Prone en bloc sacrectomy with proctectomy: a surgical approach to the inaccessible and hostile pelvis.

AIM: Reoperative pelvic surgery is rarely hostile and unsafe. Kraske's procedure has historically been used to approach the mid-rectum and to resect retrorectal tumors. However, it provides limited access to the pelvis and is best in the 'virgin' pelvis. We have encountered a select group of patients who required completion proctectomy or resection of a disconnected ileoanal J-pouch where trans-abdominal access to the pelvis was not possible and access to the pelvis could only be safely gained by a prone en bloc sacrectomy. METHOD: We describe a prone approach that provides an alternative route of access to the hostile pelvis. After exposure of the sacrum and coccyx and transection of the sacrum, access to the mesorectal plane is achieved and a proctectomy (or resection of an ileoanal J-pouch) can be completed. The procedure is similar to the Kraske approach but requires a higher and wider exposure similar to the extent of an abdominal resection; however, the operation is performed in 'reverse'. RESULTS: We found that this approach was feasible and safe in the previously operated, hostile pelvis. We employed it in one patient to excise a disconnected J-pouch with chronic sepsis and in another patient for a completion proctectomy. Both patients had an uneventful recovery and clear margins were obtained with no complications. CONCLUSION: The en bloc prone sacrectomy approach is a useful alternative in a very select group of patients with difficult trans-abdominal access to the pelvis. Experience in pelvic surgery and identification of clear anatomical landmarks is paramount to avoid catastrophic uncontrollable bleeding.

Prognostic factors and patterns of failure after surgery for T4 rectal cancer in the beyond total mesorectal excision era.

BACKGROUND: Despite advances in the rates of total mesorectal excision (TME) for rectal cancer surgery, decreased local recurrence rates and increased 5-year survival, there still exists large variation in the quality of treatment received. Up to 30 per cent of rectal cancers are locally advanced at presentation and approximately 5-10 per cent still breach the mesorectal plane and invade adjacent structures despite neoadjuvant therapy. With the evolution of extended resections for rectal cancers beyond the TME plane, proponents advocate that these resections should be performed only in specialist centres. The aim was to assess the prognostic factors and patterns of failure after beyond TME surgery for T4 rectal cancers. METHODS: Data were collected from prospective databases at three high-volume institutions specializing in beyond TME surgery for T4 rectal cancers between 1990 and 2013. The primary outcome measures were overall survival, local recurrence and patterns of first failure. RESULTS: Three hundred and sixty patients were identified. The negative resection margin (R0) rate was 82·8 per cent (298 patients) and the local recurrence rate was 12·5 per cent (45 patients). The type of surgical procedure (Hartmann's: hazard ratio (HR) 4·49, 95 per cent c.i. 1·99 to 10·14; P = 0·002) and lymphovascular invasion (HR 2·02, 1·08 to 3·77; P = 0·032) were independent predictors of local recurrence. The 5-year overall survival rate for all patients was 61 (95 per cent c.i. 55 to 67) per cent. The 5-year cumulative incidence of first failure was 8 per cent for local recurrence, 6 per cent for local and distant disease, and 18 per cent for distant disease. CONCLUSION: This study has demonstrated that a coordinated approach in specialist centres for beyond TME surgery can offer good oncological and long-term survival in patients with T4 rectal cancers.

ANTECEDENTES: A pesar de las mejoras en los porcentajes de extirpación total del mesorrecto (total mesorectal excision, TME) en la cirugía de cáncer de recto, la disminución de los porcentajes de recidiva local y el aumento de la supervivencia a 5 años, todavía existe una gran variabilidad en la calidad del tratamiento recibido. Hasta el 30% de los cánceres de recto están localmente avanzados en el momento del diagnóstico y aproximadamente el 5-10% sobrepasarán el plano mesorrectal e invadirán las estructuras adyacentes a pesar del tratamiento neoadyuvante. Con la evolución de las resecciones ampliadas para los cánceres de recto que sobrepasan el plano de la TME, los defensores recomiendan que estas resecciones solo se realicen en centros especializados. El objetivo fue evaluar los factores pronósticos y los patrones de recidiva después de la cirugía ampliada más allá de la TME para los cánceres de recto T4. MÉTODOS: Los datos se recogieron a partir de bases de datos prospectivas de tres instituciones de alto volumen especializadas en resecciones ampliadas más allá de la TME para el cáncer de recto T4 entre 1990 y 2013. Los criterios de valoración principal fueron la supervivencia global, la recidiva local y los patrones de la primera recidiva. RESULTADOS: Se identificaron 360 pacientes. El margen de resección fue negativo (R0) en el 82,8% (n = 298) y el porcentaje de recidiva local fue de 12,5% (n = 45). El tipo de cirugía realizada (Hartmann: cociente de riesgos instantáneos, hazard ratio, HR 4,49; i.c. del 95%: 1,99-10,14; P = 0,002) y la invasión linfovascular (HR 2,02; i.c. del 95%: 1,08-3,77; P = 0,032) fueron factores predictivos independientes de recidiva local. La supervivencia global a 5 años para todos los pacientes fue del 61% (i.c. del 95%: 55-67). La incidencia acumulada a los 5 años de la primera recidiva fue de 8% para la recidiva local, 6% para la recidiva local y a distancia, y 18% para la recidiva a distancia. CONCLUSIÓN: Este estudio demuestra que un abordaje coordinado en centros especializados para cirugía más allá de la TME puede ofrecer una buena supervivencia oncológica y a largo plazo en pacientes con cáncer de recto T4.

A functional macrophage migration inhibitory factor promoter polymorphism is associated with reduced diffusing capacity.

Cigarette smoke exposure is the leading modifiable risk factor for chronic obstructive pulmonary disease (COPD); however, the clinical and pathologic consequences of chronic cigarette smoke exposure are variable among smokers. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of COPD. Within the promoter of the MIF gene is a functional polymorphism that regulates MIF expression (-794 CATT5-8 microsatellite repeat) ( rs5844572 ). The role of this polymorphim in mediating disease susceptibility to COPD-related traits remains unknown. We performed a cross-sectional analysis of DNA samples from 641 subjects to analyze MIF-794 CATT5-8 ( rs5844572 ) polymorphism by standard methods. We generated multivariable logistic regression models to determine the risk of low expressing MIF alleles for airflow obstruction [defined by forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio <0.70] and an abnormal diffusion capacity [defined by a diffusion capacity for carbon monoxide (DLCO) percent predicted <80%]. We then used generalized linear models to determine the association of MIF genotypes with FEV1 percent predicted and DLCO percent predicted. The MIF-794 CATT5 allele was associated with an abnormal diffusion capacity in two cohorts [odds ratio (OR): 9.31, 95% confidence interval (CI): 1.97-4.06; and OR: 2.21, 95% CI: 1.03-4.75]. Similarly, the MIF-794 CATT5 allele was associated with a reduced DLCO percentage predicted in these two cohorts: 63.5 vs. 70.0 ( P = 0.0023) and 60.1 vs. 65.4 ( P = 0.059). This study suggests an association between a common genetic polymorphism of an endogenous innate immune gene, MIF, with reduced DLCO, an important measurement of COPD severity.

Posterior high sacral segmental disconnection prior to anterior en bloc exenteration for recurrent rectal cancer.

This article describes a novel technique for en bloc resection of locally recurrent rectal cancer that invades the high sacral bone (above S3). The involved segment of the sacrum is mobilised with osteotomes during an initial posterior approach before an anterior abdominal phase where the segment of sacral bone is delivered with the specimen. This allows en bloc resection of the involved sacrum while preserving uninvolved distal and contralateral sacral bone and nerve roots. The goal is to obtain a clear bony margin and offer a chance of cure while improving functional outcomes by maintaining pelvic stability and minimising neurological deficit.

Survival after pelvic exenteration for T4 rectal cancer.

BACKGROUND: The purpose of this study was to analyse retrospectively the pooled results after pelvic exenteration for locally advanced T4 rectal cancer. Historically, patients with T4 rectal cancers requiring pelvic exenteration have been offered only palliative surgery or no operation. METHODS: The basic treatment principle was preoperative (chemo)radiotherapy, radical surgery and, in some patients, adjuvant chemotherapy. Risk factors for local recurrence, distant metastases and overall survival were studied in univariable and multivariable analyses. RESULTS: Ninety-five patients with T4 rectal cancer who underwent pelvic exenteration in two tertiary referral centres up to 2013 were studied. Clear margins (R0) were achieved in 87 per cent of patients. Adjuvant chemotherapy was administered in 33 per cent, independent of the resection margin, lymph node status and postoperative T category. The 5-year local recurrence rate was 17 per cent, with a distant metastasis rate of 16 per cent and overall survival rate of 62 per cent. In multivariable analysis the only factor associated with death was omission of adjuvant chemotherapy (P = 0.016). The effect of adjuvant chemotherapy was more pronounced in the elderly: patients aged over 70 years who had chemotherapy had a 5-year overall survival rate of 80 per cent, compared with 39 per cent of elderly patients who did not receive chemotherapy (P = 0.019). CONCLUSION: Pelvic exenteration led to an R0 resection rate of 87 per cent for T4 rectal cancer, giving good local control and overall survival comparable to population-based colorectal cancer survival rates. Adjuvant chemotherapy may improve overall survival further, even in the elderly.

The kidney as a new target for antidiabetic drugs: SGLT2 inhibitors.

WHAT IS KNOWN AND OBJECTIVE: A novel class of antidiabetic drugs - SGLT2 (Na(+) /glucose cotransporter type 2) inhibitors - target renal reabsorption of glucose and promote normal glucose levels, independent of insulin production or its action at receptors. We review this new mechanistic approach and the reported efficacy and safety of clinical testing of lead compounds. METHODS: Information was obtained from various bibliographic sources, including PubMed and others, on the basic science and the clinical trials of SGLT2 inhibitors. The information was then summarized and evaluated from the perspective of contribution to a fuller understanding of the potential and current status of the lead clinical candidates. RESULTS AND DISCUSSION: Diabetes mellitus is a spectrum of disorders that involves inadequate insulin function resulting in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses either insulin production at the pancreatic ß-cells or insulin action at insulin receptors. These drugs have less than full clinical effectiveness and sometimes therapy-limiting adverse effects. The third major component of glucose balance, namely elimination, has not been a significant therapeutic target to date. SGLT2 inhibitors are a novel approach. WHAT IS NEW AND CONCLUSION: A sufficient number of clinical trials have been conducted on sufficiently chemically diverse SGLT2 inhibitors to reasonably conclude that they have efficacy (HbA1c reductions of 0·4-1%), and thus far, the majority of adverse effects have been mild and transitory or treatable, with the caveat of possible association with increased risk of breast cancer in women and bladder cancer in men.

Pelvic exenteration for recurrent squamous cell carcinoma of the pelvic organs arising from the cloaca--a single institution's experience over 16 years.

AIM: Minimal data are available on the role of pelvic exenteration in patients with recurrent squamous cell carcinoma (SCC) of the pelvic organs. This study aimed to highlight our experience of pelvic exenteration in patients with recurrent and re-recurrent SCC of the pelvic organs. METHOD: A retrospective review of all patients who underwent pelvic exenteration for recurrent SCC of the pelvic organs arising from the embryological cloaca from 1994 to 2010 was performed. RESULTS: Twenty-four patients (median age 59, range, 27-79 years) underwent pelvic exenteration for recurrent SCC of the anus (18), cervix and upper vagina (2), lower vagina (1) and the vulva (3). Nine patients with anal SCC had undergone abdominoperineal excision prior to pelvic exenteration. Ten (41.7%) patients underwent a complete pelvic exenteration procedure, while sacrectomy was performed in 13 (54.2%) patients. There was no 30-day inpatient mortality. An R0 resection was achieved in 15 (62.5%) patients. Three (12.5%) had R1 resections while 6 (25%) had R2 resections. In the 15 patients with an R0 resection, 7 (46.7%) developed metastatic disease at a median of 18 (range 10-131) months. After a median follow-up of 26 (range 4-169) months, 1- and 2-year overall survival rates were 64% [95% confidence interval (CI), 44-84%] and 57% (95% CI 35-79%), respectively. CONCLUSION: Pelvic exenteration for recurrent SCC of the cloaca is safe and feasible even after previous salvage surgery. An R0 resection can be achieved in 62.5% of the patients with reasonable early survival though less than published recurrent rectal cancer studies.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk.

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Atoms in a radio-frequency-dressed optical lattice.

We load cold atoms into an optical lattice dramatically reshaped by radio-frequency coupling of state-dependent lattice potentials. This radio-frequency dressing changes the unit cell of the lattice at a subwavelength scale, such that its curvature and topology departs strongly from that of a simple sinusoidal lattice potential. Radio-frequency dressing has previously been performed at length scales from mm to tens of mum, but not at the single-optical-wavelength scale. At this length scale significant coupling between adiabatic potentials leads to nonadiabatic transitions, which we measure as a function of lattice depth and dressing amplitude. We also investigate the dressing by measuring changes in the momentum distribution of the dressed states.

Enlargement of the proximal pituitary stalk associated with spontaneous recovery from multiple pituitary hormone deficiencies.

We report the case of a child with multiple pituitary hormone deficiencies and a truncated pituitary stalk on MR imaging who had recovery of normal secretion of pituitary hormones in early adulthood. Follow-up MR imaging examination after recovery revealed marked enlargement of the proximal pituitary stalk. The case of our patient helps to explain the mechanism whereby some patients experience recovery of hormonal function.

Sacrococcygeal pilonidal disease.

BACKGROUND: Sacrococcygeal pilonidal is a common disease in active young adults. Many surgical methods have been proposed, although no clear consensus as to the optimal treatment has been reported. This review looks at the different surgical techniques available and examines the reported results of primary healing, recurrent disease and complications (including delayed healing). METHOD: A literature search using the Medline database was performed to locate English language articles on surgery for pilonidal disease. Further articles were obtained from the references cited in the literature initially reviewed. RESULTS: Management should be tailored according to the individual and whether the disease is acute or chronic. Treatment should take into consideration hospital stay and return to work. Simple excision, curettage, partial lateral wall excision, or marsupialisation, are simple techniques with good results. They can be used for the initial surgery but their use is not recommended for recurrent disease. The modified rhomboid flap for recurrent disease has consistently shown positive results in terms of complication rates and recurrence. CONCLUSION: We would recommend tailored treatment with simple excision for initial presentation and the modified rhomboid flap for recurrent disease.

The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.

The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.

BACKGROUND: The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size. METHODS: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). INTERPRETATION: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.

Depression in adults with Fabry disease: a common and under-diagnosed problem.

BACKGROUND: Anderson-Fabry disease (AFD), an X-linked lysosomal storage disorder, leads to multi-organ dysfunction and premature mortality. Depression in adults with AFD has been reported, but no large study has been done. We have examined the adult Fabry population in the United Kingdom to describe the prevalence, associated factors and frequency of diagnosis of depression. METHODS: Postal questionnaires were sent from four adult clinics to 296 AFD patients. A response rate of 62% (n = 184; 74 male, 110 female) formed the data set. Questionnaires collected demographic and Fabry-specific information. Depression status was assessed using the Centre for Epidemiological Studies depression scale (CES-D). RESULTS: Responders were aged between 18 and 76 years (mean 44). The prevalence of depression was 46%, of which 28% were consistent with 'severe clinical depression'. Unlike the normal population, males with AFD report a higher prevalence of severe depression than females (36% males; 22% females). Interference of AFD symptoms with individuals' lives (particularly acroparaesthesiae or anhidrosis) showed the largest odds of association with depression. Relationship and financial status proved strong predictors of depression: 88% of those with mild-moderate depression and 72% with severe depression were undiagnosed. CONCLUSION: Depression is common and under-diagnosed in AFD. Proper assessment of and treatment for depression could improve the quality of life of these patients.