Amyloidosis is a disease with many faces.

Amyloidosis is a severe disease caused by protein misfolding and deposition in tissues and organs. Thirty-eight different proteins are known to be amyloidogenic. Amyloidosis is categorized into inherited or acquired, and systemic or localized. Light-chain (AL)- and transthyretin (ATTR) amyloidosis are the two most common subtypes. Awareness, early diagnosis, accurate subtyping and relevant treatment are crucial for the management. Novel therapies of systemic AL and ATTR amyloidosis have considerably improved outcome and survival. The aim of this review is to increase awareness and knowledge on diagnosing amyloidosis.

Clinically-suspected cast nephropathy: A retrospective, national, real-world study.

Presentation with severe acute kidney injury due to cast nephropathy (CN) is a medical emergency in multiple myeloma (MM), with high risk of dialysis-dependent renal failure and death. Accrual of patients with CN into interventional studies is difficult, while phase III trials exclude patients with severe renal insufficiency. Real-world data are warranted. We assessed 2252 patients from the population-based Danish Multiple Myeloma Registry (DMMR) who were diagnosed between 2013 and 2017. We identified 204 patients with clinically-suspected CN, defined as serum creatinine concentration >177 µmol/L and serum free light chain (sFLC) concentration >1000 mg/L at the time of diagnosis. The median age was 72 years. Thirty-one percent of patients presented with dialysis-dependent renal failure. Kidney biopsies were performed in 19% of patients and showed CN in 74% of cases. Despite prompt initiation of bortezomib-based therapy in 94% of patients, 33% of patients died in the first year after diagnosis. Compared with the rest of the patients in the DMMR with symptomatic MM, patients with clinically-suspected CN had worse overall survival (OS) irrespective of transplant eligibility. Achievement of renal recovery was associated with deep reductions of involved sFLC. Achievement of very good partial response or better in the first line of therapy and/or deep reduction of involved sFLC at 3 months after initiation of therapy were associated with superior OS. In conclusion, MM patients presenting with clinically-suspected CN have an alarmingly high one-year mortality when treated with current standards of care. Early and deep hematologic response is crucial for survival.

Clinicopathological features of plasmablastic multiple myeloma: a population-based cohort.

Multiple myeloma (MM) is a common malignant hematological disease displaying considerable heterogeneity. Historical data indicate a prognostic significance of plasmablastic morphology, proliferation, and adverse cytogenetics, but there is little knowledge on the degree of interdependency of these parameters. The aim of this study was to study the degree of overlap between these variables. In a consecutive population-based cohort of 194 untreated MM patients, morphology, and proliferation index, using immunohistochemical double staining for Ki-67 and CD138, was analyzed. In addition, cytogenetic changes were studied by karyotyping and fluorescence in situ hybridization (FISH). Plasmablastic morphology correlated with unfavorable clinical features, high proliferation index, high percentage of plasma cell infiltration in the bone marrow, abnormal karyotype, and del(13q) detected by karyotyping, which indicates that plasmablastic morphology reflects advanced and highly proliferative disease. However, plasmablastic morphology did not correlate with established adverse prognostic cytogenetics identified by FISH, for example, t(4;14), t(14;16) and del(17p).

Evaluation of the serum free light chain (sFLC) analysis in prediction of response in symptomatic multiple myeloma patients: rapid profound reduction in involved FLC predicts achievement of VGPR.

BACKGROUND: Observational data from clinical studies indicate that the goal of first-line therapy in newly diagnosed patients with symptomatic multiple myeloma (MM) should be very good partial response (VGPR) or better, preferably before high-dose treatment. We evaluated the value of early measurements of involved free light chains (iFLC) in prediction of high-quality responses. Measuring iFLC has a potential advantage due to a short half-life compared to the half-life of the M-protein. METHODS: In 36 multiple myeloma (MM) patients, we measured serial changes in iFLC and M-protein after start of treatment. iFLC and M-protein were measured before treatment, the following 5 wk days, 2, 3 and 6 wks after start of treatment. RESULTS: Median iFLC and M-protein half-life was 2.75 and 11.9 d, respectively. All patients with an iFLC >75 mg/L had an initial significant reduction (>20%) in iFLC, even patients with no response to treatment. The mean per cent reduction in iFLC 3 d after start of treatment was 52.3% and 23.6% (P = 0.021) in patients achieving ≥VGPR and PR, respectively. The mean per cent reduction in M-protein in patients achieving ≥VGPR and PR was not significantly different in the 6-wk study period. As a predictor of VGPR, an 80% reduction in iFLC at day 21 resulted in a sensitivity of 87.5% and a specificity of 100%. CONCLUSION: Changes in iFLC could be a tool for early identification of responders to anti-myeloma therapy. Early, sequential measurements of iFLC within the first week after start of treatment are not meaningful.

Dosing related effects of zoledronic acid on bone markers and creatinine clearance in patients with multiple myeloma and metastatic breast cancer.

UNLABELLED: Zoledronic acid (Zol) is frequently used for the treatment of bone disease in patients with multiple myeloma and breast cancer with metastasis to bone. Therefore, there is also an interest in finding the optimal dosing regimen to optimize effects, minimize side effects and reduce costs. In our phase II clinical trial we investigated the effect of Zol treatment on the serum levels of the bone markers collagen type 1 cross-linked C-telopeptide (CTX) and bone specific alkaline phosphatase (bALP) as well as on creatinine clearance (kidney function) in response to dosing and duration of treatment for each individual patient. METHODS: We enrolled 30 multiple myeloma (MM) and 30 breast cancer (BC) patients whereof 10 of each had never received bisphosphonate and 20 had received at least six prior Zol treatments. RESULTS: We found that Zol treatment strongly reduced CTX (Spearman's correlation, rs = -0.59, p = 0.0007) and bALP (Spearman's correlation, rs = -0.51, p = 0.0042) in MM patients while only CTX (Spearman's correlation, rs = -0.42, p = 0.024) was significantly affected in BC patients. Multiple linear regression analyses done on the entire cohort showed that the average time between each dose of Zol had the strongest impact on CTX (p < 0.001) and bALP (p = 0.011) levels while the total accumulated number of Zol infusions had a less pronounced effect on CTX levels (p = 0.015). In contrast, multiple linear regression analysis showed that the total number of Zol infusions had a strong negative impact on kidney function (p = 0.014) while the average time between each dose of Zol had no significant impact. CONCLUSION: Thus, if MM and BC patients are not treated regularly every month with Zol bone turnover is not fully suppressed, while prolonged treatment with zoledronic acid compromises kidney function. We believe that these data significantly contribute to the knowledge needed to find the optimal Zol treatment schedule.

Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis?

Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease-specific factors may differently influence Zol retention in MM and BC patients. We tested this hypothesis in an investigator initiated phase II clinical trial in which we compared the whole-body retention (WBrt) of Zol in a cohort of 30 multiple myeloma (MM) and 30 breast cancer (BC) (20 Zol naive and 40 with six or more previous administrations). On average, 62% of the administered Zol was retained in the skeleton of both MM and BC patients and independently of the number of treatments. WBrt of Zol did not correlate with cross-linked C-telopeptide (CTX) levels, but linear regression analyses showed that WBrt of Zol correlated with bone-specific alkaline phosphatase (bALP) levels in BC (p = 0.001), and with CTX/bALP in Zol naive MM patients (p = 0.012). Especially in BC patients, WBrt correlated with age (p = 0.014) independently of kidney function. In MM patients WBrt was found to primarily correlate with the extent of bone disease (p = 0.028). Multivariate linear regression analyses of the entire cohort pointed out that WBrt of Zol was best predicted by age (p < 0.000), osseous lesions (p < 0.001), and the preceding Zol dosing (p < 0.005) (r(2) = 0.97). Comparing bone scintigrams with CT/X-ray images showed a poor correlation between sites of active bone disease and binding of scintigraphy bisphosphonate in 36% of MM patients and in 13% of BC patients. We conclude that WBrt of Zol is primarily determined by two non-disease related factors and only one disease related, but that there may be differences in retention or drug delivery at individual sites of bone disease between MM and BC patients. In order to find the optimal dosing of Zol, these observations should be taken into account.

Clinical and preclinical validation of the serum free light chain assay: identification of the critical difference for optimized clinical use.

OBJECTIVES: The use of the assay for the measurements of free light chains in serum (sFLCs) is increasing. However, there are technical limitations that potentially affect the use in serial measurements. We need further knowledge on the standards of analytical precision, the utility of conventional population-based reference values and the critical difference (CD) between serial results required for significance. To answer these questions, the biological variation must be known. METHODS: We determined the biological variation in healthy individuals and patients with plasma cell dyscrasia (PCD). We assessed the imprecision of the analysis in use from FreeLite™. We determined the reference interval (RI) in 170 healthy individuals. RESULTS: The biological variation is identical for healthy individuals and patients with PCD. The imprecision of the sFLC analysis cannot fulfil the desirable performance standards for a laboratory test, but are within the manufacturer's ±20% variation for quality control samples. RI showed a significant increase for κ FLC and κ/λ ratio with age, but not for λ. Critical difference was calculated to be 24% and 23% for κ and λ, respectively. CONCLUSIONS: We suggest the use of an age-dependent RI. When monitoring patients with PCD, their own former results are the best reference, and knowledge on CD is a valuable tool, which we describe for the first time. Also, it challenges the recently proposed International Myeloma Working Group 'paraprotein relapse criteria', recommending an increase of more than 25% in the involved FLC to indicate the need for initiation of retreatment. We recommend revision of this criterion.

Transfusion rate and prevalence of unexpected red blood cell alloantibodies in women undergoing hysterectomy for benign disease.

OBJECTIVE: To determine transfusion rates, risk factors for transfusion and the prevalence of unexpected red blood cell alloantibodies in women undergoing hysterectomy for benign disease. In addition, we aimed to evaluate the necessity of the pretransfusion testing for red blood cell alloantibodies. DESIGN: Retrospective cohort study. SETTING: The Danish Hysterectomy Database and a regional computerized blood bank register. POPULATION: The 4 181 hysterectomies in 2004 reported to the Hysterectomy Database. The blood bank registers 2 603 hysterectomies performed between 1997 and 2005. METHODS: From the hysterectomy database, information about indications for the hysterectomy, surgical procedures, re-operations, number of blood transfusions, and demographic, descriptive and clinical characteristics were extracted. Urgency of the transfusion episodes was evaluated by a retrospective review of the patients' medical records. From the regional blood bank register, results of the screening for red blood cell alloantibodies were extracted. MAIN OUTCOME MEASURES: Transfusion rates, prevalence of unexpected red blood cell alloantibodies. RESULTS: In all, 242 women (5.8%) received blood transfusions, but only 32 of the 4 181 women (0.77%) were urgently transfused. Re-operations were frequently associated with urgent blood transfusions. Nine of the 2 603 women from the regional register (0.35%) had newly detected, clinically significant red blood cell alloantibodies. CONCLUSIONS: The risk of a hemolytic transfusion reaction was estimated to be less than 1 in 17 000 hysterectomies (upper confidence limit) if the routine pretransfusion test were to be omitted. We suggest that reconsideration of the necessity for routine preoperative pretransfusion testing for women undergoing hysterectomy for benign disease is indicated.

Timing of heparin prophylaxis and bleeding complications in hysterectomy a nationwide prospective cohort study of 9,949 Danish women.

OBJECTIVE: To examine bleeding complications and thromboembolic events in relation to timing of heparin prophylaxis after hysterectomy. DESIGN: Nationwide prospective cohort study with 30 days post-operative follow-up within the Danish Hysterectomy Database (DHD). SETTING: All gynecological departments in Denmark (n=31). SAMPLE: 9,949 women who had an elective hysterectomy for benign indication between October 2003 and May 2006 and were reported to DHD (national response rate: 88-99% throughout 2004-2005). MAIN OUTCOME MEASURES: Odds ratios (OR) of peri-operative bleeding complications (> or =1,000 ml bleeding during surgery or post-operative wound/vaginal-vault/intraabdominal bleeding or hematoma) and number of events of venous thromboembolism. Logistic regression analysis adjusting for: age, body mass index, alcohol, smoking, meno-/metrorrhagia, uterine weight, department volume, surgeon's experience, route and type of hysterectomy and additional surgery, and stratification on assistant's experience, peri-operative pain prophylaxis with NSAID and daily use of Acetyl Salicylic Acid (ASA)/NSAID. RESULTS: 9,051 women (92%) received thromboprophylaxis with heparin, initiated pre-operatively in 48% and post-operatively in 52%. At least one bleeding complication was noted in 881 women (10%). Post-operative heparin administration was associated with a reduced risk of bleeding complications; OR=0.85 (95% confidence interval 0.73-0.99) compared to pre-operative administration. Excluding cases with potential impaired hemostasis at baseline, the OR was 0.78 (0.64-0.94). There was no fatal embolism. Three of seven pulmonary embolisms and one of three symptomatic deep venous thromboses occurred with the post-operative heparin administration. CONCLUSION: Post-operative rather than pre-operative administration of heparin prophylaxis may reduce the risk of bleeding complications after hysterectomy without apparent risk of increased thromboembolic events.

Risk factors for chronic pain after hysterectomy: a nationwide questionnaire and database study.

BACKGROUND: Women scheduled to undergo hysterectomy for benign indications frequently have preoperative pelvic pain, but it is largely unknown why pain in some cases persists or even develops after surgery. This nationwide questionnaire and database study describes pain and identifies risk factors for chronic postsurgical pain 1 yr after hysterectomy for benign indications. METHODS: A pain questionnaire was mailed to 1,299 women 1 yr after hysterectomy. The response rate was 90.3%, and the presence of persistent pain was correlated to indication for surgery, surgical procedure, type of anesthesia, and other perioperative data. RESULTS: Pain was reported by 31.9% 1 yr after hysterectomy (chronic pain), and 13.7% had pain more than 2 days a week. Pain was not present before surgery in 14.9% of women with chronic postsurgical pain. Risk factors for chronic pain were preoperative pelvic pain (odds ratio [OR], 3.25; 95% confidence interval [CI], 2.40-4.41), previous cesarean delivery (OR, 1.54; CI, 1.06-2.26), pain as the main indication for surgery (OR, 2.98; CI, 1.54-5.77), and pain problems elsewhere (OR, 3.19; CI, 2.29-4.44). Vaginal hysterectomy versus total abdominal hysterectomy was not significantly associated with a lower risk of chronic pain (OR, 0.70; CI, 0.46-1.06). Importantly, spinal versus general anesthesia was associated with less chronic pain (OR, 0.42; CI, 0.21-0.85). CONCLUSIONS: Thirty-two percent had chronic pain after hysterectomy, and risk factors were comparable to those seen in other operations. Interestingly, spinal anesthesia was associated with a lower frequency of chronic pain, justifying prospective study of spinal anesthesia for patients with a high risk for development of chronic postsurgical pain.