Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer.

BACKGROUND: The optimal treatment for localised oesophageal squamous cell carcinoma (SCC) is uncertain. We assessed the feasibility of an RCT comparing neoadjuvant treatment and surgery with definitive chemoradiotherapy. METHODS: A feasibility RCT in three centres examined incident patients and reasons for ineligibility using multi-disciplinary team meeting records. Eligible patients were offered participation in the RCT with integrated qualitative research involving audio-recorded recruitment appointments and interviews with patients to inform recruitment training for staff. RESULTS: Of 375 patients with oesophageal SCC, 42 (11.2%) were eligible. Reasons for eligibility varied between centres, with significantly differing proportions of patients excluded because of total tumour length (P=0.002). Analyses of audio-recordings and patient interviews showed that recruiters had challenges articulating the trial design in simple terms, balancing treatment arms and explaining the need for randomisation. Before analyses of the qualitative data and recruiter training no patients were randomised. Following training in one centre 5 of 16 eligible patients were randomised. CONCLUSIONS: An RCT of surgical vs non-surgical treatment for SCC of the oesophagus is not feasible in the UK alone because of the low number of incident eligible patients. A trial comparing diverse treatment approaches may be possible with investment to support the recruitment process.

Assessment and comparison of recovery after open and minimally invasive esophagectomy for cancer: an exploratory study in two centers.

BACKGROUND: Minimally invasive esophagectomy (MIE) may lead to early restoration of health-related quality of life, but few prospective comparative studies have been performed. This exploratory study compared recovery between totally minimally invasive esophagectomy (MIE), laparoscopically assisted esophagectomy (LAE) and open surgery (OE). METHODS: A prospective study in 2 specialist centers recruited consecutive patients undergoing OE, LAE, or MIE for high-grade dysplasia or cancer. Patients completed validated questionnaires, the Multi-Dimensional Fatigue Inventory (MFI-20), modified Katz Scale, and modified Lawton and Brody Scale (assessing activities of daily living) before and 6 weeks and 3 and 6 months after surgery. RESULTS: A total of 97 patients (26 women; median age 64 years) were scheduled for surgery that was abandoned in 11 due to occult low-volume metastatic disease. In the remaining 86 (OE = 19, LAE = 31, and MIE = 36), there were 4 in-hospital deaths (4 %), and 54 postoperative complications (OE = 12, LAE = 19, and MIE = 23). Overall questionnaire compliance was high (77 %) and baseline scores similar in all groups, although clinical differences between groups were observed with earlier tumors and more squamous cell cancers selected for MIE. Following surgery fatigue levels increased dramatically and activity levels reduced in all groups. These gradually recovered to baseline following MIE and LAE within 6 months, but the ability to perform activities of daily living and most parameters of fatigue had not returned to baseline levels in the OE group. CONCLUSIONS: This exploratory prospective nonrandomized study of recovery after different types of surgery for esophageal cancer showed possible small benefits to MIE. A much larger study is needed to confirm these findings.

Effects of changing work patterns on general surgical training over the last decade.

BACKGROUND There is concern across all medical specialties that shift patterns and reduced working hours are detrimental to training, and that craft specialties have been most affected. This study aimed to examine the effects of these changes to training on the quantity of operating performed by surgical trainees in a UK teaching hospital. METHODS This retrospective study of prospectively collected computerised theatre data examined elective and emergency general surgical operations performed over four time periods: 1996 (Calman), 2001 (New Deal), 2004 and 2009 (European Working Time Directive). Procedures were analysed according to grade of surgeon and time of day. RESULTS In 1996, most appendicectomies (72.2%) were performed by senior house officers (SHOs), compared with 3.8% in 2009. By 2009, SHOs did not perform any emergency procedures other than abscess drainage and appendicectomy. The proportion of emergency operating performed by specialist registrar (SpRs) has remained constant, but elective operating has reduced from 34.6% (1996) to 15.7% (2009). Supervision of both SHOs and SpRs has increased between 1996 and 2009 in both elective and emergency work. CONCLUSIONS The proportion of operating performed by SpRs and SHOs has fallen over the last decade, coinciding with implementation of structural changes to training, the advent of minimally invasive techniques, and the drive for a consultant led health service. Trainees may therefore require increased supervision as well as protected theatre sessions to balance operative training with ward based duties. Education must be integrated into working practice in order for trainees to achieve expected competencies and ultimately produce adequately experienced consultants.

Demonstration of the IDEAL recommendations for evaluating and reporting surgical innovation in minimally invasive oesophagectomy.

BACKGROUND: The Idea, Development, Evaluation, Assessment and Long term study (IDEAL) framework makes recommendations for evaluating and reporting surgical innovation and adoption, but remains untested. METHODS: A prospective database was created for the introduction of minimally invasive techniques for oesophagectomy. IDEAL stages of development and evaluation were examined retrospectively in a series of patients undergoing laparoscopically assisted oesophagectomy (LAO), two- or three-phase minimally invasive oesophagectomy (MIO) and open oesophagectomy. RESULTS: A total of 192 patients were involved. In IDEAL stages 1 and 2a, LAO in 16 patients was uneventful, but two-phase MIO in six patients was abandoned following consecutive technical complications. Two-phase MIO was modified to a three-phase MIO procedure, and the results of LAO (67 patients), three-phase MIO (35) and open techniques (68) were studied in IDEAL stage 2b. Major complications (Clavien-Dindo grades III and IV) occurred in 12 (18 per cent), nine (26 per cent) and 14 (21 per cent) LAO, three-phase MIO and open procedures respectively. There were four in-hospital deaths (2 LAO and 2 open). CONCLUSION: The IDEAL framework is a feasible method for documenting the development and implementation of a procedure. MIO should now be compared with open surgery in a randomized controlled trial (IDEAL stage 3).

Evidence implicating a mid-region sequence of IGFBP-3 in its specific IGF-independent actions.

Insulin-like growth factor binding protein-3 (IGFBP-3) is one of six high affinity-binding proteins that share a common function in regulating the bioavailability of the insulin-like growth factors. The six binding proteins have highly conserved C- and N-terminals that are essential to this function. Additionally, they all have specific functions on cellular homeostasis independent to the regulation of the insulin-like growth factors. It has previously been shown that insulin-like growth factor binding protein-3 can accentuate UV-induced apoptosis in a human carcinoma cell line. Using the KYSE 190 oesophageal carcinoma cell line we have demonstrated that a 15 amino acid (aa) peptide that lies within the mid-region of the protein can mimic the effect of the intact protein. This region contains the serine residues Ser(111) and Ser(113). Using two protocols, we modified these serine residues and have shown that both phosphorylation and derivatization of IGFBP-3 can negate the accentuation of UV-induced cell death. These three independent pieces of evidence support the hypothesis that the variable mid-region is responsible for the specific pro-apoptotic functions of IGFBP-3, and suggest that phosphorylation may provide a mechanism for regulation of this action.

IGFBP-3 prolongs the p53 response and enhances apoptosis following UV irradiation.

Neoplastic transformation is characterised by an imbalance in favour of cell growth over programmed cell death (apoptosis). The tumour-suppressor gene p53, responsible for maintaining cell-cycle control, is mutated in the majority of human cancers. Loss of function of the target genes of p53 are therefore important in tumourigenesis. One such target gene is the insulin-like growth factor binding protein-3 (IGFBP-3), an extracellular protein responsible for the carriage of IGF-I but which can act independently of IGF-I, inhibiting cell growth and enhancing apoptosis. Using the KYSE 190 oesophageal carcinoma cell line, we have demonstrated that IGFBP-3 alone has no effect on cell growth or cell survival. However, it significantly enhanced apoptosis, with a 67% increase in the pre-G1 peak on flow cytometry following UV irradiation. The increase in p53 was enhanced and prolonged when cells are stressed in the presence of IGFBP-3. These data suggest an autocrine/paracrine feedback loop exists between IGFBP-3 and p53, which may provide the social control necessary to maintain normal tissue homeostasis.