Retrospective cohort analysis of neoadjuvant treatment and survival in resectable and borderline resectable pancreatic ductal adenocarcinoma in a high volume referral centre.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. Neoadjuvant therapy (NA) with chemotherapy (NAC) and radiotherapy (RT) prior to surgery provides promise. In the absence of prospective data, well annotated clinical data from high-volume units may provide pilot data for randomised trials. METHODS: Medical records from a tertiary hospital in Sydney, Australia, were analysed to identify all patients with resectable or borderline resectable PDAC. Data regarding treatment, toxicity and survival were collected. RESULTS: Between January 1 2010 and April 1 2016, 220 sequential patients were treated: 87 with NA and 133 with upfront operation (UO). Forty-three NA patients (52%) and 5 UO patients (4%) were borderline resectable at diagnosis. Twenty-four borderline patients received NA RT, 22 sequential to NAC. The median overall survival (OS) in the NA group was 25.9 months (mo); 95% CI (21.1-43.0 mo) compared to 26.9 mo (19.7, 32.7) in the UO; HR 0.89; log-ranked p-value = 0.58. Sixty-nine NA patients (79%) were resected, mOS was 29.2 mo (22.27, not reached (NR)). Twenty-two NA (31%) versus 22 UO (17%) were node negative at operation (N0). In those managed with NAC/RT the mOS was 29.0 mo (17.3, NR). There were no post-operative deaths with NA within 90-days and three in the UO arm. DISCUSSION: This is a hypothesis generating retrospective review of a selected real-world population in a high-throughput unit. Treatment with NA was well tolerated. The long observed survival in this group may be explained by lymph node sterilisation by NA, and the achievement of R0 resection in a greater proportion of patients.

Transverse closure of mesenterico-portal vein after vein resection in pancreatoduodenectomy.

BACKGROUND: Resection of the involved mesenteric-portal vein (MPV) is increasingly performed in pancreatoduodenectomy. The primary aim of this study is to assess the rate of R0 resection in transverse closure (TC) versus segmental resection with end-to-end (EE) closure and the secondary aims are to assess the short-term morbidity and long-term survival of TC versus EE. METHODS: Patients undergoing pancreatoduodenectomy with MPV resection were identified from a prospectively database. The reconstruction technique were examined and categorized. Clinical, pathological, short-term and long-term survival outcomes were compared between groups. RESULTS: 110 patients underwent PD with MPV resection of which reconstruction was performed with an end-to-end technique in 92 patients (84%) and transverse closure technique in 18 patients (16%). Patients undergoing transverse closure tended to have had a shorter segment of vein resected (≤2 cm) compared to the end-to-end (83% vs. 43%; P = 0.004) with no difference in R0 rate. Short-term morbidity was similar. The median and 5-year survival was 30.0 months and 18% respectively for patients undergoing transverse closure and 28.6 months and 7% respectively for patients undergoing end-to-end reconstruction (P = 0.766). CONCLUSION: Without compromising the R0 rate, transverse closure to reconstruct the mesenteric-portal vein is shown to be feasible and safe in the setting when a short segment of vein resection is required during pancreatoduodenectomy. Synopsis - We describe a vein closure technique, transverse closure, which avoids the need for a graft, or re-implantation of the splenic vein when resection of the mesenteric-portal vein confluence is required during pancreatoduodenectomy.

Postoperative bladder and sexual function in patients undergoing surgery for rectal cancer: a systematic review and meta-analysis of laparoscopic versus open resection of rectal cancer.

There have been conflicting opinions regarding the superiority of open and laparoscopic surgery in preserving bladder and sexual function after rectal cancer surgery. This systematic review and meta-analysis aims to pool the available data comparing the impact of surgical approaches on postoperative sexual and urinary function. A search of Pubmed, Medline, Cochrane and Embase was undertaken and studies from January 2000 to February 2013 were identified. We included, in our meta-analysis, both prospective and retrospective studies that compared laparoscopic surgery and open surgery for rectal cancer. A total of 876 patients undergoing rectal cancer surgery (lap n = 468, open n = 408) were examined. In men, postoperative ejaculatory function and erectile dysfunction evaluated from two studies comprising of 74 patients showed no difference between groups. The rate of overall sexual dysfunction evaluated from five studies comprising of 289 patients revealed a rate of 34 % in both the open and lap groups. Postoperative urinary function evaluated from five studies comprising of 312 patients showed no difference between groups. In women, postoperative sexual and urinary function were evaluated from five studies comprising of 321 patients. Three studies (n = 219) reported no difference in sexual function between groups. Postoperative urinary function evaluated from four studies comprising of 212 patients was found to be comparable. The available data are limited, but suggest that neither form of surgical approach be it laparoscopy or open surgery demonstrate superiority in preservation of sexual and bladder function. Further research into the technical aspects of surgery and evaluating newer minimally invasive technologies such as the robot may prove to be useful in improving functional outcomes of rectal cancer patients.

A systematic review of local excision combined with chemoradiotherapy for early rectal cancer.

AIM: Local excision of early rectal cancer is a less morbid alternative to major abdominal surgery. This review evaluates the role of local excision with neoadjuvant or adjuvant chemoradiotherapy to identify a select group of patients where local excision is appropriate without significantly compromising the oncological outcome. METHOD: MEDLINE, PubMed and the Cochrane Central Register of Controlled Trials databases were searched to identify relevant articles investigating the role of local excision with adjuvant or neoadjuvant chemoradiotherapy in patients with T1/T2N0M0 disease. Eleven studies comprising 455 patients were selected. Oncological end-points included overall survival, disease-free and disease-specific survival, recurrence rates as well as perioperative morbidity and mortality. RESULTS: At a range of 30.5-115.2 months, median overall survival, disease-specific and disease-free survival were 75% (66-80.6%), 89% (75-93.3%) and 74% (64-85.2%), respectively. Median local, distant and overall recurrence rates were 10% (4.8-25%), 4.7% (4-11.8%) and 13.1% (10.7-23.5%), respectively. Mortality was 0% in all studies except one (2.9%). Most reported complications were minor and were treated conservatively. CONCLUSION: This systematic review provides data suggesting that selected patients with T1/T2N0M0 rectal cancer may undergo local excision without compromising the oncological outcome otherwise conferred by total mesorectal excision. It may be a particularly useful option in patients in whom radical surgery is contraindicated. Randomized trials comparing both management strategies to consolidate this finding may lead to a paradigm change in the management of early rectal cancer.

Repeat cytoreductive surgery (CRS) for recurrent colorectal peritoneal metastases: yes or no?

PURPOSE: To clarify the role of repeat CRS for recurrent colorectal carcinoma (CRC) through: (i) Systematic review of the literature (ii) Analysis of survival outcomes in a prospective cohort. METHODS: (i) Pubmed and MEDLINE from 1980 to July 2013 searched using terms: colorectal carcinoma, peritonectomy, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), redo, repeat, and iterative. (ii) Kaplan-Meier Survival analysis of consecutive patients undergoing repeat CRS at St George Hospital between Jan 2000 and July 2013. RESULTS: (i) The search strategy yielded 309 articles, 5 meeting inclusion criteria, reporting on 91 patients. Median overall survival from first CRS ranged from 39 to 57.6 months with 3-yr survival of 50%, and 5-year survival of 30%. Median survival from second CRS was 20-months with 1-yr survivals of 72% and 66% and 2-year survivals of 50% and 44%. (ii) Repeat CRS performed on 18 patients found median survival from first CRS was 59 months, with 1, 3, and 5-year survival of 100%, 52% and 26% respectively. Median survival from repeat CRS was 22.6 months with 1, 2, and 3-year survival of 94%, 48% and 12% respectively. CONCLUSION: The current data on repeat CRS in CRC is relatively immature and more data is required before drawing clear conclusions. Patient selection should be on a case by case basis conducted through a MDT process with emphasis on surrogate markers for favourable outcomes.

Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: a review.

Although there have been recent advances in the treatment of metastatic colorectal cancer, particularly with systemic chemotherapy, new biological agents and surgical metastasectomy, the disease remains difficult to treat. To personalise the management of mCRC and optimise patient outcomes, it is vital to acquire a deeper understanding of its natural history and mechanisms behind disease progression. This may be achieved by extensive study of tumour biomarkers: proteins or genetic alterations within neoplastic cells or their surrounding stroma that may be used to predict patient outcomes, disease trajectory and response to various therapies. The discovery of mutant Kirsten-RAS in determining patients who may be refractory to anti-epidermal growth factor receptor treatments has reinvigorated and reiterated the importance of our attempts to individualise cancer care. While many biomarkers have been studied and shown promise in the setting of mCRC, they are, with the exception of K-ras testing not used currently in a clinical setting due to conflicting results, small patient samples and methodological variations. Larger, multi-centric studies with uniform methods of tumour marker study are required to effectively tailor systemic therapies and select appropriate candidates for surgical metastasectomy.

Palliative resection of the primary tumour in patients with Stage IV colorectal cancer: systematic review and meta-analysis of the early outcome after laparoscopic and open colectomy.

AIM: Resection of the primary tumour in patients with Stage IV colorectal cancer may be performed to avoid future tumour-related complications whilst on systemic treatment. We compared the safety and efficacy of laparoscopic and open colectomy in this patient group. METHOD: PubMed, MEDLINE and the Cochrane Library were searched in the English literature for studies between January 2000 and October 2012 dealing with laparoscopic resection of the primary tumour in Stage IV disease. Single-arm laparoscopic studies were systematically reviewed. Prospective and retrospective studies were included for meta-analysis. End-points include safety, complications, mortality and cancer specific outcome including 5-year and median survival. RESULTS: Eleven studies comprising 1165 patients undergoing palliative laparoscopic colectomy for Stage IV colorectal cancer were included. Five studies were comparative studies of laparoscopic and open colectomy. The former took longer (pooled mean difference (MD) = 41.52, 95% CI = 11.47-71.56, Z = 2.71, P = 0.007), but resulted in a shorter length of stay (pooled MD = -2.41, 95% CI = -3.84 to -0.99, Z = 3.32, P = 0.0009), with fewer postoperative complications (pooled odds ratio = 0.53, 95% CI = 0.32-0.87, Z = 2.51, P = 0.01) and lower estimated blood loss (pooled MD = -47.71, 95% CI = -80.00 to -15.42, Z = 2.90, P = 0.004). Median survival ranged between 11.4 and 30.1 months. CONCLUSION: Palliative colectomy performed laparoscopically is associated with a better perioperative outcome than open colectomy. Survival is dependent on the response to systemic chemotherapy.

Impact of peritoneal carcinomatosis in the disease history of colorectal cancer management: a longitudinal experience of 2406 patients over two decades.

BACKGROUND: Recent therapeutic developments demand for an update of information on natural history, risk factors and prognosis of peritoneal carcinomatosis (PC) of colorectal origin. Therefore, prospective registry data should provide information about incidence, predictors and outcome. METHODS: From a prospectively expanded single-institutional database with 2406 consecutive patients with colorectal cancer (CRC), clinical, histological and survival data were analysed for independent risk factors and prognosis. Findings were then stratified to the era of treatment without chemotherapy, 5-Fluorouracil-only and contemporary systemic chemotherapy, respectively. RESULTS: Overall, 256 (10.6%) patients were diagnosed with PC thereof 141 (5.85%) with metachronous PC. Independent risk factors for the development of metachronous PC were age <62 years, N2-status, T4-status, location of the primary in the left colon or appendix. In the era of contemporary systemic chemotherapy, prognosis for PC improved only not-significantly (median survival of 17.9 months vs 7.03 months, P=0.054). CONCLUSION: Despite improvement in the overall outcome with prolonged median survival for the complete patient cohort with CRC, those patients with PC have not experienced the same benefit. In the era of contemporary systemic chemotherapy, progress in treatment resulted in only limited survival benefit. Thus, continuous efforts for further therapeutic advancements should be undertaken in these patients diagnosed with PC.

Importance of gender in diffuse malignant peritoneal mesothelioma.

BACKGROUND: Combined therapy involving cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy has been shown to improve survival outcomes for patients with diffuse malignant peritoneal mesothelioma (DMPM). The present study aims to investigate gender as a potential prognostic factor on overall survival. PATIENTS AND METHODS: Over a period of two decades, 294 patients who underwent CRS and perioperative intraperitoneal chemotherapy were selected from a large multi-institutional registry to assess the prognostic significance of gender on overall survival. RESULTS: Female patients were shown to have a significantly improved survival outcome than male patients (P < 0.001). Staging according to a recently proposed tumor-node-metastasis categorization system was significant in both genders. Older female patients had significantly worse survival than younger female patients (P = 0.019), a finding that was absent in male patients. Female patients with low-stage disease were found to have a very favorable long-term outcome after combined treatment. CONCLUSIONS: Gender has demonstrated a significant impact on overall survival for patients with DMPM after CRS and perioperative intraperitoneal chemotherapy. An improved understanding of the role of estrogen in the pathogenesis of DMPM may improve the prognostication of patients and determine the role of adjuvant hormonal treatment in the future.

Multi-institutional experience of diffuse intra-abdominal multicystic peritoneal mesothelioma.

BACKGROUND: This study was undertaken to measure survival of patients with multicystic peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy through a multi-institutional collaboration. METHODS: A multi-institutional data registry, established by the Peritoneal Surface Oncology Group, was used to identify patients with peritoneal mesothelioma and the subgroup with multicystic tumours, treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Outcomes for this subgroup are reported. The primary endpoint was overall survival. A secondary endpoint was the incidence of treatment-related complications. RESULTS: Of 405 patients with peritoneal mesothelioma, 26 (6·4 per cent) had multicystic tumours. There were 20 women and six men with a mean(s.d.) age of 42(12) years. The median peritoneal carcinomatosis index (PCI) was 14 (range 6-39). There was no perioperative mortality. Six patients developed grade III or IV complications. After a median follow-up of 54 (range 5-129) months, all 26 patients were still alive. CONCLUSION: Multicystic peritoneal mesothelioma appears to be a distinct subtype of peritoneal mesothelioma, where long-term survival may be achieved through cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Long-term outcome of image-guided percutaneous radiofrequency ablation of lung metastases: an open-labeled prospective trial of 148 patients.

BACKGROUND: Image-guided percutaneous radiofrequency ablation (RFA) has been proposed as an efficacious local therapy for lung metastases in nonsurgical candidates. Reports of long-term outcome from this treatment have been limited. METHODS: A prospective open-labeled trial of RFA was initiated in November 2000 for treatment of lung metastases in nonsurgical candidates. RFA was carried out under fluoroscopic computed tomography. Treatment complications and survival parameters were analyzed. RESULTS: Of 148 patients treated, 66 patients (46%) had a complete response, 38 patents (26%) had a partial response, 57 patients (39%) had stable disease and 23 patients (16%) had progressive disease. The median progression-free survival was 11 months [95% confidence interval (CI) 9-14]. The median overall survival and 3- and 5-year survivals were 51 months (95% CI 19-83) and 60% and 45%, respectively. Disease-free interval (P = 0.013) and response to treatment (P = 0.002) were independent predictors for overall survival. Complications occurred in up to 45% of patients, of which 45 patients (30%) required chest tube placement. CONCLUSION: This analysis confirms that RFA of lung metastases may achieve long-term survival in nonsurgical candidates with an acceptable complication rate hence supporting its incorporation into the oncosurgical management of lung metastases for the purposes of cure, stabilization and disease prolongation.

Peritoneal carcinomatosis and liver metastases from colorectal cancer treated with cytoreductive surgery perioperative intraperitoneal chemotherapy and liver resection.

BACKGROUND: An aggressive therapy comprising of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) and liver resection/ablation is generally not offered to patients with both colorectal peritoneal carcinomatosis (CRPC) and liver metastases (LM) as it no longer represents a loco-regional disease. We review the outcomes of patients who underwent an aggressive treatment with a curative intent for both CRPC and LM as a prelude towards determining the suitability of this treatment. METHODS: Patients with CRPC were treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy in our institution. Patients with LM underwent additional treatment of liver resection/ablation. The characteristics and survival of patients with isolated CRPC and those with both CRPC and LM were compared. RESULTS: Fifty-five patients underwent complete cytoreductive surgery for treatment of CRPC, amongst which 16 patients had LM. The overall median survival was 36 months. Fourteen of the 16 patients treated for CRPC and LM underwent synchronous treatment. When patients with CRPC alone or CRPC with LM were compared, patients with CRPC and LM had a lower PCI (p=0.03), received less HIPEC infusion (p<0.001), received less of both HIPEC and EPIC infusion (p=0.007), had a shorter procedural duration (p=0.001) and required less blood transfusion (p=0.02). There was no difference in survival between patients who had CRPC alone or CRPC with LM who underwent aggressive treatment (p=0.77). CONCLUSIONS: A curative procedure may be offered to selected patients with CRPC and LM, especially in those with a low peritoneal cancer index.

Effects of inhalation and intravenous anesthetic agents on pressor response to NG-nitro-L-arginine.

The effects of anaesthetic agents on pressor effect of NG-nitro-L-arginine (L-NNA), a potent inhibitor of nitric oxide (NO) synthesis, were examined in rats. I.v. bolus of L-NNA (1-32 mg/kg) in conscious rats dose dependently increased mean arterial pressure (MAP) to a maximum value of 53 +/- 2 mmHg at 16 mg/kg with ED50 value of 4.7 +/- 0.9 mg/kg. The effects of a single i.v. bolus dose (32 mg/kg) of L-NNA were examined in conscious rats and rats anaesthetised with pentobarbital, chloralose, ketamine, althesin (mixture of alphaxalone and alphadolone), urethane, enflurane or halothane. In conscious rats, peak MAP (51 +/- 3 mmHg) was reached 10 min after i.v. injection and the effect lasted more than two hours. The magnitudes of peak MAP differed under the influence of anaesthetic agents with the following rank order: althesin greater than conscious = pentobarbital = chloralose = ketamine = urethane greater than enflurane much greater than halothane (in which there was negligible change in MAP). The onsets were delayed in rats anaesthetised with pentobarbital, althesin, chloralose and enflurane but not altered with ketamine and urethane compared to that in conscious rats. Therefore, L-NNA caused intense and prolonged pressor response in conscious rats and rats anaesthetised with the i.v. anaesthetic agents pentobarbital, chloralose, ketamine, althesin and urethane. MAP effect of L-NNA was markedly attenuated by the inhalation anaesthetics halothane and enflurane.