[Secondary fracture prevention/Update osteoporosis guidelines 2023 of the Umbrella Organization Osteology]. / Sekundäre Frakturprävention/Update Leitlinie Osteoporose 2023 des Dachverbandes Osteologie.

The S3 guidelines on the prophylaxis, diagnostics and treatment of osteoporosis 2023 were completely revised and updated between 2021 and 2023 in accordance with the Association of the Scientific Medical Societies of Germany (AWMF) regulations. The guideline committee consisted of delegates from the 20 specialist societies of the Umbrella Organization Osteology (Dachverband Osteologie, DVO) as well as delegates from the German Society of General Medicine and Family Medicine (DEGAM), the German Society for Nephrology (DGfN) and the Federal Self-help Association for Osteoporosis (BfO).The guidelines focus on preventive measures, diagnostic procedures and treatment approaches for osteoporosis in men aged 50 years and over and postmenopausal women. The main aim is the optimization of care processes, reduction of fracture incidences and maintenance or improvement of the quality of life and functional capacity of patients affected by fractures. A major update to the guidelines includes the introduction of a new risk calculator that can take more risk factors (n = 33) into account and that can estimate the risk of vertebral body and proximal femoral fractures for a 3-year period (previously 10 years). This results in new thresholds for diagnostics and treatment. The programmed app is currently not yet certified as a medical product and a paper version is therefore currently available for patient care with the planned integration of a web-based version of the risk calculator. From the perspective of trauma surgery, the recommendations and innovations for manifest osteoporosis are of particular clinical importance. The focus of the DVO guidelines update is therefore on the implementation of secondary fracture prevention in trauma surgery, orthopedic and geriatric traumatology in the clinical and practical daily routine.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

Hypogonadism is frequent in very old men with multimorbidity and is associated with anemia and sarcopenia.

BACKGROUND: Clinical data regarding hypogonadism in very old men with multimorbidity are rare. Hypogonadism can contribute to osteoporosis, anemia and sarcopenia and is therefore a relevant problem for geriatric patients. METHODS: A total of 167 men aged 65-96 years (mean 81 ± 7 years) admitted to an acute geriatric ward were included in a cross-sectional study. Body composition derived from dual-energy X­ray absorptiometry, bone mineral density, handgrip strength, multimorbidity, polypharmacy and laboratory values were obtained from the routine electronic clinical patient file. RESULTS: Hypogonadism was present in 62% (n = 104) of the study participants, of whom 83% showed clinical manifestation of hypogonadism (hypogonadism in combination with anemia, sarcopenia and/or low T­score). The subgroups showed a distribution of 52% primary and 48% secondary hypogonadism. Compared to the eugonadal patients, hypogonadal patients had reduced handgrip strength (p = 0.031) and lower hemoglobin levels (p = 0.043), even after adjustment for age, body mass index and glomerular filtration rate. CONCLUSION: Hypogonadism is common in geriatric patients. If chronic anemia, sarcopenia, or osteoporosis are diagnosed, testosterone levels should be determined in geriatric settings.

Oral health in patients with neurodegenerative and cerebrovascular disease: a retrospective study.

PURPOSE: This retrospective study investigates oral health and oral care in patients with neurodegenerative and cerebrovascular diseases (CVDs) treated in a dental facility for people with disabilities. METHODS: Oral health indices decayed, missing, and filled teeth (DMFT), periodontal screening index (PSI), treatment spectrum, and oral hygiene were evaluated in 152 patients with multiple sclerosis, Parkinson's disease, dementia, and CVD and 30 controls. Regression analyses identified group differences and influencing factors on DMFT. RESULTS: Patients with neurodegenerative or CVD had a significantly higher DMFT (21.2 ± 5.8 vs. 18.3 ± 5.9), more decayed teeth (4.3 ± 4.8 vs. 1 ± 1.9), fewer filled teeth (7.9 ± 5.5 vs. 11 ± 5.6), and a higher number of surgical (39.5% vs. 20%) treatments but significantly less conservative (49.3% vs. 73.3%) and prosthetic (15.1% vs. 56.7%) treatments than the control group (p< 0.05). The frequency of toothbrushing and the use of an electric toothbrush were related to lower DMFT in patients with neurodegenerative and CVD. Smoking was associated with higher DMFT. CONCLUSIONS: Poor oral health was found in all individuals with disabilities, suggesting that limitations in oral care attributed to aging and neurological disorders negatively affect oral health. Oral rehabilitation of patients with disabilities requires awareness of oral health limitations and early intervention through dental care. Implications for rehabilitationPoor oral health and oral hygiene is common among older people with disabilities.To optimize oral rehabilitation of patients with disabilities, early intervention, individualized treatment plans and an adapted time frame for dental treatment are required.Education of dentists, caregivers, and family members is essential for oral rehabilitation and improvement of oral hygiene in patients with disabilities.

Preoperative Imaging with [18F]-Fluorocholine PET/CT in Primary Hyperparathyroidism.

Primary hyperparathyroidism (pHPT) is a common endocrine disorder due to hyperfunctioning parathyroid glands. To date, the only curing therapy is surgical removal of the dysfunctional gland, making correct detection and localization crucial in order to perform a minimally invasive parathyroidectomy. 18F-Fluorocholine positron emission tomography/computed tomography (18F-FCH PET/CT) has shown promising results for the detection of pHPT, suggesting superiority over conventional imaging with ultrasounds or scintigraphy. A total of 33 patients with pHPT who had negative or equivocal findings in conventional imaging received 18F-FCH PET/CT preoperatively and were retrospectively included. A pathological hyperfunctional parathyroid gland was diagnosed in 24 cases (positive PET, 72.7%), 4 cases showed equivocal choline uptake (equivocal PET, 12.1%), and in 5 cases, no enhanced choline uptake was evident (negative PET, 15.2%). Twelve of the twenty-four detected adenoma patients underwent surgery, and in all cases, a pathological parathyroid adenoma was resected at the site detected by PET/CT. Two of the six patients without pathological choline uptake who received a parathyroidectomy revealed no evidence of parathyroid adenoma tissue in the histopathological evaluation. This retrospective study analyzes 18F-FCH PET/CT in a challenging patient cohort with pHPT and negative or equivocal conventional imaging results and supports the use of 18F-FCH for the diagnosis of hyperfunctional parathyroid tissue, especially in this patient setting, with a 100% true positive and true negative detection rate. Our study further demonstrates the importance of 18F-FCH PET/CT for successful surgical guidance.

Patients with low IGF-I after curative surgery for Cushing's syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy.

BACKGROUND: Glucocorticoid excess leads to muscle atrophy and weakness in patients with endogenous Cushing's syndrome. Insulin-like growth factor I (IGF-I) is known to have protective effects on muscle loss. We hypothesized that individual serum IGF-I concentrations might be predictive for long-term myopathy outcome in Cushing's syndrome. PATIENTS AND METHODS: In a prospective longitudinal study of 31 patients with florid Cushing's syndrome, we analyzed IGF-I and IGF binding protein 3 (IGFBP 3) concentrations at the time of diagnosis and following surgical remission over a period of up to 3 years. We assessed muscle strength by grip strength measurements using a hand grip dynamometer and muscle mass by bio-impedance measurements. FINDINGS: Individual serum IGF-I concentrations in the postoperative phase were strongly predictive of long-term grip strength outcome (rs = 0.696, P ≤ 0.001). Also, lower IGF-I concentrations were associated with a lower muscle mass after 3 years (rs = 0.404, P = 0.033). While patients with high IGF-I s.d. scores (SDS; >1.4) showed an improvement in grip strength within the follow-up period (P = 0.009), patients with lower IGF-I SDS (≤-0.4) had a worse outcome with persisting muscle dysfunction. In contrast, preoperative IGF-I concentrations during the florid phase of Cushing's syndrome did not predict long-term muscle function outcome (rs = 0.285, P = 0.127). CONCLUSION: Lower individual IGF-I concentrations 6 months after curative surgery for Cushing's syndrome are associated with adverse long-term myopathy outcome and IGF-I might be essential for muscle regeneration in the early phase after correction of hypercortisolism.

Sulfated glycolipid PG545 induces endoplasmic reticulum stress and augments autophagic flux by enhancing anticancer chemotherapy efficacy in endometrial cancer.

The sulfated glycolipid PG545 shows promising antitumor activity in various cancers. This study was conducted to explore the effects and the mechanism of PG545 action in endometrial cancer (EC). PG545 exhibited strong synergy as assessed by the Chou-Talalay-Method in vitro when combined with cisplatin, or paclitaxel in both type I (Hec1B) and type II (ARK2) EC cell lines. While PG545 showed antitumor activity as monotherapy, a combination of PG545 with paclitaxel and cisplatin was highly effective in reducing the tumor burden and significantly prolonged survival of both Hec1B and ARK2 xenograft bearing mice. Mechanistically, PG545 elicits ER stress as an early response with resultant induction of autophagy. Our data demonstrated an increase in pERK, Bip/Grp78, IRE1α, Calnexin and CHOP/GADD153 within 6-24 hrs of PG545 treatment in EC cells. In parallel, PG545 also blocked FGF2 and HB-EGF mediated signaling in EC cells. Moreover, melatonin-mediated ER stress inhibition reduced PG545-mediated autophagy and PG545 in combination with cisplatin further heightened this stress response. Collectively these data indicate that PG545 exhibits strong synergistic effects with chemotherapeutics in vitro and showed promising antitumor activity in vivo. Our preclinical data indicates that in future studies PG545 can be a useful adjunct to chemotherapy in endometrial cancer.

The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study.

Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long-term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen-IN-propeptide (PINP), alkaline bone phosphatase, CTX-I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex-, age-, and body mass index (BMI)-matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T-score = -1.4 ± 1.1). Two years after successful surgery, the T-score had improved in 78% of patients (mean T-score 2 years postoperatively -1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX-I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three- to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

How We Manage Bone Marrow Edema-An Interdisciplinary Approach.

Bone marrow edema (BME) is a descriptive term for a common finding in magnetic resonance imaging (MRI). Although pain is the major symptom, BME differs in terms of its causal mechanisms, underlying disease, as well as treatment and prognosis. This complexity together with the lack of evidence-based guidelines, frequently makes the identification of underlying conditions and its management a major challenge. Unnecessary multiple consultations and delays in diagnosis as well as therapy indicate a need for interdisciplinary clinical recommendations. Therefore, an interdisciplinary task force was set up within our large osteology center consisting of specialists from internal medicine, endocrinology/diabetology, hematology/oncology, orthopedics, pediatrics, physical medicine, radiology, rheumatology, and trauma surgery to develop a consenus paper. After review of literature, review of practical experiences (expert opinion), and determination of consensus findings, an overview and an algorithm were developed with concise summaries of relevant aspects of the respective underlying disease including diagnostic measures, clinical features, differential diagnosis and treatment of BME. Together, our single-center consensus review on the management of BME may help improve the quality of care for these patients.

Fibroblast Growth Factor 23-Producing Phosphaturic Mesenchymal Tumor with Extraordinary Morphology Causing Oncogenic Osteomalacia.

A possible cause of hypophosphatemia is paraneoplastic secretion of fibroblast growth factor 23 (FGF-23). Tumors secreting FGF-23 are rare, mostly of mesenchymal origin, usually benign, and may be located anywhere in the body, including hands and feet, which are often not represented in conventional imaging. A 50-year-old woman presented with diffuse musculoskeletal pain and several fractures. Secondary causes of osteoporosis were excluded. Laboratory analysis revealed hypophosphatemia and elevated alkaline phosphatase, parathyroid hormone, and FGF-23. Thus, oncogenic osteomalacia due to neoplastic FGF-23 secretion was suspected. FDG-PET-CT and DOTATATE-PET-CT imaging demonstrated no tumor. Cranial MRI revealed a tumorous mass in the left cellulae ethmoidales. The tumor was resected and histopathological examination showed a cell-rich tumor with round to ovoid nuclei, sparse cytoplasm, and sparse matrix, resembling an olfactory neuroblastoma. Immunohistochemical analysis first led to diagnosis of olfactory neuroblastoma, which was later revised to phosphaturic mesenchymal tumor. Following the resection, FGF-23 and phosphate levels normalized. In conclusion, we here describe a patient with an FGF-23-secreting phosphaturic mesenchymal tumor with an unusual morphology. Furthermore, we emphasize diagnostic pitfalls when dealing with FGF-23-induced hypophosphatemia.

Ward round competences in surgery and psychiatry - a comparative multidisciplinary interview study.

BACKGROUND: The ward round is a key element in everyday hospital inpatient care irrespective of the medical speciality. The underperformance in conducting ward rounds of junior clinicians has already been described. Therefore, necessary skills and competences of clinicians need to be defined, taught and delivered for curricular instruction. In addition to published data on ward round competences in internal medicine this study aims to determine the common competences for surgical and psychiatric ward rounds in order to find differences depending on the speciality. METHODS: Semi-structured interviews with surgical (N = 30) and psychiatric ward staff (N = 30) of a university hospital and five community hospitals were conducted. Competences necessary for performing ward rounds as well as structural aspects were identified by systematic content analysis and frequency analysis, supported by adequate statistics. RESULTS: Relevant competences for both fields are: collaborative clinical reasoning, communication with the patient and the team, organization, teamwork, management of difficult situations, self-management, error-management, teaching, empathy, nonverbal communication, patient-management and professionalism. Clinical skills were mentioned more often in surgical interviews, while nonverbal communication was described more often in psychiatric interviews. Empathy and communication with the team were more frequently attributed to psychiatric residents. CONCLUSION: The competences which were identified as necessary for conducting a ward round in surgery and psychiatry are similar and correspond to previously reported competences in internal medicine. Clinical skills are of greater importance in surgery than in psychiatry. Concerning empathy and nonverbal communication, further research is needed to determine whether they are of minor importance in surgery or whether there is a lack of awareness of these competences.

Values of Cytokines and Tryptophan Metabolites over a 12 Weeks Time Course in Patients with Depression and Somatoform Disorder.

OBJECTIVE: Previous studies have suggested alterations in the kynurenine pathway as a major link between cytokine and neurotransmitter abnormalities in psychiatric disorders. Most of these studies used a cross-sectional case-control study design. However, knowledge is still lacking regarding the stability over time of kynurenine pathway metabolites and the functionally related cytokines. Therefore, we studied the stability of cytokines and tryptophan (TRP) parameters over a period of 12 weeks. METHODS: A total of 117 participants-39 with major depression, 27 with somatoform disorder, and 51 healthy controls were enrolled. Four evaluations, including blood withdrawal and psychometric testing, were performed over a period of 12 weeks. We used ELISA to measure interleukin (IL)-6, IL-1 receptor antagonist (RA) and tumor necrosis factor α (TNF α). High-performance liquid chromatography was used to analyze neurotransmitter variables, i.e. TRP, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), 3-OH-kynurenine (3-HK), and kynurenic acid (KYNA). RESULTS: We found no significant fluctuations of TRP, its metabolites (5-HIAA, KYN, KYNA, and 3-HK), or the cytokines (IL-1RA, IL-6, and TNF α) in any of the groups over the 12 weeks. CONCLUSION: To our knowledge, this is the first longitudinal study performed in psychiatric patients to verify the stability and consequently the reliability of the biological parameters we investigated. Our data indicate that TRP metabolites and cytokines are reliable biological parameters in psychiatric research because they do not fluctuate significantly over time.

Say, What Is on Your Mind? Surgeons' Evaluations of Realism and Usability of a Virtual Reality Vertebroplasty Simulator.

BACKGROUND: Virtual reality (VR)-based simulations offer rich opportunities for surgical skill training and assessment of surgical novices and experts. A structured evaluation and validation process of such training and assessment tools is necessary for effective surgical learning environments. OBJECTIVE: To develop and apply a classification system of surgeon-reported experience during operation of a VR vertebroplasty simulator. METHODS: A group of orthopedic, trauma surgeons and neurosurgeons (n = 13) with various levels of expertise performed on a VR vertebroplasty simulator. We established a mixed-methods design using think-aloud protocols, senior surgical expert evaluations, performance metrics, and a post-simulation questionnaire. Verbal content was systematically analyzed using structured qualitative content analysis. We established a category system for classification of surgeons' verbal evaluations during the simulation. Furthermore, we evaluated intraoperative performance metrics and explored potential associations with surgeons' characteristics and simulator evaluation. RESULTS: Overall, 244 comments on realism and usability of the vertebroplasty simulator were collected. This included positive and negative remarks, questions, and specific suggestions for improvement. Further findings included surgeons' approval of the realism and usability of the simulator and the observation that the haptic feedback of the VR patient's anatomy requires further improvement. Surgeon-reported evaluations were not associated with performance decrements. DISCUSSION: This study is the first to apply think-aloud protocols for evaluation of a surgical VR-based simulator. A novel classification approach is introduced that can be used to classify surgeons' verbalized experiences during simulator use. Our lessons learned may be valuable for future research with similar methodological approach.

Cushing's syndrome: a model for sarcopenic obesity.

PURPOSE: Obesity and its metabolic impairments are discussed as major risk factors for sarcopenia leading to sarcopenic obesity. Cushing's syndrome is known to be associated with obesity and muscle atrophy. We compared Cushing's syndrome with matched obese controls regarding body composition, physical performance, and biochemical markers to test the hypothesis that Cushing's syndrome could be a model for sarcopenic obesity. METHODS: By propensity score matching, 47 controls were selected by body mass index and gender as obese controls. Fat mass and muscle mass were measured by bioelectrical impedance analysis. Muscle function was assessed by chair rising test and hand grip strength. Biochemical markers of glucose and lipid metabolism and inflammation (hsCRP) were measured in peripheral blood. RESULTS: Muscle mass did not differ between Cushing's syndrome and obese controls. However, Cushing's syndrome patients showed significantly greater chair rising time (9.5 s vs. 7.3 s, p = 0.008) and significantly lower hand grip strength (32.1 kg vs. 36.8 kg, p = 0.003). Cushing's syndrome patients with impaired fasting glucose have shown the highest limitations in hand grip strength and chair rising time. CONCLUSIONS: Similar to published data in ageing medicine, Cushing's syndrome patients show loss of muscle function that cannot be explained by loss of muscle mass. Impaired muscle quality due to fat infiltration may be the reason. This is supported by the observation that Cushing's syndrome patients with impaired glucose metabolism show strongest deterioration of muscle function. Research in sarcopenic obesity in elderly is hampered by confounding comorbidities and polypharmacy. As Cushing's syndrome patients are frequently free of comorbidities and as Cushing's syndrome is potentially curable we suggest Cushing's syndrome as a clinical model for further research in sarcopenic obesity.

Investigation and management of osteoporosis in aged trauma patients: a treatment algorithm adapted to the German guidelines for osteoporosis.

BACKGROUND: Osteoporosis-associated fractures are of increasing importance in trauma surgery. Systematic diagnostics and treatment of osteoporosis during a hospital stay, however, remain inadequate. Therefore, a specific algorithm for diagnosing and treating osteoporosis in trauma surgery patients was developed based on the DVO (German Osteology Society) guideline for osteoporosis from 2014. METHODS: In a first step, the individuals' age and risk profile for osteoporosis is identified considering specific fractures indicating osteoporosis and risk factors assessed by a specific questionnaire. In addition, physical activity, risk of falls, dietary habits and the individuals' medication are considered. Basic osteoporosis laboratory tests, a bone densitometry by dual-energy X-ray absorptiometry (DXA) and, if needed, X-rays of the spine are carried out to identify prevalent vertebral body fractures. RESULTS: Based on the treatment algorithm adapted to the new guidelines for osteoporosis in the majority of proximal femoral fractures, treatment of osteoporosis could already be indicated without prior DXA. In case of preexisting glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted given the table of T-scores. CONCLUSIONS: The treatment algorithm for diagnosing and treating osteoporosis in in-patient trauma surgery patients can help identify high-risk patients systematically and efficiently. As a result, osteoporosis-associated fractures or failure of osteosynthesis could be reduced, yet a prospective validation of the algorithm has to be completed.

Persistence of myopathy in Cushing's syndrome: evaluation of the German Cushing's Registry.

BACKGROUND: Cushing's syndrome (CS) is characterized by an excessive secretion of glucocorticoids that results in a characteristic clinical phenotype. One feature of clinical hypercortisolism is breakdown of protein metabolism translating into clinical consequences including glucocorticoid-induced myopathy. While surgery is effective in control of cortisol excess, the effect of biochemical remission on muscular function is yet unclear. METHODS: In a cross-sectional study we analyzed 47 patients with CS during the florid phase (ActiveCS). 149 additional patients were studied 2-53 years (mean: 13 years) after surgery in biochemical long-term remission (RemissionCS). Also, 93 rule-out CS patients were used as controls (CON). All subjects were assessed for grip strength using a hand grip dynamometer and underwent the chair rising test (CRT). RESULTS: Hand grip strength (85% vs 97% of norm, P = 0.002) and the CRT performance (9.5 s vs 7.1 s, P = 0.001) were significantly lower in ActiveCS compared to the CON group. Six months after treatment grip strength further decreased in CS (P = 0.002) and CRT performance remained impaired. The RemissionCS group (mean follow-up 13 years) had reduced hand grip strength (92% compared to normal reference values for dominant hand, P < 0.001). The chair rising test performance was at 9.0 s and not significantly different from the ActiveCS group (P = 0.45). CONCLUSION: CS affects muscle strength in the acute phase, but functional impairment remains detectable also during long-term follow-up despite biochemical remission.

An ETV6-ABL1 fusion in a patient with chronic myeloproliferative neoplasm: Initial response to Imatinib followed by rapid transformation into ALL.

We report the case of a 26 year-old patient presenting with a persistent leukocytosis and CML-like marrow but no evidence of a BCR/ABL1 fusion. Molecular cytogenetics revealed that a portion of the ETV6 locus was inserted into the ABL1 locus. An ETV6/ABL1 fusion transcript could subsequently be confirmed. The patient was started on imatinib and went into complete cytomorphological remission. QRT-PCR measurements showed a 4 log reduction of the ETV6/ABL1 fusion. 15 months later, the disease transformed into ALL and the patient expired. Thus, an ETV6/ABL1 fusion positive MPN has the potential to transform very rapidly into ALL.

Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741).

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study.

The mammalian target of rapamycin plays an important role in multiple myeloma. The allosteric mammalian target of rapamycin inhibitor everolimus has long been approved for immunosuppression and has shown activity in certain cancers. This investigator-initiated phase I trial explored the use of everolimus in relapsed and/or refractory multiple myeloma patients who had received two or more lines of prior treatment. Following a dose-escalation design, it called for a fixed dose of oral everolimus. Blood drug levels were monitored and the biological activity of everolimus was evaluated in bone marrow. Seventeen patients were enrolled (age range, 52 to 76 years). All had been previously treated with stem cell transplantation and proteasome inhibitors and almost all with immunomodulatory drugs. No dose-limiting toxicity was observed and the intended final daily dose of 10 mg was reached. Only one severe adverse event was assessed as possibly related to the study drug, namely atypical pneumonia. Remarkably few infections were observed. Although the trial was mainly designed to evaluate feasibility, anti-myeloma activity, defined as clinical benefit, was documented in ten of 15 evaluable patients at every dose level including eight patients with stable disease, one patient with minor remission and one with partial remission. However, the median time to progression was 90 days (range, 13 to 278 days). The biomarker study documented on-target activity of everolimus in malignant plasma cells as well as the microenvironment. The observed responses are promising and allow further studies to be considered, including those testing combination strategies addressing escape pathways. This trial is registered with EudraCT number 2006-002675-41.