Treatment sequences and drug costs from diagnosis to death in multiple myeloma.

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

Ex vivo cultures and drug testing of primary acute myeloid leukemia samples: Current techniques and implications for experimental design and outcome.

New treatment options of acute myeloid leukemia (AML) are rapidly emerging. Pre-clinical models such as ex vivo cultures are extensively used towards the development of novel drugs and to study synergistic drug combinations, as well as to discover biomarkers for both drug response and anti-cancer drug resistance. Although these approaches empower efficient investigation of multiple drugs in a multitude of primary AML samples, their translational value and reproducibility are hampered by the lack of standardized methodologies and by culture system-specific behavior of AML cells and chemotherapeutic drugs. Moreover, distinct research questions require specific methods which rely on specific technical knowledge and skills. To address these aspects, we herein review commonly used culture techniques in light of diverse research questions. In addition, culture-dependent effects on drug resistance towards commonly used drugs in the treatment of AML are summarized including several pitfalls that may arise because of culture technique artifacts. The primary aim of the current review is to provide practical guidelines for ex vivo primary AML culture experimental design.

A survey on surgeon practice shows lack of consensus on the management of primary shoulder stiffness.

Shoulder stiffness is a condition of painful restriction in active and passive glenohumeral range of motion, which can arise spontaneously or as consequence of a known cause. Numerous therapeutic approaches are available; however, no consensus has been reached on the best algorithm for successful treatment. The aim of this study was to investigate local practice patterns regarding management of primary shoulder stiffness. Randomized controlled trials reporting results of shoulder stiffness treatment were collected and analyzed prior to study begin. Controversial elements in the treatment of primary shoulder stiffness were identified and a survey was created and administrated to clinicians participating at an annual national congress dedicated to shoulder pathologies and their treatment. 55 completed questionnaires were collected. Physical therapy was recommended by 98% of the interviewed. The use of oral corticosteroids was considered by 58% and injections of corticosteroids by 60%. Injective therapy with local anaesthetics was considered by 56% of the clinicians and acupuncture by 36%. 38% of the interviewed did never treat shoulder stiffness surgically. Various strategies to manage shoulder stiffness have been proposed and high-level evidence has been published. Numerous controversial points and a substantial lack of consensus emerged both from literature reviews and from this survey. The treatment of shoulder stiffness should be tailored to the patient's clinical situation and the stage of its pathology, aiming primarily at identifying risk factors for recurrence, reducing pain, restoring range of motion and function and shortening the duration of symptoms.

Inter-rater reliability of classification systems of scapular dyskinesis.

Prevalence of scapular dyskinesis varies across records, with overhead athletes being more frequently affected than non-overhead athletes A number of methods have been described to evaluate scapular kinematics and scapular dyskinesis. The "yes/no" and the "4-type" classification systems are widely accepted and diffusely used among orthopaedics and physical therapists. The inter-rater reliability for both the "yes/no" and the "4-type" classification systems may be different. Moreover, differences between physical therapists and orthopaedic surgeons may exist. Seven examiners (2 orthopaedic surgeons and 5 physical therapists) were asked to evaluate a mixed sequence of video recordings of healthy subjects and patients affected by shoulder, scapular or clavicular disorders and to assess scapular dyskinesis using the "yes/no" and the "4-type" classification systems. Cohen's kappa coefficient (κ) and weighted kappa were used to measure inter-rater reliability. Twenty-four subjects were enrolled. In general, the "4- type" system has higher κ values than ''yes/no'' classification system and orthopaedic surgeons achieve higher reliability than physical therapists for both systems. The clinical evaluation of active shoulder movements permits reproducible assessment and classification of scapular dyskinesis, in particular for the "4-type" classification system. The "4-type" classification system can be used to assess and classify scapular dyskinesis, especially among orthopaedic surgeons.

Microfracture combined with anterior cruciate ligament reconstruction compared to isolated microfractures for osteochondral lesions.

There is limited evidence whether increased growth-factor and stem-cell influx during bone tunnel drilling for ACL-reconstruction enhances clinical results of microfracture treatment of small cartilage defects. The goal of this study was to compare clinical and radiological results in patients treated with microfracture alone and patients treated with microfracture plus ACL-reconstruction. A total of 67 patients that were either treated with microfracture alone (primary stable knees, n= 40) or microfracture plus ACL-reconstruction (ACL deficient knees, n= 27) were included and prospectively evaluated. Subjects were preoperatively assessed radiologically using the MR-based AMADEUS-score (Area Measurement and Depth & Underlying Structures) and clinically using the Lysholm-score before the intervention. At minimum 24-month follow-up, the regenerate tissue was assessed by the MR-based MOCART-score (Magnetic resonance observation of cartilage repair tissue) and by use of the Lysholm-Tegner-score for clinical evaluation. Preoperatively both groups had similar AMADEUS-scores. The Lysholm-score was significantly higher in the microfracture group (p < 0.001). In the postoperative assessment there was a significant difference (p = 0.04) in the MOCART-score in favor of the microfracture plus ACL-reconstruction group. The Lysholm-score significantly improved (p <0.001) in the microfracture plus ACL-reconstruction group and was significantly higher than in the microfracture group (p = 0.004). Conclusion: A combination of microfracture and ACL-reconstruction leads to comparable functional results, yet superior MOCART-scores as compared to microfracture alone. ACL reconstruction enhances biological healing responses in microfracture treated cartilage and thus improves clinical outcomes by additional bone marrow influx from bone tunnels.

[Influence of the trauma mechanism on cervical spine injuries]. / Einfluss des Unfallmechanismus auf die Verletzungen der Halswirbelsäule.

BACKGROUND: The influence of trauma-related kinematics on the injury pattern of the cervical spine is currently not considered in the available classification systems, only the force vector. Whether the strength of the trauma has an additional influence on the number and complexity of the injuries and whether this can be classified, has not yet been finally investigated. OBJECTIVE: What influence do different kinematics apart from the traumatic force vector have on injuries of the cervical spine? MATERIAL AND METHODS: Based on the AOSpine classification system for the upper and subaxial cervical spine, data from 134 trauma patients from a first level trauma center were retrospectively analyzed. Analogue to the S3 guidelines on polytrauma, patients were assigned to six trauma groups and the injuries were classified on the basis of computed tomography (CT) cross-sectional imaging. RESULTS: A higher trauma energy had a significant impact on the number of cervical spine injuries (p = 0.005). In low velocity accidents C2 was the most frequently injured vertebra (51%; p = 0.022) and high velocity accidents showed more C7 fractures (37%; p = 0.017). Furthermore, upper cervical spine injuries occurred more often in low energy trauma and older female patients (e.g. falling from a standing position). Subaxial cervical spine involvement was found significantly more often in high velocity accidents and younger male patients (p = 0.012). CONCLUSION: Exact knowledge of the trauma mechanism is helpful in the primary treatment of an injured person. Injury patterns can be better estimated and the appropriate diagnostics can be initiated. The results underline the importance of immediate cervical spine immobilization even after minor trauma. In high velocity trauma, patients more often suffer from lower cervical spine injuries, especially C7. Due to the accumulation of multilevel spinal injuries in high velocity trauma, radiographic imaging of the whole spine is advisable.

Risk factors for post-operative shoulder stiffness: are there new candidates?

The aim of this study was to document the incidence of postoperative shoulder stiffness (SS) after arthroscopic rotator cuff repair and evaluate the role of risk factors for its development. Seventy-five consecutive patients that underwent arthroscopic rotator cuff repair were included. The incidence of postoperative SS was prospectively investigated and the presence of 20 potential risk factors was documented retrospectively. The incidence of post-operative SS was 10.4%. All patients were women, and sex was significantly associated to pathology development (p=0.0067). The presence of gastroesophageal diseases was found to be significantly associated with post-operative SS development (p=0.0046). A significant association between the occurrence of post-operative SS and the presence of gastroesophageal diseases was identified. This finding, not yet reported in literature, deserves further investigation. The incidence of postoperative SS fell among previously reported ranges, with females significantly more affected than men.

Quality of life gains in frail and intermediate-fit patients with multiple Myeloma: Findings from the prospective HOVON123 clinical trial.

BACKGROUND: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent. METHODS: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID). RESULTS: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients. CONCLUSION: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.

ARoCuS Web application promotes standardized treatment and documentation of rotator cuff tears.

PURPOSE: To program a Web application for simplified calculation of the Advanced Rotator Cuff tear Score (ARoCuS), which is a 5-part, 18-item treatment-oriented intraoperative scoring system for intraoperative evaluation of rotator cuff tears. METHODS: ARoCuS characteristics (torn tendon, tear size, tissue quality and tear pattern) were assessed intraoperatively on 40 consecutive patients with rotator cuff tears for calculation of defect category ΔV. Video recordings were used to re-calculate the ARoCuS after surgery and to assess inter-observer reliability. RESULTS: The Web application "ARoCuS App" was built using Angular and transformed to a native iOS application. The intraoperative use of the app proved to be simple and intuitive. There were inter-/intra-observer differences neither in ARoCuS defect categories ΔV nor in ARoCuS characteristics (p > 0.05). CONCLUSION: The ARoCuS app is a supportive tool for integration of standardized treatment procedures and documentation of rotator cuff tears in clinical routine.

[Endoprosthetic replacement of the proximal humerus in revision shoulder arthroplasty]. / Der proximale Humerusersatz in der Revisionssituation.

OBJECTIVE: Reconstruction of proximal humeral bone defects in the setting of shoulder revision arthroplasty by implantation of a modular humeral component. INDICATIONS: Severe segmental humeral bone defects in revision total shoulder arthroplasty, after tumor resection, trauma, pathological fractures, post-infectious or after failed osteosynthesis. CONTRAINDICATIONS: Acute or chronic local infections, large diaphyseal bone defects preventing adequate anchorage of the prosthesis, very short life expectancy (<3 months). SURGICAL TECHNIQUE: Removal of the implant using an extended deltopectoral approach. Periarticular arthrolysis with preservation of neurovascular structures. Resection of the meta-diaphyseal bone and reconstruction of the humeral length with the help of different extension sleeves and a modular humeral component. Soft tissue management is crucial, especially with reverse shoulder arthroplasty. POSTOPERATIVE MANAGEMENT: Three weeks postoperatively immobilization in a shoulder sling, active assisted movement therapy by gradual pain-adapted increase of movement, muscle coordination, and strength. RESULTS: The results of 11 consecutive patients treated with a modular humeral component due to a failed shoulder arthroplasty between 2008 and 2016 were evaluated retrospectively. Mean length of reconstruction was 100 mm. Due to recurrent dislocations one patient required revision and conversion to a reverse component. No cases of aseptic loosening or periprosthetic infection were observed.

Reliability of anterior medial collateral ligament plication of the elbow.

PURPOSE: The aim of this study is to describe a new surgical procedure to plicate the anterior bundle medial collateral ligament (aMCL) into its humeral footprint using a suture anchor, and to present the results of a preliminary clinical series. METHODS: Eight patients with posttraumatic medial elbow pain and signs of medial elbow instability underwent aMCL plication with suture anchors and decompression of ulnar nerve. Arthroscopic evaluation permitted to define signs of minor medial elbow instability; 70°-scope was used to document from an intra-articular point of view of the aMCL status. The patients were then retrospectively evaluated with the Oxford Elbow Score (OES), Mayo Elbow Performance Score (MEPI) and single-assessment numeric evaluation (SANE) by an independent examiner. RESULTS: In all cases, the 70°-scope allowed direct visualization of the aMCL. Lateral subluxation of the coronoid process into the trochlea was observed in all patients. Postoperative median SANE was 50 [35-74.5] points; postoperative median OES was 17 [15.5-31.5] points; postoperative median MEPI was 65 [57.5-72.5] points. None of the patients reported further episodes of medial elbow instability or pain and all patients returned to normal daily activities. CONCLUSIONS: The 70°-scope arthroscopic evaluation of the joint allows a direct evaluation of the inner aMCL status. Lateral subluxation of the coronoid process into the trochlea was observed and can be considered a sign of minor medial elbow instability. Mini-open suture anchor aMCL plication is an original technique that enables an anatomic and minimally invasive ligament retension. CLINICAL RELEVANCE: The authors introduce a valid and safe treatment of posttraumatic medial elbow laxity.

It's time to change perspective! New diagnostic tools for lateral elbow pain.

PURPOSE: The presence of intra-articular findings that may complement the extra-articular pathology in lateral epicondilytis has been suggested, and a role for minor instability of the elbow as part of the causative process of this disease has been postulated. This study was designed to describe two new clinical tests, aimed at detecting intra-articular pathology in patients affected by recalcitrant lateral epicondylitis and investigate their diagnostic performance. METHODS: Ten patients suffering of atraumatic lateral elbow pain unresponsive to conservative treatment were considered in this study. Two clinical tests were developed and administrated prior to arthroscopy: Supination and Antero-Lateral pain Test (SALT); Posterior Elbow Pain by Palpation-Extension of the Radiocapitellar joint (PEPPER). Sensitivity, specificity, predictive values and accuracy of SALT and PEPPER as diagnostic tests for seven intra-articular findings were calculated. RESULTS: In 90% of the patients, at least one test was positive. All patients with signs of lateral ligamentous patholaxity or intra-articular abnormal findings had a positive response to at least one of the two tests. SALT proved to have a high sensitivity but a low specificity and is accurate in detecting the presence of intra-articular abnormal findings, especially synovitis. PEPPER test was sensible, specific and accurate in the detection of radial head chondropathy. CONCLUSIONS: Two new diagnostic tests (SALT and PEPPER) were specifically designed to evoke pain from intra-articular structures. These tests could be a valid support in the diagnostic algorithm of recalcitrant lateral elbow pain. Positive findings may be indicative of a minor instability of the lateral elbow condition. LEVEL OF EVIDENCE: Diagnostic study, development of diagnostic criteria on basis of consecutive patients, level II.

Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma.

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.