Neoadjuvant chemotherapy in non-metastatic breast cancer: The surgeon's perspective.

Breast cancer is the most common non-skin cancer in Australia, affecting 1 in 7 women by the age of 85 years. Current management of early breast cancer is becoming increasingly variable and complex. The typical range of treatments include some combination of surgery, chemotherapy and targeted therapy, immunotherapy, radiotherapy, and endocrine therapy. Neoadjuvant chemotherapy (NACT) in carefully selected patients can facilitate increased rates of breast conservation therapy, and when successful, offers improved cosmesis due to less extensive resection of tissue. A neoadjuvant approach also provides biological insight into a patient's tumour, prognostication based on a patient's response to therapy, as well as enabling their treating oncologist to personalise adjuvant strategies based on the presence or absence of residual cancer at surgery. Neoadjuvant chemotherapy has become an integral element in the provision of breast conserving surgery to selected early-stage breast cancer patients. Appreciating the indications and understanding the likely outcomes from NACT in select situations, can result in significant improvements in patient tailored care.

Complete mesocolic excision versus standard resection for colon cancer: a systematic review and meta-analysis of perioperative safety and an evaluation of the use of a robotic approach.

PURPOSE: Complete mesocolic excision (CME) has been associated with improved oncological outcomes in treatment of colon cancer. However, widespread adoption is limited partly because of the technical complexity and perceived risks of the approach. The aim of out study was to evaluate the safety of CME compared to standard resection and to compare robotic versus laparoscopic approaches. METHODS: Two parallel searches were undertaken in MEDLINE, Embase and Web of Science databases 12 December 2021. The first was to evaluate IDEAL stage 3 evidence to compare complication rates as a surrogate marker of perioperative safety between CME and standard resection. The second independent search compared lymph node yield and survival outcomes between minimally invasive approaches. RESULTS: There were four randomized control trials (n = 1422) comparing CME to standard resection, and three studies comparing laparoscopic (n = 164) to robotic (n = 161) approaches. Compared to standard resection, CME was associated with a reduction in Clavien-Dindo grade 3 or higher complication rates (3.56% vs. 7.24%, p = 0.002), reduced blood loss (113.1 ml vs. 137.6 ml, p < 0.0001) and greater mean lymph node harvest (25.6 vs. 20.9 nodes, p = 0.001). Between the robotic and laparoscopic groups, there were no significant differences in complication rates, blood loss, lymph node yield, 5-year disease-free survival (OR 1.05, p = 0.87) and overall survival (OR 0.83, p = 0.54). CONCLUSIONS: Our study demonstrated improved safety with CME. There was no difference in safety or survival outcomes between robotic and laparoscopic CME. The advantage of a robotic approach may lie in the reduced learning curve and an increased penetration of minimally invasive approach to CME. Further studies are required to explore this. PROSPERO ID: CRD42021287065.

Transanal mesorectal excision: early outcomes in Australia and New Zealand.

BACKGROUND: Transanal total mesorectal excision (taTME) aims to overcome some of the technical challenges faced when operating on mid and low rectal cancers. Specimen quality has been confirmed previously, but recent concerns have been raised about oncological safety. This multicentre prospective study aimed to evaluate the safety of taTME among early adopters in Australia and New Zealand. METHODS: Data from all consecutive patients who had taTME for rectal cancer from July 2014 to February 2020 at six tertiary referral centres in Australasia were recorded and analysed. RESULTS: A total of 308 patients of median age of 64 years underwent taTME. Some 75.6 per cent of patients were men, and the median BMI was 26.8 kg/m2. The median distance of tumour from anal verge was 7 cm. Neoadjuvant chemoradiotherapy was administered to 57.8 per cent of patients. The anastomotic leak rate was 8.1 per cent and there was no mortality within 30 days of surgery. Pathological examination found a complete mesorectum in 295 patients (95.8 per cent), a near-complete mesorectum in seven patients (2.3 per cent), and an incomplete mesorectum in six patients (1.9 per cent). The circumferential resection margin and distal resection margin was involved in nine patients (2.9 per cent), and two patients (0.6 per cent) respectively. Over a median follow-up of 22 months, the local recurrence rate was 1.9 per cent and median time to local recurrence was 30.5 months. CONCLUSION: This study showed that, with appropriate training and supervision, skilled minimally invasive rectal cancer surgeons can perform taTME with similar pathological and oncological results to open and laparoscopic surgery.

Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis.

AIM: Peritoneal metastases from colorectal cancer confer the worst survival among all metastatic sites. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with isolated colorectal peritoneal metastases (CRPM) a favourable long-term survival. There are numerous factors postulated to influence survival in patients undergoing CRS and HIPEC. The aim of this study was to identify the key perioperative prognostic factors that influence survival in patients undergoing CRS and HIPEC for isolated CRPM. METHOD: A systematic review and meta-analysis were conducted to evaluate prognostic factors influencing survival in patients undergoing CRS and HIPEC for isolated CRPM. RESULTS: Thirty-three studies fitted the inclusion criteria for the systematic review, with 25 studies included in the meta-analysis. On pooled analysis, incomplete cytoreduction, increasing peritoneal carcinoma index (PCI) and lymph node involvement were significantly associated with a worse survival. Additionally, a rectal primary [hazard ratio (HR) 1.93, 95% CI 1.10-3.37], adjuvant chemotherapy (HR 0.71, 95% CI 0.54-0.93) and perioperative grade III/IV morbidity (HR 1.59, 95% CI 1.17-2.16) were also found to significantly influence survival. Notably, tumour differentiation and signet ring cell histology did not influence survival on pooled analysis. CONCLUSION: This meta-analysis confirms that in patients undergoing CRS and HIPEC for isolated CRPM, incomplete cytoreduction, high PCI and lymph node involvement have a negative influence on survival. In addition, a rectal primary, adjuvant chemotherapy use and grade III/IV morbidity are important factors that also significantly influence survival.

Abdominoperineal excision in Australasia: clinical outcomes, predictive factors and recent trends of nonrestorative rectal cancer surgery.

AIM: The decision to perform an abdominoperineal excision (APR) rather than restorative bowel resection relies on a number of clinical factors. There remains great variability in APR rates internationally. The aim of this study was to demonstrate trends of APR surgery in low rectal cancer (< 6 cm from the anal verge) in Australasia and identify predictors of nonrestoration. METHOD: This study reviewed a prospectively maintained colorectal registry - the Binational Colorectal Cancer Audit (BCCA) - from general/colorectal surgical units across Australia and New Zealand. Data were analysed to determine factors predictive of nonrestorative resection. Patients were analysed based on the presence (control) or absence (comparison) of a primary anastomosis. RESULTS: Of 3628 patients with rectal cancer, 2096 were diagnosed with low rectal cancer between 2007 and 2017. The incidence of APR remained constant over the study period, with 58% of all resections of low rectal cancer being APR. The majority of resections were performed by consultants in urban hospitals (86% vs 14%). Tumours ≤ 3 cm from the anal verge, T4, M1 disease and neoadjuvant therapy were the greatest predictors of APR (P < 0.001). A significantly increased rate of restorative surgery was observed in public hospital settings (59% vs 41%, P < 0.05). The rate of positive circumferential resection margin (CRM) was 7.95%, with significantly increased rates in patients undergoing APR (12.2% vs 6.2%, P < 0.001). CRM positivity was increased in open approaches, T4, N2 and M1 staged disease and in an emergency/urgent setting (P < 0.001 and P < 0.045, respectively). Significantly increased wound and pulmonary complications were observed in the APR cohort (P < 0.01). CONCLUSION: The rates of APR in Australia and New Zealand remain high but are comparable to international figures, with one-third of rectal cancers being treated by APR. The main determinants of APR are tumour height, T stage and neoadjuvant therapy requirement. CRM positivity was higher in APR patients.

Robotic transanal minimally invasive surgery - technical, oncological and patient outcomes from a single institution.

AIM: Robotic transanal minimally invasive surgery (R-TAMIS) is gaining traction around the globe as an alternative to laparoscopic conventional TAMIS for local excision of benign and early malignant rectal lesions. The aim was to analyse patient and oncological outcomes of R-TAMIS for consecutive cases in a single centre. METHODS: A prospective analysis of consecutive R-TAMIS procedures over a 12-month period was performed. Data were collated from hospital databases and theatre registers. RESULTS: Eleven patients (six men, five women), mean age 69.81 years (51-92 years), underwent R-TAMIS over 12 months utilizing a da Vinci Xi platform. The mean lesion size was 36 mm (20-60 mm) with a mean distance from the anal verge of 7.5 cm (3-14 cm). Five lesions were posterior in anatomical location, four anterior, one right lateral and one left lateral. All procedures were performed in the lithotomy position using a GelPOINT Path Platform. Mean operative time was 64 min (40-100 min). Complete resection was achieved in 10/11 patients with two patients being upgraded to a diagnosis of adenocarcinoma. Nine patients were diagnosed with dysplastic lesions. Four patients had a false positive diagnosis of an invasive tumour on MRI. Six patients required suturing for full-thickness resections. One patient had a postoperative bleed requiring repeat endoscopy and clipping. One patient (full-thickness resection of T3 tumour) proceeded to a formal resection without difficulty with no residual disease (T0N0, 0/22). One patient with a fully resected T2 tumour is undergoing a surveillance protocol. The mean length of stay was 1 day with two patients having a length of stay of 2 days and one patient of 4 days. CONCLUSION: R-TAMIS could potentially represent a safe novel approach for local resection of rectal lesions.

Outcomes of extended radical resections for locally advanced and recurrent pelvic malignancy involving the aortoiliac axis.

AIM: Currently, there is no clear consensus on the role of extended pelvic resections for locally advanced or recurrent disease involving major vascular structures. The aims of this study were to report the outcomes of consecutive patients undergoing extended resections for pelvic malignancy involving the aortoiliac axis. METHODS: Prospective data were collected on patients having extended radical resections for locally advanced or recurrent pelvic malignancies, with aortoiliac axis involvement, requiring en bloc vascular resection and reconstruction, at a single institution between 2014 and 2018. RESULTS: Eleven patients were included (median age 60 years; range 31-69 years; seven women). The majority required resection of both arterial and venous systems (n = 8), and the technique for vascular reconstruction was either interposition grafts or femoral-femoral crossover grafts. The median operative time was 510 min (range 330-960 min). Clear resection margins (R0) were achieved in nine patients. The median length of stay was 25 days (range 7-83 days). Seven patients did not suffer an early complication. There was one serious complication (Clavien-Dindo ≥ 3), an arterial graft occlusion secondary to thrombus in the immediate postoperative period, requiring a return to theatre and thrombectomy. The median length of follow-up in this study was 22 months (range 4-58 months). CONCLUSION: This series demonstrates that en bloc major vascular resection and reconstruction can be performed safely and can achieve clear resection margins in selected patients with locally advanced or recurrent pelvic malignancy at specialist surgery centres.

Successful patient-oriented surgical outcomes in robotic vs laparoscopic right hemicolectomy for cancer - a systematic review.

AIM: Minimally invasive surgical approaches for cancer of the right colon have been well described with significant patient and equivalent oncological benefits. Robotic surgery has advanced in its ability to provide multi-quadrant abdominal access, leading the surgical community to widen its application outside of the pelvis to other abdominal compartments. Globally it is being realized that a patient's surgical episode of care is becoming the epicentre of cancer treatment. In order to establish the role of robotic surgery in a patient's episode of care, 'successful patient-oriented surgical' parameters in right hemicolectomy for malignancy were measured. The objective was to examine the rates of successful patient-oriented surgical outcomes in robotic right hemicolectomy (RRH) compared to laparoscopic right hemicolectomy (LRH) for cancer. METHODS: A systematic search of MEDLINE (Ovid: 1946-present), PubMed (NCBI), Embase (Ovid: 1966-present) and Cochrane Library was conducted using PRISMA for parameters of successful patient-oriented surgical outcomes in RRH and LRH for malignancy alone. The parameters measured included postoperative ileus, anastomotic complication, surgical wound infection, length of stay (LOS), incisional hernia rate, conversion to open, margin status, lymph node harvest and overall morbidity and mortality. RESULTS: There were 15 studies which included 831 RRH patients and 3241 LRH patients, with a median age of 62-74 years. No study analysed the concept of successful patient-oriented surgical outcomes. There was no significant difference in the incidence of postoperative ileus, with less time to first flatus in RRH (2.0-2.7 days, compared with 2.5-4.0 days, P < 0.05). Anastomotic leak rate in one study reported a significant increase in LRH compared to RRH (P < 0.05, 0% vs 8.3%). Significantly decreased LOS following RRH was outlined in six studies. One study reported a significantly higher rate of incisional hernias following LRH with extracorporeal anastomoses compared to RRH with intracorporeal anastomoses. Overall rates of conversion to open surgery were less with RRH (0%-3.9% vs 0%-18%, P < 0.001, 0.05). One study outlined significantly higher rates of incomplete resection with an open right hemicolectomy compared with minimally invasive laparoscopic and robotic resections, with positive margin rates of 2.3%, 0.9% and 0% respectively (P < 0.001). Two studies reported significantly higher lymph node harvest in RRH (P < 0.05). Overall morbidity and 30-day mortality were comparable in both approaches. CONCLUSION: Thirty-day morbidity and mortality were comparable between the two approaches, with patients undergoing RRH having lower anastomotic complications, increased lymph node harvest, and reduced LOS, conversion to open and incisional hernia rates in a number of studies. There are limited data on surgical approach and impact on quality of life and what patients deem successful surgical outcomes. There is a further need for a randomized controlled trial examining successful patient-oriented outcomes in right hemicolectomy for malignancy.

Robotic multivisceral pelvic resection: experience from an exenteration unit.

BACKGROUND: Pelvic exenteration remains a viable and effective treatment option for the management of locally advanced or recurrent pelvic malignancy. The aim of this study was to present an early experience of robotic multivisceral resection of pelvic malignancy, and to compare this experience with similar series through a systematic review of the literature. METHODS: A retrospective study was performed on patients who had robotic-assisted multi-visceral resection for pelvic malignancy at a single Colorectal Surgical unit based between two tertiary academic hospitals. Primary outcomes observed included operation type, operation time, perioperative complications, and hospital length of stay. Secondary outcomes included R0 resection status, lymph node harvest, and rate of recurrence at clinical follow-up. RESULTS: Eight cases of robotic multivisceral resection were performed for primary locally advanced pelvic malignancy involving a rectal resection as part of their operative management. The median age of patients undergoing resection was 56 years (range 29-83 years). The male:female ratio was 6:2. The mean total operating time was 8.3 h (range 6-10 h). Perioperative blood transfusion requirements were minimal. Mean hospital length of stay was 15 days (range 7-26 days). No patients experienced any serious postoperative morbidity or mortality. All patients had clear margins on histological assessment and no patients have recurrence at 12-month follow-up. CONCLUSIONS: Robotic multivisceral resection for malignant disease of the pelvis is a safe and feasible minimally invasive approach in highly selected cases.

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.

Pelvic fat volume reduction with preoperative very low energy diet (VLED): implications for rectal cancer surgery in the obese.

BACKGROUND: Obese patients have higher complication rates after pelvic surgery. Laparoscopic rectal surgery may not be possible in the obese individual due to mesorectal, total pelvic and general visceral fat volumes. Very low energy diets reduce visceral fat but the changes within the pelvis and mesorectum are unknown. The aim of the present study was to quantify the proportion of fat lost from total pelvic and mesorectal fat with a very low energy diet (VLED) and define simple, accessible measurements that correlate with expected volume reduction. METHODS: A study was conducted on proportion change in mesorectal and intrapelvic fat volumes in patients on a VLED prior to bariatric surgery at the Alfred Hospital in Melbourne. The VLED was a standardized 4-week meal replacement. Proportion change in mesorectal and intrapelvic fat volumes were measured. Patients had standardized pre-diet and post-diet magnetic resonance imaging (MRI) of the pelvis. Body mass index, weight and girth measures were obtained. Adipose quantification analysis was performed using Q-Fat. RESULTS: Nine patients were included in this study, who were preparing for bariatric (not colorectal) surgery (5 females, median age 42 years, range 27-59 years) pre-protocol body mass index was 55.8 (range 39.5-60.6 kg/m2); median weight was 163 kg. Median mesorectal fat reduction was 29.9% (range 11.6-66.6%). Linear regression showed a relationship between the amount of mesorectal fat reduction and two variables: patient height and the distance from S1 to the posterior aspect of the rectum on MRI. The relationship predicted response to the diet (R2 67%, p = 0.040). CONCLUSIONS: Very low energy diets result in a clinically significant reduction in mesorectal fat with a lesser change in total pelvic fat, suggesting that very low energy diets may be useful for preparation for pelvic surgery in the obese. The distance from S1 to the posterior rectum correlates well with mesorectal reduction, making this a valuable clinical tool when volumetric analysis is not possible. This analysis is limited to the quantification of the effect of the diet and cannot comment on the safety of this approach before pelvic cancer surgery.

Correction to: Pelvic fat volume reduction with preoperative very low energy diet (VLED): implications for rectal cancer surgery in the obese.

Due to substantial contributions by Dr. Phillip Malouf and Dr. Stephen Bell.

Surgical techniques in the management of rectal cancer: a modified Delphi method by colorectal surgeons in Australia and New Zealand.

BACKGROUND: Technological developments have allowed advances in minimally invasive techniques for total mesorectal excision such as laparoscopy, robotics, and transanal surgery. There remains an ongoing debate about the safety, benefits, and appropriate clinical scenarios for which each technique is employed. The aim of this study was to provide a panel of expert opinion on the role of each surgical technique currently available in the management of rectal cancer using a modified Delphi method. METHODS: Surveys were designed to explore the key patient- and tumor-related factors including clinical scenarios for determining a surgeon's choice of surgical technique. RESULTS: Open surgery was favoured in obese patients with an extra-peritoneal tumor and a positive circumferential resection margin (CRM) or T4 tumor when a restorative resection was planned. Laparoscopy was favoured in non-obese males and females, in both intra- and extra-peritoneal tumors with a clear CRM. Robotic surgery was most commonly offered to obese patients when the CRM was clear and if an abdominoperineal resection was planned. Transanal total mesorectal excision (taTME) was preferred in male patients with a mid or low rectal cancer, particularly when obese. Transanal endoscopic microsurgery/transanal minimally invasive surgery local excision was only offered to frail patients with small, early stage tumors. CONCLUSIONS: All surgical techniques for rectal cancer dissection have a role and may be considered appropriate. Some techniques have advantages over others in certain clinical situations, and the best outcomes may be achieved by considering all options before applying an individualised approach to each clinical situation.

Transcriptional landscape changes during human embryonic stem cell derivation.

STUDY QUESTION: What are the transcriptional changes occurring during the human embryonic stem cell (hESC) derivation process, from the inner cell mass (ICM) to post-ICM intermediate stage (PICMI) to hESC stage, that have downstream effects on pluripotency states and differentiation? SUMMARY ANSWER: We reveal that although the PICMI is transcriptionally similar to the hESC profile and distinct from ICM, it exhibits upregulation of primordial germ cell (PGC) markers, dependence on leukemia inhibitory factor (LIF) signaling, upregulation of naïve pluripotency-specific signaling networks and appears to be an intermediate switching point from naïve to primed pluripotency. WHAT IS KNOWN ALREADY: It is currently known that the PICMI exhibits markers of early and late-epiblast stage. It is suggested that hESCs acquire primed pluripotency features due to the upregulation of post-implantation genes in the PICMI which renders them predisposed towards differentiation cues. Despite this current knowledge, the transcriptional landscape changes during hESC derivation from ICM to hESC and the effect of PICMI on pluripotent state is still not well defined. STUDY DESIGN, SIZE, DURATION: To gain insight into the signaling mechanisms that may govern the ICM to PICMI to hESC transition, comparative RNA sequencing (RNA-seq) analysis was performed on preimplantation ICMs, PICMIs and hESCs in biological and technical triplicates (n = 3). PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Primed hESCs (XX) were maintained in feeder-free culture conditions on Matrigel for two passages and approximately 50 cells were collected in biological and technical triplicates (n = 3). For ICM sample collection, Day 3, frozen-thawed human embryos were cultured up to day five blastocyst stage and only good quality blastocysts were subjected to laser-assisted micromanipulation for ICM collection (n = 3). Next, day six expanded blastocysts were cultured on mouse embryonic fibroblasts and manual dissection was performed on the PICMI outgrowths between post-plating Day 6 and Day 10 (n = 3). Sequencing of these samples was performed on NextSeq500 and statistical analysis was performed using edgeR (false discovery rate (FDR) < 0.05). MAIN RESULTS AND THE ROLE OF CHANCE: Comparative RNA-seq data analysis revealed that 634 and 560 protein-coding genes were significantly up and downregulated in hESCs compared to ICM (FDR < 0.05), respectively. Upon ICM to PICMI transition, 471 genes were expressed significantly higher in the PICMI compared to ICM, while 296 genes were elevated in the ICM alone (FDR < 0.05). Principle component analysis showed that the ICM was completely distinct from the PICMI and hESCs while the latter two clustered in close proximity to each other. Increased expression of E-CADHERIN1 (CDH1) in ICM and intermediate levels in the PICMI was observed, while CDH2 was higher in hESCs, suggesting a role of extracellular matrix components in facilitating pluripotency transition during hESC derivation. The PICMI also showed regulation of naïve-specific LIF and bone morphogenetic protein signaling, differential regulation of primed pluripotency-specific fibroblast growth factor and NODAL signaling pathway components, upregulation of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTORC), as well as predisposition towards the germ cell lineage, further confirmed by gene ontology analysis. Hence, the data suggest that the PICMI may serve as an intermediate pluripotency stage which, when subjected to an appropriate culture niche, could aid in enhancing naïve hESC derivation and germ cell differentiation efficiency. LARGE-SCALE DATA: Gene Expression Omnibus (GEO) Accession number GSE119378. LIMITATIONS, REASONS FOR CAUTION: Owing to the limitation in sample availability, the sex of ICM and PICMI have not been taken into consideration. Obtaining cells from the ICM and maintaining them in culture is not feasible as it will hamper the formation of PICMI and hESC derivation. Single-cell quantitative real-time PCR on low ICM and PICMI cell numbers, although challenging due to limited availability of human embryos, will be advantageous to further corroborate the RNA-seq data on transcriptional changes during hESC derivation process. WIDER IMPLICATIONS OF THE FINDINGS: We elucidate the dynamics of transcriptional network changes from the naïve ICM to the intermediate PICMI stage and finally the primed hESC lines. We provide an in-depth understanding of the PICMI and its role in conferring the type of pluripotent state which may have important downstream effects on differentiation, specifically towards the PGC lineage. This knowledge contributes to our limited understanding of the true nature of the human pluripotent state in vitro. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by the Concerted Research Actions funding from Bijzonder Onderzoeksfonds University Ghent (BOF GOA 01G01112).The authors declare no conflict of interest.

The effect of increasing body mass index on laparoscopic surgery for colon and rectal cancer.

AIM: Obesity is common in Western countries and its prevalence is increasing. Colorectal cancer is common, and surgery for colorectal cancer is technically more challenging in obese patients. Laparoscopic surgery for colon cancer has been shown to be oncologically equivalent, with improved short- term outcomes. Laparoscopic surgery for rectal cancer has proven technically challenging, and recent results have raised concerns about oncological equivalence. Our aim was to evaluate the effect of body mass index (BMI) on the clinical and oncological outcomes of surgery for colorectal cancer, including the rate at which laparoscopic surgery is attempted and the rate at which laparoscopic surgery is converted to open surgery. METHOD: A retrospective analysis of prospectively collected data from two tertiary institutions was performed. Data were obtained from the Cabrini Monash University colorectal neoplasia database for patients having surgical resection for colon and rectal cancers between 1 January 2010 and 30 June 2015. Surgical and medical complications, tumour recurrence and overall survival and laparoscopic surgery and conversion rates were investigated. RESULTS: This large case series of 1464 patients undergoing elective surgery for colorectal cancer has demonstrated that an elevated BMI is associated with a lower likelihood of attempting laparoscopic surgery and a higher conversion rate to open surgery when laparoscopy is attempted. Conversion was 1.9 times more likely in obese patients with colon cancer and 4.1 times more likely in obese patients with rectal cancer. The critical BMI for colon cancer patients was > 35 kg/m2 , and for rectal cancer patients > 30 kg/m2 . Obesity is also associated with increased rates of surgical complications, including anastomotic leakage and wound complications. Pathological parameters, tumour recurrence and survival were not affected by elevated BMI. CONCLUSION: In the surgical management of colorectal cancer, obesity is associated with a lower likelihood of laparoscopic surgery being attempted, a higher likelihood of conversion to open surgery when laparoscopic surgery is attempted, and a higher rate of surgical complications.

An assessment of an Australasian pathway for the introduction of transanal total mesorectal excision (taTME).

AIM: To evaluate the use of a pathway for the introduction of transanal total mesorectal excision (taTME) into Australia and New Zealand. METHOD: A pathway for surgeons with an appropriate level of specialist training and baseline skill set was initiated amongst colorectal surgeons; it includes an intensive course, a series of proctored cases and ongoing contribution to audit. Data were collected for patients who had taTME, for benign and malignant conditions, undertaken by the initial adopters of the technique. RESULTS: A total of 133 taTME procedures were performed following the introduction of a training pathway in March 2015. The indication was rectal cancer in 84% of cases. There was one technique-specific visceral injury, which occurred prior to that surgeon completing the pathway. There were no cases of postoperative mortality; morbidity occurred in 27.1%. The distal resection margin was clear in all cases of rectal cancer, and the circumferential resection margin was positive in two cases. An intact or nearly intact total mesorectal excision was obtained in more than 98% of cases. CONCLUSION: This study demonstrates the safe and controlled introduction of a new surgical technique in a defined surgeon population with the use of a pathway for training. The authors recommend a similar pathway to facilitate the introduction of taTME to colorectal surgical practice.

Prognostic value of tumour regression grade in locally advanced rectal cancer: a systematic review and meta-analysis.

AIM: The current standard of care for locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. There is a spectrum of response to neoadjuvant therapy; however, the prognostic value of tumour regression grade (TRG) in predicting disease-free survival (DFS) or overall survival (OS) is inconsistent in the literature. METHOD: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was undertaken using Ovid MEDLINE, Embase and Google Scholar. Inclusion criteria were Stage II and III locally advanced rectal cancer treated with long-course CRT followed by radical surgery. The aim of the meta-analysis was to assess the prognostic implication of each TRG for rectal cancer following neoadjuvant CRT. Long-term prognosis was assessed. The main outcome measures were DFS and OS. A random effects model was performed to pool the hazard ratio (HR) from all included studies. RESULTS: There were 4875 patients from 17 studies, with 775 (15.9%) attaining a pathological complete response (pCR) and 719 (29.9%) with no response. A significant association with OS was identified from a pooled-estimated HR for pCR (HR = 0.47, P = 0.002) and nonresponding tumours (HR = 2.97; P < 0.001). Previously known tumour characteristics, such as ypN, lymphovascular invasion and perineural invasion, were also significantly associated with DFS and OS, with estimated pooled HRs of 2.2, 1.4 and 2.3, respectively. CONCLUSION: In conclusion, the degree of TRG was of prognostic value in predicting long-term outcomes. The current challenge is the development of a high-validity tests to predict pCR.

A case series of anal melanoma including the results of treatment with imatinib in selected patients.

AIM: Anal melanoma is a rare malignancy with a poor prognosis. METHOD: All patients with a diagnosis of anal melanoma treated at a single institution between 2000 and 2012 were identified and their treatment and outcome were evaluated. RESULTS: Sixteen patients had a median survival of 2.9 years. Fourteen had Stage I or II disease with a median survival of 4.0 years and progression-free survival of 1.5 years. When used for disease staging, whole body positron emission tomography/CT identified an additional three sites of metastasis in five patients compared with CT of the chest, abdomen and pelvis. Surgery involved wide local excision or abdominoperineal excision with respective local recurrence rates of 50% and 66%. Eleven patients underwent testing for c-Kit mutations, of whom five were positive. Four of these were treated with the tyrosine kinase inhibitor imatinib, and showed rapid response of metastases outside the central nervous system. CONCLUSION: The outcome of this malignancy remains poor. PET is the modality of choice for disease staging. Testing tumours for c-Kit mutations may allow selected patients to participate in trials of tyrosine kinase inhibitors.

Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review.

AIM: Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit. METHOD: A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation', 'tumor response'. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected. RESULTS: Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation. CONCLUSION: At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality.