The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.     

Lens autofluorescence is increased in newly diagnosed patients with NIDDM

Summary Lens and cornea autofluorescence has been shown to be increased in patients with insulin-dependent diabetes mellitus and to be positively correlated to glycaemic control and duration of diabetes. We have studied lens and cornea autofluorescence at the clinical onset of non-insulin-dependent diabetes mellitus (NIDDM), in comparison with age-matched subjects with normal glucose tolerance. Fourteen subjects with NIDDM diagnosed less than 6 months prior to the examination were characterised by ocular fluorometry, glycosylated hemoglobin A_1c, plasma lipid status, arterial blood pressure, and an oral glucose tolerance test (OGTT). Eleven age- and gender-matched healthy subjects without a family history of diabetes and with a normal glucose tolerance underwent the same examinations. In 11 of the 14 diabetic patients lens autofluorescence was increased to levels higher than the age-related mean + 2 SD of healthy subjects. For the entire study population, control and diabetic subjects, lens fluorescence was positively correlated with HbA_1c (p < 0.0001, r = 0.73), fasting plasma glucose (p = 0.002, r = 0.60) and the plasma glucose level 2 h after an OGTT (p = 0.004, r = 0.55). Cornea autofluorescence was also significantly increased in the group of newly diagnosed NIDDM patients, but only 9 patients had values above the mean + 2 SD of the healthy subjects. NIDDM could be detected by ocular fluorometry with a sensitivity of 79 % and a specificity of 100 %. We conclude that lens and cornea autofluorescence is abnormally increased in the majority of patients with newly diagnosed NIDDM. The sensitivity and specificity of the method indicate that lens fluorometry may potentially be useful for screening for undiagnosed NIDDM in the general population. Additionally, we propose that the method may be a clinically useful indicator of cumulative glycaemia and risk of development of secondary complications in patients with diabetes. [Diabetologia (1996) 39: 1524–1527] Received: 28 June 1996 and in revised form: 24 September 1996     

Age as a predictor of diagnostic and initial treatment intensity in newly diagnosed breast cancer patients

Newly diagnosed breast cancer patients (N = 494) aged 45-90 years were studied to determine if age was associated with appropriate diagnostic and prognostic evaluations, and initial definitive therapy. Women 75 years of age and older were less likely to receive an appropriate diagnostic evaluation than were younger women, but age was not associated with an appropriate prognostic evaluation. Older patients with local disease who were undergoing lumpectomy were less likely to receive follow-up radiation; older patients with regional disease undergoing mastectomy were less likely to receive adjuvant chemotherapy (including hormonal therapy). Physicians' attitudes about appropriateness of therapy appear to be the major determinant of what treatment is received.     

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.     

Renal autoregulation is normal in newly diagnosed, normotensive, NIDDM patients

Summary Abnormalities of renal autoregulation with glomerular hyperfiltration and raised intraglomerular pressure have been suggested as important factors in the initiation and development of diabetic nephropathy. Angiotensin converting enzyme (ACE) inhibition appears to have a specific reno-protective role in diabetic nephropathy, possibly by reducing intraglomerular pressure. The acute effects of ACE inhibition on renal haemodynamics in normotensive, non-insulin-dependent diabetes mellitus (NIDDM) have not been previously reported. We measured simultaneous glomerular filtration rate (GFR) and renal plasma flow (RPF) in 29 (4 female) subjects, mean age 52 years (range 27–70), using ⁵¹Cr EDTA and ¹²⁵I Hippuran. Clearances were corrected to 1.73 m^–2. All patients were normotensive (blood pressure < 75^th centile for age and sex), newly diagnosed ( < 30 days), taking no antihypertensive or hypoglycaemic medication. Subjects were randomly allocated (double blind) to receive the ACE inhibitor trandolapril 4 mg day^–1 (H) (hypotensive dose), trandolapril 0.5 mg day^–1 (L) (non-hypotensive dose) or placebo (P) for 10 days after which renal haemodynamics were remeasured. For all subjects baseline GFR, RPF and filtration fraction (FF) were 97 ± 21 ml min^–1 mean ± SD, 439 ± 120 ml min^–1 and 22.3 ± 2.9 % respectively. Glomerular hyperfiltration (GFR > 120 ml min^–1) was only demonstrated in 3 subjects (10.3 %). In group H mean arterial pressure (103 ± 8 vs 93 ± 9 mmHg, p < 0.001) and FF (23.8 ± 2.3 vs 20.0 ± 4.0 %, p = 0.03) fell while RPF increased (376 ± 111 vs 426 ± 60 ml min^–1, p = 0.02), there was no significant change in GFR. No significant change in mean arterial pressure, GFR, RPF or FF occurred in groups P and L. These studies suggest that in newly diagnosed normotensive NIDDM subjects normal renal autoregulation occurs and glomerular hyperfiltration is uncommon. [Diabetologia (1998) 41: 206–211] Received: 2 July 1997 and in revised form: 16 September 1997     

How accurate is the smoking history in newly diagnosed diabetic patients?

A smoking history was obtained from 94 consecutive newly diagnosed diabetic patients referred to an adult diabetic clinic. The smoking load was measured using urinary cotinine/creatinine ratios (COT/Cr). Fifty-six patients (60%) claimed to be non-smokers, but COT/Cr suggested active smoking in five of these. The patients who admitted to smoking were given standardised anti-smoking advice. At 3 months, 32 smoking patients were reviewed and 21 (66%) claimed to have reduced or stopped smoking. However, the median COT/Cr in the 32 patients showed no significant reduction (11.15 vs. 9.30 μg/mg). Urinary COT/Cr indicated that 6 patients had stopped smoking (median COT/Cr 6.98 fell to 0.97 μg/mg), but several patients had a marked rise in COT/Cr, demonstrating that their smoking habit had increased considerably. Therefore the smoking history obtained from new diabetic patients can be very misleading. An objective measure of smoking habits in the initial assessment and follow-up of diabetes may be worthwhile. Anti-smoking counselling at diagnosis of diabetes may persuade some smokers to stop.     

TWEAK is not elevated in patients with newly diagnosed inflammatory bowel disease

Objective: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may be involved in the pathogenesis of inflammatory bowel disease. The aim was to investigate if TWEAK may reflect disease activity in inflammatory bowel disease.

Materials and methods: In this cohort study, 139 consecutive patients with newly diagnosed and previously untreated inflammatory bowel disease – 95 with ulcerative colitis (UC) and 44 with Crohn’s disease (CD) – underwent colonoscopy. Disease activity was assessed by the Mayo score and the Mayo endoscopic score (MES) for UC, or the Simple Endoscopic Score (SES) for CD. Serum C-reactive protein (CRP) and fecal calprotectin were measured in IBD patients, as were plasma TWEAK levels in patients and 85 healthy subjects. Associations between TWEAK levels and disease activity markers were explored.

Results: In the total IBD group, the median (interquartile range) TWEAK level was 430?pg/ml (109–6570), in UC 502?pg/ml (109–4547) and in CD patients 352?pg/ml (101–9179), respectively. Healthy subjects had a median (IQR) TWEAK of 307?pg/ml (63–3492). There were no significant differences in TWEAK levels between the total IBD group and healthy control subjects, nor between UC and CD, or between UC/CD and healthy subjects. Furthermore, we found no significant associations between Mayo scores, MES-UC, SES-CD, CRP, and fecal calprotectin with plasma TWEAK levels.

Conclusions: Plasma TWEAK levels do not reflect disease activity or the grade of inflammation in patients with newly diagnosed inflammatory bowel disease. NCT01551563.     

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular‐interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib‐based therapy combined with high cut‐off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL^?1 and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) creatinine equation, was 8 mL/min/1.73 m². Serum free light chain (sFLC) median concentration was 6,040 mg L^?1. Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3‐year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI. Am. J. Hematol. 90:647–652, 2015. © 2015 Wiley Periodicals, Inc.     

Genotyping is a valuable diagnostic complement to neonatal screening for congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.

To evaluate genotyping as a diagnostic complement to neonatal screening for congenital adrenal hyperplasia, 91 children who had been diagnosed with this condition between 1986 and 1997 were analyzed for mutations in the steroid 21-hydroxylase gene. Screening levels of 17-hydroxyprogesterone were compared in patients representing different genotypes. Genotyping was performed using allele-specific PCR, the patients were divided into four groups according to the severity of their mutations, and screening results were compared between these groups as well as with 141 values representing false positive samples. The screening levels of 17-hydroxyprogesterone were significantly different in the five groups of samples. Values above 500 nmol/L were clearly associated with the most severe genotypes, whereas conclusions concerning disease severity could not be drawn from individual samples representing lower levels. For example, values around 150-200 nmol/L could be seen in children with all degrees of disease severity and could also constitute false positive samples. We conclude that genotyping is a valuable diagnostic tool and a good complement to neonatal screening, especially in confirming or discarding the diagnosis in cases with slightly elevated 17-hydroxyprogesterone levels. An additional benefit is that it provides information on disease severity, which reduces the risk of overtreatment of mildly affected children.