of this study was to determine the impact of surgery on health-related quality of life and function after acetabular resection. METHODS: Eighty-one patients with a pelvic sarcoma underwent acetabular resection at a single institution. Functional evaluation and quality-of-life examination were performed in forty-five patients, and these patients comprised the study group. Quality of life was assessed with use of the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. Function was assessed with use of the Musculoskeletal Tumor Society system. RESULTS: The median age of the patients was 30.4 years at the time of the acetabular resection and 35.7 years at the time of follow-up. The median time interval from the index operation to the latest follow-up was sixty-nine months. At the latest follow-up evaluation, the mean functional status score was 14.5 points of a maximum of 30 points. In a comparison of endoprosthetic replacement and hip transposition following resection, significantly better functional results (p = 0.017) and a lower number of complications were found in patients who had a hip transposition. Quality-of-life assessment results were also better in patients with a hip transposition, especially in role functioning (p = 0.043). CONCLUSIONS: On the basis of the low complication rate and the good functional and quality-of-life results, hip transposition after acetabular resection seems to be the optimal technique for treating patients with a pelvic sarcoma involving the acetabulum.

Treatment of primary malignant bone tumours of the distal tibia.

We treated 15 patients with primary malignant bone tumours of the distal tibia of which 14 were treated by limb salvage surgery. Reconstructions were done by allografts with or without microvascular fibula transfer, by bone transport, by fibula transfer alone or by endoprosthetic replacement. The most successful methods were bone transport and endoprosthetic replacement. However, serious complications with deep infections leading to secondary amputation occurred in four patients and in all reconstruction groups. After a mean follow up of 7 years, no local recurrence occurred, and all patients were alive and free of disease. After radical resection, bone transport in defects less than 15 cm is a viable option. In larger defects in children, allograft with vascularised fibula is an acceptable alternative, but amputation still has a role in this group. In adults, endoprosthetic replacement with proper soft tissue coverage is a viable option in cases with large bony defects.

Endoprosthetic replacement of the humerus combined with trapezius and latissimus dorsi transfer: a report of three patients.

INTRODUCTION: To improve the functional outcome after proximal and/or total humerus replacement, we combined the surgical procedures described by Bateman and Gerber. MATERIALS AND METHODS: In three patients after wide tumor resection, endoprosthetic replacement with a modular tumor endoprosthesis (MUTARS System) was performed. In addition to a capsular and muscular reconstruction using the Trevira tube, a trapezius transfer onto the Trevira tube in combination with a latissimus dorsi transfer onto the Trevira tube was performed. The patients were immobilized for 6 weeks after surgery with an abductor cast. RESULTS: After a follow-up of 1 year, there was no significant improvement of the shoulder function in comparison with patients who did not undergo the combined muscle transfer (control group n=16: mean abduction 37.5 degrees ; mean anteversion 35.0 degrees ; mean internal rotation 15.2 degrees ; mean external rotation 25.2 degrees ). CONCLUSION: In our patients, the combination of the Gerber and the Bateman procedures did not improve the shoulder function in patients with proximal and/or total humerus replacements. Therefore, the functional results do not justify two separate approaches and a prolonged operation time.

Primary multifocal osseous Hodgkin disease: a case report and review of the literature.

PURPOSE: Hodgkin disease (HD) typically involves the lymphatic system at one or more sites. Rarely, Hodgkin disease presents as an osseous lesion without involvement of lymph nodes. Therefore, the histologic diagnosis of osseous HD can be problematic. We present a rare case of multifocal osseous HD and a review the literature with special emphasis on treatment and prognosis. METHODS: Osteomyelitis and lymphoma are the main differential diagnoses and can only be excluded histologically by the presence of Sternberg Reed cells or by immunohistochemical examinations. This case reports a 21-year old man with a Hodgkin lymphoma located at the proximal femur and the proximal tibia. RESULTS: Staging studies revealed no other tumor manifestations. Regarding the Ann Arbor classification, the presented case should be a stage IV disease. The patient is without evidence of disease 4 years after curettage, local radiation therapy, and systemic chemotherapy despite the poor prognosis considering the Ann Arbor classification. CONCLUSION: Reviewing the few reported cases, osseous HD must be distinguished from systemic HD with diffuse bone marrow involvement and from osseous metastases in advanced stage of disease because it seems to have a better prognosis.

[Rotationplasty in the surgical treatment plan of primary malignant bone tumors. Possibilities and limits]. / Umkehrplastik im operativen Behandlungsplan der primär malignen Knochentumoren. Möglichkeiten und Grenzen.

Long-term survival of patients with a malignant bone tumor increased with a combined therapeutic approach using chemotherapy and possibly radiation therapy. Today up to 80% of patients with an osteosarcoma or Ewing's sarcoma survive. Therefore, it is important that the functional outcome and the quality of life are good after resection of the tumor. Before the era of endoprosthetic devices, rotationplasty, which was introduced in 1974 by Salzer for surgery of malignant bone tumors and modified by Winkelmann, protected many patients from an amputation. Although many authors favor limb-saving procedures today, rotationplasty obtained excellent functional and psychosocial results. Rotationplasty can be recommended in tumors with a large soft tissue component, in tumors located in the proximal femur and proximal tibia, and in children under 10 years of age. Furthermore, rotationplasty can be used in patients in whom a limb-salvage procedure failed because of infection or repeated changes of the endoprosthesis.

[Options for surgical treatment of malignant bone tumors]. / Chirurgische Therapieoptionen bei malignen Knochentumoren.

Beside the susceptibility to a (neo-) adjuvant therapy, the surgical margin is the most important prognostic factor in the treatment of primary malignant bone tumors. If adjuvant therapy is not possible, the outcome of the disease depends on the selected surgical treatment. Limb salvage has proven to be a safe procedure for local tumor control and provides good functional results. The surgeon has to consider the best surgical option depending on the site and size of the tumor but also depending on the patient's age and the overall prognosis. Surgical techniques and possible complications of the most common procedures in tumor surgery are described.

Reconstruction of the proximal humerus after wide resection of tumours.

In 45 patients we assessed the functional results and complications for three different reconstructive procedures after resection of primary tumours of the proximal humerus. An osteoarticular allograft was used in 11, a clavicula pro humero operation in 15 and a tumour prosthesis in 19. The glenoid was resected with the proximal humerus in 25 patients. The axillary nerve was resected in 42 patients. The complication rate was lowest after reconstruction with a tumour prosthesis. The clavicula pro humero operation resulted in the most revisions. Cumulative survival rates for all the reconstructive procedures were similar. At follow-up at two years the functional results for the three reconstructive procedures were the same with a mean functional rating of 79% (Musculoskeletal Tumor Society). Excision of the glenoid had no influence on the functional result. Our findings indicate that the use of a tumour prosthesis is the most reliable limb-salvage procedure for the proximal humerus. The clavicula pro humero is an appropriate procedure if a prosthesis cannot be used.

Stump lengthening after hip disarticulation using a modular endoprosthesis in 5 patients.

To reduce the disability after hip disarticulation, we developed a special surgical procedure in patients having a proximal femoral tumor with a large tumor involving the sciatic nerve or neoplasms involving the tibia and femur. The hip was disarticulated, but we preserved a musculocutaneous flap. A modular endoprosthesis was then placed in the acetabulum or, in case of an extraarticular resection of the hip joint, it was placed in the iliac bone. A trevira tube was used for reconstruction of the joint capsule and fixation of soft tissues. We performed this procedure in 5 patients who had a good functional outcome.

Mechanical quality of tissue engineered cartilage: results after 6 and 12 weeks in vivo.

Traumatic events are a primary cause for local lesions of articular cartilage. If treated early, restoration of the initial joint geometry and integrity may be achieved. In large defects, sufficient material is not available to bridge the affected area. Heterologeous transplantation is not well accepted due to the risk of infection and immune response. Alternatives are cartilage-like structures, which may be cultured in vitro and transplanted into the defect site. Critical to the success of these new tissues are their mechanical properties. Goals of this study were to generate a hyaline-like cartilage structure, to evaluate its performance in vivo and to verify that its cellular and material properties meet those of native cartilage. Hyaline-like cartilage specimens were generated in vitro and implanted in the backs of nude mice. Specimens were explanted after 6 and 12 weeks, mechanically tested using an indentation test and histologically examined. In mechanical testing, stiffness and failure load significantly increased between weeks 6 and 12. At 12 weeks, mechanical properties of the hyaline-like cartilage were comparable to those of native nasal septal cartilage. Compared to native articular cartilage, the engineered tissue achieved up to 30-50% in strength and mechanical stiffness. In histological examination, specimens showed neocartilage formation. The mechanical testing procedure proved to be sufficiently sensitive to identify differences in properties between cartilage specimens of different origin and at different stages of healing. As an adjunct to histological analysis, mechanical testing may be a valuable tool for judging the utility of engineered cartilage prior to a broad clinical usage.

Examination of cognitive variables relevant to sunscreen use.

The present study is an examination of the underlying psychological variables relevant to a sun-damage preventive behavior, sunscreen use. The focus of the research was to examine cognitive predictors of sunscreen use, utilizing a decision theoretic framework. Two hundred thirty subjects were recruited from psychology classes and administered questionnaires assessing sunscreen behavioral tendencies, attitudes toward sunscreen use, and internal- and external-based cognitions relevant toward sunscreen use. In contrast to previous work that had examined only one or two of these predictor variables in isolation, the present study evaluated the relative impact of these variables on sunscreen use tendencies. The findings revealed evidence of a multivariate model (using structural equation modeling; LISREL VIII) relating perceived need for, perceived efficacy of, perceived consequences of, and social normative influences on sunscreen use. The findings are discussed with respect to improving the effectiveness of short-term education efforts to increase sunscreen use.

Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation.

The suppression of male-specific, GH pulse-induced, liver transcription in adult female rats has been linked to the down-regulation of STAT5b activation by the female plasma pattern of near-continuous GH exposure. The mechanism underlying this down-regulation was studied in the rat liver cell line CWSV-1, where continuous GH suppressed the level of activated (tyrosine- phosphorylated) STAT5b to approximately 10-20% of the maximal GH pulse-induced STAT5b signal within 3 h. In contrast to the robust JAK2 kinase-dependent STAT5b activation loop that is established by a GH pulse, JAK2 kinase signaling to individual STAT5b molecules was found to be short lived in cells treated with GH continuously. Moreover, maintenance of the low-level STAT5b signal required ongoing protein synthesis and persisted for at least 7 days provided that GH was present in the culture continuously. Increased STAT5b DNA-binding activity was observed in cells treated with the proteasome inhibitor MG132, suggesting that at least one component of the GH receptor (GHR)-JAK2-STAT5b signaling pathway becomes labile in response to continuous GH treatment. The phosphotyrosine phosphatase inhibitor pervanadate fully reversed the down-regulation of STAT5b DNA-binding activity in continuous GH-treated cells by a mechanism that involves both increased STAT5b activation and decreased STAT5b dephosphorylation. Moreover, the requirement for ongoing GH stimulation and active protein synthesis to maintain STAT5b activity in continuous GH-treated cells were both eliminated by pervanadate treatment, suggesting that phosphotyrosine dephosphorylation may be an obligatory first step in the internalization/degradation pathway for the GHR-JAK2 complex. Finally, the sustaining effect of the serine kinase inhibitor H7 on GH pulse-induced JAK2 signaling to STAT5b was not observed in continuous GH-treated cells. These findings suggest a model where continuous GH exposure of liver cells down-regulates the STAT5b pathway by a mechanism that involves enhanced dephosphorylation of both STAT5b and GHR-JAK2, with the latter step leading to increased internalization/degradation of the re-ceptor-kinase complex.

Termination of growth hormone pulse-induced STAT5b signaling.

STAT5b (signal transducer and activator of transcription 5b) is a key mediator of the effects of plasma GH pulses on male-specific liver gene expression. STAT5b is activated in liver cells in vivo by physiological pulses of GH and then is rapidly deactivated. Investigation of the cellular events involved in this activation/deactivation cycle using the rat liver cell line CWSV-1 established that a brief exposure to GH and the associated activation of JAK2 (Janus kinase 2) tyrosine kinase activity are both necessary and sufficient to initiate all of the downstream steps associated with STAT5b activation by tyrosine phosphorylation and the subsequent deactivation of both JAK2 kinase and STAT5b. JAK2 signaling to STAT5b at the conclusion of a GH pulse could be sustained by the protein synthesis inhibitor cycloheximide or by the proteasome inhibitor MG132, indicating that termination of this JAK2-catalyzed STAT activation loop requires synthesis of a labile or GH-inducible protein factor and is facilitated by the proteasome pathway. This factor may be a phosphotyrosine phosphatase, since the phosphatase inhibitor pervanadate both sustained GH pulse-induced JAK2 signaling to STAT5b and blocked the rapid deactivation of phosphorylated STAT5b (t(1/2) = 8.8 +/- 0.9 min) seen in its absence. Finally, the serine kinase inhibitor H7 blocked down-regulation of JAK2 signaling to STAT5b in a manner that enabled cells to respond to a subsequent GH pulse without the need for the approximately 3-h interpulse interval normally required for full recovery of GH pulse responsiveness. Termination of GH pulse-induced STAT5b signaling is thus a complex process that involves multiple biochemical events. These are proposed to include the down-regulation of JAK2 signaling to STAT5b via a cycloheximide- and H7-sensitive step, proteasome-dependent degradation of a key component or regulatory factor, and dephosphorylation leading to deactivation of the receptor-kinase signaling complex and its STAT5b substrate via the action of a phosphotyrosine phosphatase.