Outpatient secondary care pathways for head and neck cancer referral result in patient delays for cancer treatment.

INTRODUCTION: The majority of head and neck cancer referrals are received through primary care. A proportion of cancer referrals are received through secondary care specialties. Local delivery plan (LDP) targets in Scotland for cancer investigation are set at 31 days for diagnosis and 62 days to start treatment. The aim was to audit referrals made through non-primary care pathways compared with the standard primary care pathways against LDP targets. METHODS: New head and neck cancer patients between 1 January 2014 and 1 January 2019 were included. Pathway points were recorded between referral to outpatient clinic, time to multidisciplinary team discussion (MDT) and finally MDT to treatment. RESULTS: 1,276 new patient referrals were received over a 5-year period. Of these, 136 (10%) were referred via non-primary care pathways. The mean time for urgent suspicion of cancer (USoC) referrals to start treatment was 77 days (15 days over target) and for outpatient secondary care referrals was 102 days (40 days over target) (p<0.05). When treatment intent was considered, 841/1,131 (75%) of patients referred via primary care were treated curatively compared with 49/99 (49%) (p<0.05) of patients referred through the secondary outpatient pathway. CONCLUSION: Patients with head and neck cancer referred from other outpatient specialties face delays commencing cancer treatment and are also associated with a greater likelihood of being treated with palliative intent.

Malnutrition, zinc supplementation and catch-up growth: changes in insulin-like growth factor I, its binding proteins, bone formation and collagen turnover.

OBJECTIVE: Zinc may be a limiting factor in restricting catch-up growth in severely malnourished children. This study had two aims: (i) to examine the effect of different zinc supplementation regimens on IGF-I, its binding proteins and on markers of bone and collagen turnover in severely malnourished children and (ii) to investigate mechanisms underlying catch-up growth by examining changes in these markers during nutritional rehabilitation, their inter-relationships and their relationships with ponderal and linear growth. DESIGN: Double-blind randomized intervention study of three regimens of oral zinc supplementation. PATIENTS: One hundred and forty-one children, aged 6-36 months, mean (SD) age 15.4 (8.7) months, with day 1 weight-for-height SD score (whz) -2.6 (0.93) and height-for-age SD score (haz) -3.79 (1.29). MEASUREMENTS: Weight, height, lower leg length (by knemometry) at 15-day intervals from day 1 to day 90 of nutritional rehabilitation. Blood collection on days 1, 15 and 30 for IGF-I, IGFBP3, IGFBP2, bone alkaline phosphatase (BAP, osteoblast marker), procollagen type I C-terminal propeptide (PICP, marker of type I collagen synthesis), procollagen type III N-terminal propeptide (P3NP, marker of soft tissue type III collagen synthesis) and type I collagen telopeptide (ICTP, marker of type I collagen breakdown). RESULTS: There was early rapid weight gain during refeeding, whereas height gain occurred later in the trial. IGF-I, IGFBP3, BAP, PICP and P3NP were low or very low on day 1 compared to well-nourished age-matched European children, and all increased within 15 days (P < 0.001), with PICP and P3NP reaching levels higher than European norms. IGFBP2 and ICTP were high on day 1 and decreased over the same period (P < 0.001). There were no differences in anthropometric outcome or marker responses among zinc regimens. Day 1 whz was correlated with BAP, PICP and P3NP (P < 0.001). Changes in IGF-I, IGFBP3, BAP, PICP and P3NP over 30 days correlated with ponderal growth (whz change) over the same period (all P < 0.01). However, changes in these markers over 30 days correlated better with lower leg growth (all P < 0.01) and linear growth (haz change, P < 0.01 for PICP and P3NP, P < 0.05 for IGFBP3) measured over 90 compared with 30 days. At most time points, there were strong positive correlations (i) among IGF-I, IGFBP3, BAP, PICP and P3NP (P < 0.01) and (ii) between IGFBP2 and ICTP (P < 0.01). Conversely, IGFBP2 was negatively correlated with IGF-I, IGFBP3, BAP, PICP and P3NP at most time points (P < 0.01). CONCLUSIONS: We found no difference among zinc regimens in growth, IGF-I and its binding proteins or markers of bone and collagen turnover. Severe malnutrition was associated with low rates of bone and collagen synthesis and high rates of collagen degradation, and nutritional rehabilitation was associated with full or partial 'normalization' of the markers studied. Early weight gain and subsequent linear growth were associated with early increments in IGF-I, IGFBP3 and markers of bone and collagen formation. The study of these markers has provided additional insights into the mechanisms of the effects of malnutrition and refeeding on growth.

Zinc and rehabilitation from severe protein-energy malnutrition: higher-dose regimens are associated with increased mortality.

A randomized, double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition, with particular reference to linear growth. One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka, Bangladesh, and randomly assigned to receive elemental zinc by mouth, 1.5 mg/kg for 15 d, 6.0 mg/kg for 15 d, or 6.0 mg/kg for 30 d, and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length, midupper arm circumference, subscapular and triceps skinfold thicknesses, and change in height-for-age, weight-for-age, and weight-for-height z scores. Higher zinc doses were not associated with significant change in any anthropometric measurement, but mortality was significantly greater in children who received high-dose zinc (6.0 mg/kg) initially as opposed to those who received low-dose zinc supplementation (1.5 mg/kg) (Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53; 95% CI: 1.09 < risk ratio < 18.8). We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children.

RNA splicing regulates the activity of a SH2 domain-containing protein tyrosine phosphatase.

A cDNA which encodes a protein tyrosine phosphatase with two src homology 2 (SH2) domains was isolated from a rat brain cDNA library. This phosphatase appears to be a rat homologue of PTP1D based on its amino acid sequence. The gene is expressed in a variety of tissues, and its mRNA is enriched in the brain, skeletal muscle, and lung. An RNA splice variant (PTP1Di) was also isolated which has four additional amino acid residues (Ala-Leu-Leu-Gln) in the catalytic domain. The catalytic domains of PTP1D and PTP1Di were expressed in Escherichia coli as glutathione S-transferase fusion proteins and purified to near homogeneity. Whereas both PTP1D and PTP1Di had catalytic activity, the Vmax of PTP1Di relative to that of PTP1D was 8-fold lower for para-nitrophenylphosphate, 20-fold lower for nicotinic acetylcholine receptor, and 14-fold lower for myelin basic protein. The Km values of PTP1Di were lower than those of PTP1D for both nicotinic acetylcholine receptor and myelin basic protein, suggesting a higher affinity of PTP1Di for a protein substrate. These two forms also differed in optimum pH for para-nitrophenylphosphate and sensitivity to the inhibitory effects of vanadate, molybdate, and spermidine. In order to see if this insert would affect the catalytic activity of other related phosphatases, the 4-amino acids were inserted in the corresponding region of the catalytic domain of PTP1C. Whereas both the wild type and PTP1Ci which contained the 4-amino acid insert dephosphorylated para-nitrophenylphosphate, nicotinic receptor, and myelin basic protein, the enzyme activity of PTP1Ci was only 11-24% of that of PTP1C wild type. These results demonstrate that the 4-amino acid insert in the catalytic domains of PTP1D down-regulates its phosphatase activity and suggests that RNA splicing may serve as a regulatory mechanism of protein tyrosine phosphatase activity.