Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

[Osteosarcopenia]. / Osteosarkopenie.

Osteoporosis is nowadays understood as an increased risk of fractures, with bone density measurement by dual-energy X­ray absorptiometry (DXA) being a useful diagnostic criterion and a potent fracture predictor; however, especially in geriatric patients the result is often falsely negative, so that the diagnosis, indications for treatment and treatment selection should be based on an overall clinical evaluation of the individual situation. Sarcopenia is defined as a geriatric syndrome characterized by a generalized loss of skeletal mass and muscle function. Sarcopenia is associated with an increased likelihood of adverse outcomes including falls, fractures, disability and mortality. Since 2018 it is possible in Germany to encode sarcopenia in the International Statistical Classification of Diseases and Related Health Problems, 10th revision, German modification (ICD-10-GM, M62.50). In the case of a high fracture risk and indications for the presence of sarcopenia, the whole body composition should be assessed by DXA within the framework of the measurement of bone mineral density. In the treatment of osteosarcopenia non-pharmacological measures must be initiated in addition to pharmacological measures. It is particularly important to clarify and if necessary to resolve the cause of falls resulting in fractures as well as to regularly reevaluate the treatment goals.

Assessment of Bone and Muscle Measurements by Peripheral Quantitative Computed Tomography in Geriatric Patients.

The loss of bone and muscle mass increases the risk of osteoporotic fractures. Dual energy X-ray absorptiometry (DXA) loses sensitivity in older age. The purpose of this study was to evaluate bone and muscle measurements of peripheral quantitative computed tomography (pQCT) in a geriatric cohort with osteoporosis. Bone mineral density and muscle area of 168 patients aged 65 years and older (76.3 ± 6.5) were measured with pQCT at distal forearm additionally to an osteoporosis assessment consisting of anamnesis, blood test and DXA of lumbar spine and hip. Prior fractures were categorized in minor and major osteoporotic fractures. Logistic regression was used to show the association of bone mineral density and muscle area with major fractures. 54.8% of the participants had at least one major fracture. Bone mineral density measured with pQCT and muscle area were significantly associated with these fractures (total and trabecular bone mineral density OR 2.243 and 2.195, p < 0.01; muscle area OR 2.378, p < 0.05), whereas DXA bone mineral density showed no significant association. These associations remained after adjustment for age, sex, BMI, physical activity and other factors. In all models for patients >75 years only muscle area was significantly associated (OR 5.354, p < 0.05) with major fractures. Measurement of bone mineral density and muscle area with pQCT seems to have advantage over DXA in fracture association in geriatric patients. Measuring muscle area also adds useful information to estimate the presence of osteosarcopenia.

[Differential diagnoses of osteoporosis]. / Differenzialdiagnosen der Osteoporose.

The differential diagnoses of osteoporosis in geriatric and trauma patients are very important as they may induce different therapies. On average approximately 20% of women and 50% of men have secondary causes of osteoporosis. The foundation of the diagnostics is a basic osteological laboratory investigation with which the most important secondary causes can be identified. From a geriatric and traumatological point of view vitamin D deficiency with secondary hyperparathyroidism, primary hyperparathyroidism, male hypogonadism, multiple myeloma and monoclonal gammopathy of unclear significance (MGUS) are of particular importance.

[New DVO guideline for osteoporosis management 2014 and its importance for trauma surgeons]. / Neue Osteoporose-Leitlinie DVO 2014 und ihre Bedeutung für den Unfallchirurgen.

Osteoporosis-associated fractures represent a growing challenge in the treatment of orthopedic patients. In November 2014 a new revision of the guidelines on osteoporosis by the German Osteology Society (Dachverband Osteologie DVO) was adopted, in which additional risk factors for fractures and further treatment options have been included. On the one hand the existing model used to diagnose osteoporosis and estimate a high fracture risk as a guidance for the use of specific anti-osteoporotic therapy in patients without a fragility fracture was maintained and further refined. On the other hand the guideline includes the option to initiate a specific osteoporosis therapy without a prior bone densitometry in patients with typical radiographs of a proximal femur fracture and higher grade vertebral fractures, suspicious for osteoporosis, depending on the overall clinical context. This may reduce the treatment gap of osteoporosis in Germany. In this paper the changes in the DVO guidelines 2014 on osteoporosis are summarized, focusing on the most important changes with practical relevance for orthopedic surgeons.

[Identification, diagnostics and guideline conform therapy of osteoporosis (DVO) in trauma patients : a treatment algorithm]. / Identifikation, Diagnostik und leitliniengerechte Osteoporosetherapie (DVO) unfallchirurgischer Patienten : Ein Behandlungsalgorithmus.

Osteoporosis-associated fractures are of increasing importance in trauma surgery. The implementation of systematic diagnostics and treatment of osteoporosis during hospitalization, however, remains insufficient; therefore, a specific algorithm for the diagnosis and treatment of osteoporosis in trauma surgery patients was developed based on the German Osteology Society (Dachverband Osteologie, DVO) guidelines for osteoporosis from 2014. In a first step, the individual patient age and risk profile for osteoporosis are identified considering specific fractures indicative of osteoporosis. For these patients a questionnaire is completed which detects specific risk factors. In addition, the physical activity, risk of falls, dietary habits and the individual medication are collated as these can have a decisive influence on the subsequent therapy decisions. Prior to a specific treatment, laboratory osteoporosis tests, bone densitometry by dual energy X-ray absorptiometry (DXA) and if needed X-rays of the spine are carried out. For proximal femoral fractures the treatment of osteoporosis could already be indicated. With pre-existing glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted according to the table of T-scores detected by DXA. The treatment algorithm for diagnostics and treatment of osteoporosis in hospitalized trauma surgery patients can systematically and efficiently improve the identification of patients at risk. Thus, further fractures associated with osteoporosis or failure of internal fixation could be reduced in future. A prospective validation of the algorithm has already be initiated.

[Osteological interdisciplinary management : exemplified by a bilateral proximal humeral fracture]. / Osteologisch-interdisziplinäres Management : Am Beispiel einer bilateralen proximalen Humerusfraktur.

Following locking plate osteosynthesis of a proximal humeral fracture, a 62-year-old male patient suffered mild secondary dislocation. Subsequent bone densitometry identified an osteoporosis. Laboratory testing and sonography revealed an underlying primary hyperparathyroidism. In the short term, the patient suffered a similar proximal humeral fracture of the contralateral side. Given the knowledge about the underlying osteoporosis a cement-augmented locking plate osteosynthesis was carried out to treat the fracture. Parathyroidectomy was performed shortly thereafter and laboratory parameters returned to normal. Secondary fractures did not arise. Treatment of this patient in a certified osteoporosis center with a multimodal management led to systematic interdisciplinary diagnostics, a specific surgical therapy and ended in an excellent result.

Determination of intrarenal resistance index (RI) in patients with multiple myeloma.

BACKGROUND: Renal impairment is a common complication of multiple myeloma occurring in up to 50 % of patients at some stage in their disease. Due to occurrence of cast nephropathies we hypothesized circulatory dysregulation (vasoconstriction) in the kidneys with measurable elevation of the resistance index among these patients which would have a diagnostic impact. SUBJECTS AND METHODS: 36 patients with treated multiple myeloma (21 females, 15 males, mean age 61.6 +/- 8.5 years) were prospectively examined by conventional abdominal ultrasound with focussed investigation of the kidneys. First, length of the organs, parenchymal width and characterization of parenchymal echogenicity were determined. Then, intrarenal RI values were measured in segmental and arcuate arteries, respectively, in both kidneys. Additionally, serum creatinine, BUN and GFR of each patient were evaluated. RI values were compared to values of 78 healthy control subjects. RESULTS: Mean renal RI was 0.68 +/- 0.07 which was slightly higher than in controls with 0.62 +/- 0.05, but without statistical significance. Due to the laboratory analyses patients were subdivided in those with normal ( group 1, n = 21) and those with impaired (group 2, n = 15) renal function. In both groups kidney size and parenchymal width were normal. Significant more group 2 patients (60%) revealed hyperechogenic parenchyma than group 1 patients (24%) (p<0.01). Mean renal RI indices were 0.67 +/- 0.06 (right) and 0.69 +/- 0.06 (left) in group 1 patients and 0.71 +/- 0.08 (right) and 0.71 +/- 0.07 (left) in group 2 patients and showed no significant difference (p = 0.06 and 0.15). CONCLUSION: Renal RI values are not significantly elevated in patients with multiple myeloma even in those with renal impairment so that no hints to a relevant vasoconstriction could be evaluated. RI seems not to be a relevant parameter for the diagnosis of cast nephropathy of multiple myeloma patients. Routinely performed ultrasound examination should be more focussed on the qualification of parenchymal echogenicity.

ANTI-ADHESION evolves to a promising therapeutic concept in oncology.

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.

Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.

BACKGROUND/AIMS: Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. METHODS: A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. RESULTS: ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. CONCLUSION: This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

[Cancer--the desire for a second opinion is prompted by a need for orientation]. / Kein Misstrauen, sondern wichtige Orientierungshilfe. Die Zweitmeinung in der Onkologie.

After learning that they have cancer, increasing numbers of patients seek a second opinion from another specialist. The heavy burden of the diagnosis, together with the flood of information they receive can confuse the patients. The search for orientation and support can be made easier by a second specialist provided he/she provides comprehensive and relevant advice covering tumor-specific, psychological, social, physiotherapeutic and alternative-medical aspects. In this sense, a second opinion is a major element of modern oncology. Openness with regard to the second opinion strengthens the doctor-patient relationship rather than weakening it. For the primary physician it is important to know that the patient's motivation for obtaining a second opinion is, as a rule, a need for reorientation and an ability to cope with a feeling of helplessness, but not dissatisfaction with the primary physician.

[Enlarged lymph nodes--rapid diagnosis of infectious and neoplastic causes]. / Entscheidungshilfe bei vergrösserten Lymphknoten. Aggressiv abklären oder ruhig abwarten?

Although lymphadenopathy is usually an expression of a harmless, self-limiting immune reaction, it may nevertheless also signify the presence of a malignant tumor or relevant infectious disease--in particular when the swelling is sizeable, rapidly progressive, and associated symptoms are present. If, however, unfavorable criteria are definitely absent (Table 1), a wait-and-see policy with re-evaluation in three to four weeks may initially be adopted.

Helper T cells (CD3 + /CD4 + ) within the autologous peripheral blood stem cell graft positively correlate with event free survival of multiple myeloma patients.

BACKGROUND: The microenvironment in the bone marrow - including lymphocytes - is part of the pathophysiology of multiple myeloma (MM). High dose chemotherapy followed by autologous stem cell transplantation is standard of care for younger patients. AIM: To determine the influence of reinfused lymphocyte subsets on event free survival (EFS) and overall survival (OS). METHODS: In peripheral blood (PB) and aphaeresis products (AP) of 41 MM patients lymphocyte subsets were determined by flow cytometry and were correlated with clinical outcome. RESULTS: PB lymphocyte subsets did not influence EFS or OS. Residual plasma cells in the AP were not correlated with poor outcome, whereas a high percentage of B cells (CD19+) showed a trend towards reduced EFS (P = 0.051). A high amount of CD4 cells and an increased CD4/CD8 ratio were significantly associated with prolonged EFS. In contrast, high percentage of HLA-DR positive lymphocytes showed negative impact on EFS and OS (P = 0.03 and 0.02, respectively). CONCLUSION: Obtained data suggest the non-activated (HLA-DR negative) helper CD4+ T cells in the AP to be tumour protective.

Cell-cell contact mediated signalling - no fear of contact.

Cancer research with sole focus on the cancer cell and possibly growth factors cannot faithfully reproduce the environmental interaction, such as adhesion of tumor cells to e.g. stromal cells, which may determine the response of these tumors to therapy. Methodologically cell adhesion studies are often difficult since complete but careful detachment is the prerequisite for most signal transduction assays. We describe for the first time an alternative method for the co-incubation of multiple myeloma cells on long term primary bone marrow stromal cultures using the bone marrow stromal cell line HS-5. The methods are precisely described, advantages and disadvantages are discussed, and troubleshooting advises are given.

Correlation of residual leukocyte subsets with neutropenic fever during severe leukopenia after high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: High-dose chemotherapy with autologous stem cell transplantation is the standard treatment of eligible patients with multiple myeloma. However, this treatment is associated with a substantial risk of infectious complications during leukopenia. The aim of our pilot study was to determine the residual leukocyte subsets during severe cytopenia after high-dose melphalan and to correlate this with the occurrence of neutropenic fever. METHODS: Residual leukocyte subsets in the peripheral blood on days 4-7 following autologous stem cell transplantation were analyzed by three-color flow cytometry in 20 patients with multiple myeloma. In addition, we determined the number of T cells that were transfused with the autografts. RESULTS: Absolute numbers of lymphocytes (mean 25/microL) and monocytes (mean 4/microL) were strongly reduced but rather constant during the period of severe neutropenia. Neutrophil engraftment and duration of neutropenia were very similar in patients with and without neutropenic fever. Low absolute lymphocyte counts and absolute CD4+ T-cell counts on days 4-7 after stem cell transplantation correlated with neutropenic fever. Furthermore, T-cell numbers in the autologous stem cell grafts that the patients received were significantly lower in patients with neutropenic fever. DISCUSSION: These observations suggest that the number of T cells, and in particular CD4+ T cells, in the blood during severe cytopenia is playing a role in defense of infection. T-cell numbers in the graft could provide a predictive factor for the risk of infection in the post-transplant period. However, this needs to be confirmed in a larger study.

Vascular ectasia of the whole intestine as a cause of recurrent gastrointestinal bleeding after high-dose chemotherapy.

We present the first case in the literature of vascular ectasia of the whole intestine as a cause of recurrent and profuse gastrointestinal bleeding in a patient with relapsing Hodgkin's disease. The 17-year-old patient experienced early relapse of his Hodgkin's disease after first-line chemotherapy. Salvage chemotherapy was followed by high-dose chemotherapy and autologous stem cell transplantation. Complete remission was achieved after another relapse by means of a second transplant. The patient presented with profuse gastrointestinal bleeding 5 months later, however. Gastric antral vascular ectasia following hematopoietic stem cell transplantation was diagnosed by endoscopy, with histological confirmation. Similar lesions were found in the duodenum, the ileum, and throughout the entire colon. In conclusion, vascular ectasia of the whole intestine should be considered as cause of acute gastrointestinal bleeding after stem cell transplantation. Physicians should be aware of this complication because its onset is typically delayed. Importantly, this disease is not limited to patients who have undergone allogeneic transplantation, but can also occur after autologous transplantation.