On the way to specifically targeting minimal residual disease?

The target of all adjuvant systemic therapies after surgery in breast cancer is the eradication of a minimal subclinical residual disease. Although it is well known that tumor cell dissemination takes place already at an early stage of the disease, little is known about the tumorbiological parameters of these residual cells. Selection of patients eligible for adjuvant endocrine therapies is based on the analysis of receptor expression in the primary tumor – although the analysis is directed against disseminated tumor cells, these cells may vary in receptor expression in comparison with the primary tumor.     

Concomitant chemoradiotherapy for muscle-invasive bladder cancer: the way forward for bladder preservation?

Muscle-invasive bladder cancer is a common malignancy with a high mortality rate. Despite ongoing debates about the optimal primary intervention, radical cystectomy remains the cornerstone of first-line therapy in many institutions. Over the past decade, bladder-preserving strategies involving transurethral resection (TUR), chemotherapy and radiotherapy have evolved. However, the advantage of these approaches over radiation treatment as monotherapy has yet to be fully evaluated. In other tumour models, most notably cervical and anal cancer, radiation and chemotherapy delivered concomitantly have resulted in significant survival advantages. Here, we consider the potential value of this approach in the treatment of invasive bladder cancer. Concomitant chemoradiotherapy is currently the mainstay of several bladder-preserving programmes reported in the medical literature. Overall, local control and survival rates compare favourably with contemporary cystectomy series; however, difficulties in drawing valid conclusions are highlighted. Concomitant chemoradiotherapy may have a role in the management of certain patient subgroups, and the debate should remain open. Further large-scale randomised trials are needed, and information regarding bladder function and quality of life after treatment is lacking at present. The importance of close follow-up and prompt salvage cystectomy is emphasised.     

Robotic donor hepatectomy: a niche advancement or the way forward? A perspective from the world's largest center

The application of minimally invasive liver surgery (MILS) in the field of living donor hepatectomy has been exceedingly slow, and its impact is limited to a ha...     

Setting priorities versus managing closures--what is the ethically most sound way of handling changes in the health care system?

The answer to the question of the title depends on a number of circumstances, and I go through and comment on five of them. Then an attempt is made to keep some of these circumstances constant and vary others in order to highlight the importance of their ethical points of departure. The pros and cons of various choices are discussed and conclusions are suggested. To make further progress, the original question in the title is replaced by two new questions: under what conditions is managing closures the ethically soundest way of handling changes in the health-care system? And, under what conditions is setting priorities the ethically soundest way of handling changes in the health care system? Some tentative answers to these questions are outlined towards the end of this paper.     

Do men and their wives see it the same way? Congruence within couples during the first year of prostate cancer

Objective: The purpose of this study was to determine the psychosocial adjustment congruence within couples through the first year of prostate cancer experience, and to explore the personal variables that could predict congruence within couples. Method: Eighty‐one couples were interviewed at the time of diagnosis; 69 participated at 3 months and 61 at 12 months. Paired t‐tests were used to examine dyadic congruence on seven domains of psychosocial adjustment. Repeated Measures ANOVAs were used to examine the congruence over time. Multiple regressions were used to determine whether mood disturbance, urinary and sexual bother, sense of coherence, and social support were predictors of congruence within couples on each of the adjustment domains. Results: At time 1, couples had incongruent perceptions in 3 of 7 domains: health care, psychological, and social adjustment. Three months later, health care, psychological, and sexual domains showed incongruence within couples. One year after the diagnosis, there were incongruent perceptions only in sexual and psychological domains. There was little variation of the congruence within couples over time. Husbands and wives' mood disturbance, urinary and sexual bother, sense of coherence, and social support accounted for 25–63% of variance in couple congruence in the adjustment domains in the study periods. Conclusion: The findings suggested that there is couple congruence. Domains in which incongruence was observed are important targets for clinical interventions. Greater attention needs to be directed to assisting couples to recognize the differences between their perceptions, especially the ones related to the sexual symptoms and psychological distress. Copyright © 2010 John Wiley & Sons, Ltd.     

MRI directed multidisciplinary team preoperative treatment strategy: the way to eliminate positive circumferential margins?

Histopathological audit of positive circumferential resection margins (CRMs) can be used as a surrogate measure of the success of rectal cancer treatment. We audited CRM involvement in rectal cancer patients and the impact of the multidisciplinary team (MDT) on implementing a magnetic resonance imaging (MRI)-based preoperative treatment strategy. Data were collected on all newly diagnosed rectal cancer patients treated in our network between January 1999 and December 2002. Data were analysed for MRI prediction and histopathological assessment of CRM together with the MDT meeting treatment decisions. The CRM+ve rate of those discussed at MDT vs those not discussed were compared. We re-audited the CRM+ve rates 1 year after introducing a policy of mandatory preoperative MRI-based MDT discussion. Of the 298 patients diagnosed with rectal cancer, 39 (13%) were deemed palliative, 178 underwent surgery alone and 81 underwent neoadjuvant therapy. Of these, 62 out of 178 patients underwent surgery alone without MRI-based MDT discussion resulting in positive CRM in 16 cases (26%) as compared to 1 out of 116 (1%) in those patients with MDT discussion of MRI. Overall CRM+ve rate in all nonpalliative patients with or without MDT discussion was 12.5% (32 out of 256), significantly lower than the <20% rate (P<0.001) quoted in national guidelines. Re-audit in 98 consecutive patients following a change of policy produced a lower CRM+ve rate of 3% (1 out of 37) for all surgery alone patients and an overall CRM+ve rate of 7% (5 out of 70). In conclusion, MDT discussion of MRI and implementation of a preoperative treatment strategy results in significantly reduced positive CRM in rectal cancer patients.     

Pre-operative chemo-radiotherapy in locally advanced rectal cancer: Is this the way of future management?

The purpose of the present paper was to update a prospective analysis (H Elsaleh et al. unpubl. data, 1997) investigating the effectiveness and toxicity of pre-operative pelvic radiotherapy with modest dose 5-fluorouracil (5-FU) in locally advanced rectal cancer (T₃–T₄). A total of 31 patients were assessed (28 T₃ and three T₄ tumours). Pre-operative pelvic radiotherapy was delivered in four fields, 45 Gy to the International Commission on Radiation Units and Measurements (ICRU) point in 25 fractions over 5 weeks. A radiosensitizing dose of 5-FU was delivered at 500 mg/m² on days 1, 2 and 3, and days 22, 23 and 24. Mesorectal excision of the rectal tumour either by anterior or abdomino-perineal resection was planned at 4–6 weeks from completion of pre-operative treatment. Response to therapy was assessed by fresh macroscopic measurement of the surgical specimen. Patients had a low toxicity profile; an estimated 50% or greater response was seen in 24 out of 31 (two complete responses). There were no surgical difficulties achieving resection. No late complications were documented, although follow-up was short. In locally advanced rectal cancer, pre-operative chemo-radiotherapy had a low toxicity profile. Appropriately fractionated pre-operative chemo-radiotherapy is a reasonable option in this disease and should be further evaluated. The optimal method of delivery of the radiosensitizing agent (5-FU) is the subject of further investigation.     

Malignant salivary gland tumours: Can fast neutron therapy results point the way to carbon ion therapy?

Background and purpose

To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams.

Materials and methods

Neutrons at iThemba LABS are produced by the reaction of 66 MeV protons on a beryllium target. A median dose 20.4 Gy, in 12 fractions in 4 weeks or 15 fractions in 5 weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours.

Results

Locoregional control was 60.6% at 5 years and 39.1% at 10 years and DSS was 66.8% and 53.7% at 5 and 10 years respectively.In the univariate analysis T4, >4 cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6 cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6 cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease.

Conclusions

Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.     

Necroptosis: A new way of dying?

This review embarks upon a cell death journey from the discovery of apoptosis and necrosis through to the coalescence of these: necroptosis. The mechanisms of 2 emerging necrotic cell death pathways, pyroptosis and ferroptosis, will be explored before delving into apoptotic and necroptotic signaling cascades, highlighting the complex interplay between molecular players. The involvement of the ripoptosome, interferon signaling and DNA damage in necroptosis will be discussed briefly. The major focus is on necroptosis initiation by tumor necrosis factor-α (TNFα) and its cognate receptor TNFR1, caspase-independent RIP1/RIP3/MLKL necrosome activation and cell death propagation by damage-associated molecular pattern (DAMP) release. Finally, the implications of a complex cell death signaling network will be revealed in the context of cancer biology and therapy. The clinical contribution of the discovery of necroptosis as an unequivocally new way of dying is monumental and could drastically alter cancer therapy strategies in the future.     

An increasing use of defunctioning stomas after low anterior resection for rectal cancer. Is this the way to go?

Background

The last decade there has been an increased awareness of the problem of anastomotic leakage after low anterior resection for rectal cancer, which may have led to more defunctioning stomas. In this study, current use of defunctioning stomas was assessed and compared to the use of defunctioning stomas at the time of the TME-trial together with associated outcomes.

Methods

Eligible patients with rectal cancer undergoing low anterior resection were selected from the Dutch Surgical Colorectal Audit (DSCA, n = 988). Similar patients were selected from the TME-trial (n = 891). The percentages of patients with a defunctioning stoma, anastomotic leakage and postoperative mortality rates were studied. Multivariable models were used to study possible confounding on the outcomes.

Results

At the time of the TME-trial, 57% of patients received a defunctioning stoma. At the time of the DSCA, 70% of all patients received a defunctioning stoma (p < 0.001). Anastomotic leakage rates were similar (11.4% and 12.1%; p = 0.640). The postoperative mortality rate differed (3.9% in the TME-trial vs. 1.1% in the DSCA; p < 0.001), but was not associated with a more frequent use of a stoma (OR 1.80, 95% CI 0.91–3.58).

Conclusion

In current surgical practice, 70% of patients undergoing LAR for rectal cancer receives a defunctioning stomas. This percentage seems increased when compared to data from the TME-trial. Clinically relevant anastomotic leakage rates remained similar. Therefore, current routine use of defunctioning stomas should be questioned.     

On our way to targeted therapy for cachexia in cancer?

PURPOSE OF REVIEW: Cachexia, the occurrence of involuntary weight loss due to loss of adipose tissue and skeletal muscle mass, is among the most common and devastating symptoms in patients with advanced cancer. It is a significant factor contributing to the poor performance status and high mortality rate of these patients, and is a distressing problem for both patients and their families. Despite extensive research in an attempt to better understand the mechanisms involved, progress in the management of cancer cachexia has been slow. RECENT FINDINGS: The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumour-derived factors are known to play a significant role, thereby representing suitable therapeutic targets. Moreover, recent advances in the field of molecular biology have shed light on other mediators involved in the mechanisms leading to muscle wasting, thus increasing potential targets for new therapies. SUMMARY: This review will focus on recent findings in relation to the molecular pathways leading to muscle wasting that have improved our current understanding of cachexia and will direct the future management of cachexia in cancer towards targeted therapies.