Association between pretreatment haemoglobin levels and morphometric characteristics of the tumour, response to neoadjuvant treatment and long-term outcomes in patients with locally advanced rectal cancers

Aim The study was carried out to investigate whether pretreatment haemoglobin (Hb) levels act as a biomar- ker in the management of patients with locally advanced rectal cancer. Method\ud We prospectively collected data on all patients within our cancer network with localized low rectal cancer treated with preoperative radiotherapy/chemora- diotherapy at Mount Vernon Centre for Cancer Treat- ment between March 1994 and July 2008. Pretreatment Hb level was assessed as an independent variable for the whole study sample and dichotomised at a value of 12 g/dl. A multivariate analysis of covariance (MANCOVA) was conducted on parameters that had significant association on univariate analysis of covariance (ANCOVA) and cor- relational (Kendall tau/Pearson) analyses. Kaplan – Meier survival analysis and Cox proportional hazard models were used to determine significant prognostic markers. Statistical significance was set at 0.05. Results 463 patients (male/female 2:1; median age = 66 years, interquartile range = 56.5 – 73.0) were included in the analysis. There was significant tumour response of T stage ( P < 0.001) and N stage ( P < 0.001), with 17.6% of patients achieving a pathological complete response. Pretreatment Hb value was inversely related to the craniocaudal vertical tumour length ( P = 0.02) and pretreatment T stage of the tumour ( P = 0.01). Patients with Hb levels of < 12 g/dl and moderately differenti- ated adenocarcinoma were less responsive. Local recur- rence was more common in patients with a pretreatment Hb of < 12 g/dl (hazard ratio = 1.78) over a median follow up of 24 months, but this was not statistically significant ( P = 0.08). Conclusion The pretreatment Hb level might be used as a biomarker of rectal tumour morphology, response to neoadjuvant chemoradiation and risk of local recur- renc

The effect of ultrasound-related stimuli on cell viability in microfluidic channels

Background: In ultrasonic micro-devices, contrast agent micro-bubbles are known to initiate cavitation and streaming local to cells, potentially compromising cell viability. Here we investigate the effects of US alone by omitting contrast agent and monitoring cell viability under moderate-to-extreme ultrasound-related stimuli.Results: Suspended H9c2 cardiac myoblasts were exposed to ultrasonic fields within a glass micro-capillary and their viability monitored under different US-related stimuli. An optimal injection flow rate of 2.6 mL/h was identified in which, high viability was maintained (~95%) and no mechanical stress towards cells was evident. This flow rate also allowed sufficient exposure of cells to US in order to induce bioeffects (~5 sec), whilst providing economical sample collection and processing times. Although the transducer temperature increased from ambient 23 [degree sign]C to 54[degree sign]C at the maximum experimental voltage (29 Vpp), computational fluid dynamic simulations and controls (absence of US) revealed that the cell medium temperature did not exceed 34[degree sign]C in the pressure nodal plane. Cells exposed to US amplitudes ranging from 0--29 Vpp, at a fixed frequency sweep period (tsw = 0.05 sec), revealed that viability was minimally affected up to ~15 Vpp. There was a ~17% reduction in viability at 21 Vpp, corresponding to the onset of Rayleigh-like streaming and a ~60% reduction at 29 Vpp, corresponding to increased streaming velocity or the potential onset of cavitation. At a fixed amplitude (29 Vpp) but with varying frequency sweep period (tsw = 0.02-0.50 sec), cell viability remained relatively constant at tsw &gt;= 0.08 sec, whilst viability reduced at tsw &lt; 0.08 sec and minimum viability recorded at tsw = 0.05 sec.Conclusion: The absence of CA has enabled us to investigate the effect of US alone on cell viability. Moderate-to-extreme US-related stimuli of cells have allowed us to discriminate between stimuli that maintain high viability and stimuli that significantly reduce cell viability. Results from this study may be of potential interest to researchers in the field of US-induced intracellular drug delivery and ultrasonic manipulation of biological cells.<br/

Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus. Results of a post-hoc analysis from the randomized phase III ACT II trial

PURPOSE: Concurrent chemoradiation is standard-of-care for patients with squamous cell carcinoma of the anus (SCCA). Poor compliance to chemotherapy, radiotherapy treatment interruptions and unplanned breaks may impact adversely on long-term outcomes. METHODS: The ACT II trial recruited 940 patients with localized SCCA, and assigned patients to mitomycin (week 1) or cisplatin (weeks 1 and 5), with fluorouracil (weeks 1 & 5) and radiotherapy (50·4Gy in 28 fractions over 38 days). This post-hoc analysis examined the association between baseline factors (age, gender, site, T-stage and N-stage), and compliance to treatment (radiotherapy and chemotherapy), and their effects on loco-regional failure-free survival (LRFFS), progression-free survival (PFS) and overall survival (OS). Compliance was categorized into groups. Radiotherapy: 6 groups according to total dose (TD) and overall treatment time (OTT). Chemotherapy: 3 groups (A = per-protocol; B = dose reduction or delay; C = omitted). RESULTS: 931/940 patients were evaluable for radiotherapy and 936 for chemotherapy compliance. Baseline Glomerular filtration rate (GR) 42 days is associated with worse PFS and OS (HR:1.72 (95%CI:1.17-2.54), p=0.006). CONCLUSION: Poor compliance to chemotherapy and radiotherapy were associated with worse LRFFS, PFS and OS. Treatment interruptions should be minimized, and OTT and TD maintained

A micro electromagnetic generator for vibration energy harvesting

Vibration energy harvesting is receiving a considerable amount of interest as a means for powering wireless sensor nodes. This paper presents a small (component volume 0.1 cm3, practical volume 0.15 cm3) electromagnetic generator utilizing discrete components and optimized for a low ambient vibration level based upon real application data. The generator uses four magnets arranged on an etched cantilever with a wound coil located within the moving magnetic field. Magnet size and coil properties were optimized, with the final device producing 46 µW in a resistive load of 4 k? from just 0.59 m s-2 acceleration levels at its resonant frequency of 52 Hz. A voltage of 428 mVrms was obtained from the generator with a 2300 turn coil which has proved sufficient for subsequent rectification and voltage step-up circuitry. The generator delivers 30% of the power supplied from the environment to useful electrical power in the load. This generator compares very favourably with other demonstrated examples in the literature, both in terms of normalized power density and efficiency

A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150 mg m−2) were given on days 2 and 30, followed by low-dose LV (20 mg m−2) and 5FU (350 mg m−2), both given on days 1–5 and 29–33. Surgery was performed 6–10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31–79), 24 males and eight females. The MTD was reached at 150 mg m−2 when four out of six patients experienced DLT. Dose-limiting grade 3 or 4 diarrhoea was reported in two out of six patients at 85 mg m−2, 5 out of 20 at 130 mg m−2 and four out of 6 at 150 mg m−2. Grade 3 neuropathy was reported at 130 mg m−2 (1 out of 20) and at 150 mg m−2 (two out of six), and serious haematological toxicity was minimal; one grade 3 anaemia at 150 mg m−2. In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR+Tmic 5 out of 27 (19%), pT0–2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150 mg m−2 given days 2 and 30 when added to the described 5FU LV and 45 Gy radiation preoperatively. The acceptable toxicity and compliance at 130 mg m−2 recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management

Toxicity, Tolerability, and Compliance of Concurrent Capecitabine or 5-Fluorouracil in Radical Management of Anal Cancer With Single-dose Mitomycin-C and Intensity Modulated Radiation Therapy: Evaluation of a National Cohort

Purpose: Chemoradiation therapy (CRT) with mitomycin C (MMC) and 5-fluorouracil (5-FU) is established as the standard of care for the radical treatment of patients with anal squamous cell carcinoma (ASCC). The use of the oral fluoropyrimidine-derivative capecitabine is emerging as an alternative to 5-FU despite limited evidence of its tolerability and toxicity. Methods and Materials: A national cohort evaluation of ASCC management within the United Kingdom National Health Service was undertaken from February to July 2015. The toxicity rates were prospectively recorded. For the present analysis, we report data from ASCC patients who underwent intensity modulated RT and a single dose of MMC with either 5-FU (5-FU/MMC) or capecitabine (capecitabine/MMC). All were treated with radical intent and intensity modulated radiation therapy (IMRT) was delivered in accordance with UK guidance. Results: Of the 242 patients received from 40 centers across the United Kingdom, 147 met the inclusion criteria; 52 of whom were treated with capecitabine/MMC and 95 with 5-FU/MMC. No treatment-related deaths and no overall difference were found in the proportion of patients experiencing any grade ≥3 toxicity between the capecitabine and 5-FU groups (45% vs 55%; P = .35). However, significantly fewer patients in the capecitabine/MMC group experienced grade 3 hematologic toxicity (4% vs 27%; P = .001). A lower proportion of patients completed their planned chemotherapy course in the capecitabine cohort, although this did not reach statistical significance (81% vs 90%; P = .21). The median RT duration was 38 days (interquartile range 38-39) for both groups. No difference was found in the 1-year oncologic outcomes. Conclusions: Capecitabine/MMC resulted in similar levels of grade 3/4 toxicity overall compared with 5-FU/MMC as CRT for ASCC, although differences were found in the patterns of observed toxicities, with less hematologic toxicity with capecitabine. Further studies of capecitabine/MMC are required to understand the acute toxicity profile and long-term oncologic outcomes of this combination with intensity modulated RT for ASCC

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