Multicenter randomized controlled trial to evaluate the efficacy and tolerability of frozen gloves for the prevention of chemotherapy-induced peripheral neuropathy.

BACKGROUND: This study investigated the efficacy and tolerability of wearing frozen gloves (FGs) during chemotherapy to prevent chemotherapy-induced peripheral neuropathy (CIPN) as reported by patients and influence on quality of life (QoL). PATIENTS AND METHODS: Cancer patients starting treatment with oxaliplatin, docetaxel or paclitaxel between February 2013 and May 2016 at the medical oncology department were eligible. Patients were randomized into groups wearing FGs on both hands during treatment and those not wearing FGs during treatment. Self-reported CIPN and QoL were measured with the European Organisation for the Research and Treatment of Cancer Quality of Life (EORTC QLQ) CIPN20 and QLQ-C30 at four time points: baseline (t0), after three cycles (t1), end of chemotherapy (t2) and after 6 months (t3). RESULTS: The study included 180 patients with 90 patients in both arms. They mostly underwent treatment of colorectal or breast cancer. Thirty-one patients (34%) discontinued FGs, mainly due to discomfort. Intention-to-treat analyses showed no important differences in reported EORTC QLQ CIPN20 subscales between the FG group and control group; however, the analyses showed the patients experienced reduced tingling in fingers/hands [ß = -10.20, 95% confidence interval (CI) = -3.94 to -3.14, P = 0.005] and less trouble opening a jar or bottle due to loss of strength in hands (ß = -6.97, 95% CI = -13.53 to -0.40, P = 0.04) in the FG group compared with the control group. Per-protocol analyses showed similar results: reduced aching or burning pain in fingers/hands (ß = -4.37, 95% CI = -7.90 to -0.83, P = 0.02) and cramps in hands (ß = -3.76, 95% CI = -7.38 to -0.14, P = 0.04). Differences in tingling in fingers/hands at t1 were clinically relevant. In addition, those treated with FGs reported overall better QoL (ß = 4.79, 95% CI = 0.37 to 9.22, P = 0.03) and physical functioning (ß = 5.66, 95% CI = 1.59 to 9.73, P = 0.007) than the control. No difference in dose reductions was observed. CONCLUSIONS: No difference in CIPN subscales was reported between intervention arms. Wearing FGs might reduce some neuropathy symptoms in the hands, potentially resulting in a better QoL; however, one-third of the FG group discontinued the study before the end of treatment. Future studies should focus on the method of limb hypothermia to prevent CIPN. TRIAL REGISTRATION NUMBER: NL39650.015.12.

Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone hepcidin appears to play a role. Ways of diagnosing iron overload include measurement of the serum iron parameters, i.e. serum transferrin saturation and serum ferritin, by a liver biopsy or by calculating the amount of mobilisable body iron withdrawn by phlebotomies. Clinical signs attributed to HFE-related HH include liver failure, arthralgia, chronic fatigue, diabetes mellitus and congestive heart failure. organ failure can be prevented by phlebotomies starting before irreversible damage has occurred. Therefore, screening to facilitate early diagnosis is desirable in individuals at risk of developing HFE-related iron overload. over time it appeared that the clinical penetrance of the HFE mutations was much lower than had previously been thought. This changed the opinion about a suitable screening modality from case detection, via population screening, to family screening as the most appropriate method to prevent HFE-related disease. However, before the implementation of family screening it is vital to have thorough information on the relevance of the specific health problem involved, on the clinical penetrance of C282Y homozygosity and on the effectiveness of the screening approach.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

BACKGROUND: Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. METHODS: Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. RESULTS: A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. CONCLUSION: In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

[Hereditary haemochromatosis: novel genes, novel diseases and hepcidin]. / Hereditaire hemochromatose: nieuwe genen, nieuwe ziekten en hepcidine.

Since the discovery of the HFE gene of hereditary haemochromatosis in 1996 several new genetic defects have been identified, enabling explanation of the cause and variety of this disease. To date, at least 5 major types of hereditary haemochromatosis have been recognised. All these genes encode for proteins that are involved in metabolic pathways relevant to hepcidin synthesis in the liver. Hepcidin is a small protein that regulates the activity of the iron exporting protein ferroportin in the basolateral membrane of duodenal cells and the cell membrane of macrophages and thereby controls serum iron concentration. Plasma hepcidin concentration is elevated in body iron excess and by inflammatory stimuli, and is lowered in erythroid iron demand, hypoxia and most types of hereditary haemochromatosis. It is the clinician's task to diagnose hereditary haemochromatosis before irreversible tissue damage arises and at the same time to differentiate between ongoing iron accumulation and increasingly prevalent disorders with elevated serum ferritin such as the metabolic syndrome.

Impact of the introduction of a guideline on the targeted detection of hereditary haemochromatosis.

BACKGROUND: In 1998 a clinical guideline for the targeted, accurate and early detection and treatment of HFE-related hereditary haemochromatosis (HH), which comprises a test for the causative HFE-gene mutations, was introduced in our outpatient department. METHODS: The impact of this guideline was evaluated retrospectively. Data were acquired from medical records of patients with discharge diagnosis codes suggestive of HH (n=878 patients), obtained from a period before (n=422) and after guideline introduction (n=456). RESULTS: Combined measurements of serum transferrin saturation and serum ferritin rose from 12.2% (n=53) to 29.5% (n=138, p<0.001), leaving 70% of the patients eligible for HH not tested for iron parameters. The HFE-gene mutation detection test was correctly used in II (40.7%) of 27 tested patients and improperly interpreted in six (22.2%) of these 27 patients. Five new HH patients were diagnosed before and 13 after introduction. Seven of these 13 patients appeared to be incorrectly diagnosed, due to misinterpretation of laboratory results. Diagnostic costs of case detection for each accurately diagnosed patient were euro 2380 before and euro 2600 after introduction of the guideline. CONCLUSION: Evaluation of the introduction of a practical guideline for targeted HH detection reveals a low compliance with the guideline, resulting in both a small percentage of patients tested for HH and overdiagnosis of HH. Therefore, the introduction of the guideline should be combined with a more appropriate implementation strategy which includes education on its most critical points, i.e. the indication and interpretation of the iron parameters and the HFE genotype.

PTU-associated cutaneous vasculitis with ANCA anti-MPO and anti-PR3 antibodies.

A 36-year-old woman presented at our clinic with symmetrical, tender, palpable purpuric lesions on her lower legs and buttocks after restarting PTU therapy for relapsing Graves' disease. PTU-induced vasculitis was diagnosed with remarkable ANCA anti-MPO and anti-PR3 antibody positivity. The purpuric skin lesions resolved immediately after discontinuation of the drug and the ANCA titres lowered. In the presence of activated neutrophils, PTU could induce a high cytotoxity and injure the vessel walls. Treatment of choice is discontinuation of the drug. Sometimes more aggressive therapy as cyclophosphamide or plasmapheresis is warranted.

[From gene to disease; HFE-mutations in primary haemochromatosis]. / Van gen naar ziekte; HFE-mutaties bij primaire hemochromatose.

Primary haemochromatosis is an autosomal recessive disorder with a high prevalence (1 in 200-400) among North-Europeans. Approximately 64-100% of patients with primary haemochromatosis are homozygous for a missense mutation that alters a major-histocompatibility-complex class I-like protein designated HFE (from 'haemochromatosis'). This predominant mutation is a substitution of cysteine to tyrosine at amino acid residue 282 (Cys282Tyr) in the alpha 3-domain of the HFE protein. This mutation in the HFE protein in the intestinal crypt cells is supposed to lead to up-regulation of iron transporters for dietary iron in the mucosal cells at the tip of the duodenal villi. As a consequence, an excess of absorbed iron accumulates in the major organs of the HFE-mutated patients, leading to multi-organ dysfunction. A second mutation, His63Asp, in the HFE-gene is enriched in primary haemochromatosis patients who are concomitantly heterozygous for the Cys282Tyr-mutation. However, its role in the pathophysiology of primary haemochromatosis is not yet clear. A small subgroup of patients with primary haemochromatosis do not have mutations in HFE; for some of them the genetic basis has been determined. Homozygosity for the Cys282Tyr-mutation plus biochemical and clinical evidence of iron overload renders the diagnosis of HFE-related primary haemochromatosis indisputable. In other cases, liver biopsy remains the gold standard for the diagnosis of primary haemochromatosis. First-degree relatives of index patients should be screened for the disease.

[Diagnosis of 5 patients with possible primary hemochromatosis]. / Diagnostiek bij 5 patiënten met mogelijk primaire hemochromatose.

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.

[Results from a general training hospital for the implementation of a diagnostic workup for pulmonary embolism according to the Dutch Institute for Health Care Improvement]. / Resultaten van het invoeren van diagnostiek naar longembolie volgens de CBO-richtlijn in een algemeen opleidingsziekenhuis.

OBJECTIVE: To evaluate the active implementation of the Dutch Institute for Healthcare Improvement's guideline for the diagnostic work-up for pulmonary embolism in a general training hospital, and to analyse reasons for not following the guideline strategy. DESIGN: Partly retrospective and partly prospective. METHOD: The diagnostic strategy was analysed for all consecutive patients with clinically suspected pulmonary embolism who underwent a perfusion lung scintigraphy. The extent to which the guideline was followed was investigated in the year before (July 1999-June 2000; n = 384) and the year after (July 2000-June 2001; n = 380) its active implementation. The possible reasons for not completing the strategy in the prospective cohort of the study were also analysed. RESULTS: Following a non-high-probability perfusion-ventilation scan, the guideline was completed in 23/117 (20%) patients prior to the implementation and in 50/109 (46%) patients after the implementation of the guideline. In 27% and 60%, respectively, an additional duplex ultrasound of the legs was made to check for deep vein thrombosis, and in 65% and 70% respectively, pulmonary angiography was performed after a normal ultrasound result. The main reasons for not following the diagnostic work-up included low clinical probability (41%, without a proper alternative diagnosis), an alternative diagnosis (36%; pneumonia, heart failure, malignancy) and a reluctance to perform angiography. The mean age of the patients for whom the guideline was completed was lower (51 years) compared to patients for whom the guideline was not followed (65 years; p < 0.001). The risk of not completing the diagnostic workup in accordance with the guideline was six-fold higher for patients > or = 80 years compared with patients < 40 years of age, whereas an alternative diagnosis was not more prevalent in patients > or = 65 years. CONCLUSION: Although active implementation of the guideline-based diagnostic work-up for pulmonary embolism increased the number of adequate diagnoses, the diagnostic work-up was not completed in half of the patients with inconclusive lung scans. The main reasons for this were the advanced age of the patient, alternative diagnoses, and a reluctance to perform pulmonary angiography.

Non-transferrin-bound iron is associated with plasma level of soluble intercellular adhesion molecule-1 but not with in vivo low-density lipoprotein oxidation.

BACKGROUND: Excess body iron is associated with increased cardiovascular disease risk, possibly via non-transferrin-bound iron (NTBI)-mediated enhancement of inflammation and oxidation of low-density lipoprotein (LDL). METHODS: We assessed this proposed atherosclerotic mechanism of body iron by determining the relationship of levels of serum iron parameters, including NTBI, with plasma markers of inflammation and LDL oxidation in 232 subjects who visited the outpatient clinic for hemochromatosis family screening. RESULTS: Plasma level of soluble intercellular adhesion molecule-1 (sICAM-1) was positively related to ferritin (standardized beta coefficient 0.16) and to NTBI (0.185) and negatively to total iron-binding capacity (TIBC, -0.166). Significant higher levels of sICAM-1 were found for subjects in the highest quartile of NTBI compared to the lowest quartile of NTBI (122 microg/L (107-141) and 106 microg/L (89-125), median (interquartile range), p<0.001). Odds ratio of subjects having sICAM-1 level above 134 microg/L (75th percentile) in the highest and lowest quartile of NTBI amounted 2.3. White blood cell count was positively related to ferritin (0.149). High-sensitivity C-reactive protein, interleukin-6, interleukin-8, oxidized LDL, oxidized LDL/apolipoprotein B and IgG and IgM antibodies to oxidized LDL were not related to any of the markers of iron status. CONCLUSION: Excess body iron, reflected by elevated serum ferritin and NTBI and decreased TIBC, is associated with increased plasma level of sICAM-1 but not with markers of in vivo LDL oxidation.