Clinicopathological features and oncological outcomes of patients with young-onset rectal cancer.

BACKGROUND: The incidence of rectal cancer among adults aged less than 50 years is rising. Survival data are limited and conflicting, and the oncological benefit of standard neoadjuvant and adjuvant therapies is unclear. METHODS: Disease-specific outcomes of patients diagnosed with rectal cancer undergoing surgical resection with curative intent between 2006 and 2016 were analysed. RESULTS: A total of 797 patients with rectal cancer were identified, of whom 685 had surgery with curative intent. Seventy patients were younger than 50 years and 615 were aged 50 years or more. Clinical stage did not differ between the two age groups. Patients aged less than 50 years were more likely to have microsatellite instability (9 versus 1·6 per cent; P = 0·003) and Lynch syndrome (7 versus 0 per cent; P < 0·001). Younger patients were also more likely to receive neoadjuvant chemoradiotherapy (67 versus 53·3 per cent; P = 0·003) and adjuvant chemotherapy (41 versus 24·2 per cent; P = 0·006). Five-year overall survival was better in those under 50 years old (80 versus 72 per cent; P = 0·013). The 5-year disease-free survival rate was 81 per cent in both age groups (P = 0·711). There were no significant differences in the development of locoregional recurrence or distant metastases. CONCLUSION: Despite accessing more treatment, young patients have disease-specific outcomes comparable to those of their older counterparts.

ANTECEDENTES: La incidencia de cáncer de recto entre adultos menores de 50 años está aumentando. Los datos de supervivencia son limitados y contradictorios, y el beneficio oncológico de los tratamientos neoadyuvantes y adyuvantes estándares no está claro. MÉTODOS: Se analizaron los resultados específicos relacionados con la enfermedad en pacientes diagnosticados de cáncer de recto operados con intención curativa entre 2006 y 2016. RESULTADOS: Se identificaron un total de 797 pacientes con cáncer de recto, de los cuales 685 fueron intervenidos quirúrgicamente con intención curativa. Setenta tenían menos de 50 años y 615 tenían 50 años o más. No hubo diferencias en el estadio clínico entre los dos grupos de edad. Los pacientes menores de 50 años tenían más probabilidades de tener inestabilidad de microsatélites (9% versus 2%, P = 0,003) y síndrome de Lynch (7% versus 0%, P ≤ 0,001). La supervivencia global a los 5 años fue mayor en los pacientes de menos de 50 años (80% y 72%; P = 0,013). La supervivencia libre de enfermedad a los 5 años fue del 81% en ambos grupos de edad (P = 0,711). No hubo diferencias significativas en el desarrollo de recidiva locorregional o metástasis a distancia. Los pacientes más jóvenes tenían más probabilidades de recibir quimiorradioterapia neoadyuvante (67% versus 53%, P = 0,003) y quimioterapia adyuvante (41% versus 24%, P = 0,006). CONCLUSIÓN: A pesar de tener acceso a más tratamientos, los pacientes jóvenes han presentado resultados específicos relacionados con la enfermedad comparables a sus homólogos de mayor edad.

Minimally invasive approaches to the management of anastomotic leakage following restorative rectal cancer resection.

AIM: Management of anastomotic leakage (AL) following rectal resection has evolved with increasing use of less invasive techniques. The aim of this study was to review the management of AL following restorative rectal cancer resection in a tertiary referral centre. METHOD: A retrospective review of a prospectively maintained database was performed. The primary outcome was successful management of AL. The secondary outcome was the impact of AL on oncological outcome. RESULTS: Five hundred and two restorative rectal cancer resections were performed during the study period. The incidence of AL was 9.9% (n = 50). AL occurred more commonly following neoadjuvant chemoradiotherapy (n = 31/252, 12.3%) than in those who did not receive neoadjuvant chemoradiotherapy (n = 19/250, 7.6%; P = 0.107); however, this was not statistically significant. Successful minimally invasive drainage was achieved in 28 patients (56%, radiological n = 24, surgical n = 4). Trans-rectal drainage was the most common drainage method (n = 14). The median duration of drainage was longer in the neoadjuvant group (27 vs 18 days). Surgical intervention was required in 11 patients, with anastomotic takedown and end-colostomy formation was most commonly required. Successful management of AL with drainage (maintenance of the anastomosis without the need for further intervention) was achieved in 26 of the 28 patients. There were no significant differences in overall or disease-free survival when patients with AL were compared with patients without AL (69.4% vs 72.6%, P = 0.99 and 78.7% vs 71.3%, P = 0.45, respectively). CONCLUSION: In selected patients, AL following restorative rectal resection can be effectively controlled using minimally invasive radiological or surgical drainage without the need for further intervention.

The lymph node ratio does not provide additional prognostic information compared with the N1/N2 classification in Stage III colon cancer.

AIM: The ratio of positive nodes to total nodes, the lymph node ratio (LNR), is a proposed alternative to the current N1/N2 classification of nodal disease. The true clinical benefit of adopting the LNR, however, has not been definitively demonstrated. This study compared the LNR with the current N1/N2 classification of Stage III colon cancer. METHOD: Patients with Stage III colon cancer were identified from a prospectively maintained database (1996-2012). The specificity and sensitivity of the N1/N2 classification in the prediction of overall survival were determined using R. A cut-off point for the LNR was determined by setting the specificity the same as for the N1/N2 classification. The sensitivity of the two methods was then compared, and bootstrapping 1000-fold was performed. This was then repeated for disease-specific survival. RESULTS: The specificity and sensitivity of the N1/N2 classification in predicting 3-year overall survival in this cohort (n = 402) was 62.2% and 52.1%, respectively. The cut-off point for the LNR was determined to be 0.27 for these data. On comparing LNR with the N1/N2 classification showed that for a given specificity, the LNR did not provide a statistically significant improvement in sensitivity (52.8% vs 52.1%, P = 0.31). For disease-specific death at 3 years, the specificity and sensitivity were 60.8% and 54.6%, respectively. The LNR did not provide a statistically significant improvement (55.4% vs 54.6%, P = 0.44). CONCLUSION: Both the N1/N2 system and the LNR predict survival in colon cancer, but both have low specificity and sensitivity. The LNR does not provide additional prognostic value to current staging for overall or disease-specific survival for a given cut-off point.

Multicentre randomized controlled trial comparing ferric(III)carboxymaltose infusion with oral iron supplementation in the treatment of preoperative anaemia in colorectal cancer patients.

BACKGROUND: At least a third of patients with a colorectal carcinoma who are candidate for surgery, are anaemic preoperatively. Preoperative anaemia is associated with increased morbidity and mortality. In general practice, little attention is paid to these anaemic patients. Some will have oral iron prescribed others not. The waiting period prior to elective colorectal surgery could be used to optimize a patients' physiological status. The aim of this study is to determine the efficacy of preoperative intravenous iron supplementation in comparison with the standard preoperative oral supplementation in anaemic patients with colorectal cancer. METHODS/DESIGN: In this multicentre randomized controlled trial, patients with an M0-staged colorectal carcinoma who are scheduled for curative resection and with a proven iron deficiency anaemia are eligible for inclusion. Main exclusion criteria are palliative surgery, metastatic disease, neoadjuvant chemoradiotherapy (5 × 5 Gy = no exclusion) and the use of Recombinant Human Erythropoietin within three months before inclusion or a blood transfusion within a month before inclusion. Primary endpoint is the percentage of patients that achieve normalisation of the haemoglobin level between the start of the treatment and the day of admission for surgery. This study is a superiority trial, hypothesizing a greater proportion of patients achieving the primary endpoint in favour of iron infusion compared to oral supplementation. A total of 198 patients will be randomized to either ferric(III)carboxymaltose infusion in the intervention arm or ferrofumarate in the control arm. This study will be performed in ten centres nationwide and one centre in Ireland. DISCUSSION: This is the first randomized controlled trial to determine the efficacy of preoperative iron supplementation in exclusively anaemic patients with a colorectal carcinoma. Our trial hypotheses a more profound haemoglobin increase with intravenous iron which may contribute to a superior optimisation of the patient's condition and possibly a decrease in postoperative morbidity. TRIAL REGISTRATION: ClincalTrials.gov: NCT02243735 .

Multicentre study of circumferential margin positivity and outcomes following abdominoperineal excision for rectal cancer.

BACKGROUND: Rectal cancer outcomes following abdominoperineal excision (APE) have been inferior to those for anterior resection, including more positive circumferential resection margins (CRMs). An erroneously conservative interpretation of APE (rather than a radical resection termed 'extralevator') has been proposed as the cause. In this multicentre study, factors contributing to CRM positivity were examined following APE according to its original description. METHODS: Data were collected from five hospital databases up to June 2011 including small- and larger-volume units (3 hospitals had 5 or fewer and 2 hospitals had more than 5 APE procedures per year). Primary outcome measures were CRM status; secondary outcomes were local recurrence and death. RESULTS: Of 327 patients, 302 patients had complete data for analysis. Some 50·0 per cent of patients had neoadjuvant chemoradiotherapy. Histopathological examination showed that 62·9 per cent had tumour category T3 or T4 cancers, 42·1 per cent had node-positive disease and the CRM positivity rate was 13·9 per cent. Multivariable analysis showed only pathological tumour category pT4 (odds ratio 19·92, 95 per cent confidence interval 6·48 to 68·61) and node positivity (odds ratio 3·04, 1·32 to 8·05) to be risk factors for a positive circumferential margin. CRM positivity was a risk factor for local recurrence (P = 0·022) and decreased overall survival (P = 0·001). Hospital volume had no impact on the likelihood of CRM positivity (P = 0·435). CONCLUSION: In patients undergoing APE by appropriately trained surgeons using a standardized approach, margin positivity was dictated by tumour stage, but not by centre or surgeon.

Oestrogen inhibits human colonic motility by a non-genomic cell membrane receptor-dependent mechanism.

BACKGROUND: Classical effects of oestrogen involve activation of target genes after binding nuclear receptors. Oestrogenic effects too rapid for DNA transcription (non-genomic) are known to occur. The effect of oestrogen on colonic motility is unknown despite the prevalence of gastrointestinal symptoms in pregnant and premenopausal women. METHODS: Histologically normal colon was obtained from proximal resection margins of colorectal carcinoma specimens. Circular smooth muscle strips were microdissected and suspended in organ baths under 1 g of tension. After equilibration, they were exposed to 17beta-oestradiol (n = 8) or bovine serum albumin (BSA)-conjugated 17beta-oestradiol (n = 8). Fulvestrant, an oestrogen receptor antagonist, was added to some baths (n = 8). Other strips were exposed to calphostin C or cycloheximide. Carbachol was added in increasing concentrations and contractile activity was recorded isometrically. RESULTS: Oestrogen inhibited colonic contractility (mean difference 19.7 per cent; n = 8, P < 0.001). In keeping with non-genomic, rapid-onset steroid action, the effect was apparent within minutes and reversible. It was observed with both 17beta-oestradiol and BSA-conjugated oestrogen, and was not altered by cycloheximide. Effects were inhibited by fulvestrant, suggesting receptor mediation. CONCLUSION: Oestrogen decreases contractility in human colonic smooth muscle by a non-genomic mechanism involving cell membrane coupling.

Effects of CDX2 on prognosis and chemotherapy responsiveness in mismatch repair-deficient colorectal cancer.

BACKGROUND: Caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor implicated in tumour differentiation, proliferation, cell adhesion and migration. Negative CDX2 status (CDX2-) is associated with worse prognosis in colorectal cancer and may identify high-risk stage II disease that benefits from adjuvant chemotherapy. This observational study investigated whether CDX2- is associated with prognosis or response to chemotherapy in the mismatch repair-deficient (dMMR) phenotype of colorectal cancer. METHODS: Patients with resectable dMMR colorectal cancer were eligible for inclusion. The prognostic and predictive value of CDX2 expression on the presence of lymph node metastasis (LNM) and survival was investigated. CDX2 status was determined via immunohistochemistry using the Leica Bond™ CDX2 (clone EP25) ready-to-use primary antibody. RESULTS: Some 235 of 238 consecutive dMMR tumours were assessed for CDX2 status. CDX2- was observed in 15·7 per cent of colorectal cancer. Interobserver agreement was excellent (κ = 0·863; P < 0·001). CDX2- was significantly associated with female sex, increased size, advanced stage, worse conventional and poorly differentiated cluster (PDC) grade, mucinous morphology, perineural and lymphovascular invasion, and pN status (all P ≤ 0·038). CDX2- was not associated with LNM or survival in multivariable analysis. Independent predictors of LNM were PDC grade (odds ratio (OR) 4·12, 95 per cent c.i. 1·76 to 9·63; P = 0·001) and extramural venous invasion (OR 3·79, 1·62 to 8·85; P = 0·002). Budding (hazard ratio (HR) 2·79, 95 per cent c.i. 1·60 to 4·87; P < 0·001), pT status (HR 3·59, 1·29 to 10·01; P = 0·015) and adjuvant chemotherapy (HR 2·07, 1·15 to 3·74; P = 0·016) were independently associated with worse disease-free survival. CONCLUSION: CDX2- does not confer a worse prognosis in the dMMR phenotype of colorectal cancer. The MMR status of patients with colorectal cancer should be determined before assessing CDX2 status.

Familial colorectal cancer: Patient assessment, surveillance and surgical management.

Germline mutations account for 5-10% of colorectal cancer. Most mutations are autosomal dominant with high penetrance and affected patients benefit greatly from appropriate treatment. This review presents the current knowledge regarding familial colorectal cancer and provides practical information based on international guidelines and the best available evidence regarding patient assessment, surveillance and surgical management. Surgeons are often the first point of contact and frequently, the main provider of care for families with cancer syndromes or patients with familial cancer. Patients with a polyposis phenotype should undergo appropriate genetic testing. In non-polyposis patients with a cancer diagnosis, tumor testing for Lynch syndrome can guide the use of genetic testing. In patients without a personal history of cancer or polyposis, a carefully obtained family history with testing of available tumor tissue or of a living relative affected by colorectal cancer informs the need for genetic testing. Surveillance and surgical management should be planned following thorough assessment of familial cancer risk. Evidence exists to provide guidance as to the surveillance strategies required, the specific indications of genetic testing and the appropriate timing of operative intervention. A carefully obtained family history with selective genetic testing should inform surveillance and surgical management in patients who have a genetic predisposition for the development of colorectal cancer.

Microsatellite instability is associated with reduced disease specific survival in stage III colon cancer.

BACKGROUND: Up to 15% of colorectal cancers exhibit microsatellite instability (MSI), where errors in replication go unchecked due to defects in the mismatch repair system. This study aimed to determine survival in a large single-centre series of 1250 consecutive colorectal cancers subjected to universal MSI testing. METHODS: Clinical and pathological features of patients with colorectal cancer identified on prospectively maintained colorectal and pathology databases at St. Vincent's University Hospital from 2004 to May 2012 were examined. Mismatch repair (MMR) status was determined by immunohistochemistry. Kaplan-Meier curves, the log-rank test and Cox regression were used to associate survival with clinical and pathological characteristics. RESULTS: Of the 1250 colorectal cancers in the study period, 11% exhibited MSI (n = 138). Patients with MSI tumours had significantly lower rates of lymph node and distant metastases (MSI N+ rate: 24.8% compared with MSS N+ rate: 46.2%, p < 0.001). For Stage I and II disease MSI was associated with improved disease free survival (DSS) compared with MSS colon cancer. However, patients with Stage III MSI colon cancers had a worse DSS than those with MSS tumours. Stage III MSI tumours exhibited higher rates of lymphovascular invasion and perineural invasion than Stage I/II MSI tumours. CONCLUSION: MSI is associated with a reduced risk of nodal and distant metastases, with an improved DSS in Stage I/II colon cancer. However, when MSI tumours progress to Stage III these patients had worse outcomes and pathological features. New strategies for this cohort of patients may be required to improve outcomes.

Adjuvant therapies in the treatment of stage II and III malignant melanoma.

BACKGROUND: The incidence of cutaneous melanoma has increased during the past three decades. The development of sentinel lymph node biopsy has facilitated better staging. Despite these improvements, 5-year survival rates for American Joint Committee on Cancer stage II and III disease range from 50%-90%. METHODS: A review of the current literature concerning adjuvant therapies in patients with stage II and III malignant melanomas was undertaken. RESULTS: The focus of adjuvant therapies has shifted from radiotherapy, BCG and levamisole to newer biological agents. Interferon, interleukin and vaccines have been evaluated but none of these agents have demonstrated an increase in overall survival in patients with stage II and III melanoma. Interferon can prolong disease-free interval. CONCLUSION: At present, no adjuvant therapy improves overall survival in patients with stage II and III melanoma. New staging allows more accurate stratification of patients for clinical trials.

Improving acute care through use of medical device data.

The Medical Information Bus (MIB) is a data communications standard for bedside patient connected medical devices. It is formally titled IEEE 1073 Standard for Medical Device Communications. MIB defines a complete seven layer communications stack for devices in acute care settings. All of the design trade-offs in writing the standard were taken to optimize performance in acute care settings. The key clinician based constraints on network performance are: (1) the network must be able to withstand multiple daily reconfigurations due to patient movement and condition changes; (2) the network must be 'plug-and-play' to allow clinicians to set up the network by simply plugging in a connector, taking no other actions; (3) the network must allow for unambiguous associations of devices with specific patients. A network of this type will be used by clinicians, thus giving complete, accurate, real time data from patient connected devices. This capability leads to many possible improvements in patient care and hospital cost reduction. The possible uses for comprehensive automatic data capture are only limited by imagination and creativity of clinicians adapting to the new hospital business paradigm.

New IEEE standard enables data collection for medical applications.

The IEEE has gone to ballot on a "Standard for Medical Device Communications", IEEE P1073. The lower layer, hardware portions of the standard are expected to be approved by the IEEE Standards Board at their December 11-13, 1994 meeting. Other portions of the standard are in the initial stages of the IEEE ballot process. The intent of the standard is to allow hospitals and other users to interface medical electronic devices to host computer systems in a standard, interchangeable manner. The standard is optimized for acute care environments such as ICU's, operating rooms, and emergency rooms. [1] IEEE General Committee and Subcommittee work has been on-going since 1984. Significant amounts of work have been done to discover and meet the needs of the patient care setting. Surveys performed in 1989 identified the following four key user requirements for medical device communications: 1) Frequent reconfiguration of the network. 2) Allow "plug and play" operation by users. 3) Associate devices with a specific bed and patient. 4) Support a wide range of hospital computer system topologies. Additionally, the most critical difference in the acute care setting is patient safety, which has an overall effect on the standard. The standard that went to ballot meets these requirements. The standard is based on existing ISO standards. P1073 is compliant with the OSI seven layer model. P1073 specifies the entire communication stack, from object-oriented software to hospital unique connectors. The standard will be able to be put forward as a true international standard, much in the way that the IEEE 802.x family of standards (like Ethernet) were presented as draft ISO standards.(ABSTRACT TRUNCATED AT 250 WORDS)

Perspectives on development of IEEE 1073: the Medical Information Bus (MIB) standard.

Automated data capture from bedside patient medical devices is now possible using a new Institute of Electrical and Electronic Engineering (IEEE) and American National Standards Institute (ANSI) Medical Information Bus (MIB) data communications standard (IEEE 1073). The first two standard documents, IEEE 1073.3.1 (Transportation Profile) and IEEE 1073.4.1 (Physical Layer), define the hardware protocol for bedside device communications. With the above noted IEEE MIB standards in place, hospitals can now start designing customized applications for acquiring data from bedside devices such as bedside monitors, i.v. pumps, ventilators, etc. for multiple purposes. The hardware 'plug and play' features of the MIB will enable nurses and physicians to establish communications with these devices simply and conveniently by plugging them into a bedside data connector. No other action will be necessary to establish identification of the device or communications with the device. Presently to connect bedside devices, technical help from hardware and software experts are required to establish such communications links. As a result of standardization of communications, it will be easy to establish a highly mobile network of bedside devices and more promptly and efficiently collect patient related data. Collection of data automatically should lead to the design of new medical computing applications that will tie in directly with the emerging mission and operations of hospitals. The MIB will permit acquisition of patient data more efficiently with greater accuracy, more completeness and more promptly. The above noted features are all essential to the development of computerized treatment protocols and should lead to improved quality of patient care. This manuscript provides the rational and historical overview of the development of the MIB standard.