Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy

Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m², 2–5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m², 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later.     

What does fetal autopsy unmask in oligohydramnios?

Objective: We aimed to determine the value of autopsy in fetuses with antenatally diagnosed oligohydramnios.

Patients and methods: We evaluated all fetal losses over a period of 6.5 years. Those with oligohydramnios on antenatal scan were critically analyzed. Oligohydramnios was defined as amniotic fluid index of less than five objectively or as an obvious lack of liquor at subjective assessment. A detailed postmortem examination was carried out in all the fetuses after obtaining an informed consent.

Results: Fetal autopsy was conducted in 255 cases. Fifty-five (21.5%) fetuses were diagnosed to have oligohydramnios on antenatal ultrasonography. On analysis of antenatal causes of oligohydramnios, maternal/placental factors were noted in 18%, ultrasound findings known to affect amniotic fluid in 27% while cause remained unidentified in 54.5% of cases. On autopsy, fetal malformations were noted in 61.8% cases, intrauterine growth retardation in 21.8% fetuses and no obvious malformations in 16.3% fetuses. Renal anomalies were noted in 40% cases and non-renal malformations in 21.8% cases.

Conclusion: The postmortem examination helped us to identify the cause of fetal loss in 46 (83.6%) fetuses with antenatal oligohydramnios. A working diagnosis could not have been established without autopsy in 19 (34.5%) cases.     

Coinheritance of two rare genodermatoses (Papillon-Lefèvre syndrome and oculocutaneous albinism type 1) in two families: a genetic study

The co-occurrence of two rare recessive genetic conditions in apparently unrelated individuals or families is extremely rare. Two geographically distant and apparently unrelated families were identified in which individuals were simultaneously affected by two rare recessive mendelian syndromes, Papillon-Lefevre syndrome and type 1 oculocutaneous albinism. The families were tested for mutations in the causative genes, cathepsin C (CTSC) and tyrosinase (TYR), respectively, by direct sequencing. To assess the relationship of the two families, both families were tested for polymorphisms at eight microsatellite markers spanning both CTSC and TYR loci. Independent mutations (c.318-1G-->A and c.817G-->C/p.W272C) were identified in CTSC and TYR, respectively, that were shared by the affected individuals in both families. The two affected genes lie close together on chromosome bands 11q14.2-14.3, and studies with linked genetic markers suggested that the families shared a small chromosomal segment carrying both mutations that had been transmitted intact from a remote common ancestor. The co-occurrence of the two rare diseases in multiple families depends on their shared chromosomal location, but not on any shared pathogenic mechanism.     

Head-up tilt testing in children and young people: a retrospective observational study

Aim: Head‐up tilt testing (HUTT) is the gold standard investigation for adults with transient loss of consciousness (TLOC), but it is controversial in children and young people, because of a lack of systematic investigation and because the test can be uncomfortable. As it was introduced recently for children attending our hospital, we undertook a retrospective registered clinical audit of its usefulness. Methods: The medical records of 100 consecutive patients aged less than 18 years undergoing HUTT from October 2001 to December 2008 were reviewed. Information about their episodes, prodromes, triggers, previous tests, indications for the HUTT, the HUTT and clinical outcomes was extracted. Results: Children were 6–17 years old; 68/100 were female. In 32/100, no trigger was reported. The most reported triggers included standing up (20%) and prolonged standing (18%). Dizziness (64%) and altered vision (39%) were the most experienced prodromal symptoms. Twenty‐eight of 100 had a positive test, with reproduction of symptoms in 24. Seventeen of 100 tests were negative but symptomatic; 55/100 had a negative asymptomatic test. In 17/28 positive HUTTs, the tilt confirmed the suspected diagnosis and elucidated the mechanism. Two of 28 were started on medication. However, in 9/28, neither was the diagnosis clarified nor was therapy instigated. Conclusions: Potentially useful information about the TLOC was obtained in 45/100 cases. The 17/100 with negative but symptomatic results may have had medically unexplained TLOC or emotional attacks, although without concurrent electroencephalogram, some uncertainty remains. Therefore, a new protocol with video–electroencephalogram–polygraphy and beat‐to‐beat finger blood pressure recording, and more explicit clinical reporting is being developed.     

Horizontal transmission of group B streptococcus in a neonatal intensive care unit

The incidence of early-onset group B streptococcal (GBS) sepsis in the neonatal population has decreased substantially since the introduction of maternal intrapartum antibiotic prophylaxis and routine prenatal screening. However, these strategies have not reduced the incidence of late-onset GBS infections. Additional research pertaining to the transmission of late-onset GBS infections is required to develop effective preventive methods. The present report describes probable horizontal transmission of late-onset GBS infection among three infants in a neonatal intensive care unit. GBS strain confirmation was based on the microbiological picture, antibiogram and pulsed-field gel electrophoresis. These cases highlight the morbidity associated with late-onset GBS disease and the importance of considering horizontal transmission as an etiological factor in GBS infection in the newborn period. Further studies assessing horizontal transmission in late-onset GBS disease may improve prevention and early intervention.     

Aortic valve calcification - a commonly observed but frequently ignored finding during CT scanning of the chest

Aim: To describe the frequency and severity of Aortic valve calcification (AVC) in an unselected cohort of patients undergoing chest CT scanning and to assess the frequency with which AVC was being reported in the radiology reports. Methods and Results: Consecutive CT scan images of the chest and the radiological reports (December 2009 to May 2010) were reviewed at the district general hospital (DGH). AVC on CT scan was visually graded on a scale ranging from 0 to IV (0 = no calcification, IV = severe calcification). Total of 416 (232 male; 184 female) CT chest scans [Contrast enhanced 302 (72%), unenhanced 114 (28%)] were reviewed. Mean age was 70.55 ± 11.48 years. AVC in CT scans was identified in 95 of the 416 patients (22.83%). AVC classification was as follows: Grade I: 60 (63.15%), Grade II: 22 (23.15%), Grade III: 9 (9.47%), Grade IV: 4 (4.21%). Only one CT report mentioned AVC. Only 31 of 95 AVC had Transthoracic echocardiogram (TTE). The interval time between CT scan and TTE was variable. Conclusion: Aortic valve calcification in CT chest scans is a common finding and studies have shown that it is strongly related to the presence and severity of aortic valve disease. As CT scans are considered as a valuable additional screening tool for detection of aortic stenosis, AVC should always be commented upon in the radiology reports. Furthermore, patients with at least Grade III and IV AVC should be sent for TTE.     

A retrospective cohort study of dermatological problems observed in paediatric intensive care unit

Background Dermatological manifestations are often encountered in paediatric intensive care units (PICU). Spectrum of dermatological problems that may arise in critically ill children in intensive care unit remains unknown. Objectives The aim of this study was to find out the burden of dermatological problems and to describe the proportional distribution of paediatric dermatoses in ICU set‐up. Methods In a retrospective cohort study, we analysed all types of paediatric dermatological conditions manifesting in children admitted to a tertiary level ICU in South India. Results During the study period of 25 months, 1180 new cases were admitted to PICU. A total of 318 children with 361 skin manifestations were observed. Majority of the skin lesions were minor and were secondary to systemic disease. Infection was the leading cause of dermatoses in ICU. Dengue infection was detected in 64% of total cases included in the study. Stevens–Johnson syndrome was the only primary dermatological condition leading to PICU admission in the present cohort. Conclusions The spectrum and proportional distribution of skin conditions in children differ from adult ICU‐data. Further large‐scale investigations are needed to define the characteristics and distribution of infections along with other disease conditions leading to ICU‐admissions and mortality among critically ill paediatric patients.     

Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation.

A classical twin study was performed to assess the relative contribution of genetic and environmental factors to bone metabolism, calcium homeostasis, and the hormones regulating them. It was examined further whether the genetic effect is menopause dependent. The subjects were 2136 adult twins (98.3% female): 384 monozygotic (MZ) and 684 dizygotic (DZ) twin pairs. The intraclass correlations were calculated, and maximum likelihood model fitting was used to estimate genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in MZ twin pairs. The heritabilities (95% CIs) obtained from model fitting for hormones regulating bone metabolism and calcium homeostasis were parathyroid hormone (PTH), 60% (54-65%); 25-hydroxyvitamin D [25(OH)D]; 43% (28-57%), 1,25-hydroxyvitamin D [1,25(OH)], 65% (53-74%); and vitamin D binding protein 62% (56-66%). The heritabilities (95% CIs) for markers of bone formation also were assessed; bone-specific alkaline phosphatase (BSAP), 74% (67-80%), and osteocalcin, 29% (14-44%); marker of bone resorption deoxypyridinoline (DPD), 58% (52-64%); and measure of calcium homeostasis 24 h urine calcium, creatinine (Cr), 52% (41-61%). The magnitude of genetic influence differed with menopause for most variables. This study provides evidence for the importance of genetic factors in determining bone resorption and formation, calcium excretion, and the hormones regulating these processes. It shows for the first time a clear genetic effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion. The genes controlling bone hormones and markers are likely to be useful therapeutic and diagnostic targets.