Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. CONCLUSIONS: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer.

BACKGROUND: In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS: Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS: Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION: ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

The effect of a surgery-specific cardiac output-guided haemodynamic algorithm on outcomes in patients undergoing pancreaticoduodenectomy in a high-volume centre: a retrospective comparative study.

In this retrospective observational study performed in a high-volume hepatobiliary-pancreatic unit, we evaluated the effect of a surgery-specific goal-directed therapy (GDT) physiologic algorithm on complications and length of hospital stay. We compared patients who underwent pancreaticoduodenectomy with either a standardised Enhanced Recovery After Surgery program (usual care group), or a standardised Enhanced Recovery After Surgery program in combination with a surgery-specific cardiac output-guided algorithm (GDT group). We included 145 consecutive patients: 47 in the GDT group and 98 in the usual care group. Multivariable associations between GDT and lengths of stay and complications were investigated using negative binomial regression. Postoperative complications were common and occurred at similar frequencies amongst the GDT and usual care groups: 64% versus 68% respectively, P=0.71; odds ratio 0.82; (95% confidence interval 0.39-1.70). There were fewer cardiorespiratory complications in the GDT group. Median (interquartile range) length of hospital stay was ten days (8.0-14.0) in the GDT group compared to 13 days (8.8-21.3) in the usual care group, P=0.01. Median (interquartile range) total intraoperative fluid was 3,000 ml (2,050-4,175) in the GDT group compared to 4,500 ml (3,275-5,325) in the usual care group, P <0.0001; but by day one, the median (interquartile range) fluid balance was similar (1,198 ml [700-1,729] in the GDT group versus 977 ml [419-2,044] in the usual care group, P=0.96). Use of vasoactive medications was higher in the GDT group. In our patients undergoing pancreaticoduodenectomy, GDT was associated with restrictive intraoperative fluid intervention, fewer cardiorespiratory complications and a shorter hospital length of stay compared to usual care. However, we could not exclude an influence of surgical caseload, which we have previously found to be an important variable. We also could not relate the increased hospital length of stay to cardiorespiratory complications in individual patients. Therefore, these observational retrospective findings would require confirmation in a prospective randomised study.

The effects of plasmalyte-148 vs. Hartmann's solution during major liver resection: a multicentre, double-blind, randomized controlled trial.

BACKGROUND: The acid-base, biochemical and hematological effects of crystalloid solutions have not been comprehensively evaluated in patients with liver resection. DESIGN: multicenter, prospective, double-blind randomized controlled trial investigating the biochemical effects of Hartmann's solution (HS) or Plasmalyte-148 (PL) in 60 patients undergoing major liver resection. PRIMARY OUTCOME: base excess immediately after surgery. SECONDARY OUTCOMES: changes in blood biochemistry and hematology. RESULTS: At completion of surgery, patients receiving HS had equivalent mean standard base excess (-1.7±2.2 vs. -0.9±2.3 meq/L; P=0.17) to those treated with PL. However, patients treated with HS were more hyperchloremic (difference 1.7 mmol/L, 95% CI: 0.2 to 3.2, P=0.03) and hyperlactatemic (difference 0.8 mmol/L, 95% CI: 0.2 to 1.3; P=0.01). In contrast, patients receiving PL had higher mean plasma magnesium levels and lower ionized calcium levels. There were no significant differences in pH, bicarbonate, albumin and phosphate levels. Immediately after surgery, mean PT and aPTT were significantly lower in the PL group. Intraoperatively, the median (IQR) blood loss in the PL group was 300 mL (200:413) vs. 500 mL (300:638) in the HS group (P=0.03). Correspondingly, the postoperative hemoglobin was higher in the PL group. Total complications were more frequent in the HS Group (56% vs. 20%, relative risk 2.8; 95% CI: 1.3 to 6.1; P=0.007). CONCLUSION: In liver resection patients, HS and PL led to similar base excess values but different post operative plasma biochemistry and hematology values. Understanding of these effects may help clinicians individualize fluid therapy in these patients.

Anaesthetic aspects of implanting diaphragmatic pacing in patients with spinal cord injury.

Some patients with high cervical spinal cord injury are largely or completely dependent on mechanical ventilator support. Diaphragmatic phrenic nerve pacing is a new technique that offers some patients greater independence from mechanical ventilation. In selected patients, electrodes are placed on the abdominal side of the diaphragm via laparoscopy. An external pacing box provides the pacing stimulus. We report our experience with four patients with spinal cord injury in a pilot project, presenting for laparoscopic insertion of diaphragmatic phrenic nerve pacing leads inserted. The surgery took about two hours and diaphragmatic mapping precluded muscle relaxants. We used desflurane with remifentanil for maintenance. Apart from transferring the patients to and from their usual ventilators, other anaesthesia issues were difficult venous and arterial access for lines and long-term tracheostomies with no cuff or cuffs filled with water While hypotension was a frequent problem, one patient also developed intraoperative hypertension secondary to autonomic dysreflexia. Preoperative testing predicted pacing outcome with three of the four patients having successful pacing with tidal volumes of up to 10 ml/kg at the end of surgery. This initial Australian experience may lead to greater use of the technique.

Patterns of heat shock protein (HSP70) expression and Kupffer cell activity following thermal ablation of liver and colorectal liver metastases.

The time course and extent of thermal ablative injury differs in liver compared to tumour tissue. This may be influenced by differences in the expression of heat shock proteins (HSP) and the response of Kupffer cells to thermal injury. This study determines the expression and response of HSP70 and Kupffer cells to thermal ablative injury in a Murine model of colorectal liver metastases. Thermal ablation by laser (Nd-YAG wavelength 1064 nm) was induced in liver and colorectal cancer liver metastases in CBA strain mice. Laser energy was applied at 2 W for 50 s and produced incomplete tumour ablation. Established tissue injury was assessed in separate groups of animals at time points ranging from 12 h to 21 days following therapy. HSP70 and Kupffer cell expression at the margins of coagulated tissue was determined by immunohistochemical staining for HSP70 and F4/80 antigens, respectively. HSP70 was faintly expressed in the cytoplasm of all tumour cells, with distinct clusters exhibiting intense cytoplasmic and nuclear HSP70 staining (130+/-19 cells mm-2). Comparatively, HSP70 expression was uncommon in untreated control liver specimens (2+/-2 cells mm-2, p<0.001). Thermal ablation increased expression of HSP70 at coagulated tissue margins. The peak response in tumours occurred at 2 days post-ablation and was significantly greater than the peak response in liver, occurring at 12 h (809+/-80 cells mm-2 vs. 454+/-52 cells mm-2, p<0.001). HSP70 expression remained significantly elevated for 7 days following therapy in tumour tissue, compared to 3 days in liver. Kupffer cell numbers in untreated control tumours were significantly lower than in untreated control livers (285+/-23 cells mm-2 vs. 451+/-30 cells mm-2, p<0.001). Following thermal ablation, there was an initial decrease in Kupffer cell numbers at the margin of coagulation with subsequent persistent increases thereafter. In liver tissue, the peak Kupffer cell response occurred at 5 days post-therapy and was significantly greater than the peak response in tumour tissue 3 days post-thermal ablation (1074+/-34 cells mm-2 vs. 860+/-53 cells mm-2, p=0.007). Thermal ablation produces a greater and more prolonged HSP70 response in colorectal liver metastases than in liver tissue. It also induces persistent increases in Kupffer cell activity in liver and tumour tissue.

Selective endoscopic cholangiography for the detection of common bile duct stones in patients with cholelithiasis.

BACKGROUND AND STUDY AIMS: The detection and management of common bile duct (CBD) stones in patients undergoing laparoscopic cholecystectomy continues to be controversial. Several diagnostic and therapeutic strategies have been suggested. These include intraoperative cholangiography, selective endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography, and endoscopic ultrasonography. The aim of this study was to evaluate the efficacy of selective ERCP in detecting CBD stones in patients with cholelithiasis before laparoscopic cholecystectomy. PATIENTS AND METHODS: In a prospective study, patients with cholelithiasis who presented during a 6-year period were assessed on a selective basis with ERCP for suspected CBD stones before laparoscopic cholecystectomy. ERCP was carried out if the patient had any of the following criteria: a dilated CBD on ultrasound, gallstone pancreatitis, or abnormal liver function tests. Intraoperative cholangiography was not performed in any of the patients. Long-term follow-up was undertaken. RESULTS: The study included 427 patients. On the basis of selective criteria, ERCP was carried out in 41 patients (9.6 %), with confirmed CBD stones in 22 cases (53.7 %). The most useful predictor of CBD stones on ERCP was the presence of a dilated CBD in association with abnormal liver function tests. In this situation, CBD stones were identified in 14 of 17 cases (82 %). Abnormal liver function tests alone had a sensitivity of 50 % (four of eight). All other parameters used in isolation had a lower detection rate. During a median follow-up period of 6 years (range 1-10 years), six of 386 patients (1.6 %) with initially normal imaging and biochemical tests presented again with retained stones. All were successfully managed by ERCP and sphincterotomy. There were no major complications. CONCLUSIONS: Preoperative selective ERCP is effective in detecting clinically significant CBD stones. However, there is a high false-negative rate when a single criterion is used to guide therapy. Multivariate analysis of preoperative parameters for risk stratification, in conjunction with other imaging modalities, may make it possible to minimize unnecessary ERCPs.

Primary hepatic carcinoid tumours.

BACKGROUND: Carcinoid tumours of the liver are predominantly metastases from the gastrointestinal tract. Primary hepatic carcinoids are extremely rare. DISCUSSION: In contrast to metastases, primary hepatic carcinoids are usually solitary and resectable. It is important that these tumours are differentiated from metastases. Complete surgical resection should be contemplated and is generally curative.

Scanning electron microscopy study of the blood supply of human colorectal liver metastases.

AIMS: The failure of hepatic artery directed treatment of colorectal liver metastases may reflect a major portal venous contribution to tumour blood supply. This study provides ultrastructural details of the blood supply of colorectal liver metastases and their association with the portal vein and hepatic artery. METHODS: Resected liver specimens from six patients with colorectal liver metastases were examined by histology and scanning electron microscopy (SEM), following vascular resin casting. RESULTS: Nine metastatic colorectal adenocarcinomas were identified. The main feature of all tumours on SEM was direct communication between hepatic sinusoids and tumour vessels. A direct portal venous connection with tumour vessels was observed in a single specimen, whilst a direct arteriole connection was not identified. CONCLUSIONS: It appears that both the hepatic artery and portal vein contribute to the blood supply of colorectal liver metastases through sinusoidal connections with tumour specific blood vessels. SEM provides useful additional information on the morphological features of tumour vasculature.

Interstitial laser thermotherapy for liver tumours.

BACKGROUND: Primary hepatocellular carcinoma (HCC) and metastases from colorectal cancer are the most common malignant liver tumours. Surgical resection is the optimum treatment in suitable patients. Interstitial laser thermotherapy (ILT) is gaining acceptance for the treatment of irresectable liver tumours and as a potential alternative to surgery. An understanding of the principles of therapy and review of clinical outcomes may allow better use of this technology. METHOD: An electronic search using the Medline database was performed for studies on the treatment of hepatic malignancy published between January 1983 and February 2003. RESULTS: Current information on the efficacy of ILT is based on prospective studies. ILT appears to be a safe and minimally invasive technique that consistently achieves tumour destruction. The extent of destruction depends on the fibre design, delivery system, tumour size and tumour biology. Real-time magnetic resonance imaging provides the most accurate assessment of laser-induced tumour necrosis. In selected patients with HCC and colorectal cancer liver metastases, ILT achieves complete tumour necrosis, provides long-term local control, and improves survival, compared with the natural history of the disease. In addition, ILT has survival benefits for patients with other tumour types, especially those with isolated liver metastases from a breast cancer primary. CONCLUSION: ILT improves overall survival in specific patients with liver tumours. Advances in laser technology and refinements in technique, and a better understanding of the processes involved in laser-induced tissue injury, may allow ILT to replace surgery as the procedure of choice in selected patients with liver malignancies.

Interstitial laser hyperthermia and the biological characteristics of tumor: study in a murine model of colorectal liver metastases.

BACKGROUND DATA: Percutaneously applied interstitial laser hyperthermia (ILH) is a minimally invasive therapy that is currently used in the treatment of liver metastases. Despite its documented efficacy, theoretical considerations and evidence based on animal studies suggest the potential for stimulating tumor growth, especially following surgery. This study investigates the influence of ILH on tumor behaviour in an animal model of colorectal liver metastases. MATERIALS AND METHODS: A model of colorectal cancer liver metastases in male inbred CBA mice was used. Laser hyperthermia was applied to tumor tissue using a bare optical quartz from a Medilas fibertom 4100 Nd:YAG surgical laser generator. Liver injury by ILH was initially produced in three experimental groups of animals at different time points in the development of metastases. ILH was applied (i) to normal liver 10 days prior to tumor induction, (ii) immediately prior to tumor induction, and (iii) 15 days after tumor induction to achieve approximately 8% liver destruction. Animals were killed 21 days after tumor induction, and the effects of ILH on overall tumor development were compared with controls using stereological assessment of tumor volume and by histology. In a separate experimental group, the effects of ILH on fully established tumors were examined. Suitable tumors were selected 21 days after induction and partially destroyed by ILH at a standard energy setting. Animals were then killed 15 days later, and the growth rate of the residual viable tumors was compared to control tumors having undergone sham procedures. RESULTS: No significant stimulation of tumor growth was evident in any of the experimental groups following ILH, irrespective of the time of application. Incomplete tumor destruction also had no influence on subsequent tumor growth. CONCLUSION: ILH does not influence the biological characteristics of tumors during any stage of the metastatic process.

Pancreatic resection for metastatic melanoma.

BACKGROUND: The pancreas is an occasional site of metastases from melanoma. It may be the only location of metastatic disease, but more often the melanoma metastasis to other organs as well. Treatment options are somewhat limited, and the role of operative treatment is poorly defined. CASE OUTLINES: Two patients presenting with abdominal pain were found to have pancreatic lesions. A 45-year-old woman had a pylorus-preserving pancreatoduodenectomy for a mass in the head of pancreas; concurrent liver nodules were treated by segmental liver resection. A 55-year-old man had a total pancreatectomy for multiple pancreatic tumours. Both patients gave a history of ocular melanoma, diagnosed >10 years previously. They had no evidence of malignancy elsewhere. Histology of resected specimens confirmed metastatic melanoma with features consistent with an ocular primary. All resection margins were clear of malignancy, and no lymph node metastases were detected. At 6 months follow-up there were no signs of tumour recurrence. DISCUSSION: Complete surgical resection offers potential cure in selected patients with metastatic melanoma involving the pancreas, when there is no evidence of widespread disease.

Local resection of ampullary adenocarcinomas of the duodenum.

BACKGROUND: Pancreaticoduodenectomy (PD) is considered to be the optimal treatment for ampullary adenocarcinomas. Local resection (LR) is a less invasive and potentially equally effective alternative for cancers with favourable prognostic features. Identification of these prognostic parameters may allow selection of patients suitable for LR. METHODS: Twenty-five patients were treated for a primary Vater's ampulla adenocarcinoma at the Alfred Hospital, Melbourne, Australia, between January 1989 and January 2000. Risk factors for cancer recurrence were evaluated and the specific role of LR was defined. RESULTS: Fourteen patients had PD, five had LR and six had bypass procedures (five biliary stents; one operative bypass). Presenting symptoms included jaundice (64%), abdominal pain (54%) and weight loss (32%). Adenocarcinomas that were resected had a median diameter of 2.5 cm, and were limited to the ampulla in 26% (T1), invaded the duodenal wall in 42% (T2) and infiltrated 2 cm or less into the pancreas in 32% (T1) of cases. Locally resected cancers were confined to the ampulla or invaded the duodenum and recurred in one patient following excision. Six recurrences occurred in total, influenced significantly by T staging (P = 0.009). Patient age, preoperative symptoms, laboratory tests, tumour size, differentiation, ulceration, lymphovascular spread and perineural invasion had no effect on recurrence. Patients undergoing LR had lower morbidity and mortality, reduced blood transfusion requirements and shorter hospital stay than those treated by PD. CONCLUSIONS: T staging predicts the risk of tumour recurrence and can be determined using endoscopic ultrasound. Local resection is a suitable alternative to pancreaticoduodenal resection in patients with T1 and T2 adenocarcinomas with a maximum diameter of 3 cm or less.