Therneau, Terry M.

AbstractThe median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 × 109/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) affects 3% of persons age 50 yrs or greater. Reliable predictors of progression of MGUS to myeloma or related malignancy are needed. We hypothesized that the presence of monoclonal unbound (free) kappa or lambda immunoglobulin light chains in MGUS, as detected by an abnormal serum kappa/lambda free light chain (FLC) ratio would indicate clonal evolution in the neoplastic plasma cell and increase risk of progression to malignancy. Methods: Patients (pts) from Southeastern Minnesota with MGUS seen at the Mayo Clinic from Jan 1, 1960 through Dec 31, 1994 who had baseline serum samples collected and stored at the time MGUS was first recognized were studied. Free kappa and lambda chains were measured using the serum FLC assay (FREELITETM, The Binding Site Ltd). Results: Of 1384 pts with MGUS during the defined time period, baseline serum samples obtained within 30 days of diagnosis of MGUS were available in 1148 pts. At a median follow-up of 15 yrs, malignant progression has occurred in 87 (7.6%) pts: myeloma (53 pts), IgM lymphoma (17), primary amyloidosis (6), macroglobulinemia (6), chronic lymphocytic leukemia (3) and plasmacytoma (2). An abnormal kappa/lamda FLC ratio (kappa/lambda ratio <0.26 or >1.65) indicating presence of monoclonal FLC was detected in 379 (33%) pts. In a Cox proportional hazards model, the risk of progression in pts with an abnormal kappa/lamda FLC ratio was significantly higher (hazard ratio 3.5, 95% CI 2.3–5.5; p<0.001) compared to pts with a normal ratio. After adjusting for the size of the serum monoclonal (M) protein by multivariate analysis, the hazard ratio was only slightly reduced to 2.8, p<0.001. The risk of progression to myeloma or related malignancy at 10 years was 17% with an abnormal kappa/lambda FLC ratio versus 5% with a normal ratio; corresponding rates at 20 years were 35%, and 13%, respectively. MGUS pts with both an abnormal serum FLC ratio and high serum M protein had a risk of progression at 20 years of 46% (high-risk), versus 26% with one of two risk factors (intermediate-risk) and 7% with no risk factors (low-risk) (Table). The true life-time (28 year) risk of myeloma or related malignancy in the low-risk group was only 5.3% when other competing causes of death were taken into account. Conclusions: Presence of monoclonal FLC in the serum as detected by an abnormal kappa/lamda FLC ratio is a major independent risk factor for progression of MGUS to myeloma or a related malignancy. The new risk-stratification identifies a low-risk subset with a remarkably small life-time risk of progression, a finding of significant importance for the management of MGUS. Risk-stratification of MGUS using the size of the serum M spike and free light chain ratio Risk Group No. of patients Hazard ratio Absolute risk of progression at 20 years Low-risk (Serum M protein <1.5 gm/dL and normal FLC ratio [0.26–1.65]) 606 1 7% Intermediate-risk (Either risk factor present) 373 3.5 26% High-risk (Serum M protein >/=1.5 gm/dL and abnormal FLC ratio [<0.26 or >1.65]) 169 6.8 46%

Abstract Chronic Idiopathic Bence Jones Proteinuria (first reported in 1982) is an asymptomatic plasma cell proliferative disorder that is associated with a risk of progression to symptomatic multiple myeloma (MM) or primary amyloidosis (AL). We defined it as the presence of a monoclonal light chain in the urine, absence of an intact immunoglobulin M protein (IgH expression) in the serum, fewer than 10% bone marrow plasma cells (if done), and no evidence of MM, AL or other related plasma cell proliferative disorders. Following approval by the Mayo Clinic Institutional Review Board, we searched a computerized database and reviewed the records of all patients who were seen at Mayo Clinic within 30 days of the recognition of a monoclonal light chain (Bence Jones protein) in the urine between 1960 and 1996. Patients found to have end-organ damage at diagnosis as the result of the plasma cell proliferative disorder (including MM or AL), received chemotherapy, or had a nephrotic syndrome were excluded. Follow-up included review of each subject’s medical record at Mayo Clinic as well as review of death certificates for patients who died. Patients were sent letters of inquiry if they had not visited Mayo Clinic in the preceding year. The risk of progression to MM and AL was compared to those expected on the basis of Surveillance, Epidemiology and End Results (SEER) rates for MM in Iowa and the prevalence of AL in Olmsted County, Minnesota. Two-hundred twenty-three patients fulfilled the criteria for Idiopathic Bence Jones Proteinuria during the 37-year period (1960 – 1996). The median age at diagnosis was 69 yrs (range, 36–90 yrs) and only 1% were < 40 years of age. Sixty-seven percent were male. The urine M protein ranged from unmeasurable to 4.7 g/24h. The median was 0.09 g/24h and only 8% were > 1 g/24h. Kappa light chain accounted for 57% while lambda was present in 43%. Eighty-one percent of patients died during follow-up. Twenty-six percent had a monoclonal light chain in the serum on immunofixation. Concentrations of uninvolved (normal, polyclonal or background) immunoglobulins were reduced in 45%. During 1408 person years of follow-up, 11 patients developed symptomatic MM (relative risk 28.5; 95% CI, 14.3 – 51.1) and an additional 9 patients developed AL (relative risk 61.8; 95% CI, 28.3 – 117.4). The cumulative probability of progression to active MM or AL was 7% at 5 yrs, 13.5% at 10 yrs., and 18% at 15 yrs. The factors evaluated with respect to predicting progression to MM or AL included sex, hemoglobin value, serum albumin, amount of urine M protein/24h, type of urine light chain (kappa or lambda), reduction of uninvolved (background) immunoglobulins, and elevation of serum calcium or creatinine. The amount of the urine M protein/24h was the only significantly predictive parameter for progression. As a continuous variable, a higher urine M protein was associated with an increased risk of progression (hazard ratio = 2.1 for a 1g increase, p=0.003). The amount of the urine M protein was also significant as a dichotomous variable. Patients who had a urine M protein ≥ 1g/24h had an increased risk of progression (hazard ratio = 3.6, p=0.007). We conclude that patients with Idiopathic Bence Jones Proteinuria are at risk for the development of MM or AL and need to be followed indefinitely.

The median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 × 109/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.

Abstract Abstract 1861 Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria), first reported in 1982, is an asymptomatic plasma cell proliferative disorder associated with an elevated risk of progression to symptomatic MM or amyloidosis (AL). We defined it as the presence of a monoclonal light chain in the urine ≥200 mg/24h, absence of an intact immunoglobulin M protein (IGH expression) in the serum and no evidence of MM, AL or other related plasma cell proliferative disorders. Following approval by our Institutional Review Board, we searched a computerized database and reviewed the records of all patients seen at Mayo Clinic within 30 days of the recognition of a monoclonal light chain (Bence Jones protein) in the urine from January 1, 1960 through June 30, 2004. Patients with end-organ damage at diagnosis resulting from the plasma cell proliferative disorder (including MM or AL), or who had received chemotherapy or had a nephrotic syndrome were excluded. Follow-up included review of each patient's medical record at Mayo Clinic, as well as review of death certificates for patients who died. Patients were sent letters of inquiry if they had not visited Mayo Clinic in the preceding year. The risks of progression to MM and AL were compared to those expected on the basis of Surveillance, Epidemiology and End Results (SEER) rates for MM in Iowa and the incidence of AL in Olmsted County, Minnesota. One-hundred and one patients fulfilled the criteria for diagnosis during the 44-year period (1960–2004). The median age at diagnosis was 67 years (range 18–90 years), and only 2% were < 40 years old. Seventy-three percent were male. The urine M protein ranged from 200 mg/24h to 4.7 g/24h (median value, 500 mg/24h); 29% had > 1 g/24h. Kappa light chain accounted for 50% while the remaining 50% were lambda. Fifty-seven (56%) had a monoclonal light chain in the serum on immunofixation. Concentrations of uninvolved (normal, polyclonal or background) immunoglobulins were reduced in 62%. Eighty-eight percent of patients died during follow-up. During 900 person years of follow-up, 29 patients developed symptomatic MM (relative risk, 140.3; 95% CI, 93.9–201.5) and an additional 9 patients developed AL (relative risk, 104.4; 95% CI, 47.8–198.4). Four patients had both multiple myeloma and AL amyloidosis. The cumulative probability of progression to active MM or AL was 19% at 5 years, 31% at 10 years and 42% at 15 years. The factors associated with progression to MM or AL included size of urine M protein, percentage of bone marrow plasma cells, serum free light chain ratio < 1/100 or > 100, serum creatinine and reduction of all 3 uninvolved immunoglobulins. We conclude that patients with Idiopathic Bence Jones Proteinuria (Smoldering Monoclonal Light-Chain Proteinuria) are at risk for the development of MM or AL and must be followed indefinitely. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION: The discontinuous BALAD and continuous BALAD-2 scores derived from bilirubin, albumin, alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-gamma-carboxyprothrombin (DCP) are effective in predicting HCC patient mortality, but have not been validated in North America. We validated the BALAD and BALAD-2 scores in North America. METHODS: Data from 148 HCC patients seen from 2000–2015 with results for all five biomarkers at diagnosis were abstracted. Hazard ratios (HR) and C-statistics were calculated. RESULTS: 75 of the 148 patients died during a median follow-up of 33 months (0.3-145 months),. The 1-year and 3-year survival rates were 70.8% and 47.6%, respectively. 114 (77%) patients had cirrhosis with a median MELD of 9.5 (range 6.4-29.5). HCC etiologies were HCV (34%), NASH (34%), alcohol (14%), and HBV (10%). Primary treatments were liver transplant, 21 (14%), surgical resection, 32 (22%), local ablation, 10 (7%), transarterial chemoembolization or radioembolization, 47 (32%), chemotherapy, 11 (7%), best supportive care, 9 (6%), and unknown treatment, 18 (12%). MELD, tumor size (cm), ≥2 tumors, tumor number, and neutrophil-lymphocyte ratio >4 significantly increased mortality with HR (95%CI) of 1.12 (1.06–1.18) per unit increase in MELD, 1.06 (1.0004–1.12) per cm increase in size, 1.21 (1.03–1.43) per number of tumor, and 1.93 (1.16–3.24). For the BALAD score analysis, 12, 49, 40, 31, 16 and 0 patients had BALAD scores of 0–5 respectively. The HR (95%CI) for death were 1.24 (0.42–3.67), 1.79 (0.61–5.26), 2.83 (0.95–8.38), and 7.19 (2.26–22.91) for BALAD scores 1, 2, 3, and 4 vs. BALAD 0. For the BALAD-2 analysis, 58, 35, 33, and 22 patients were BALAD-2 classes 1, 2, 3, and 4. The HR (95%CI) for death were 1.25 (0.65–2.40), 1.75 (0.94–3.23), and 6.20 (3.29–11.68) for BALAD-2 classes 2, 3, and 4 vs. BALAD-2 class 1. A multivariate model incorporating maximal tumor diameter, tumor number, neutrophil-lymphocyte ratio and BALAD had HR of 1.43 (1.14–1.81) per increase of 1 BALAD score. A similar multivariate model with BALAD-2 had HR of 1.50 (1.18–1.90) per increase of 1 BALAD-2 class. BALAD, BALAD-2 and BCLC had similar C-statistics of 0.69, 0.68, and 0.67. CONCLUSION: The BALAD score and BALAD-2 class at HCC diagnosis can predict survival of HCC patients in North America. AFP, AFP-L3, and DCP in the BALAD models incorporate HCC tumor biology and make the BALAD model distinguish from other previous predictive models.

OBJECTIVES: Cardiovascular (CV) disease is the top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Female sex is protective against CV disease. We aimed to determine whether female sex remains a protective factor against CV disease (myocardial infarction, angina, and stroke) in NAFLD. METHODS: We identified all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 and selected an age- and sex-matched (1:4) referent cohort from the general population. NAFLD was ascertained using a code-based algorithm with high validity tested by medical record review. The impact of female sex on incident CV events was examined using Cox proportional hazards regression analysis stratified by standard clinical risk factors. RESULTS: A total of 3,869 NAFLD and 15,209 age- and sex-matched referent subjects were identified. After a median follow-up time of 7 (range 1–20) years, 3,851 CV events were recorded. Female sex was protective for ischemic CV events in the general population (hazard ratio = 0.71, 95% confidence interval 0.62–0.80, P < 0.001), but the impact was significantly diminished among those with NAFLD (hazard ratio = 0.90, 95% confidence interval 0.74–1.08, P = 0.25), even after stratification by time-dependent CV risk factors and control for diagnostic testing (liver enzymes and ultrasound) during routine medical evaluations, as a surrogate of access to care. Among those with NAFLD, excess events were higher in women than in men: CV disease (18% vs 9%) and mortality (9% vs 6%). DISCUSSION: Women with NAFLD lose the CV protection conferred by the female sex, and their risk is underestimated by current estimating methods in clinical practice.

See Gordon and Tijms (doi:10.1093/brain/awz278) for a scientific commentary on this article. Jack et al. examine relationships between the bivariate distribution of β-amyloid and tau on PET and established neurocognitive clinical syndromes. Amyloidosis appears to be required for high levels of 3R/4R tau deposition. Whereas abnormal amyloid PET is compatible with normal cognition, highly abnormal tau PET is not.

Abstract Objectives: Biliary tract cancers (BTCs) comprise the second most common type of hepatobiliary cancer. Given the increase in global BTC incidence, with associated morbidity and mortality, together with the limited therapeutic options, there is increasing interest in strategies for disease prevention. We performed a population-based cohort study to determine the association between low dose aspirin, non-aspirin NSAIDs, statins, metformin, other risk factors and the risk of biliary tract cancer (BTC), while assessing confounding by sex. Methods: We conducted a nationwide Swedish population-based cohort study using the Swedish Prescribed Drug Registry, which virtually completely enumerates use of prescribed medications nationwide since 2005. BTC diagnosis (intrahepatic cholangiocarcinoma [iCCA], extrahepatic cholangiocarcinoma [eCCA] or gallbladder cancer [GBC]) was ascertained from the Swedish Cancer Registry. Age-scaled Cox models, with exposure as time-varying covariates, were used to calculate hazard ratios (HRs), separately for men and women. Results: In the 5.7 million person cohort, the risk of iCCA was significantly lower in men using statins (HR 0.62,95%CI 0.39-1.00,p=0.05), with a non-significant reduction in women. Statin use was associated with a significantly decreased risk of eCCA in both women (HR 0.60,0.38-0.94,p=0.03) and men (HR 0.47,0.28-0.80,p=0.01). Low dose aspirin (HR 0.76,0.60-0.97,p=0.03) was associated with a lower risk of GBC only in women, while statins (HR 0.72,0.55-0.93,p=0.01) showed a significantly decreased risk of GBC in women and a non-significant reduction in men. For all BTC subtypes, combined use of low dose aspirin and statins did not confer additional risk reductions beyond those achieved by statins alone. Male and female users of non-aspirin NSAIDs appeared to be at increased risk of BTC and its subtypes. Metformin did not significantly affect risk of BTC. Conclusion: We performed the largest population-based cohort study evaluating risk and protective factors for BTC. Our results provide strong evidence in favor of the chemopreventive roles of low dose aspirin and statins in a subtype-and sex-specific manner. Individual risk factors contribute to development of BTC subtypes in different magnitudes. If randomized controlled clinical trials validate our findings and provide favorable evidence of the efficacy and safety of these drugs in the prevention of BTCs, our results could potentially be practice-changing, leading to improvements in the outcomes in this population. Citation Format: Lorena Marcano-Bonilla, Cathy D. Schleck, W. Scott Harmsen, Omid Sadr-Azodi, Mitesh J. Borad, Tushar Patel, Gloria M. Petersen, Terry M. Therneau, Lewis R. Roberts, Nele Brusselaers. Associations of aspirin, non-aspirin NSAIDs, statins, and metformin with risk of biliary tract cancer: A Swedish population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5049.