Predicting response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer with serum biomarkers.

Introduction The aim of this study was to identify patient factors including serum biomarkers that may predict response to neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer staged on magnetic resonance imaging. Prediction of response may be helpful when selecting patients for a non-operative programme. Methods A retrospective review was carried out of patients undergoing neoadjuvant CRT for rectal cancer, conducted at the Royal Devon and Exeter Hospital. All patients were managed through the multidisciplinary team. Receiver operating characteristic (ROC) curve analysis was undertaken to assess the ability of biomarkers to predict response to neoadjuvant CRT. The biomarkers assessed included neutrophils, lymphocytes, monocytes, haemoglobin, platelets, C-reactive protein and carcinoembryonic antigen. Results Seventy-three patients underwent neoadjuvant CRT between January 2006 and December 2011. Nine (12.3%) of these experienced a clinical complete response and were managed with a 'watch and wait' approach. An additional ten patients (13.7%) had a pathological complete response following surgery. Using ROC curve analysis, the biomarkers with the largest area under the curve (AUC) were pre-CRT haemoglobin and post-CRT lymphocyte concentrations, producing AUC values of 0.673 and 0.618 respectively for clinical complete response. Pre-CRT haemoglobin and neutrophil concentrations produced the highest AUC values for pathological complete response at 0.591 and 0.614 respectively. Conclusions None of the assessed biomarkers offer the ability to predict response to neoadjuvant CRT in patients with rectal cancer. They cannot therefore assist in identifying complete clinical or pathological responders who could be considered for a non-operative, observational approach.

A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management?

AIM: The aim of the study was to assess the outcome of patients who received chemoradiotherapy (CRT) for locally advanced rectal cancer, specifically those with complete clinical response (CCR) and who were then managed nonoperatively with a 'Watch and Wait' follow-up protocol. METHOD: A retrospective study was carried out of patients undergoing preoperative CRT for rectal cancer, conducted in a district general hospital managing rectal cancer through the multidisciplinary team process. RESULTS: Forty-nine patients received preoperative CRT over a 5-year period (2004-2009). Twelve (24%) were considered potentially to have had a complete response on MRI. Of these, six subsequently had clinical evidence of residual disease, leading to surgery (mean time to surgery, 24 weeks; range, 12-36 weeks). The remaining six had CCR, avoiding surgery (mean follow up, 26 months; range, 12-45 months), with all six patients disease free to date. A further six patients had complete pathological response (CPR) following surgery after comprehensive histopathological assessment of the specimen. CONCLUSION: In this consecutive series of patients with locally advanced rectal cancer treated with CRT, 12% demonstrated a CCR and have been actively managed conservatively, thereby avoiding surgery. With further improvements in diagnostic assessment of response to CRT, this figure may rise.

Interaction of bisphosphonates with calcitonin in monitoring medullary carcinoma of the thyroid.

We report the case history of a patient with long standing recurrent medullary carcinoma of the thyroid. Elevation of the serum marker calcitonin coincided with the introduction of biphosphonate therapy and recurrence of tumour was not established. The interaction of biphosphonates with calcitonin is not previously recorded.

Variations in dose and dose intensity of adjuvant CMF chemotherapy for breast cancer throughout the UK.

Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a commonly prescribed regimen for the adjuvant treatment of early breast cancer in the UK and in other countries with a high incidence of breast carcinoma. A number of variations in dose and scheduling of these drugs have been reported in the literature, with all of these being recognized under the generic term 'CMF'. To investigate the extent of differences in CMF regimens used for the adjuvant treatment of early breast cancer we sent a postal questionnaire to all consultant medical and clinical oncologists in the UK seeking details of their practice. CMF drug doses were then converted into dose intensity parameters for comparison. The results showed a wide variation in the number of CMF schedules (n = 36) and CMF dose intensities (n = 33) used. The potential consequences of such variation and the evidence for and against dose intensity as an important parameter in the adjuvant treatment of early breast cancer are discussed.

Cadmium toxicity in rat pheochromocytoma cells: studies on the mechanism of uptake.

The uptake and toxicity of cadmium were compared in two rat pheochromocytoma cell lines: PC12 cells, which express voltage-sensitive calcium channels, and PC18 cells, which do not. PC12 but not PC18 cells responded to depolarization with an increase in 45Ca2+ uptake and an increase in the concentration of cytoplasmic free calcium ion, [Ca2+]i. These responses were blocked by the dihydropyridine calcium channel antagonist nimodipine and amplified by the agonist BAY K8644, drugs selective for L-type channels. Cadmium caused death of PC12 cells with an LC50 of 12 microM. Inclusion of high K+ with the agonist BAY K8644 shifted the kill curve to the left (LC50 = 6 microM). whereas nimodipine protected against cadmium toxicity (LC50 = 30 microM). In contrast, drugs acting on L-type calcium channels did not affect Cd2+ toxicity for PC18 cells (LC50 15 microM). Fura 2 was used to measure intracellular free Cd2+ by fluorescence ratio methods. Addition of 25 microM Cd2+ to both PC12 and PC18 cells caused a rise in the 340/380 fluorescence ratio attributable to the uptake of Cd2+, since it was almost completely reversed by chelating extracellular Cd2+ and adding a membrane-permeant chelator of heavy metals. Cd2+ addition resulted in a gradual increase in Fura 2 fluorescence in both PC12 and PC18 cells, but depolarization with BAY K8644 increased the apparent rate of Cd2+ uptake only for the PC12 cells. Cd2+ fluorescence appeared to be concentrated near the plasma membrane. The results confirm the potential involvement of calcium channels in cadmium transport and extend the use of intracellularly trapped fluorescent dyes to monitor intracellular free cadmium ion concentration.