Screening for malnutrition in emergency laparotomy patients: a comparison of three tools.

INTRODUCTION: Malnourished patients undergoing emergency laparotomy are at risk of significant morbidity. The optimum screening tool to identify such patients in practice and research is yet to be determined. This study aims to compare the performance of three nutrition risk tools in predicting time without enteral nutrition in this population. METHODS: A prospective cohort study (NCT04696367) was conducted across two sites, recruiting patients undergoing National Emergency Laparotomy Audit eligible procedures. Data collected included demographics, diagnosis, procedure and outcomes. Nutrition risk was assessed using three tools: Malnutrition Universal Screening Tool (MUST) score, Nutritional Risk Index (NRI) and Nutritional Risk Score 2002 (NRS-2002). Complications were assessed with the Comprehensive Complication Index. Quality of life was measured at baseline and 5 days postsurgery using EQ-5D-5L. RESULTS: A total of 59 patients were recruited. Median age was 69 years. Of the 59 participants, 23 were judged high risk using MUST score, 13 using NRS and 8 using NRI. Median time to restart enteral intake was 7 days (interquartile range 7-14). Time without intake was correlated with increasing score using MUST (r=0.463, p<0.001) and NRS-2002 (r=0.296, p=0.03) but not NRI (r=-0.121, p=0.38). High-risk nutritional groups also had increased length of hospital stay, but not complication scores. CONCLUSIONS: Patients undergoing emergency laparotomy spend a prolonged time without enteral nutrition. Although all nutritional tools demonstrated some propensity to identify patients at higher risk of needing nutritional support, their performance was variable. Nevertheless, some may be useful in future clinical studies.

Neighborhoods and functionality in metals.

The fundamental construct of organic chemistry involves understanding molecular behavior through functional groups. Much of computational chemistry focuses on this very principle, but metallic materials are rarely analyzed using these techniques owing to the assumption that they are delocalized and do not possess inherent functionality. In this paper, we propose a methodology that recovers functional groups in metallic materials from an energy perspective. We characterize neighborhoods associated with functional groups in metals by observing the evolution of Bader energy of the central cluster as a function of cluster size. This approach can be used to conceptually decompose metallic structure into meaningful chemical neighborhoods allowing for localization of energy-dependent properties. The generalizability of this approach is assessed by determining neighborhoods for crystalline materials of different structure types, and significant structural defects such as grain boundaries and dislocations. In all cases, we observe that the neighborhood size may be universal-around 2-3 atomic diameters. In its practical sense, this approach opens the door to the application of chemical concepts, e.g., orbital methods, to investigate a broad range of metallurgical phenomena, one neighborhood at a time.

Genomic context of NTRK1/2/3 fusion-positive tumours from a large real-world population.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are rare oncogenic drivers in solid tumours. This study aimed to interrogate a large real-world database of comprehensive genomic profiling data to describe the genomic landscape and prevalence of NTRK gene fusions. NTRK fusion-positive tumours were identified from the FoundationCORE® database of >295,000 cancer patients. We investigated the prevalence and concomitant genomic landscape of NTRK fusions, predicted patient ancestry and compared the FoundationCORE cohort with entrectinib clinical trial cohorts (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). Overall NTRK fusion-positive tumour prevalence was 0.30% among 45 cancers with 88 unique fusion partner pairs, of which 66% were previously unreported. Across all cases, prevalence was 0.28% and 1.34% in patients aged ≥18 and <18 years, respectively; prevalence was highest in patients <5 years (2.28%). The highest prevalence of NTRK fusions was observed in salivary gland tumours (2.62%). Presence of NTRK gene fusions did not correlate with other clinically actionable biomarkers; there was no co-occurrence with known oncogenic drivers in breast, or colorectal cancer (CRC). However, in CRC, NTRK fusion-positivity was associated with spontaneous microsatellite instability (MSI); in this MSI CRC subset, mutual exclusivity with BRAF mutations was observed. NTRK fusion-positive tumour types had similar frequencies in FoundationCORE and entrectinib clinical trials. NTRK gene fusion prevalence varied greatly by age, cancer type and histology. Interrogating large datasets drives better understanding of the characteristics of very rare molecular subgroups of cancer and allows identification of genomic patterns and previously unreported fusion partners not evident in smaller datasets.

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Prehabilitation in elective abdominal cancer surgery in older patients: systematic review and meta-analysis.

BACKGROUND: Prehabilitation has emerged as a strategy to prepare patients for elective abdominal cancer surgery with documented improvements in postoperative outcomes. The aim of this study was to assess the evidence for prehabilitation interventions of relevance to the older adult. METHODS: Systematic searches were conducted using MEDLINE, Web of Science, Scopus, CINAHL and PsychINFO. Studies of preoperative intervention (prehabilitation) in patients undergoing abdominal cancer surgery reporting postoperative outcomes were included. Age limits were not set as preliminary searches revealed this would be too restrictive. Articles were screened and selected based on PRISMA guidelines, and assessment of bias was performed. Qualitative, quantitative and meta-analyses of data were conducted as appropriate. RESULTS: Thirty-three studies (3962 patients) were included. Interventions included exercise, nutrition, psychological input, comprehensive geriatric assessment and optimization, smoking cessation and multimodal (two or more interventions). Nine studies purposely selected high-risk, frail or older patients. Thirty studies were at moderate or high risk of bias. Ten studies individually reported benefits in complication rates, with meta-analyses for overall complications demonstrating significant benefit: multimodal (risk difference -0·1 (95 per cent c.i. -0·18 to -0·02); P = 0·01, I2  = 18 per cent) and nutrition (risk difference -0·18 (-0·26 to -0·10); P < 0·001, I2  = 0 per cent). Seven studies reported reductions in length of hospital stay, with no differences on meta-analysis. CONCLUSION: The conclusions of this review are limited by the quality of the included studies, and the heterogeneity of interventions and outcome measures reported. Exercise, nutritional and multimodal prehabilitation may reduce morbidity after abdominal surgery, but data specific to older patients are sparse.

ANTECEDENTES: La pre-habilitación ha surgido como una estrategia para preparar a los pacientes para la cirugía electiva del cáncer abdominal con mejoras documentadas en los resultados postoperatorios. El objetivo de este estudio fue evaluar la evidencia sobre las intervenciones de pre-habilitación relevantes en adultos de edad avanzada. MÉTODOS: Se realizaron búsquedas sistemáticas utilizando MEDLINE, Web of Science, Scopus, CINAHL y PsychINFO. Registro PROSPERO: CRD42019120381. Se incluyeron estudios de intervención preoperatoria (pre-habilitación) en pacientes sometidos a cirugía oncológica abdominal que describiesen resultados postoperatorios. No se fijaron límites en la edad dado que las búsquedas preliminares revelaron que ello sería demasiado restrictivo. Los artículos fueron examinados y seleccionados en base a las guías PRISMA y se realizó una evaluación del sesgo. Se llevó a cabo un análisis cualitativo, cuantitativo y metaanálisis de los datos según fuese apropiado. RESULTADOS: Se incluyeron 33 estudios (3.962 patients). Las intervenciones incluyeron ejercicio, nutrición, intervención psicológica, evaluación geriátrica global y optimización, abandono del tabaquismo y multimodal (dos o más intervenciones). Nueve estudios seleccionaron expresamente una población de pacientes de elevado riesgo, frágiles o de edad avanzada. Treinta estudios presentaban un riesgo moderado/alto de sesgo. Diez estudios describieron de forma individual beneficios en las tasas de complicaciones con metaanálisis para las complicaciones globales demostrando un beneficio significativo: multimodal (diferencia de riesgo -0,1 (i.c. del 95% −0,18 a −0,02); P = 0,01, I2 = 18%) e intervención nutricional (diferencia de riesgo −0,18 (i.c. del 95% −0,26 a −0,10); P < 0,001, I2 = 0%). Siete estudios describieron reducciones en la duración de la estancia hospitalaria, sin diferencias en el metaanálisis. CONCLUSIÓN: Las conclusiones de esta revisión están limitadas por la calidad de los estudios incluidos, heterogeneidad de las intervenciones y descripción de las medidas de resultados. Las intervenciones de pre-habilitación de ejercicio, nutricionales y multimodales puede reducir la morbilidad tras cirugía abdominal, pero los datos concretos en pacientes de edad avanzada son escasos.

Current management of small bowel obstruction in the UK: results from the National Audit of Small Bowel Obstruction clinical practice survey.

AIM: Small bowel obstruction (SBO) is associated with high rates of morbidity and mortality. The National Audit of Small Bowel Obstruction (NASBO) is a collaboration between trainees and specialty associations to improve the care of patients with SBO through national clinical audit. The aim of this study was to define current consultant practice preferences in the management of SBO in the UK. METHOD: A survey was designed to assess practice preferences of consultant surgeons. The anonymous survey captured demographics, indications for surgery or conservative management, use of investigations including water-soluble contrast agents (WSCA), use of laparoscopy and nutritional support strategies. The questionnaire underwent two pilot rounds prior to dissemination via the NASBO network. RESULTS: A total of 384 responses were received from 131 NASBO participating units (overall response rate 29.2%). Abdominal CT and serum urea and electrolytes were considered essential initial investigations by more than 80% of consultants. Consensus was demonstrated on indications for early surgery and conservative management. Three hundred and thirty-eight (88%) respondents would consider use of WSCA; of these, 328 (97.1%) would use it in adhesive SBO. Two hundred (52.1%) consultants considered a laparoscopic approach when operating for SBO. Oral nutritional supplements were favoured in operatively managed patients by 259 (67.4%) respondents compared with conservatively managed patients (186 respondents, 48.4%). CONCLUSION: This survey demonstrates consensus on imaging requirements and indications for early surgery in the management of SBO. Significant variation exists around awareness of the need for nutritional support in patients with SBO, and on strategies to achieve this support.

Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers.

BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Randomized, phase II, placebo-controlled trial of onartuzumab and/or bevacizumab in combination with weekly paclitaxel in patients with metastatic triple-negative breast cancer.

BACKGROUND: Increased hepatocyte growth factor/MET signaling is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer (TNBC). We evaluated the benefit of adding onartuzumab, a monoclonal anti-MET antibody, to paclitaxel with/without bevacizumab in patients with TNBC. PATIENTS AND METHODS: Women with metastatic TNBC were randomized to receive onartuzumab plus placebo plus weekly paclitaxel (OP; n = 60) or onartuzumab plus bevacizumab plus paclitaxel (OBP; n = 63) or placebo plus bevacizumab plus paclitaxel (BP; n = 62). The primary end point was progression-free survival (PFS); additional end points included overall survival (OS), objective response rate (ORR), and safety. This trial was hypothesis generating and did not have power to detect minimum clinically meaningful differences between treatment arms. RESULTS: There was no improvement in PFS with the addition of onartuzumab to BP [hazard ratio (HR), 1.08; 95% confidence interval (CI) 0.69-1.70]; the risk of a PFS event was higher with OP than with BP (HR, 1.74; 95% CI 1.13-2.68). Most patients had MET-negative tumors (88%); PAM50 subtype analysis showed basal-like tumors in 68% of samples. ORR was higher in the bevacizumab arms (OBP: 42.2%; 95% CI 28.6-57.1; BP: 54.7%; 95% CI 41.0-68.4) compared with OP (27.5%; 95% CI 15.9-40.6). Median OS was shorter with OBP (HR, 1.36; 95% CI 0.75-2.46) and OP (HR, 1.92; 95% CI 1.03-3.59), than with BP. Peripheral edema was more frequent in the onartuzumab arms (OBP, 51.8%; OP, 58.6%) versus BP (17.7%). CONCLUSION: This study did not show a clinical benefit of the addition of onartuzumab to paclitaxel with/without bevacizumab in patients with predominantly MET-negative TNBC. CLINICALTRIALSGOV: NCT01186991.

Utility of contrast enema to assess anastomotic integrity and the natural history of radiological leaks after low rectal surgery: systematic review and meta-analysis.

PURPOSE: There is no clear consensus on how to assess low rectal anastomotic integrity and patency prior to reversal of de-functioning stoma. The aim of this systematic review was to assess the utility of contrast enema (CE) in this context and to clarify the natural history of radiological leaks. METHODS: Keyword search of electronic databases (Embase, MEDLINE, Cochrane Library, Google Scholar) and bibliographic cross-referencing were performed to identify appropriate studies. Data extraction and synthesis was performed with the primary outcomes being the sensitivity and specificity of CE for detecting clinically significant abnormalities. Statistical analysis was performed using Open Meta-Analyst software. Narrative review of outcomes including those of clinical and radiological leaks was also undertaken. RESULTS: A total of 1,142 CE from 11 articles were included in the final meta-analysis. CE had high specificity (95.4; 95 % confidence interval = 92.0-97.4) and negative predictive value (98.4; 97.4-99.1) and moderate sensitivity (79.9; 63.9-89.9) and positive predictive value (64.6; 55.5-72.9) for the detection of clinically significant anastomotic problems. There was a high degree of correlation between CE and clinical examination findings (96.7 %). Occult radiological leaks were seen in 5.7 % of CE, and all but one (97 %) eventually underwent successful reversal. Only three quarters of patients with clinical leak underwent successful reversal. CONCLUSION: CE is effective at excluding clinically significant anastomotic problems, especially after clinical anastomotic leaks. However, false positive results can be observed in asymptomatic patients, and it is unclear how much additional information CE provides over clinical assessment in the low uncomplicated anastomosis.

The morbidity of negative appendicectomy.

INTRODUCTION: The increased use of diagnostic laparoscopy for management of right iliac fossa pain may have lowered the threshold for removing normal appendices, particularly as there is a perception that this practice carries little additional morbidity. The aim of this retrospective audit was to determine the negative appendicectomy rate after laparoscopic appendicectomy (LA) in our busy district hospital, and to compare the relative incidence and severity of complications after removal of an inflamed or non-inflamed appendix. METHODS: Adult patients who underwent LA in 2011-2012 were identified from theatre registers. Histology results were reviewed to differentiate between inflamed and normal appendices. Postoperative complications and events following discharge were identified via electronic patient records. Complication severity was stratified using the Clavien-Dindo classification. RESULTS: Over 2 years, 467 LAs were performed, of which 143 (30.6%) were for normal appendices. Significantly more negative appendicectomies were performed in women (43%) than in men (17%) (p<0.0001). Complications were seen in 62 patients (13.3%). There was no significant difference between the complication rates for those who had an inflamed (16.6%) or non-inflamed (11.9%) appendix (p=0.141). Similarly, there was no difference in the severity of complications between these groups. Reoperation or invasive intervention was required after four negative appendicectomies (2.8%). CONCLUSIONS: LA carries a similar morbidity regardless of whether the appendix is inflamed. Negative appendicectomy should not be undertaken routinely during laparoscopy for right iliac fossa pain.

Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer.

The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.

The success of rectus and gracilis muscle flaps in the treatment of chronic pelvic sepsis and persistent perineal sinus: a systematic review.

AIM: Chronic pelvic sepsis is a challenging problem, which may require muscle flaps to fill the pelvic cavity. The aim of this systematic review was to determine the relative success of rectus and gracilis flaps used for this purpose. METHOD: A systematic review was conducted to identify papers that reported the outcome of rectus or gracilis myocutaneous flaps in the treatment of persistent perineal sinuses or chronic pelvic sepsis. Reports of muscle flaps used for reconstruction or treatment of fistula in the absence of chronic sepsis were excluded. A successful outcome was defined as complete perineal healing within 12 months of surgery. RESULTS: The review identified 19 studies reporting the outcome of 73 rectus and 87 gracilis flaps. Their respective success was 84% and 64%. Heterogeneity of the underlying cases did not allow for direct comparison of the flaps. Full healing of the flaps was generally achieved within 3 months. Donor site morbidity was minimal. CONCLUSION: The surgical treatment of chronic pelvic sepsis should be tailored to the individual, but the rectus flap has a reasonable success rate with little morbidity.

Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer.

Agents targeting the PI3K/mTOR signaling axis have shown promise in early-phase clinical trials and are currently being studied in later stages of clinical development in multiple indications. Experience with other targeted agents suggests that clinical responses may be short-lived because of acquired resistance to therapy. Here, we report preclinical modeling of acquired resistance in a HER2-positive, PIK3CA mutant breast cancer cell line, KPL-4. We identified a heretofore-unreported mechanism of resistance, specifically high-level amplification of the mutant allele of PIK3CA, which resulted in a marked upregulation of PI3K signaling, enabling resistant cells to regain proliferative capacity at clinically relevant concentrations of the PI3K inhibitor, GDC-0941. We show that knockdown of the amplified PIK3CA mutant allele in these cells by small interfering RNA restored pathway signaling and sensitivity to PI3K inhibition at levels comparable to parental cells. These novel preclinical findings suggest that, in addition to assessment of other previously reported mechanisms of resistance, evaluation of PI3K copy number variation should be integrated into the exploratory analysis of biopsies obtained at disease progression.

Influence of enhanced recovery after surgery pathways and laparoscopic surgery on health-related quality of life.

AIM: This study set out to compare the postoperative health related quality of life (HQoL) of patients undergoing elective open colorectal surgery using a well-established enhanced recovery after surgery (ERAS) pathway with those undergoing laparoscopic surgery without an established an ERAS pathway. METHOD: Using a power calculation, it was estimated that 40 patients would be required in each group. HQoL of the two groups was prospectively assessed using SF-12 (Short Form 12) and EORTC QLQ 30 (European Organisation of Research and Treatment of Cancer, Quality of Life Questionnaire) preoperatively, and at 2 and 6 weeks after discharge. RESULTS: Data were collected from 83 patients, 41 in the laparoscopic group and 42 in the open-ERAS group. There was a significant difference between the median length of stay of the open-ERAS (5 days) and laparoscopic (7 days, P = 0.028) groups. There were no significant differences between the HQoL score of the two groups at any stage. In both groups, the majority of HQoL scores had improved considerably by 6 weeks. CONCLUSION: Laparoscopic and open-ERAS surgery have a similar impact on postoperative HQoL. HQoL tends to improve by the 6-week stage.

Raised intraocular pressure (IOP) and perioperative visual loss in laparoscopic colorectal surgery: a catastrophe waiting to happen? A systematic review of evidence from other surgical specialities.

BACKGROUND: Case reports of healthy patients experiencing total perioperative visual loss (POVL) after elective laparoscopic surgery, including colorectal resection, are appearing increasingly frequently in the literature. We reviewed the literature exploring the relationship between patient positioning and intraocular pressure (IOP) across all surgical specialties. This was then applied to the potential risk of developing POVL in patients undergoing laparoscopic colorectal surgery. METHODS: A systematic review of the relevant literature was performed to identify all studies exploring the relationship between intraocular pressure and patient positioning. RESULTS: Eight relevant studies on both elective patients and healthy non-anaesthetised volunteers in the spinal, neurosurgical and urological fields were identified which explore the changes in IOP according to patient positioning. These all reported significant rises in IOP in both head-down positioning and prone positioning, and the strongest effects were seen in those patients placed in combined head-down and prone position (such as prone jackknife). Rises in IOP were time-dependent in all studies. CONCLUSIONS: Patients undergoing laparoscopic colorectal surgery in a prolonged head-down position are likely to experience raised IOP and thus are at risk of POVL. Those having a laparoscopic abdominoperineal excision with prone positioning for the perineal component are probably those in the greatest danger. Surgeons need to be aware of this under-recognised but potentially catastrophic complication.

A qualitative study of patient perspectives of health-related quality of life in colorectal cancer: comparison with disease-specific evaluation tools.

AIM: Little is known about the factors that patients with colorectal cancer (CRC) consider as important in shaping their health-related quality of life (HrQoL) and whether these are adequately represented by currently used HrQoL instruments. The aim of this study was to determine which areas of HrQoL are important to patients with CRC and to establish whether these areas are represented by validated questionnaires. METHOD: Semi-structured interviews were conducted with 20 patients who were undergoing treatment or follow up for potentially curable CRC. The areas of HrQoL that were important to the patients were identified from the interview data using a qualitative thematic framework analysis. These themes were then compared with the item content of two CRC-specific HrQoL questionnaires, FACT-C and QLQ-C30/CR38. RESULTS: The interviews identified 10 themes considered by patients to be important determinants of their HrQoL. These comprised control, normality, fatigue, uncertainty, information, emotional support, self-image, coping, symptoms and emotionally challenging events. Both HrQoL instruments contained questions that concerned some of the themes identified, but none of the FACT-C scales and only three from QLQ-C30/CR38 produced scores from which clinicians could identify problems in these areas. CONCLUSION: Identifying and addressing areas of concern for patients may assist clinicians in improving HrQoL outcomes. However, validated instruments currently used in CRC provide little information with regard to these areas.

Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing.

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

Anti-apoptotic mechanisms of drug resistance in cancer.

Resistance to chemotherapy is a major obstacle in the treatment of cancer. Despite the advent of new chemotherapies and molecular-targeted therapies, approximately 90% of patients with metastatic cancer succumb to their disease. Drug resistance, either acquired or intrinsic, often prevents tumour cells from undergoing sufficient levels of programmed cell death or apoptosis, resulting in cancer cell survival and treatment failure. In pre-clinical disease models, agents that target the apoptotic pathway have been shown to sensitize tumour cells to chemotherapy and radiotherapy. Such therapies include small molecule inhibitors and antisense strategies that inhibit the activity of anti-apoptotic proteins, or treatment with recombinant pro-apoptotic proteins or antibodies that can activate the apoptotic pathway. This review will discuss apoptosis and the mechanisms by which it can become dysregulated in human cancer. In addition, novel therapeutic strategies that target key components of the apoptotic machinery will be discussed.

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells.

Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.