Patterns of Care in the Administration of Neo‐adjuvant Chemotherapy for Breast Cancer. A Population‐Based Study

Neo‐adjuvant chemotherapy (NAC) is used to facilitate radical surgery for initially irresectable or locally advanced breast cancer. The indication for NAC has been extended to clinically node negative (cN0) patients in whom adjuvant systemic therapy is foreseen. A population‐based study was conducted to evaluate the increasing use of NAC, breast conserving surgery (BCS) after NAC and timing of the sentinel node biopsy (SNB). All female breast cancer patients, treated in 10 hospitals in the Eindhoven Cancer Registry area in the Netherlands between January 2003 and June 2012 were included (N = 18,427). In total, 1,402 patients (7.6%) received NAC. The administration increased from 2.5% in 2003 to 13.0% in 2011 (p < 0.001). Use of NAC increased from 0.5% to 2.3% for cT1 tumors, from 2.8% to 27.0% for cT2, from 30.6% to 70.9% for cT3, and from 40.5% to 58.1% for cT4 tumors (p < 0.001). In cN0 patients, use of NAC increased from 1.0% to 4.4% and in clinically node positive patients from 12.0% to 57.5% (p < 0.001). Downsizing of the tumor and BCS are achieved increasingly. In 2011, in three hospitals NAC was administered in <10% of patients, in five hospitals in 10–15% and in two hospitals the proportion of patients receiving NAC was >20% (p < 0.001). Of the 1,402 patients with NAC, 495 patients underwent SNB, 91.5% of whom prior to NAC. In the Netherlands up to one in eight patients receive NAC. The administration of NAC and the percentage of BCS increased over the past decade, especially in cT2 tumors. Considerable hospital variation in the administration of NAC exists.     

Treatment with 3‐aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation

Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3‐Aminobenzamide (3‐AB), an inhibitor of poly(ADP‐ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3‐AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3‐AB: 1 hour WI + 3 hours EVLP + 3‐AB (1 mg^.mL^?1) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin‐6 and 10 (IL‐6, IL‐10) in BAL and plasma. 3‐AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3‐AB also attenuated the IL‐6/IL‐10 ratio in BAL and plasma, supporting an improved balance between pro‐ and anti‐inflammatory mediators. Thus, 3‐AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.     

[11C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain

The PET tracer [¹¹C]5-hydroxytryptophan ([¹¹C]5-HTP), which is converted to [¹¹C]5-hydroxytryptamine ([¹¹C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [¹¹C]5-HTP in rat? Male rats were scanned with [¹¹C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [¹¹C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [¹¹C]5-HTP uptake, and the k₃. This was unexpected as NSD 1015 directly inhibits the enzyme converting [¹¹C]5-HTP to [¹¹C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [¹¹C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.     

Reliability of a functional magnetic resonance imaging task of emotional conflict in healthy participants

Task‐based functional neuroimaging methods are increasingly being used to identify biomarkers of treatment response in psychiatric disorders. To facilitate meaningful interpretation of neural correlates of tasks and their potential changes with treatment over time, understanding the reliability of the blood‐oxygen‐level dependent (BOLD) signal of such tasks is essential. We assessed test–retest reliability of an emotional conflict task in healthy participants collected as part of the Canadian Biomarker Integration Network in Depression. Data for 36 participants, scanned at three time points (weeks 0, 2, and 8) were analyzed, and intra‐class correlation coefficients (ICC) were used to quantify reliability. We observed moderate reliability (median ICC values between 0.5 and 0.6), within occipital, parietal, and temporal regions, specifically for conditions of lower cognitive complexity, that is, face, congruent or incongruent trials. For these conditions, activation was also observed within frontal and sub‐cortical regions, however, their reliability was poor (median ICC < 0.2). Clinically relevant prognostic markers based on task‐based fMRI require high predictive accuracy at an individual level. For this to be achieved, reliability of BOLD responses needs to be high. We have shown that reliability of the BOLD response to an emotional conflict task in healthy individuals is moderate. Implications of these findings to further inform studies of treatment effects and biomarker discovery are discussed.     

Comparison of selective media for isolation of Campylobacter jejuni/coli

A comparison of Skirrow's, Butzler's, Blaser's, Campy-BAP and Preston media for Campylobacter spp was made using human, animal and environmental specimens. Butzler's medium gave the lowest isolation rate and Preston medium, which was the most selective, the highest isolation rate. Enrichment culture using Preston enrichment broth gave a higher isolation rate than direct plating onto Preston medium.     

Intramuscular mixed tumour with clonal chromosomal changes

 A case of an entirely intramuscular mixed tumour occurred in an 82-year-old man, who presented with a large mass in the region of the right triceps muscle. A lobulated tumour was seen, with plump, round epithelioid cells embedded in a chondromyxoid stroma. Immunohistochemical examination showed strong S100 protein and pancytokeratin positivity in most of the tumour cells. Cytogenetic analysis revealed complex clonal chromosomal changes: 47, XY, +i (2) (q10), –15, der (17)t(15;17) (q11; p12), +r. Differential diagnosis against extraskeletal myxoid chondrosarcoma (EMC) may be problematic, particularly in an incisional biopsy. Chromosomal analysis can be very helpful in solving this problem, since EMC shows a specific reciprocal chromosome translocation characterised as t (9;22) (q22–31) (q11–12). Received: 8 July 1998 / Accepted: 22 September 1998     

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.