External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Fallibility of tattooing colonic neoplasia ahead of laparoscopic resection: a retrospective cohort study.

INTRODUCTION: Precise geographical localisation of colonic neoplasia is a prerequisite for proper laparoscopic oncological resection. Preoperative endoscopic peri-tumoural tattoo practice is routinely recommended but seldom scrutinised. METHODS: A retrospective review of recent consecutive patients with preoperative endoscopic lesional tattoo who underwent laparoscopic colonic resection as identified from our prospectively maintained cancer database with supplementary clinical chart and radiological, histological, endoscopic and theatre database/logbook interrogation. RESULTS: Some 210 patients with 'tattooed' colonic neoplasia were identified, of whom 169 underwent laparoscopic surgery (mean age 68 years, median BMI 27.8kg/m2, male-to-female ratio 95:74). The majority of tumours were malignant (149; 88%), symptomatic (133; 79%) and proximal to the splenic flexure (92; 54%). Inaccurate colonoscopist localisation judgement occurred in 12% of cases, 60% of which were corrected by preoperative staging computed tomography scan. A useful lesional tattoo was absent in 11/169 cases (6.5%) being specifically stated as present in 104 operation notes (61%) and absent in 10 (5.9%). Tumours missing overt peritumoral tattoos intraoperatively were more likely to be smaller, earlier stage and injected longer preoperatively (p=0.006), although half had histological ink staining. Eight lesions missing tattoos were radiologically occult. Four (44%) of these patients had on-table colonoscopy, and five (55%) needed laparotomy (conversion rate 55% vs 23% overall, p<0.005) with one needing a second operation to resect the initially missed target lesion. Mean (range) operative duration and postoperative length of stay of those missing tattoos compared with those with tattoos was 200 (78-300) versus 188 (50-597) min and 15.5 (4-22) versus 12(4-70) days (p>0.05). CONCLUSIONS: Tattoo in advance of attempting laparoscopic resection is vital for precision cancer surgery especially for radiologically unseen tumours to avoid adverse clinical consequence.

Clinical and surgical outcomes of patients with peritoneal mesothelioma discussed at a monthly national multidisciplinary team video-conference meeting.

BACKGROUND: Peritoneal mesothelioma (PM) is a rare primary neoplasm of the peritoneum with an increasing incidence worldwide. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise as a treatment strategy. A national PM multidisciplinary team (national PM MDT) video-conference meeting was established in the UK and Ireland in March 2016, aiming to plan optimal treatment, record outcomes and provide evidence for the benefits of centralization. This article reports on the activities and outcomes of the first 2·5 years. METHODS: Between March 2016 and December 2018, patients with PM, referred to peritoneal malignancy centres in Basingstoke, Birmingham, Manchester and Dublin, were discussed by the national PM MDT via video-conference. The MDT was composed of surgeons, radiologists, specialist nurses and pathologists. Patients were considered for CRS and HIPEC if considered fit for surgery and if radiological imaging suggested that complete surgical cytoreduction could be achieved. Morbidity and mortality following surgery were analysed. Survival analysis following MDT discussion was conducted. RESULTS: A total of 155 patients (M : F ratio 0·96) with a mean(s.d.) age of 57(17) years were discussed. To date, 22 (14·2 per cent) have had CRS and HIPEC; the median Peritoneal Cancer Index for the surgical group was 17·0. Complete cytoreduction was achieved in 19 patients. Clavien-Dindo grade I-II complications occurred in 16 patients; there was no grade III-IV morbidity or 30-day in-hospital mortality. The median follow-up for the whole cohort was 18·7 months, and the 2-year survival rate from time of first review at the national PM MDT was 68·3 per cent. CONCLUSION: The centralized national PM MDT was effective at selecting patients suitable for CRS and HIPEC, reporting a good outcome from patient selection.

ANTECEDENTES: El mesotelioma peritoneal (peritoneal mesothelioma, PM) es una neoplasia primaria del peritoneo muy poco frecuente, con una incidencia creciente en todo el mundo. La cirugía citorreductora (cytoreductive surgery, CRS) con quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) se ha mostrado prometedora como estrategia de tratamiento. En marzo de 2016, se organizó una reunión por videoconferencia del equipo multidisciplinar nacional de PM (national PM multi-Disciplinary Team, MDT) en el Reino Unido e Irlanda, con el objetivo de planificar un tratamiento óptimo, registrar los resultados y proporcionar evidencia de los beneficios de la centralización. Este manuscrito presenta las actividades y los resultados de los primeros 2,5 años. MÉTODOS: Entre marzo de 2016 y diciembre de 2018, 155 pacientes con PM, remitidos a centros de cirugía oncológica peritoneal en Basingstoke, Good Hope Hospital en Birmingham, Christie Hospital en Manchester y Mater Misericordiae en Dublín, fueron discutidos en el National PM MDT a través de una videoconferencia. El MDT estaba compuesto por cirujanos, radiólogos, enfermeras especializadas y patólogos. Los pacientes fueron considerados para CRS e HIPEC si se determinaba que eran aptos para la cirugía y si las imágenes radiológicas sugerían que se podía lograr una citorreducción quirúrgica completa. Se analizó la morbilidad y mortalidad después de la cirugía. Se realizó un análisis de supervivencia tras la discusión en el MDT. RESULTADOS: En total, se discutieron 155 pacientes (tasa varón/mujer 0,96) con una edad media de 57 ± 17 años. Hasta el momento, 22 (14,2%) habían sido sometidos a CRS y HIPEC y la mediana de PCI en el grupo quirúrgico fue de 17,0. La citorreducción completa se logró en 19 (86,4%), las complicaciones de Clavien-Dindo grado I/II ocurrieron en 16/22, sin morbilidad de grado III/IV, ni mortalidad a los 30 días. La mediana de seguimiento fue de 15,0 meses y la supervivencia a los 2 años desde el momento de la revisión en el National PM MDT fue del 66,7%. CONCLUSIÓN: El National PM MDT centralizado fue eficaz en la selección de pacientes adecuados para CRS e HIPEC, presentando un buen resultado a partir de dicha selección.

Peritoneal metastases from extra-abdominal cancer - A population-based study.

INTRODUCTION: Peritoneal metastases (PM) are predominantly seen as a manifestation of intra-abdominal malignancy such as colorectal or ovarian cancer. However, extra-abdominal primary cancer can also metastasise to the peritoneum. Population-based data on the incidence of PM from extra-abdominal cancer is lacking. This study aims to assess the patterns and survival of patients in Ireland with PM from extra-abdominal cancers. METHODS: The National Cancer Registry of Ireland database was interrogated to identify patients diagnosed with PM from extra-abdominal malignancy during the period 1994-2012. Patient demographics and tumour characteristics were analysed. RESULTS: 5791 patients were diagnosed with PM during the study period. Of these, 543 (9%) had an extra-abdominal primary malignancy. Breast (40.8%), lung (25.6%) and melanoma (9.3%) were the most common extra-abdominal cancers to develop PM. The majority of patients with peritoneal metastases of breast origin (75%) were diagnosed at a long interval (median interval 59.5 months; range = 1-485) from the diagnosis of the primary. The median survival from diagnosis of PM was 5.8 months compared with 22.6 months from diagnosis of stage IV disease without peritoneal involvement. Survival in patients with lung cancer and melanoma who developed PM was very poor and similar to that in patients with stage IV disease not involving the peritoneum. CONCLUSION: This is the first population-based study to report the incidence of PM secondary to extra-abdominal malignancy. The most common primary cancers were melanoma, breast and lung cancer. Metastatic disease to the peritoneum was uniformly associated with a poor prognosis.

Attitudes to trainee-led surgical mentoring.

BACKGROUND: Surgical mentorship remains important especially in an era of run-through training but can be hindered by the 'generation gap' between consultants and students. To cater for this, we established a trainee-led mentorship programme for medical students interested in surgery and herein report our initial findings. AIM: Our aim is to assess the attitudes of surgical mentors and mentees to a newly established surgical trainee-led mentorship programme to determine factors desirable for its successful delivery. METHODS: Six first year surgical trainees enrolled as mentors in September 2014. Ninety students enrolled as mentees. During the second semester both mentees and mentors were surveyed by an anonymous questionnaire to assess attitudes to the programme. RESULTS: Data was collected from 85 respondents. Eighty-nine percent of mentees felt their participation had positively impacted their decision to pursue a surgical career. The main benefits were found to be in improving technical skills (40%), providing surgical career guidance (35%) and information about surgical training programmes (14%). Of the mentor qualities most appreciated, 89% preferred institutional proximity while 30 and 27% valued enthusiasm and approachability. Ninety-three percent felt gender is unimportant; 49% preferred a mentor in their speciality of interest. Mentors valued this responsibility drawing greater job satisfaction. CONCLUSION: Our study, the first to describe the experience and potential benefits of a surgical trainee-led mentoring programme in Ireland, demonstrates a significant appetite amongst students and surgical trainees for mentorship. Further evaluation of the importance of mentoring programmes and the role of trainees in their delivery are necessary.

An 18 year population-based study on site of origin and outcome of patients with peritoneal malignancy in Ireland.

Peritoneal malignancy (PM) is predominantly metastatic spread from advanced gastrointestinal or gynaecological cancer. PM is generally considered incurable and therefore has rarely been the focus of novel therapeutic strategies. This study assessed patterns and survival outcomes for patients with PM in Ireland. The National Cancer Registry Ireland database was interrogated to identify patients diagnosed with PM during the period 1994-2012. Patient and tumour characteristics were retrieved and survival outcomes calculated. 5791 patients were diagnosed during the study period. Median age at diagnosis was 68 years; females accounted for 62%. The incidence increased annually from 228 in 1994 to 401 in 2012. Primary PM accounted for 3% of cases. Colorectal (22%), ovarian (16%) and gastric (13%) cancers accounted for the majority of cases of secondary PM. Almost 75% of patients had PM at initial presentation. Almost 40% of patients (n = 2274) underwent surgical intervention, while 44% (n = 2560) had tumour directed chemotherapy. The median survival (MS) in patients with secondary PM was 6.6 months, and did not improve significantly during the study period. Outcomes were best in patients with ovarian cancer (MS 15.9 months) and colorectal cancer (MS 14.3 months) and worst in patients with lung (MS 2.4 months) and pancreas (MS 1.9 months) cancers. This is the first population-based study from Ireland to report the incidence and outcomes for PM. PM is more common than previously reported and survival remains poor. These findings highlight the need for greater clinician awareness and the need to focus on new therapeutic approaches to improve patient outcomes.

Mentored experience of establishing a national peritoneal malignancy programme - Experience of first 50 operative cases.

BACKGROUND: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are considered standard of care for pseudomyxoma peritonei (PMP) and selected patients with colorectal peritoneal metastases (CPM) or peritoneal mesothelioma. A National Peritoneal Malignancy programme was established in Ireland (population of 4.5 million) in May 2013 with mentoring and support from the Peritoneal Malignancy Institute, Basingstoke UK. This study reviews the operative and oncological outcomes for the first 50 patients who underwent CRS and HIPEC in Ireland. METHODS: This is a retrospective review of all patients referred, and of the subset who underwent CRS and HIPEC, for peritoneal malignancy in Ireland between May 2013 and November 2015. RESULTS: During the study period, 130 patients were referred and 50 patients were selected for CRS and HIPEC. Three patients were found to have unresectable disease at laparotomy. Of the remaining 47 patients, eight had major tumour debulking. In total, 39 underwent complete cytoreduction and 45 received HIPEC. After a median follow-up of 12.7 months, 12 patients had developed further metastatic disease. The rates of complete cytoreduction, major complication (Clavien-Dindo III/IV) and operative mortality were 83%, 0% and 0%, respectively. 32% of patients experienced grade I/II complications. CONCLUSIONS: We report the successful establishment of a national peritoneal malignancy programme. Mentoring from an experienced centre may have shortened the known learning curve evident by our encouraging outcomes. The follow-up period is short, however our early results are comparable with internationally reported figures.

Outcomes following surgery for colorectal cancer with synchronous peritoneal metastases.

BACKGROUND: The optimal treatment of peritoneal carcinomatosis of colorectal origin appears to be a combination of systemic chemotherapy and complete surgical cytoreduction with synchronous intraperitoneal chemotherapy. The aim of this study was to assess the feasibility of, and outcomes following, surgical treatment and systemic chemotherapy alone. METHODS: Prospectively collated data from the Erlangen Registry for Colorectal Cancer were analysed for patients presenting with peritoneal carcinomatosis of colorectal origin between 1990 and 2006. Operative and adjuvant treatment, along with details of postoperative morbidity, were evaluated and correlated with survival outcomes after 5 years. RESULTS: Some 125 patients underwent surgical resection for colorectal cancer and synchronous peritoneal carcinomatosis. Two-thirds also had non-peritoneal distant metastases. R0/R1 resection was possible in 24 (59 per cent) of 41 patients with peritoneal metastases alone, and in a further seven patients with both peritoneal and distant metastases (overall R0/R1 resection rate 24·8 per cent). In-hospital morbidity and mortality rates were 32·0 and 12·0 per cent respectively. Twenty-three of the 31 patients who underwent R0/R1 resection developed recurrent disease. Median survival for the entire group was 12 months. Following R0/R1 resection median survival was 25 months and the 5-year survival rate 22 per cent. Six (4·8 per cent) of the 125 patients survived for more than 5 years. CONCLUSION: Complete resection of all metastatic disease was associated with improved survival and was possible in almost 60 per cent of patients with peritoneal metastases alone.

Complete clinical response to neoadjuvant chemotherapy in a 54-year-old male with Askin tumor.

Askin tumor is a tumor of the thoracopulmonary region that most commonly affects children and adolescents. These rare tumors are a form of primitive neuroectodermal tumor and typically carry a poor prognosis. Treatment is multimodal and consists of a combination of neoadjuvant chemotherapy, radical resection, and adjuvant chemo- and radiotherapy or all of the above. Surgery is advocated in most cases. We report a case of Askin tumor in a 54-year-old male who showed rapid and complete response to neoadjuvant chemotherapy. This allowed potentially radical surgery to be avoided. At one-year follow-up he remains disease-free.

Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

BACKGROUND: Fibroblasts isolated from strictures in Crohn's disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn's stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.

Intra-operative examination of the sentinel node in breast cancer.

Intra-operative sentinel node analysis allows immediate progression to axillary clearance in patients with node positive breast cancer and reduces the need for re-operation. Despite this, intra-operative sentinel node analysis is infrequently performed in Ireland. We report our experience using this technique. Sentinel node biopsy was performed in 47 consecutive patients with symptomatic T1-T2 clinically node negative breast cancer. Sentinel nodes were examined intra-operatively by frozen section and imprint cytology and definitive histological assessment was performed on paraffin-embedded tissue. The sentinel node was identified in 46 (98%) patients. Twelve patients had axillary metastases. The sensitivity of intra-operative analysis in identifying nodal metastases was 92%. False negative rate was 8%, negative predictive value 97%, and specificity 100%. Intra-operative analysis of the sentinel node allowed re-operation to be avoided in 92% of patients with axillary node metastases. In our experience this technique can be readily introduced with reliable outcomes.

Expression and regulation of connective tissue growth factor by transforming growth factor beta and tumour necrosis factor alpha in fibroblasts isolated from strictures in patients with Crohn's disease.

BACKGROUND: Connective tissue growth factor (CTGF) stimulates fibroblast proliferation and extracellular matrix production. Fibroblasts may initiate stricture formation in Crohn's disease through overexpression of CTGF. Stricturing that occurs in patients with Crohn's disease after treatment with anti-tumour necrosis factor (TNF) alpha may be due to dysregulation of CTGF homeostasis. The aim of this study was to examine CTGF expression and regulation in fibroblasts isolated from patients with Crohn's disease. METHODS: Fibroblasts were isolated by a primary explant technique from serosal biopsies of strictured segments of bowel in eight patients undergoing resection for Crohn's disease and from normal colon in seven patients having resection for benign or malignant colorectal disease. Cells were stimulated with transforming growth factor (TGF) beta and TNF-alpha. CTGF protein and mRNA expression were measured by western blotting and real-time polymerase chain reaction respectively. RESULTS: Mean(s.d.) CTGF protein expression in strictured Crohn's fibroblasts was higher than that in normal fibroblasts (56.5(9.7) versus 17.0(10.0) respectively; P = 0.011). In normal and strictured Crohn's fibroblasts, culture with TGF-beta increased CTGF protein and mRNA expression. Co-culture of normal fibroblasts with TNF-alpha suppressed TGF-beta-stimulated CTGF expression. CONCLUSION: : Increased expression of CTGF in strictured Crohn's fibroblasts underlies its role in fibrosis. TNF-alpha suppresses fibrosis by downregulating fibroblast CTGF expression, an effect that may be lost following anti-TNF-alpha treatment, thereby promoting stricture formation.

Traumatic lower limb fractures following complete spinal cord injury.

Patients with complete spinal cord injury experience a rapid bone mineral density loss that places them at an increased risk of lower limb fracture following trivial injury. We aimed to establish if spinal cord injured patients treated at our unit have an increased incidence of lower limb fracture, and if so to identify a cohort of patients who may benefit from prophylactic treatment to preserve bone mineral density. We reviewed 158 patients treated between January 1994 and July 2002. There was a significantly increased incidence of lower limb fracture in patients with complete spinal cord injury (5 fractures in 4 patients), when compared to the cohort of patients with spinal injury who subsequently attained mobility (no fractures). Prophylactic bisphosphonates reduce disuse osteopenia and warrant prospective assessment in patients with complete spinal cord injury in whom they may confer a protective effect against lower limb fracture.

Sentinel lymph node mapping in colorectal cancer.

BACKGROUND: Ultrastaging, by serial sectioning combined with immunohistochemical techniques, improves detection of lymph node micrometastases. Sentinel lymph node mapping and retrieval provides a representative node(s) to facilitate ultrastaging. The impact on staging of carcinoma of the colon and rectum in all series emphasizes the importance of this technique in cancer management. Now the challenge is to determine the biological relevance and prognostic implications. METHODS: The electronic literature (1966 to present) on sentinel node mapping in carcinoma of the colon and rectum was reviewed. Further references were obtained by cross-referencing from key articles. RESULTS: Lymphatic mapping appears to be readily applicable to colorectal cancer and identifies those lymph nodes most likely to harbour metastases. Sentinel node mapping carries a false-negative rate of approximately 10 per cent in larger studies, but will also potentially upstage a proportion of patients from node negative to node positive following the detection of micrometastases. The prognostic implication of these micrometastases requires further evaluation. CONCLUSION: Further follow-up to assess the prognostic significance of micrometastases in colorectal cancer is required before the staging benefits of sentinel node mapping can have therapeutic implications.