Raoul Bergner

Prediction of Progression-Free Survival in Patients With Multiple Myeloma Following Anthracycline-Based Chemotherapy Based on Dynamic FDG-PET

Methods: Dynamic positron emission tomography (PET) studies with F-18-deoxyglucose were performed in patients with multiple myeloma who received anthracycline-based chemotherapy to evaluate the impact of full kinetic analysis and assess its value with regard to progression-free survival (PFS). The evaluation included 19 patients (56 metastatic lesions) with multiple myelomas. All patients received combined anthracycline-based chemotherapy. PFS served as a reference for the PET data. All patients were examined prior to the onset of chemotherapy and on days 23 to 28 after the onset of the first cycle (prior to the second cycle). The following parameters were retrieved from the dynamic PET studies: Standardized Uptake Value (SUV), fractal dimension (FD), 2 compartment model with computation of K1, k2, k3, k4 (unit: 1/min), the fractional blood volume (vB), and the FDG-influx according to Patlak were calculated. Results: The observed PFS varied from <1 month to 64.1 months with a median PFS of 26 months. Most kinetic parameters demonstrated only small changes, primarily declining after 1 cycle. We compared the kinetic data of each study using a Wilcoxon matched-pairs signed rank test. The results were considered significant for P < 0.05. The test revealed a significant change for the SUV (z = 4.954, P < 0.0000), the FD (z = 5.036, P < 0.0000), the fractional blood volume vB (z = 4.116, P < 0.0000) and influx (z = 2.614, P < 0.0090) when the absolute values of the first and the second study were compared. We dichotomized the patients according to the PFS of 18 months and defined 2 survival groups. The data demonstrate that the correct classification rate (CCR) of group 2 (survival: >18 months) was generally higher (exceeding 94%) than for group 1. The use of the baseline SUV led to a CCR of 82% for the group 2 with the longer survival. The CCR of group 1 with the short survival varied between 55% and 70% depending on the parameter and the study used for prediction. Furthermore, the CCR for both groups based only on the data of the second study was somewhat lower (74%–75%) as compared with the baseline FDG study (75%–82%). Finally, the combined use of the 6 predictor variables, namely SUV, k3, and FD (selected by the Wilcoxon rank sum test) of each study led to the highest CCR of 85% for both groups. This combination was in particular useful for the prediction of group 2 with the longer survival with a CCR of 94%. Best cutoff-values for the differentiation between short and long PFS were SUV of 4.0 and a k3 of 0.07 of the baseline study. Conclusions: The results demonstrate, that a full kinetic analysis of the FDG studies prior and after 1 chemotherapeutic cycle in patients with multiple myeloma is helpful for the prediction of PFS and may be used to identify those patients who benefit from this chemotherapeutic protocol. A high SUV (>4.0 SUV) as well as a high k3 (>0.07) of the baseline study were bad prognostic parameters and related to a short PFS.

Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease.

Renal dysfunction is a particularly problematic adverse event that requires additional management and can prohibit the use of certain medications. Due to their renal uptake and elimination, some bisphosphonates can cause nephrotoxicity when used for the treatment of skeletal-related events in patients with bone metastases. However, clinical studies and post-marketing experience indicate that renal effects do not appear to be the same for all bisphosphonates. Zoledronic acid and pamidronate appear to be associated with a greater risk of renal toxicity, especially when given in high doses or over short infusion times. In contrast, high loading doses of intravenous ibandronate (3 × 6 mg given on days 1-3) have shown no additional renal safety concerns, and intravenous ibandronate 6 mg appears to have a renal safety profile comparable to placebo. This paper reviews the renal safety of intravenously administered bisphosphonates and makes some suggestions, based on preclinical and clinical data, as to why renal safety profiles may differ.

Distinguishing Gouty Arthritis from Calcium Pyrophosphate Disease and Other Arthritides

Objective. Differentiating gout, calcium pyrophosphate deposition disease (CPPD), and non–crystal-related inflammatory arthropathies (non-CRA) is essential but often clinically impossible. The sonographic double contour (DC) sign may have good specificity for gout in highly specialized centers, but it can be challenging to use it to distinguish gout from cartilage hyperenhancements in CPPD. We evaluated the diagnostic value of the DC sign alone and in combination with Doppler signals and uric acid (UA) levels in patients with acute arthritis. Methods. We retrospectively investigated 225 acutely inflamed joints and documented the presence of DC, Doppler hypervascularization, and serum UA (SUA) levels. All patients underwent synovial fluid (SF) analysis. Sensitivity, specificity, and positive predictive values were calculated, and correlation analyses and a binary regression model were used to investigate their diagnostic values. Results. The sensitivity of DC sign for crystalline arthritides was 85% and specificity 80%. Its specificity for gout was 64%, for CPPD 52%. In contrast to non-CRA hypervascularization, degree 2 and 3 Doppler signals were highly associated with gout and less with CPPD (p < 0.01). The combination of DC sign with hypervascularization and elevated UA levels increased specificity for gout to more than 90% and resulted in a 7-fold increase of the likelihood of diagnosis of gout (p < 0.01), but with a loss of sensitivity (42%). Conclusion. The DC sign alone is suitable for predicting crystal-related arthropathies, but it cannot reliably distinguish gout from CPPD in everyday clinical routine. Combining hypervascularization and SUA levels increases the diagnostic value, leading us to propose a diagnostic algorithm.

Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function.

In this open‐label study, the authors assessed the pharmacokinetics and safety of ibandronate in patients with multiple myeloma and varying renal function. Renal deterioration was graded at baseline depending on creatinine clearance in 4 stages (0: >80; 1: 50–79; 2: 30–49, and 3: <30 mL/min). Patients (n = 40) received intravenous ibandronate 6 mg (30‐minute infusion). Ibandronate excretion and serum levels were measured over 24 hours. Serum creatinine, creatinine clearance, and markers of tubular damage were monitored before ibandronate infusion and at 24 and 72 hours following ibandronate infusion. Ibandronate clearance, AUC0‐24, AUC0‐∞, serum t1/2, and Cmax were calculated. There was a significant positive correlation between ibandronate clearance and creatinine clearance (r = 0.858; P < .00001). The AUC for grade 3 renal insufficiency increased by ∼60% versus grade 0 (P < .01) but was not significantly different between other grades of renal function. The t1/2 did not increase significantly, and peak serum levels of ibandronate were similar for the 4 grades of renal function. Serum creatinine, creatinine clearance, and markers of tubular damage did not change significantly within 72 hours of ibandronate infusion. Despite renal function already being compromised in this patient group, there was no evidence of acute nephrotoxicity with ibandronate.

Ibandronate for the Treatment of Hypercalcemia or Nephrocalcinosis in Patients with Multiple Myeloma and Acute Renal Failure: Case Reports

Multiple myeloma disrupts calcium homeostasis by a variety of mechanisms, including bone destruction and resorption. This causes hypercalcemia. When left untreated, hypercalcemia leads to nephrocalcinosis, impairment of kidney function, and eventually renal failure. Some degree of renal dysfunction is common in myeloma patients. Here, we report case studies showing the efficacy and renal safety of the single-nitrogen bisphosphonate, ibandronate, for the treatment of hypercalcemia and/or nephrocalcinosis in multiple myeloma patients hospitalized with acute renal failure. Patients (n = 7) received either one or two intravenous infusions of ibandronate (2–6 mg). Ibandronate was well tolerated in all patients and returned elevated blood calcium levels to normal. Renal function improved for all patients and normalized in 3/7 patients. We conclude that ibandronate is involved in rapidly improving or restoring acute renal function and calcium levels to within the normal range in this patient population. To clarify the exact value of ibandronate, further investigation is warranted in randomized prospective trials.

Proteinuria in Diabetic Patients – Is It Always Diabetic Nephropathy?

Background: Diabetic nephropathy (dNP) is a consequence of type 1 and type 2 diabetes, typically occurring between 5 and 15 years after diabetes has been diagnosed. The coincidence of dNP and diabetic retinopathy (dRP) is well known. In this study we correlated the histological findings of the kidney biopsy with the clinically expected diagnosis of dNP. Patients and Methods: Over a 4-year period with a total of 326 kidney biopsies, 85 biopsies were performed on patients with diabetes. In all of these patients we had information about duration of diabetes and ophthalmological status. Additionally, data about proteinuria, urine sediment and autoantibodies were available. The nephrologist had to give the suspected diagnosis before the biopsy was performed, using the clinical data available. Results: In 57 patients (67%) dNP was predicted clinically before biopsy. In 28 patients we expected a different kind of kidney disease. Only 43 patients had dNP histologically. In 16 out of 19 patients with dRP we also found dNP. 26 patients with dNP did not have dRP. So dRP was very specific but not sensitive to predict dNP. On the other hand, all patients without dRP but acanthocytes in urine sediment had non-diabetic kidney disease (NDKD). In the case of patients with neither dRP nor acanthocytes, it was very difficult to distinguish between dNP and NDKD. Acanthocytes and antineutrophil cytoplasmatic antibodies with positive antibodies for proteinase 3 or myeloperoxidase were found only in NDKD, but ANAs were detected in a wide titer range in dNP and NDKD. The known duration of the diabetes ranged from 1 to 40 years. There were no additional parameters to differentiate this group. Conclusions: Diabetic patients with dRP and proteinuria frequently have dNP. In patients without typical retinal findings dNP is less likely, thus a kidney biopsy is necessary to confirm the diagnosis. Additional knowledge about urine sediment and autoantibodies is helpful, but is not sufficient to differentiate NDKD from dNP in the majority of patients.

The value of ultrasound in diagnosing extracranial large-vessel vasculitis compared to FDG-PET/CT: A retrospective study

Large-vessel vasculitis (LVV) is a group of diseases mainly comprised of giant-cell arteritis (GCA), Takayasu arteritis, and a series of rare diseases like Behçet’s disease, IgG4-related disease, infectious aortitis, and other unfrequent entities. Besides clinical and laboratory features, Doppler sonography (DS) can assist in establishing the diagnosis. Its diagnostic sensitivity has been evaluated in various studies, most of them, however, in temporal arteritis (TA) respectively in LVV with involvement of the temporal artery. Little is known in extracranial LVV. We retrospectively evaluated the diagnostic accuracy of DS in 30 patients with extracranial, non-temporal LVV using the highly sensitive PET/CT as method of reference in comparison to 20 controls who were found to have no LVV. We investigated ten arterial sites and documented the presence of the sonographic halo sign. Sensitivities of DS for LVV were highest in the subclavian and axillary arteries (71.4%/72.2%) and low in the abdominal aorta (26.1%) and the common femoral artery (16.7%). DS detected 24 out of 30 cases of LVV (overall sensitivity 80.0%). The LVV cases where DS was completely negative did not significantly differ in leukocyte count, C-reactive protein, or erythrocyte sedimentation rate from LVV cases with positive DS. DS is a potent method in diagnosing extracranial LVV especially in the axillary and the subclavian arteries. Aortic, intraabdominal, and lower extremity artery manifestations, however, are often missed by DS. A second imaging modality (e.g., PET/CT) is therefore required.

Tolerability of Dose Escalation of Ibandronate in Patients with Multiple Myeloma and End-Stage Renal Disease: A Case Series

Background: Bone disease is a feature of multiple myeloma (MM). Many patients have compromised renal function and sometimes develop end-stage renal disease (ESRD). For these patients, presently there exists no approved bisphosphonate, which is an elementary part of the standard therapeutic regimen of MM. Patients and Methods: We evaluated the tolerability of ibandronate 2–6 mg every 4 weeks in patients with MM and ESRD receiving regular hemodialysis over 12 weeks (open-label, single-center, observational study). Ibandronate pharmacokinetics were measured until the end of the next dialysis. Adverse events were recorded. Results: 8 patients received ibandronate (average duration 5.6 months). Urinary excretion ranged from 0.15 to 341.9 μg/24 h. Mean ibandronate peak levels increased in a dose-dependent manner (2 mg: 141.4 ± 67.0 ng/ml; 4 mg: 298.5 ± 82.0 ng/ ml; 6 mg: 564.3 ± 318.9 ng/ml). No adverse events were reported. Conclusion: Based on these results and published bisphosphonate data, we have decided to offer off-label ibandronate treatment to MM patients receiving hemodialysis.

In arthritis the Doppler based degree of hypervascularisation shows a positive correlation with synovial leukocyte count and distinguishes joints with leukocytes greater and less than 5/nL.

OBJECTIVES Power Doppler ultrasound is used to assess joint vascularity in acute arthritis. PDUS signals have been correlated with synovial histology and bone deterioration. Little is known about the correlation between power Doppler signals and synovial white blood count. In our study, we analyzed power Doppler signals in inflammatory joint diseases including gout, calcium pyrophosphate deposition disease, rheumatoid arthritis, spondyloarthritis and others and correlated power Doppler signals with synovial white blood count and with serologic markers of inflammation. METHODS We retrospectively evaluated 194 patients with arthritis. All patients underwent joint sonography, power Doppler ultrasound, synovial fluid analysis and blood examination of C-reactive protein and erythrocyte sedimentation rate. Correlation analyses (Spearman and Pearson), Chi(2) test, t-tests, a unifactorial ANOVA and regression analyses were applied. RESULTS AND CONCLUSIONS Hypervascularisation in power Doppler was most prominent in gout and calcium pyrophosphate deposition disease. Spondyloarthritis and non-inflammatory joint diseases presented with low degrees of hypervascularisation. Mean synovial white blood count did not differ significantly between crystal-related arthritides, rheumatoid arthritis, spondyloarthritis or other inflammatory joint diseases. There was a positive but weak correlation between power Doppler signals and synovial white blood count (P<0.001, rs=0.283), erythrocyte sedimentation rate (P<0.001, rs=0.387) and C-reactive protein (P<0.001, rs=0.373) over all diagnoses. This was especially relevant in rheumatoid arthritis (P<0.01, rs=0.479). Power Doppler degrees 0 and 1 were able to predict synovial leukocytes<5/nL, degrees 2 and 3 predict leukocytes≥5/nL (P<0.001).

[Female patient with Sjoegren's syndrome and cardiolipin antibodies].

Cross-reactions with cardiolipin antibodies and serological lues tests are common. We examined a 37 year old patient with neurological symptoms and signs of Sjoegrens syndrome and secondary antiphospholipid syndrome. But the lues screening test was also positive and the serological tests following approved the lues infection. When an autoimmune disease is diagnosed with the presence of cardiolipin antibodies we recommend also testing for treponema pallidum as a possible disease.