Normal Lactate Research Articles

A phase 1‐2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma

Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.

PROGNOSTIC VALUE OF ADMISSION SERUM LACTATE CONCENTRATIONS IN INTENSIVE CARE UNIT PATIENTS

Background: Although blood lactate concentrations have an established prognostic value in circulatory shock or after cardiac arrest, their relationship with morbidity and length of stay in general intensive care unit (ICU) populations has not been well defined.Methods: This study included all 433 patients (246 surgical and 187 medical) consecutively admitted to the Department of medico-surgical intensive care. Hyperlactataemia was defined as a serum lactate concentration ≥2 mEq/l.Results: On admission, 195 patients (45%) had hyperlactataemia. Hyperlactataemic patients had higher Acute Physiology and Chronic Health Evaluation (APACHE) II (13.3 ± 6.9 vs 10.0 ± 5.2) and Sequential Organ Failure Assessment (SOFA) (5.3 ± 3.3 vs 3.3 ± 2.3) scores than patients with normal lactate concentrations (both p < 0.01). There was no overall difference in length of ICU stay (LOS) between the two groups but survivors in the hyperlactataemic group had a longer LOS than survivors in the normal lactate group, whereas hyperlactataemic non-survivors had a shorter LOS than normal lactate non-survivors. Mortality was 9% in patients with normal lactate concentrations and 23% in hyperlactataemic patients. The mortality rate increased with increasing lactate concentrations, from 17% in patients with lactate concentrations from 2-4 mEq/l to 64% in those with concentrations more than 8 mEq/l. Non-survivors had higher lactate concentrations than survivors on admission, and after 24 and 48 hours. Risk factors for developing hyperlactataemia that were present on admission were SOFA score > 5, mean arterial blood pressure less than 70 mmHg, blood sugar greater than 110 mg/dl, and current use of vasopressors.Conclusions: Our study documents a direct relationship between the serum lactate level on ICU admission and not only the risk of death in ICU but also the length of ICU stay. Hyperlactataemic survivors have a longer LOS and non-survivors a shorter LOS than normal lactate survivors and non-survivors, respectively.

Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Normal Lactate: A New Mutation in the DARS2 Gene

Leukoencephalopathy with brainstem and spinal cord involvement and elevated brain lactate diagnosis is based on its highly characteristic pattern of abnormalities observed by magnetic resonance imaging and spectroscopy. Clinically, affected patients develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline. In 2007, the pathophysiology of this disorder was elucidated with the discovery of mutations in the DARS2 gene, which encodes mitochondrial aspartyl-tRNA synthetase, in affected individuals. Here, the authors present a case of leukoencephalopathy with brainstem and spinal cord involvement with normal brain lactate, in which genetic analysis revealed a new mutation in the DARS2 gene not previously described.

The role for osmotic agents in children with acute encephalopathies: a systematic review

BackgroundRaised intracranial pressure (ICP) is known to complicate both traumatic and non-traumatic encephalopathies. It impairs cerebral perfusion and may cause death due to global ischaemia and intracranial herniation. Osmotic agents are widely used to control ICP. In children, guidelines for their use are mainly guided by adult studies. We conducted this review to determine the current evidence of the effectiveness of osmotic agents and their effect on resolution of coma and outcome in children with acute encephalopathy.MethodsWe searched several databases for published and unpublished studies in English and French languages, between January 1966 and March 2009. We considered studies on the use of osmotic agents in children aged between 0 and 16 years with acute encephalopathies. We examined reduction in intracranial pressure, time to resolution of coma, and occurrence of neurological sequelae and death.ResultsWe identified four randomized controlled trials, three prospective studies, two retrospective studies and one case report. Hypertonic saline (HS) achieved greater reduction in intracranial pressure (ICP) compared to mannitol and other fluids; normal saline or ringer's lactate. This effect was sustained for longer when it was given as continuous infusion. Boluses of glycerol and mannitol achieved transient reduction in ICP. Oral glycerol was associated with lower mortality and neurological sequelae when compared to placebo in children with acute bacterial meningitis. HS was associated with lower mortality when compared to mannitol in children with non-traumatic encephalopathies.ConclusionHS appears to achieve a greater reduction in ICP than other osmotic agents. Oral glycerol seems to improve outcome among children with acute bacterial meningitis. A sustained reduction in ICP is desirable and could be achieved by modifying the modes and rates of administration of these osmotic agents, but these factors need further investigation.

Tissue Oxygenation Does Not Predict Central Venous Oxygenation in Emergency Department Patients With Severe Sepsis and Septic Shock

This study sought to determine whether tissue oxygenation (StO(2)) could be used as a surrogate for central venous oxygenation (ScVO(2)) in early goal-directed therapy (EGDT). The study enrolled a prospective convenience sample of patients aged > or =18 years with sepsis and systolic blood pressure <90 mm Hg after 2 L of normal saline or lactate >4 mmol, who received a continuous central venous oximetry catheter. StO(2) and ScVO(2) were measured at 15-minute intervals. Data were analyzed using a random coefficients model, correlations, and Bland-Altman plots. There were 284 measurements in 40 patients. While a statistically significant relationship existed between StO(2) and ScVO(2) (F(1,37) = 10.23, p = 0.002), StO(2) appears to systematically overestimate at lower ScVO(2) and underestimate at higher ScVO(2). This was reflected in the fixed effect slope of 0.49 (95% confidence interval [CI] = 0.266 to 0.720) and intercept of 34 (95% CI = 14.681 to 50.830), which were significantly different from 1 and 0, respectively. The initial point correlation (r = 0.5) was fair, but there was poor overall agreement (bias = 4.3, limits of agreement = -20.8 to 29.4). Correlation between StO(2) and ScVO(2) was fair. The two measures trend in the same direction, but clinical use of StO(2) in lieu of ScVO(2) is unsubstantiated due to large and systematic biases. However, these biases may reflect real physiologic states. Further research may investigate if these measures could be used in concert as prognostic indicators.

Hyperlactatemia in Neonates Admitted to the Cardiac Intensive Care Unit with Critical Heart Disease

Neonates with critical heart disease are at risk of significant deficiencies in systemic oxygen delivery. The incidence and clinical pattern of hyperlactatemia in neonates presenting with critical heart disease has not been described. We reviewed the lactate pattern of neonates transferred to our cardiac intensive care unit for surgical management of their heart disease over a 1-year period. Stabilization of these neonates began in the referring institutions. From 8/4/03 to 8/4/04, 75 neonates with critical heart disease were transferred to our unit for stabilization and subsequent surgery. Blood lactate was measured on admission and subsequently in any patient thought to be at risk of low systemic oxygen delivery. Lactate was measured in 59 patients on admission and in 63 patients within the first 48 h of admission. Median age on admission was 1 day (range 0–13). Median age at surgery was 8 days (range 1–30). Median length of stay was 20 days. Peak lactate was noted on admission in 51 patients, and at 12–24 h in 8 patients. Mild hyperlactatemia (2.3–5 mmol/l) was present in 30 patients on admission and moderate-to-severe hyperlactatemia (≧5 mmol/l) was present in 8 patients. Mean lactate level on admission was 3.1 ± 0.6 mmol/l, and this did not return to normal (<2.3 mmol/l) until 36 h after admission. Severe hyperlactatemia patients also were noted to have normal lactate levels by 36 h. The presence of hyperlactatemia did not affect length of stay or mortality. There were no preoperative deaths and 4 postoperative deaths (1 death in 38 patients with mild or severe hyperlactatemia). Hyperlactatemia is frequently present in neonates admitted to a tertiary care center for management of congenital heart disease. Blood lactate levels normalize within 36 h. The presence of preoperative hyperlactatemia, even when moderate-to-severe, does not have significant adverse effect on postoperative mortality.

Predictive value of pretreatment risk group and baseline LDH levels in MDS patients receiving azacitidine treatment

This study analyzed the outcomes of myelodysplastic syndrome patients treated with azacitidine. Between August 2006 and June 2008, a total of 126 patients were treated with azacitidine at a dose of 75 mg/m(2)/day subcutaneously for 7 days, which was repeated every 28 days. The median age of the patients was 64 (range, 20-82) years. Forty-three patients (33.4%) were classified as intermediate-2 and high risk according to International Prognostic Scoring System (IPSS), while 61 patients (47.3%) were classified as high and very high risk according to WHO Prognostic Scoring System (WPSS). Sixty patients (47.6%) exhibited a response at the median of 3 (range, 1-5) cycles. A complete response was observed in 21 patients (16.7%), a partial response in six patients (4.8%), and total hematologic improvement in 61 patients (48.4%). For the IPSS risk group, the median survival for the patients with intermediate-1 was 20.0 months, for intermediate-2 was 14.9 months, and for high risk was 6.3 months (p = 0.008). For the WPSS risk group, the median survival duration was 21.3 months for the very low and low risk patients, 16.5 months for intermediate risk patients, and 14.9 months for the high and very high risk patients (p = 0.003). The patients with higher than normal lactate dehydrogenase (LDH) levels at the time of diagnosis showed a poor survival (p = 0.003). The median survival duration for the patients with high LDH levels was 13.9 months, while that for the patients with normal LDH levels was 20.6 months. The multivariate analyses revealed that high LDH levels [hazard ratio (HR) 4.384, p < 0.001] and high and very high WPSS risk group (HR 3.855, p = 0.014) were significantly associated with a worse survival, whereas a response to azacitidine was identified as a good prognostic factor for survival (HR 0.224, p = 0.019). In conclusion, while the pretreatment risk group and initial LDH levels were both confirmed as important prognostic factors to predict the outcomes for patients treated with azacitidine, more effective therapies are still needed to prevent disease progression.

ACUTE DISSEMINATED ENCEPHALOMYELITIS FOLLOWING VACCINATION AGAINST HUMAN PAPILLOMA VIRUS

We report a case of severe encephalitis evolving shortly after administration of a new vaccine against human papilloma virus (HPV) recently approved for the prevention of diseases caused by HPV types 6, 11, 16, and 18. ### Case report. A 20-year-old woman developed headache, nausea, vomiting, and diplopia within 28 days of the second immunization with the quadrivalent HPV vaccine Gardasil®. She did not report signs of a preceding infection. On neurologic examination, the patient was without focal deficits. Cranial MRI showed multifocal white matter edema with abnormal patchy or streaky contrast enhancement along deep venular structures. CSF analysis disclosed 80 cells/μL consisting of lymphocytes and 2% eosinophils, increased total protein (0.8 g/L) and immunoglobulin M ratio, no oligoclonal bands (OCB), and normal lactate. Serology and PCR ruled out an infectious etiology with negative testing for Borrelia, Treponema, Listeria, herpes simplex virus 1/2, varicella zoster virus, human herpesvirus 6, HIV, enterovirus, and arbovirus. Laboratory screening revealed elevated antinuclear (1:320; ANA) and antithyroglobulin (445 IU/mL; normal ≤60) antibodies, and increased thyroid-stimulating hormone (5.2 mU/L; normal 0.4–4). ANA subspecificities, neutrophil cytoplasmic, cardiolipin, and aquaporin-4 antibodies, and routine laboratory studies were negative. …

Phlegmasia cerulea dolens: A rare cause of compartment syndrome

The patient, who had Crohn’s disease, had undergone a right hemicolectomyof the terminal ileum2weekspreviously forDukesC adenocarcinoma. He was on warfarin for a pre-operative left subclavian venous thrombosis and had an inferior vena cava filter in situ, as he had developed a right popliteal venous thrombus whilst warfarinised. His international normalised ratio on the day of attendance was 2.6 and there was no history of trauma. Clinical examination found the patient to be pale, pyrexic and tachycardic with awarm,oedematous, exquisitely tender, swollen left lower leg. His pain was exacerbated by all movements, he had normal sensation and arterial pulses and no cellulitis or erythema was visible. Plain radiographs of the lower legwere normal andhis blood tests demonstrated a white cell count 16; D-dimer 6000, C-reactive protein 228 with normal creatine kinase and lactate. A magnetic resonance imaging scanwas performeddemonstrating oedematous change within the musculature of the posterior compartment with interfascial and subcutaneous fluid and possible popliteal and proximal calf vein deep venous thrombosis. The differential diagnosis postulated was either compartment syndrome, myositis or necrotising fasciitis (Fig. 1). The patient was thought to have an impending compartment syndrome of unknown cause and underwenturgent lower legexplorationand fasciotomies.At surgery, all of the compartments of the limb were tense and bulging; most

Leigh Disease with Brainstem Involvement in Complex I Deficiency due to Assembly Factor NDUFAF2 Defect

Mitochondrial NADH: ubiquinone oxidoreductase (complex I) deficiency accounts for most defects in mitochondrial oxidative phosphorylation. Pathogenic mutations have been described in all 7 mitochondrial and 12 of the 38 nuclear encoded subunits as well as in assembly factors by interfering with the building of the mature enzyme complex within the inner mitochondrial membrane. We now describe a male patient with a novel homozygous stop mutation in the NDUFAF2 gene. The boy presented with severe apnoea and nystagmus. MRI showed brainstem lesions without involvement of basal ganglia and thalamus, plasma lactate was normal or close to normal. He died after a fulminate course within 2 months after the first crisis. Neuropathology verified Leigh disease. We give a synopsis with other reported patients. Within the clinical spectrum of Leigh disease, patients with mutations in NDUFAF2 present with a distinct clinical pattern with predominantly brainstem involvement on MRI. The diagnosis should not be missed in spite of the normal lactate and lack of thalamus and basal ganglia changes on brain MRI.

Involved-Lesion Radiation Therapy After Chemotherapy in Limited-Stage Head-and-Neck Diffuse Large B Cell Lymphoma

To report treatment outcomes after combined-modality therapy in patients with Stage I/II head-and-neck (HN) diffuse large B cell lymphoma (DLBL). Eighty-six eligible patients received sequential chemotherapy and involved-lesion radiation therapy from 1995 to 2006. After a median of four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-plus-CHOP chemotherapy, a median of 41.4 Gy was delivered to the known initial gross lesion with adequate margin (2 to 3 cm). After a median follow-up of 57 months, eight treatment failures were observed: distant metastasis in 8 patients; and locoregional failure in 4 patients. Among the 4 patients with locoregional failure, 3 presented with in-field failures, and 1 both in-field and out-of-field failure (contralateral neck). Rates of overall survival (OS) and freedom from progression (FFP) at 10 years were 74.1% and 88.9%, respectively. There was no severe side effect except 1 patient with Grade 3 mucositis during and after completion of radiation therapy. Multivariate analyses showed that absence of B symptom (p = 0.022) and normal lactate dehydrogenase (p = 0.017) were related to favorable OS, age >60 years (p = 0.033) was related to favorable FFP, and international prognostic index of 0 or 1 was related to favorable OS (p = 0.003) and FFP (p = 0.03). This study demonstrated that patients with Stage I/II HN DLBL did not need whole-neck irradiation. Involved-lesion radiation therapy might reduce radiation toxicity with favorable treatment results.

Hyperlactatemia in critical illness and cardiac surgery

We read with interest the article by Nichol and colleagues [1] in a recent issue of Critical Care. Their study of more than 7,000 medical and surgical patients supports the claim that an admission plasma lactate level in the upper normal range is associated with increased mortality. However, we are concerned about the lack of data regarding patient baseline characteristics. Specifically, although 3,166 and 1,614 patients had diagnoses of 'surgery' and 'cardiac/vascular', respectively, it is likely, but not stated, that numerous patients were admitted following cardiac surgery. This is of great importance as changes in lactate in this patient group are not homogenous in nature. In post-cardiac surgery patients, early hyperlactatemia and late hyperlactatemia (LHL) differ in both risk profile and physiological rationale. Early hyperlactatemia (on intensive care unit arrival) is associated with adverse outcome. This association is not seen in the 10% to 20% of patients who develop LHL (pooled odds ratio [OR] of death with LHL in two published trials 1.39, 95% confidence interval [CI] 0.28 to 7.04) [2-4]. Moreover, in our recent single-center review of prospectively collated data from 529 post-cardiac surgical patients in a tertiary Australian cardiac surgical intensive care unit, 25% developed LHL (>2.53 mmol/L). When compared with patients with a normal lactate profile, patients with LHL showed no increase in hospital mortality (OR 0.57, 95% CI 0.07 to 5.05) (unpublished data). Therefore, we believe that inclusion of such patients in studies of lactate in critical illness should be avoided and, as in the study by Nichol and colleagues, may actually weaken any association demonstrated between lactate levels and hospital mortality.

Restricted peri-operative fluid administration adjusted by serum lactate level improved outcome after major elective surgery for gastrointestinal malignancy

Our objective was to compare the effect of a restricted intravenous fluid regimen adjusted by serum lactate level with a standard restricted regimen on complications after major elective surgery for gastrointestinal malignancy. This is a randomized, observer-blinded, single-center trial conducted across a time span of 13 months. A total of 299 patients were allocated to either a restricted intravenous fluid regimen with supplementary intravenous fluids given based on serum lactate level (group A) or a standard restricted regimen (group R). In group A, the serum lactate level was monitored closely postoperatively to maintain a normal pre-operative serum lactate level. Group R involved patients treated with a restricted fluid regimen in whom additional fluid and electrolytes were administered when deemed necessary based on the usual clinical criteria. The primary outcome measure was complications; the secondary measures were death and adverse effects. Additional fluid supplementation was needed in some patients in both groups (group A [28%] vs group R [26%]). In group A, the time for additional fluid infusion occurred earlier in the postoperative period than group R. Patients in group A received their first supplementary fluid treatment within the first 12 h more commonly than those in group R (74% vs 37%, respectively; P < .004). The regimen adjusted by serum lactate decreased systemic postoperative complications in group A versus group R (10% vs 22%, respectively; P = .023) but not overall total complications (23% vs 33%, respectively; P = .090). In contrast, in patients who required additional fluid infusion, the difference in complications between the 2 groups was greater (overall complication, 45% vs 85%, respectively; P = .023; major complication, 16% vs 44%, respectively; P = .018; systemic complications, 19% vs 63%, respectively; P = .001). One patient died in group A and 4 died in group R (1% vs 4%, respectively; P = .206). A fluid-restricted regimen after elective gastrointestinal operations for malignancy may lead to fluid insufficiency and low tissue perfusion in up to 28% of patients. Close monitoring of serum lactate levels with adjustment of intravenous fluid administration intraoperatively and in the early postoperative period may improve the early detection and correction of inadequate tissue perfusion, thereby decreasing the rate of complications.

Serial plasma lactate measurements in haematological patients with neutropenic fever

Elevated plasma lactate and impaired lactate clearance have been associated with poor outcome in patients with severe sepsis. No data are available on the kinetics or prognostic value of plasma lactate in haematological patients with neutropenic fever. A total of 70 haematological patients with 94 episodes of neutropenic fever were included into this prospective study during the period 2006-2008. The median age of the patients was 56 (range 18-70) y. Nineteen patients received therapy for acute myeloid leukaemia and 51 patients received autologous stem cell transplantation. At the onset and on days 1, 2, and 3 of each neutropenic fever episode, plasma lactate and serum C-reactive protein were determined. Criteria for severe sepsis were fulfilled in 13 neutropenic episodes. An elevated plasma lactate level was infrequent at the start of neutropenic fever (5%). There was no association of lactate level with the development of severe sepsis. Two patients died of septic shock, 1 patient with an exceptionally high and increasing level of lactate and the other patient with a normal lactate level. An elevated plasma lactate level at the start of neutropenic fever is not common and does not indicate severe sepsis, but high lactate and an impaired lactate decrease may signify a fatal course in neutropenic fever.

D-Lactic Acidosis Presenting in Crohnʼs Disease with Short Bowel Syndrome

Purpose: D-lactic acidosis is a rare form of lactic acidosis that can occur in individuals following jejuno-ileal bypass surgery or short bowel syndrome. Symptoms typically occur after ingestion of a high-carbohydrate meal due to glucose and starch being metabolized by the colon into D-lactic acid-with subsequent absorption into circulation and systemic acidemia. D-lactate accumulates as L-lactate dehydrogenase is unable to convert this type of lactate into pyruvate. Methods: N/A Results: 48-year-old female with Crohn's disease s/p subtotal small bowel resection 3 years ago, with resultant short bowel syndrome presented with persistent weight loss, abdominal pain, postprandial nausea, headache, confusion, blurred vision, dizziness with ataxia, intermittently ongoing for several months. She complained of feeling as if she was intoxicated, although she denied any alcohol ingestion. She had a history of intestinal intussusception and CT enterography ordered 9 days prior showed dilated loops of distal small bowel consistent with partial small bowel obstruction. Lab work revealed normal CBC, LFTs, but also metabolic acidosis with serum bicarbonate at 16mmol/L, with anion gap of 12; VBG showed pH 7.15, pCO2 44mm Hg, pO2 17mmHg, bicarb 15mmol/L. However, serum lactic acid level was normal at lmmol/L. Serum D-lactate was drawn showing elevation to 6.15mmol/L — thus confirming the diagnosis of D-lactic acidosis. She was given fluids, bicarbonate and placed on Flagyl and Levaquin for bacterial overgrowth. Her acidosis along with her neurological symptoms shortly thereafter resolved. PEG tube was placed and she was started on enteral feeding for malnutrition. Her partial SBO also resolved with supportive care. Conclusion: In individuals with intact small intestine, few carbohydrates and starch reach the colon. In patients with short bowel syndrome, glucose reaches the colon, and when in combination with bacterial overgrowth (usually gram-positive anaerobes)—D-lactic acid is formed. Episodic metabolic acidosis can occur after meals with neurological symptoms including altered mental status, dysarthria, ataxia, and concentration/memory difficulties. Patients often appear drunk in the absence of ethanol consumption. D-lactic acidosis should be considered in short bowel patients with an anion gap metabolic acidosis, a normal serum lactate; characteristic neurological findings and acidosis following food intake. Diagnosis is confirmed with special enzymatic assay measuring serum D-lactate. Treatment involves sodium bicarbonate, low carbohydrate diet and antimicrobial agents to decrease bacteria overgrowth.

Prognostic Factors in Metastatic Melanoma Patients Treated with Biochemotherapy and Maintenance Immunotherapy

With no U.S. Food and Drug Administration-approved standard therapy other than high-dose interleukin-2 and dacarbazine for metastatic melanoma, biochemotherapy has shown promise, with long-term survival in selected patients. We felt that the study of prognostic factors would determine which patients might benefit from this intensive therapy. One hundred thirty-five consecutive patients with metastatic melanoma treated with decrescendo biochemotherapy followed by maintenance immunotherapy over 5 years were retrospectively studied to determine the most important prognostic factors for both overall survival and progression-free survival. The median overall survival (OS) time was 16.6 months, with 1-year and 5-year survival rates of 70% and 28%, respectively. The median progression-free survival (PFS) time was 7.6 months, with 15% of patients progression free at 5 years. PFS curves showed no relapses after 30 months, so remissions were durable. For OS, a performance status score of zero, normal lactate dehydrogenase (LDH) level, stage M1a, and nonvisceral sites of metastasis were favorable factors. The group with normal LDH levels and skin or nodes as one of their metastatic sites had a relatively good prognosis, with median survival time of 44 months and an estimated 5-year survival rate of 38%. Conversely, patients with an elevated LDH level without any skin or nodal metastases had a poor prognosis, with no long-term survivors. Metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy who have either a normal LDH level or skin or nodes as one of their metastatic sites may have durable remissions of their disease, and this therapy should be studied further in these groups.

SURF1 missense mutations promote a mild Leigh phenotype

SURF1 gene mutations are the most common cause of Leigh syndrome (LS), a rare progressive neurodegenerative disorder of infancy, characterized by symmetric necrotizing lesions and hypervascularity in the brainstem and basal ganglia, leading to death before the age of 4 years. Most of the reported mutations create premature termination codons, whereas missense mutations are rare. The aim of the study was to characterize the natural history of LS patients carrying at least one missense mutation in the SURF1 gene. Nineteen such patients (8 own cases and 11 reported in the literature) were compared with a reference group of 20 own c.845_846delCT homozygous patients, and with other LS(SURF-) cases described in the literature. Disease onset in the studied group was delayed. Acute failure to thrive and hyperventilation episodes were rare, respiratory failure did not appear before the age of 4 years. Dystonia, motor regression and eye movement dissociation developed slowly. The number of patients who survived 7 years of life totaled 9 out of 15 (60%) in the 'missense group' and 1 out of 26 (4%) patients with mutations leading to truncated proteins. (i) The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients, (ii) normal magnetic resonance imaging (MRI) findings, normal blood lactate value, and only mild decrease of cytochrome c oxidase (COX) activity are not sufficient reasons to forego SURF1 mutation analysis in differential diagnosis.

Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3–10.0) after progression and 14.4% (95% CI 10.5–18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status ( P < 0.001) and a non-abdominal primary site ( P = 0.034 for progression, and P = 0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse ( P < 0.001). Probability of survival increased by era of diagnosis. Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.

Diffusion‐weighted imaging and magnetic resonance spectroscopy findings in a case of neonatal hypoglycaemia

Rachel E Musson MBCHB MRCP, Ruth Batty MBBS MRCP FRCR, Santosh R Mordekar MD MRCP MRCPCH, Iain D Wilkinson PHD ARCP FIPEM, Paul D Griffiths PHD FRCR, Daniel JA Connolly BSC MRCP FRCR 1 Radiology Department, Royal Hallamshire Hospital, Sheffield, UK. 2 Department of Neurology, Sheffield Children's Hospital, Sheffield, UK. 3 Academic Unit of Radiology, University of Sheffield, Sheffield, UK. 4 Radiology Department, Sheffield Children's Hospital, Sheffield, UK. Correspondence to: rachel.musson@sth.nhs.uk

Diagnostic et nosologie des lymphomes au sein des hémopathies

Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18–60 years, with stage I–II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0–1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1–5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of −5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42–100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94–99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.Deutsche Krebshilfe.