Superior Capsular Reconstruction With Autologous Fascia Lata Using a Single Lateral-Row Technique Is an Effective Option in Massive Irreparable Rotator Cuff Tears: Minimum 2-Year Follow-Up.

PURPOSE: The purpose of this study was to evaluate clinical and radiologic outcomes of arthroscopic superior capsular reconstruction (ASCR) with fascia lata autograft in patients with irreparable rotator cuff tears (IRCTs) performed using a single lateral-row fixation technique. METHODS: We studied a retrospective case series of patients with large or massive IRCTs for ASCR with fascia lata autograft. Clinical outcomes were evaluated using the Visual Analog Scale (VAS) and the Constant score. Healing of the graft was assessed by magntic resonance imaging or ultrasound. Acromiohumeral distance was evaluated by radiographs. RESULTS: Thirty-one patients with an average age of 61 years and an average follow-up of 35 months (24-51 months) underwent ASCR with fascia lata autograft. There was a significant improvement in VAS (7.7-0.7), Constant score (36.0-78.7), forward elevation (115°-171°), external rotation (33°-50°), strength (0.3 kg-2.3 kg), and acromiohumeral distance (6.1 mm-8.6 mm) (P < 0.001). Graft failure was present in 13.8% of patients, as shown by magnetic resonance imaging (26 patients) or ultrasound (3 patients). Patients with failed ASCR showed worse Constant scores (68.5.8 vs 80.2, P = 0.007), worse VAS (2.5 vs 0.4, P = 0.00002), worse external rotation (20° vs 54°, P = 0.004), lower acromiohumeral distance (5mm vs 9mm, P = 0.007), and a high association with the presence of os acromiale (χ2P = 0.003). No revision or subsequent surgical procedures were required. CONCLUSIONS: ASCR, with autologous fascia lata and single lateral row configuration, is an effective option in irreparable rotator cuff tears and results in clinical and radiologic improvement. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Reverse Allograft-Prosthesis Composite with Pectoralis Major Transfer After Shoulder Osteosarcoma: A Case Report.

CASE REPORT: We present a case of a 30-year-old man with proximal humerus osteosarcoma and periarticular soft-tissue involvement. Severe humeral and glenoid bone loss was observed, with nonfunctional deltoid after limb-sparing resection and a failed attempt of stabilization. The shoulder was reconstructed using a reverse allograft-prosthesis composite, with deltoid reconstruction by pectoralis major transfer. CONCLUSIONS: To the best of our knowledge, this is the first time that this reconstruction technique has been reported in an oncological patient. Favorable clinical and radiological results were achieved at the 24-month follow-up.

Treatment of olecranon fractures using an intramedullary cancellous screw and suture tension band: minimum 2-year follow-up.

Background: Tension band wiring and plates are the most widely used treatments for transverse displaced fractures of olecranon despite high rates of hardware complications, subsequent implant removal, and associated costs. The purpose of this study was to report the outcomes of displaced transverse olecranon fractures treated with intramedullary screw and suture tension band. Methods: We performed an observational, retrospective, consecutive, monocentric, continuous multioperator study. We reviewed 31 Mayo type IIA displaced olecranon fractures treated in our institution with intramedullary 6.5 mm AO cancellous screw and high-strength suture tension band (No. 2 FiberWire®) from 2016 to 2018. Inclusion was limited to functionally independent patients with Mayo type IIA fractures and minimum 24-month follow-up for implant removal. We assessed clinical outcomes including range of motion; QuickDASH score; and Mayo Elbow Performance Score. Categorical data were analyzed with Fisher's exact test when appropriate. Continuous data were analyzed with the Student t-test or Mann-Whitney U test after assessment for normality. Statistical analysis was performed with STATA 16 software. Results: Twenty-seven patients with a mean follow-up period of 38.4 ± 6.2 months (range, 24.1-50 months) were included in the study. The average flexion was 134.5° ± 14.8° (range, 70°-140°) and the mean extension was -5.9° ± 7.0° (range, -20°-0°). Mean pronation and supination were 85.8° ± 11.9° (range, 45°-90°) and 86.9° ± 14.3° (range, 20°-90°), respectively. The mean Mayo Elbow Performance Score was 90.8 ± 9.6 (range, 70-100) with 92.3% good and excellent results. The mean QuickDASH score was 17.1 ± 16 (range, 0-54.5). There were 3 hardware-related removals (11.1%). The overall removal rate was 18.5%. Univariate analysis of the factors associated with implant removal were pain in relation to the implant (60% vs. 11%, P = 0.0482), proximal screw migration (3.7 mm vs. 1.7 mm, P = 0.05), articular angle (22.5° vs. 27.7°, P = 0.0353), and olecranon width (22.2 mm vs. 24.4 mm, P = 0.0166). In total, 26.1% of the cases presented some degree of proximal migration of the implant (2.7 ± 1.8 mm of migration; range, 1.5-6.2 mm). Univariate analysis of the factors associated with implant proximal migration were proximal ulnar dorsal angulation (1.7° vs. 6.4°, P = 0.0179), anteroposterior endomedullary canal (7.3 mm vs. 6.0 mm, P = 0.0369), and lateral endomedullary canal (7.2 mm vs. 5.0 mm, P = 0.0219). Conclusion: The functional outcomes of simple transverse olecranon fractures treated with an intramedullary cancellous screw and a suture tension band are excellent, associated with a low rate of complications and material removal.

Patellar calcar: morphometric analysis by knee magnetic resonance imaging and three-dimensional reconstruction software-assisted.

PURPOSE: Patellar calcar corresponds to a greater trabecular bone density area in the patella lateral facet, whose morphometry is uncertain. This study aimed to describe patellar calcar morphometry by knee MRI and develop a 3D reconstruction software-assisted. MATERIALS AND METHODS: Consecutive adult patients, submitted to knee MRI, between 2014 and 2017, were entered in IMPAX software. Exclusion criteria are history of patellar surgical intervention, trauma, chondromalacia, bone edema or bipartite patella. All MRI images were retrospectively reviewed by three readers. MRI patellar calcar measurements are height, width, thickness and posterior distance. 3D model protocol reconstruction: 3D Slicer software was used to design a preliminary model for each patient, and then all were automatically merged into one, which was finalized using the software segmentation tools. For 3D patellar calcar location, the transpolar axis was designed. RESULTS: 250 MRI were analyzed, patellar calcar was present in 208 (83.2%); 101 men and 107 women. Mean age was 44.3 ± 15.6 years. MEASUREMENTS: height 13.84 ± 2.42 mm (male: 14.50 ± 2.42; female: 13.21 ± 2.26) (p < 0.0001), width 12.21 ± 2.26 mm (male 13.14 ± 2.22; female 11.33 ± 1.93) (p < 0.0001). No statistically significant difference of thickness 0.56 ± 0.22 mm (male: 0.56 ± 0.25; female: 0.56 ± 0.20) and posterior distance 2.37 ± 0.80 mm (male: 2.46 ± 0.89; female: 2.29 ± 0.69) between genders was found. 3D model results: transpolar axis went through the patellar calcar in all the cases. CONCLUSIONS: This study shows in a 3D model reconstruction, what was previously described in the literature, determining for the first time the patellar calcar morphometry in the knee MRI and identifying it as a regular finding in this imaging test.

p53 modulates acquired resistance to EGFR inhibitors and radiation.

There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.

Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy.

PURPOSE: To examine the prognostic value of the 4E-BP1 activation state and related upstream/downstream signaling proteins on the clinical outcome of patients with intermediate- or high-risk early-stage cervical carcinoma treated with postoperative radiotherapy and to determine the optimal treatment of early-stage cervical carcinoma. METHODS AND MATERIALS: Immunohistochemical staining was performed on 64 formalin-fixed, paraffin-embedded cervical carcinoma surgical specimens for each protein of the panel (p4E-BP1, phosphorylated mitogen-activated protein kinase, pAkt, vascular endothelial growth factor, KDR, Bcl-2, TP53, receptor for activated C-kinase 1). The expression patterns were related to the clinical data. All patients received postoperative radiotherapy. Concurrent chemotherapy was added if high-risk features were present. The median follow-up was 40 months. RESULTS: Of the 64 patients, 13 received concomitant chemotherapy. p4E-BP1 overexpression in moderate/high-risk early-stage cervical carcinoma correlated significantly with disease-free survival (hazard ratio, 4.39; p = .009) and overall survival (hazard ratio, 4.88; p = .005). Vascular endothelial growth factor, and its receptor KDR, had positive immunoreactivity in all tumor samples. No correlation with clinical outcome was found for the remaining proteins evaluated. CONCLUSION: In this study, moderate/high-risk early-stage cervical carcinoma with low p4E-BP1 expression was highly curable with the current postoperative treatments. For tumors with p4E-BP1 overexpression, new investigational strategies are needed.

Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells.

PURPOSE: The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed. EXPERIMENTAL DESIGN: To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor-resistant lines relative to the EGFR inhibitor-sensitive lines. RESULTS: EGFR inhibitor-resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor-resistant lines showed a markedly increased proliferation rate. EGFR inhibitor-resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor-resistant lines. Finally, EGFR inhibitor-resistant lines showed cross-resistance to ionizing radiation. CONCLUSIONS: We have developed EGFR inhibitor-resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.

Insulin-like growth factor-I receptor signaling blockade combined with radiation.

Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials.

Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor.

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.

Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy.

PURPOSE: Epidermal growth factor receptor (EGFR) expression is observed in 50%-70% of colorectal carcinomas and is associated with poor prognosis. The aim of this study was to determine the EGFR expression rate in locally advanced rectal cancer and to analyze whether EGFR expression predicts tumor response to preoperative radiotherapy. METHODS AND MATERIALS: Between December 1997 and October 2000, 45 patients were included. Treatment consisted of preoperative pelvic radiotherapy and, in 21 patients, 2 courses of 5-fluorouracil leucovorin. Surgical resection was performed 4-8 weeks later. Immunohistochemistry for EGFR was determined at the preradiation diagnostic biopsy and in the resected specimens. Immunostaining was performed using EGFR monoclonal antibody (Biogenex, MU 207-UC). Immunohistochemical staining was evaluated according to extension and intensity. We defined positive staining (EGFR+) as extension of 5% or more. RESULTS: Preoperative treatment resulted in pathologic complete remission in 7 patients (15%), downstaging in 13 patients (29%), and no response in 25 patients (56%). EGFR+ was observed in 29 of 45 tumors (64%) and was associated with neither clinical tumor stage nor clinical nodal stage. The overall response rate was 34% in EGFR+ patients vs. 62% in those who were EGFR- (p = 0.07). Only 1 of the 7 pathologic complete remission patients was EGFR+ (p = 0.003). CONCLUSIONS: EGFR is expressed in a significant number of locally advanced rectal tumors. EGFR expression is an indicator for poor response to preoperative radiotherapy in advanced rectal carcinoma.