Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [177Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [225Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225. RESULTS: Cell binding and internalisation of [225Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [225Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [225Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [225Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [225Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations. CONCLUSION: [225Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.

In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [177Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [177Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC. RESULTS: A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [177Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [177Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [177Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [177Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [177Lu]Lu-DOTA-C595. CONCLUSION: [177Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [177Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.

Preliminary Development and Testing of C595 Radioimmunoconjugates for Targeting MUC1 Cancer Epitopes in Pancreatic Ductal Adenocarcinoma.

Mucin 1 is a transmembrane glycoprotein which overexpresses cancer-specific epitopes (MUC1-CE) on pancreatic ductal adenocarcinoma (PDAC) cells. As PDAC is a low survival and highly aggressive malignancy, developing radioimmunoconjugates capable of targeting MUC1-CE could lead to improvements in PDAC outcomes. The aim of this study was to develop and perform preliminary testing of diagnostic and therapeutic radioimmunoconjugates for PDAC using an anti-MUC1 antibody, C595. Firstly, p-SCN-Bn-DOTA was conjugated to the C595 antibody to form a DOTA-C595 immunoconjugate. The stability and binding affinity of the DOTA-C595 conjugate was evaluated using mass spectrometry and ELISA. DOTA-C595 was radiolabelled to Copper-64, Lutetium-177, Gallium-68 and Technetium-99m to form novel radioimmunoconjugates. Cell binding assays were performed in PANC-1 (strong MUC1-CE expression) and AsPC-1 (weak MUC1-CE expression) cell lines using 64Cu-DOTA-C595 and 177Lu-DOTA-C595. An optimal molar ratio of 4:1 DOTA groups per C595 molecule was obtained from the conjugation process. DOTA-C595 labelled to Copper-64, Lutetium-177, and Technetium-99m with high efficiency, although the Gallium-68 labelling was low. 177Lu-DOTA-C595 demonstrated high cellular binding to the PANC-1 cell lines which was significantly greater than AsPC-1 binding at concentrations exceeding 100 nM (p < 0.05). 64Cu-DOTA-C595 showed similar binding to the PANC-1 and AsPC-1 cells with no significant differences observed between cell lines (p > 0.05). The high cellular binding of 177Lu-DOTA-C595 to MUC1-CE positive cell lines suggests promise as a therapeutic radioimmunoconjugate against PDAC while further work is required to harness the potential of 64Cu-DOTA-C595 as a diagnostic radioimmunoconjugate.

Once in a Bile - the Incidence of Bile Reflux Post-Bariatric Surgery.

PURPOSE: Excellent metabolic improvement following one anastomosis gastric bypass (OAGB) remains compromised by the risk of esophageal bile reflux and theoretical carcinogenic potential. No 'gold standard' investigation exists for esophageal bile reflux, with diverse methods employed in the few studies evaluating it post-obesity surgery. As such, data on the incidence and severity of esophageal bile reflux is limited, with comparative studies lacking. This study aims to use specifically tailored biliary scintigraphy and upper gastrointestinal endoscopy protocols to evaluate esophageal bile reflux after OAGB, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). METHODS: Fifty-eight participants underwent OAGB (20), SG (15) or RYGB (23) between November 2018 and July 2020. Pre-operative reflux symptom assessment and gastroscopy were performed and repeated post-operatively at 6 months along with biliary scintigraphy. RESULTS: Gastric reflux of bile was identified by biliary scintigraphy in 14 OAGB (70%), one RYGB (5%) and four SG participants (31%), with a mean of 2.9% (SD 1.5) reflux (% of total radioactivity). One participant (OAGB) demonstrated esophageal bile reflux. De novo macro- or microscopic gastroesophagitis occurred in 11 OAGB (58%), 8 SG (57%) and 7 RYGB (30%) participants. Thirteen participants had worsened reflux symptoms post-operatively (OAGB, 4; SG, 7; RYGB, 2). Scintigraphic esophageal bile reflux bore no statistical association with de novo gastroesophagitis or reflux symptoms. CONCLUSION: Despite high incidence of gastric bile reflux post-OAGB, esophageal bile reflux is rare. With scarce literature of tumour development post-OAGB, frequent low-volume gastric bile reflux likely bears little clinical consequence; however, longer-term studies are needed. CLINICAL TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry number ACTRN12618000806268.

Combined chemotherapy and endoscopic ultrasound-guided intratumoral 32P implantation for locally advanced pancreatic adenocarcinoma: a pilot study.

BACKGROUND: This study evaluated clinical outcomes of combined chemotherapy and endoscopic ultrasound (EUS)-guided intratumoral radioactive phosphorus-32 (32P) implantation in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Consecutive patients with newly diagnosed LAPC were recruited over 20 months. Baseline computed tomography and 18F-2-fluoro-2-deoxy-D-glucose (18FDG) positron emission tomography-computed tomography were performed and repeated after 12 weeks to assess treatment response. Following two cycles of conventional chemotherapy, patients underwent EUS-guided 32P implantation followed by six chemotherapy cycles. RESULTS: 12 patients with LAPC (median age 69 years [interquartile range 61.5-73.3]; 8 male) completed treatment. Technical success was 100 % with no procedural complications. At 12 weeks, median reduction in tumor volume was 8.2 cm3 (95 % confidence interval 4.95-10.85; P = 0.003), with minimal or no 18FDG uptake in nine patients (75 %). Tumor downstaging was achieved in six patients (50 %), leading to successful resection in five (42 %), including four R0 resections (80 %). CONCLUSIONS: EUS-guided 32P implantation was feasible, well tolerated, and resulted in a 42 % surgical resection rate. Further evaluation in a larger randomized multicenter trial is warranted.

The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy.

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5-93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.

HIDA and Seek: Challenges of Scintigraphy to Diagnose Bile Reflux Post-Bariatric Surgery.

INTRODUCTION: Oesophageal bile reflux after bariatric surgery may trigger development of Barrett's oesophagus. Gastro-oesophageal reflux of bile is captured by hepatobiliary iminodiacetic acid (HIDA) scintigraphy; however, anatomical and physiological changes after bariatric surgery warrant protocol modifications to optimise bile reflux detection. METHODS: HIDA scintigraphy occurred 6 months after either sleeve gastrectomy, Roux-en-Y gastric bypass or one-anastomosis gastric bypass. Standard HIDA scanning involves (i) 6-h fast and 24-h abstinence from opioids; (ii) IV administration of 99mTc di-isopropyl iminodiacetic acid; and (iii) dual anterior/posterior 60-min dynamic scanning of the duodenum, stomach and oesophagus. Three challenges were identified, and modifications were implemented, namely, (1) anatomical localisation of refluxed bile on planar scintigraphy was improved by adding a SPECT/CT for 3D imaging; (2) impaired cholecystokinin-controlled gallbladder emptying, following bypassed duodenum, was addressed by ingestion of a 'fatty meal'; and (3) intestinal hypomotility after gastric bypass was counteracted by longer scan duration (75-90 min) to allow bile to pass beyond the gastro-jejunal anastomosis. RESULTS: HIDA scan was undertaken in 18 patients, 13 of whom underwent the modified protocol. The tailored protocol ameliorated issues identified with the standard HIDA scan protocol; thus, accurate anatomical localisation was achieved in all patients, no delayed gallbladder emptying was observed, and bile was observed beyond the gastro-jejunal anastomosis in all gastric bypass patients. The modified technique was well tolerated by patients. CONCLUSION: A tailored HIDA scan protocol with addition of a SPECT-CT scan, ingestion of a fatty meal and prolonged scanning duration results in enhanced bile reflux detection in post-bariatric surgical patients.

Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature.

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or ß-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or ß particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and ß radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE® and Scopus databases was performed to identify 34 relevant studies conducted on α or ß radioimmunotherapy of PDAC. Preclinical results demonstrated α and ß radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating ß radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%-57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and ß radioimmunotherapy in PDAC.

The utility of fluorine-18-fluorodeoxyglucose positron emission tomography in the diagnosis and monitoring of large vessel vasculitis: A South Australian retrospective audit.

AIMS: To investigate the utility of fluorine-18-labelled deoxyglucose positron emission tomography (FDG-PET) in routine clinical practice to diagnose and monitor disease activity and treatment response in large vessel vasculitis in a South Australian cohort. METHODS: We performed a retrospective clinical audit of adult patients who received a FDG-PET at a tertiary referral center between August 2010 and August 2015, where the term "vasculitis" appeared in either the request or report. RESULTS: A total of 45 patients met the inclusion criteria. Nine patients (20%) had a positive FDG-PET for large vessel vasculitis. FDG-PET was positive in 3/6 (50%) patients who met the American College of Rheumatology (ACR) criteria for giant cell arteritis or Takayasu's arteritis (TA) on retrospective review. A positive FDG-PET for large vessel inflammation assisted the primary clinician in making the diagnosis of unclassified large vessel vasculitis in six patients. Four of the seven patients who had more than one scan for large vessel vasculitis demonstrated normalized FDG uptake on subsequent scans after a period on glucocorticoid treatment. The remaining three patients persisted in having increased FDG uptake on FDG-PET imaging while on active treatment. CONCLUSION: Fluorine-18-labelled deoxyglucose positron emission tomography has a role in the diagnosis of large vessel vasculitis, particularly in patients with a high suspicion of active large vessel vasculitis who do not meet the ACR criteria. FDG-PET may have a role in monitoring disease activity in selected patients with large vessel vasculitis especially in identifying occult sites of large vessel inflammation or to titrate prednisolone therapy.

Comparative study between 68 Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer.

INTRODUCTION: The management of prostate cancer has undergone significant advances since the introduction of 68 Ga-prostate-specific membrane antigen (68 Ga-PSMA) positron emission tomography (PET) scans. Data on the use of 68 Ga-PSMA PET scans in the setting of biochemical recurrence is widely available. Data on the use of 68 Ga-PSMA PET as an initial staging modality, however, is limited. The aim of this retrospective study was to compare the staging of patients with newly diagnosed prostate cancer between 68 Ga-PSMA PET and current conventional imaging modalities. The potential impact of any change in stage will be analysed. METHODS: Details of all patients who underwent 68 Ga-PSMA PET in South Australia between March 2016 and March 2017 were obtained. One hundred and thirty-one patients with newly diagnosed prostate cancer who had 68 Ga-PSMA PET prior to consideration of definitive treatment were included in this study. The stage pre-68 Ga-PSMA PET (based on conventional imaging) and post-68 Ga-PSMA PET was recorded. The stage was classified as A - localised disease, B - presence of regional lymphadenopathy, C - oligometastatic disease (up to three metastases) and D - widespread metastases. Management plans were recorded. RESULTS: This study showed that the use of 68 Ga-PSMA PET resulted in a change of stage in 37 (28%) patients with an upstage in 17 (13%) patients and a downstage in 20 (15%) patients (P < 0.001). 68 Ga-PSMA PET excluded oligometastatic disease in 11 (8%) patients who had suspicious oligometastatic disease based on a single conventional imaging modality. These 68 Ga-PSMA PET findings impacted on management in at least 24 (18%) patients. CONCLUSION: The use of 68 Ga-PSMA PET scans in initial staging can have a significant impact on staging and management when compared to current conventional imaging modalities.

18-Fluoride labeled sodium fluoride positron emission tomography with computer tomography: the impact of pretreatment staging in intermediate- and high-risk prostate cancer.

BACKGROUND: 18-Fluoride labeled sodium fluoride (Na-18-F) positron emission tomography with computer tomography (PET/CT) has a better sensitivity and specificity than whole body bone scan (WBBS) in detecting osseous metastatic prostate cancer. We performed a pilot study of 20 men to examine what level of impact Na-18-F PET/CT has on management plans when used for staging newly diagnosed prostate cancer. MATERIALS AND METHODS: Twenty men were prospectively enrolled into the study in South Australia. Men were eligible if they had newly diagnosed, untreated, and biopsy-confirmed intermediate- or high-risk prostate cancer (D'Amico classification). WBBS and Na-18-F PET/CT scans were performed within 1 week of each other. Following review of the WBBS, treatment type and intent was documented by the treating urologist. The Na-18-F PET/CT scan was then reviewed. The impact of the Na-18-F PET/CT was measured on whether treatment modality or intent was subsequently altered: high impact = treatment intent or modality was changed; medium impact = treatment modality was modified; low impact = no change in treatment. RESULTS: In 18 men (90%), the WBBS and Na-18-F PET/CT were negative for osseous metastases. In one man (5%), the WBBS demonstrated widespread osseous metastases which were similarly demonstrated on the Na-18-F PET/CT. One man (5%) had a normal WBBS; however, the Na-18-F PET/CT demonstrated widespread osseous metastases. Subsequently, in 19 men (95%), the results of the two scans were congruent and the addition of the Na-18-F PET/CT scan demonstrated a low impact on management. In one man (5%), the addition of the Na-18-F PET/CT had a high impact as treatment type and intent was altered. CONCLUSIONS: Our pilot study is the first of its kind in Australia, and our findings suggest that Na-18-F PET/CT is a safe and feasible modality for staging prostate cancer. However, its true impact on prostate cancer management warrants further investigation.

Hybrid 99mTc-magnetite tracer for dual modality sentinel lymph node mapping.

Accuracy of sentinel lymph node identification using radioactive tracers in non-superficial cancers can be limited by radiation shine through and low spatial resolution of detection systems such as intraoperative gamma probes. By utilising a dual radioactive/magnetic tracer, sensitive lymphoscintigraphy can be paired with high spatial resolution intraoperative magnetometer probes to improve the accuracy of sentinel node detection in cancers with complex multidirectional lymphatic drainage. Dextran-coated magnetite nanoparticles (33 nm mean hydrodynamic diameter) were labelled with 99mTc and applied as a lymphotropic tracer in small and large animal models. The dual tracer could be radiolabelled with 98 ± 2% efficiency after 10 min of incubation at room temperature. Biodistribution studies of the tracer were conducted in normal rats (subdermal and intravenous tail delivery, n = 3) and swine (subdermal hind limb delivery, n = 5). In rats the dual tracer migrated through four tiers of lymph node, 20 min after subdermal injection. Results from intravenous biodistribution test for radiocolloids demonstrated no aggregation in vivo, however indicated the presence of some lower-molecular weight radioactive impurities (99mTc-dextran). In swine, the dual tracer could be effectively used to map lymphatic drainage from hind hoof to popliteal and inguinal basins using intraoperative gamma and magnetometer probes. Of the eight primary nodes excised, eight were positively identified by gamma probe and seven by magnetometer probe. The high-purity dual tracer shows early promise for sentinel node identification in complex lymphatic environments by combining sensitive preoperative lymphoscintigraphy with a high-resolution intraoperative magnetometer probe.

Effects of Fat and Protein Preloads on Pouch Emptying, Intestinal Transit, Glycaemia, Gut Hormones, Glucose Absorption, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass.

BACKGROUND: The aim was to determine the effects of fat and protein preloads on pouch emptying (PE), caecal arrival time (CAT), glucose absorption, blood glucose (BSL), gut hormones, haemodynamics and gastrointestinal (GI) symptoms in subjects who had undergone Roux-en-Y gastric bypass (RYGB) >12 months previously. METHODS: Ten RYGB subjects were studied on three occasions, in randomised order, receiving 200-ml preloads of either water, fat (30 ml olive oil) or whey protein (55 g), 30 min before a mixed meal. PE, CAT, BSL, plasma 3-O-methyl-D-glucopyranose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon, blood pressure (BP), heart rate (HR) and GI symptoms were assessed over 270 min. RESULTS: Although fat and protein preloads did not alter PE of either solids or liquids, the CAT of solids, but not liquids, was longer than that after the water preload (fat 68 ± 5 min and protein 71 ± 6 min vs. water 46 ± 5 min; P = 0.02). BSL elevated promptly after the meal on all days (P < 0.001), but after protein, the magnitude and integrated increases in the first 75 min were less than fat and water preloads (area under the curve (AUC(0-75 min)), 18.7 ± 18.2 vs. 107.2 ± 30.4 and 76.1 ± 19.3 mmol/L/min; P < 0.05). Compared to water preload, the protein and fat preloads were associated with greater increases in plasma insulin, GLP-1 and glucagon concentrations, a reduction in BP, and greater increases in HR, fullness, bloating and nausea. Plasma 3-OMG levels were lower after the protein than after the water and fat preloads (P < 0.001). CONCLUSIONS: Given its effects to attenuate post-prandial glycaemia, reduce intestinal glucose absorption and potentiate the "incretin response", without inducing more adverse post-prandial GI symptom, protein preload may prove clinically useful in RYGB patients and warrant further evaluation, particularly in those with type 2 diabetes (T2DM) and/or dumping syndrome.

Complicated and uncomplicated peptic ulcer disease: altered symptom response to a nutrient challenge linked to gastric motor dysfunction.

BACKGROUND: Bleeding peptic ulcer (BPU) frequently occurs in the absence of preceding dyspeptic symptoms. We have observed that patients with BPU had a diminished symptom response to nutrient challenge test compared to uncomplicated peptic ulcer disease (uPUD). We postulated that more symptoms are manifest in patients with uPUD than BPU because there are greater derangements in gastric motor function. AIM: To assess gastric emptying in patients with BPU, uPUD and healthy controls (HC). METHODS: We studied 17 patients with BPU, 10 with uPUD, and 15 HC. After an 8-hour fast, subjects ingested 200 ml of an enteral feeding solution, containing 5 MBq (99m)Tc-rhenium sulphide colloid, every 5 min up to a cumulative volume of 800 ml. Gastric emptying was measured by scintigraphy for the total, proximal and distal stomach. RESULTS: Patients with uPUD had significantly higher gastric retention in the proximal and total stomach at 100 min than HC and BPU, while BPU had similar percent retention to HC. Patients with uPUD had significantly higher cumulative symptom response to the nutrient challenge than did HC and BPU, while BPU had similar symptom responses to HC. CONCLUSIONS: Patients with uPUD have significantly delayed gastric emptying compared to HC and BPU. Data suggest that in addition to alterations of visceral sensory function, altered gastric motor function occurs during a nutrient challenge in uPUD but not BPU. Gastric motor function may contribute to the manifestation of dyspeptic symptoms in PUD.

Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial.

OBJECTIVE: Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. DESIGN: Prospective randomized study. SETTING: Three tertiary endoscopic centers. PATIENTS: Two hundred fifty-one patients were randomized to receive either Penthrox (n = 125, 70 men, 51.4 ± 1.1 years old) or intravenous midazolam and fentanyl (M&F; n = 126, 72 men, 54.9 ± 1.1 years old) during colonoscopy. MAIN OUTCOME MEASUREMENT: Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. RESULTS: Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 ± 1 vs 8 ± 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO(2)] < 90%) events (0/115 vs 5/126; P = .03), awoke quicker (3 ± 0 vs 19 ± 1 minutes; P < .001) and were ready for discharge earlier (37 ± 1 vs 66 ± 2 minutes; P < .001) than those receiving intravenous M&F. LIMITATIONS: Inhaled Penthrox is not yet available in the United States and Europe. CONCLUSIONS: Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection.

Accuracy of PET-CT in predicting survival in patients with esophageal cancer.

BACKGROUND: Positron emission tomography (PET) is an integral part of tumor staging for patients with esophageal cancer. Recent studies suggest a role for PET scan in predicting survival in these patients, but this relationship is unclear in the setting of neoadjuvant therapy. We examined pretreatment maximum standard uptake value (SUV(max)) of the primary tumor in patients treated with and without neoadjuvant therapy. METHODS: All patients undergoing esophagectomy with a preoperative PET scan over a nine-year period (2001-2010) were identified from a prospectively maintained database. Positron emission tomography data were obtained from computers housing the original PET scans. Overall survival was correlated with SUV(max) of the primary tumor. RESULTS: A total of 191 patients were identified, and 103 patients met inclusion criteria. Eighty-two had an adenocarcinoma (80%), and 21 (20%) had a squamous cell carcinoma. Fifty-seven (55%) patients received neoadjuvant therapy. In the surgery alone group, a SUV(max) of > 5.0 in the primary tumor was associated with poor prognosis [Hazard Ratio (HR) 0.32; p = 0.007], but this factor did not retain its significance on multivariate analysis (HR 0.65; p = 0.43). Pretreatment SUV(max) in patients who underwent neoadjuvant therapy was not significant in predicting overall survival (p = 0.10). CONCLUSIONS: This study does not support the use of SUV(max) on pretreatment PET scans as a prognostic tool for patients with esophageal cancer, especially in those who have received neoadjuvant therapy. Lymph node status is a more accurate predictor of outcome, and efforts to improve pretreatment staging should focus on this factor.

Sentinel lymph node biopsy in esophageal cancer: should it be standard of care?

INTRODUCTION: Sentinel node mapping is established in some superficial cancers but remains controversial in harder-to-access solid tumors. There are an increasing number of recent studies suggesting that isolated tumor cells have prognostic significance in predicting poor survival, in breast cancer, esophageal cancer, and others. It is for this reason that we have persevered with the sentinel lymph node concept in our esophagectomy cancer patients, and we report our results since 2008. METHODS: Thirty-one of 32 consecutive patients underwent resection for invasive esophageal cancer along with sentinel lymph node retrieval (resection rate, 97%). Peritumoral injection of (99m)Tc antimony colloid was performed by upper endoscopy prior to the operation. A two-surgeon synchronous approach via a right thoracotomy and laparotomy was performed with a conservative lymphadenectomy. Sentinel lymph nodes were identified with a gamma probe both in and ex vivo, and sent off separately for three serial sections and immunohistochemistry with AE1/AE3. RESULTS: The median patient age was 63.4 years (range, 45-75 years). Most patients (81%) had an adenocarcinoma, and 61% had received neoadjuvant therapy. At least one sentinel lymph node (median, 3) was identified in 29 of 31 patients (success rate, 94%). Sentinel nodes were present in more than one nodal station in 16 patients (55%). One false negative case led to a sensitivity of 90%. In 28 of 29 patients, the sentinel lymph node accurately predicted findings in non-sentinel nodes (accuracy, 96%). CONCLUSIONS: Sentinel lymph node biopsy is both feasible and accurate in esophageal resections with conservative lymphadenectomy. It allows targeted serial sectioning and immunohistochemical studies of those nodes and should become standard of care in patients undergoing esophagectomy for esophageal cancer.

Feasibility study of sentinel lymph node biopsy in esophageal cancer with conservative lymphadenectomy.

INTRODUCTION: Lymphoscintigraphy and sentinel node mapping is established in breast cancer and melanoma but not in esophageal cancer, even though many centers have shown that occult tumor deposits in lymph nodes influence prognosis. We report our initial experience with lymphoscintigraphy and sentinel lymph node biopsy in patients undergoing resection for esophageal cancer. METHODS: Sixteen of 17 consecutive patients underwent resection for invasive esophageal cancer along with sentinel lymph node retrieval (resection rate, 94%). Peritumoral injection of (99m)Tc antimony colloid was performed by upper endoscopy prior to the operation. A two-surgeon synchronous approach via right thoracotomy and laparotomy was performed with conservative lymphadenectomy. Sentinel lymph nodes were identified using a gamma probe both in vivo and ex vivo. Sentinel lymph nodes were sent off separately for serial sections and immunohistochemistry. RESULTS: Median patient age was 60.4 years (range, 45-75 years). Fifteen were male, and thirteen had adenocarcinoma. At least one sentinel lymph node (median, 2) was identified in 14 of 16 patients (success rate, 88%). Sentinel nodes were present in more than one nodal station in five patients (31%). In all 14 patients, the sentinel lymph node accurately predicted findings in non-sentinel nodes (accuracy, 100%). Three patients with positive sentinel lymph nodes had metastases identified in non-sentinel nodes (sensitivity, 100%). CONCLUSIONS: Sentinel lymph node biopsy is feasible in esophageal resection with conservative lymphadenectomy, and initial results suggest it is accurate in predicting overall nodal status. Further study is needed to assess impact on patient management and prognosis.