Association of Upper GI Surgery of Great Britain and Ireland (AUGIS) Delphi consensus recommendations on the adoption of robotic upper GI surgery.

BACKGROUND: The adoption of robotic platforms in upper gastrointestinal (GI) surgery is expanding rapidly. The absence of centralised guidance and governance in adoption of new surgical technologies may lead to an increased risk of patient harm. METHODS: Surgeon stakeholders participated in a Delphi consensus process following a national open-invitation in-person meeting on the adoption of robotic upper GI surgery. Consensus agreement was deemed met if >80% agreement was achieved. RESULTS: Following two rounds of Delphi voting, 25 statements were agreed on covering the training process, governance and good practice for surgeons' adoption in upper GI surgery. One statement failed to achieve consensus. CONCLUSIONS: These recommendations are intended to support surgeons, patients and health systems in the adoption of robotics in upper GI surgery.

Cost effectiveness of intraoperative laparoscopic ultrasound for suspected choledocholithiasis; outcomes from a specialist benign upper gastrointestinal unit.

INTRODUCTION: Common bile duct stones are present in 10% of patients with symptomatic gallstones. One-third of UK patients undergoing cholecystectomy will have preoperative ductal imaging, commonly with magnetic resonance cholangiopancreatography. Intraoperative laparoscopic ultrasound is a valid alternative but is not widely used. The primary aim of this study was to assess cost effectiveness of laparoscopic ultrasound compared with magnetic resonance cholangiopancreatography. MATERIALS AND METHODS: A prospective database of all patients undergoing laparoscopic cholecystectomy between 2015 and 2018 at a district general hospital was assessed. Inclusion criteria were all patients, emergency and elective, with symptomatic gallstones and suspicion of common bile duct stones (derangement of liver function tests with or without dilated common bile duct on preoperative ultrasound, or history of pancreatitis). Patients with known common bile duct stones (magnetic resonance cholangiopancreatography or failed endoscopic retrograde cholangiogram) were excluded. Ninety-day morbidity data were also collected. RESULTS: A total of 420 (334 elective and 86 emergency) patients were suspected to have common bile duct stones and were included in the study. The cost of a laparoscopic ultrasound was £183 per use. The cost of using the magnetic resonance cholangiopancreatography unit was £365 per use. Ten postoperative magnetic resonance cholangiopancreatographies were performed for inconclusive intraoperative imaging. The estimated cost saving was £74,650. Some 128 patients had common bile duct stones detected intraoperatively and treated. There was a false positive rate of 4.7%, and the false negative rate at 90 days was 0.7%. laparoscopic ultrasound use saved 129 bed days for emergency patients and 240 magnetic resonance cholangiopancreatography hours of magnetic resonance imaging. CONCLUSION: The use of laparoscopic ultrasound during laparoscopic cholecystectomy for the detection of common bile duct stone is safe, accurate and cost effective. Equipment and maintenance costs are quickly offset and hospital bed days can be saved with its use.

A rare late complication of traumatic diaphragmatic hernia repair.

We report a case of sudden cardiovascular collapse several weeks following surgical repair of a traumatic diaphragmatic hernia. The patient presented with features of circulatory shock without a clear diagnosis, therefore an urgent computed tomography scan of the chest and abdomen was undertaken, which revealed a pericardial effusion with evidence of cardiac tamponade. Ultrasound-guided needle pericardiocentesis with aspiration of blood from the pericardial sac in the Emergency Department provided an immediate response and her cardiac output improved. On review of the imaging, it is likely a surgically-placed permanent metallic fixation device, sitting near the pericardium, caused bleeding into the pericardial sac due to local trauma as a delayed postoperative complication.

Systematic reanalysis of genomic data improves quality of variant interpretation.

As genomic sequencing expands, so does our knowledge of the link between genetic variation and disease. Deeper catalogs of variant frequencies improve identification of benign variants, while sequencing affected individuals reveals disease-associated variation. Accumulation of human genetic data thus makes reanalysis a means to maximize the benefits of clinical sequencing. We implemented pipelines to systematically reassess sequencing data from 494 individuals with developmental disability. Reanalysis yielded pathogenic or likely pathogenic (P/LP) variants that were not initially reported in 23 individuals, 6 described here, comprising a 16% increase in P/LP yield. We also downgraded 3 LP and 6 variants of uncertain significance (VUS) due to updated population frequency data. The likelihood of identifying a new P/LP variant increased over time, as ~22% of individuals who did not receive a P/LP variant at their original analysis subsequently did after 3 years. We show here that reanalysis and data sharing increase the diagnostic yield and accuracy of clinical sequencing.

Laparoscopic and open inguinal hernia repair: Patient reported outcomes in the elderly from a single centre - A prospective cohort study.

BACKGROUND: With those over 65 making up over 16% of the UK's population, surgeons are counselling increasing numbers of elderly patients for hernia repair. Data is currently lacking comparing different repair methods of inguinal hernias in the elderly population with regards to patient reported outcomes. AIM: To compare open and laparoscopic hernia repair in patients >65 years old and those <65 years old with respect to patient reported outcomes. METHOD: As part of a quality assurance process patients receive a telephone consultation day 2 post procedure. This includes an optional survey with questions to quantify pain, general feeling, nausea, dizziness, drowsiness, satisfaction and vomiting since the operation. Patients were then classified into age ≥ 65 years or <65 years and subclassified into totally extraperitoneal (TEP) or open inguinal hernia repair (IHR). RESULTS: Data is presented from patients treated between January 2009 and August 2016, totalling those included 1167 of 2522 (55.5%). Only five patients (4.42%) reported moderate pain; in the >65 TEP group this was significantly lower (10.2% open IHR <65; 6.7% TEP <65; 12.8% open IHR >65). Patient satisfaction with the surgery was satisfied or very satisfied in all patients in all groups. CONCLUSION: Time off work is not an absolute appropriate measure of return to premorbid status with respect to the elderly as a substantial number of >65 year olds have retired. We therefore present this interesting insight into patient perceptions following hernia repair by age group. Overall patients over 65 can expect the same high levels of satisfaction and low levels of pain following either technique for inguinal hernia repair as younger patients.

Temporal artery biopsy in the diagnosis of giant cell arteritis: Does the end justify the means?

BACKGROUND: Early temporal artery biopsy is recommended in all patients with suspected cranial GCA (Giant Cell Arteritis) by the BSR (British Society of Rheumatology) and BHPR (British Health Professionals in Rheumatology) guidelines. This should be performed within one week ideally. AIM: To assess ACR (American College of Rheumatology) score at presentation and whether temporal artery biopsy result affects clinical management of the clinically suspected GCA patient. METHOD: Case records of all temporal artery biopsies performed within January 2012 until December 2014 were analysed for size and result of biopsy and this was correlated to clinical management following result. RESULTS: 129 temporal arteries were biopsied with a total of 17 positive biopsy results. 10 biopsy samples were insufficient to confirm or refute GCA. 8 patients within the biopsies negative for GCA had their prednisolone therapy stopped. 5 patients had unknown follow up, with the remainder (89, 87.3%) of the patients continued prednisolone management for treatment of GCA for at least 6 weeks. CONCLUSION: Overall 13.2% of our biopsies were positive for GCA and 87.3% of biopsy negative patients continued prednisolone therapy on clinical grounds. In the face of new diagnostic tests (high resolution MRI (Magnetic Resonance Imaging), colour duplex USS (Ultra Sound Scan) and PET (Positive Emission Topography) can we justify invasive surgery to all patients on histological grounds when the results may not alter management? Further investigation is needed directly comparing newer imaging modalities to histology.

Clinical thromboembolic detterrent stockings application: are thromboembolic detterrent stockings in practice matching manufacturers application guidelines.

BACKGROUND: Thromboembolic detterrent (TED) stockings have been shown to be effective in the reduction of thromboembolic events in post operative patients. These manufactured stockings create graduated compression from ankle to calf. AIM: To assess whether the manufacturers' recommendations for application were being met in a District general hospital setting and whether this achieved the desired gradient of compression. METHODS: We carried out pressure measurements on 100 legs in post-operative patients and recorded reasons for poorly fitting stockings. Pressure measurements were taken at standard positions around calf and ankle using a pre-calibrated subbandage pressure measuring device. RESULTS: About 20% of stockings were worn incorrectly by patients. Median pressure applied at the ankle was 13 mmHg (range, 6.5-18.5) compared to the manufacturers' intended compression of 18 mmHg. Only 14% of the stockings showed an acceptable gradation of reduced pressure between ankle and calf. About 23% of the stockings exerted a positive pressure at calf level compared to the ankle. CONCLUSION: Most TED stockings do not produce a standardised Siegel profile pressure gradient decrease from ankle to calf. This may be due in part to fluid changes after surgery in combination with the large variation in size of lower limbs. Our District general hospital utilises three of the six sizes of TED stocking, and remeasurement was not taking place every 24 h as per guidance. This as the result show not only negates the benefit of TED stockings but may also exert harm in terms of venous thromboembolism risk. This finding adds further weight to the argument of whether TED stockings may not be having the desired prophylactic effect and may even be resulting in harm in select cases.

Bioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.

PURPOSE: Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species. METHODS: Penclomedine was administered i.v. (200 mg/m2) and orally (250 mg/m2) in alternate sequences to patients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay. RESULTS: Penclomedine was detectable in the plasma of all patients within 1 h of oral penclomedine treatment and Cmax was reached within 1 to 4 h. Consistent with the hypothesis that an oral schedule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in Cmax values following oral administration (P=0.017). However the magnitude of this reduction was highly variable. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine ranged from 28% to 98% (median 73%). CONCLUSIONS: Oral penclomedine does produce systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.

Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet.

Paclitaxel is active in metastatic breast cancer. Combination studies have demonstrated complex interactions between paclitaxel and other cytotoxic agents, including sequence-dependent cytotoxic, toxicological, and pharmacological effects. The principal objectives of this study were to determine the maximum tolerated doses of paclitaxel (3-h infusion) and cyclophosphamide (1-h infusion) administered every 3 weeks with granulocyte colony-stimulating factor (Filgrastim) and to determine if the sequence-dependent toxicological effects that have previously been observed with this combination when paclitaxel was administered over 24 h were evident when paclitaxel was administered over 3 h. Fifteen women with metastatic breast cancer were treated. Starting doses were 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, with granulocyte colony-stimulating factor (5 micrograms/kg/day) given s.c. beginning 24 h after chemotherapy. Doses of both drugs were escalated in cohorts of at least four patients. The sequence of drug administration was alternated with each consecutive patient and with each subsequent course of therapy in each individual patient, enabling the evaluation of sequence-dependent toxicological and pharmacological effects. Severe myelosuppression was the principal dose-limiting toxicity for this regimen, precluding dose escalation above 200 mg/m2 paclitaxel and 1600 mg/m2 cyclophosphamide, the maximum tolerated dose for this combination on this schedule. As has been previously demonstrated with this combination, when paclitaxel is administered over 24 h, the hematopoietic toxicity was sequence dependent. Paired analysis of toxicity data using each patient as her own control indicated more severe hematological toxicity in courses in which paclitaxel was administered first. There was no evidence of sequence-dependent effects on the pharmacokinetics of these drugs that might account for this phenomenon. The impact of drug sequencing on toxicity should be considered in the further development of combination therapy containing alkylating agents and paclitaxel, when the latter is administered over 3 h.

Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.

Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function.

BACKGROUND: Topotecan, a topoisomerase I inhibitor that has demonstrated anticancer activity toward leukemias and solid tumors in clinical trials, is eliminated via hepatic and renal routes. However, dosing guidelines for the administration of topotecan to patients with impaired hepatic function have not yet been established. PURPOSE: We compared the maximum tolerated doses (MTDs), the toxic effects, and the pharmacokinetics and pharmacodynamics of topotecan in patients who had refractory, malignant, solid tumors and who either had or lacked hepatic injury. The potential role of three substrate markers of liver function (indocyanin green [ICG]-- a marker of hepatic blood flow; lorazepam--a substrate marker of hepatic glucuronidation; and antipyrine--a substrate marker for cytochrome P450 activity) in optimizing topotecan doses for patients with liver injury was also evaluated. METHODS: Twenty-one cancer patients, 14 of whom had hepatic injury due to metastatic disease, biliary obstruction, or cirrhosis, were treated with intravenously delivered courses of topotecan consisting of 0.5, 1.0, or 1.5 mg/m2 of drug per day for 5 days. Most patients received more than one course of treatment, with new courses initiated at 3-week intervals. Patient responses (evaluated by tumor measurements) and treatment-induced toxic effects were assessed. Prior to the initiation of topotecan treatment, patients were given intravenous injections of ICG, lorazepam, and antipyrine to determine the plasma pharmacokinetics of these compounds. The pharmacokinetics of topotecan (both the lactone and the carboxylate forms) were determined by analysis of plasma and urine samples collected on the first day of the first course of drug treatment. Scatter plots of area under the plasma concentration versus time curves in relation to percent decreases in either absolute neutrophil count or platelet count were used to explore the pharmacodynamics of topotecan. The Student's t test and the Mann-Whitney U test were used to compare pharmacokinetic parameters between patients with and without abnormal hepatic function. Correlations were assessed using the Spearman's rank correlation coefficient (rs). Reported P values are based on two-tailed tests of significance. RESULTS: Patients with hepatic injury tolerated topotecan doses up to 1.5 mg/m2, i.e., the MTD of this drug established in previous studies. The nature and severity of treatment-induced toxic effects and the pharmacokinetics of topotecan were similar in patients with and without liver injury. No differences were observed in the urinary excretion of topotecan between the two patient groups. Clearances of total topotecan and its lactone species correlated only with clearance of ICG (rs = .64, P = .004; and rs = .68, P = .0017, respectively). The pharmacodynamic effects of topotecan were not altered by liver dysfunction. CONCLUSIONS AND IMPLICATIONS: Cancer patients with hepatic injury can be treated with topotecan at a starting dose of 1.5 mg/m2, given daily for 5 days and administered every 3 weeks. Topotecan dose modifications do not appear to be required for patients with hepatic dysfunction and normal renal function.

Phase I and pharmacologic study of sequences of paclitaxel and cyclophosphamide supported by granulocyte colony-stimulating factor in women with previously treated metastatic breast cancer.

PURPOSE: Pacltaxel is active in metastatic breast cancer, but limited information is available on combinations of this agent with other cytotoxic agents. Study aims were to determine the maximum-tolerated doses (MTDs) of paclitaxel (24-hour infusion) and cyclophosphamide (1-hour infusion) administered every 21 days with granulocyte colony-stimulating factor (G-CSF, filgrastim) to determine the effect of drug sequence on toxicity and pharmacology and to evaluate the activity of this combination in women with anthracycline-resistant disease. PATIENTS AND METHODS: Thirty-seven women with metastatic breast cancer were treated. Starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2, with filgrastim 5 microG/kg/d subcutaneously beginning 24 hours after chemotherapy. Four patients were treated at each dose level. The sequence of drug administration was alternated between sequential patients, and with subsequent courses of therapy in each patient, to enable evaluation of effects of drug sequence on toxicity and pharmacology. Patients were treated every 21 days and disease status was reevaluated every two courses. RESULTS: Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 is the MTD for this combination on this schedule. The hematopoietic toxicity of therapy was sequence-dependent. Paired analysis of toxicity data indicated more severe toxicity in courses in which paclitaxel was administered first. Sequence-dependent pharmacologic effects did not account for this phenomenon. Responses were noted in 29% of patients with anthracycline-resistant disease. CONCLUSION: Paclitaxel 200 mg/m2 and cyclophosphamide 1,250 mg/m2 with filgrastim administered every 21 days are the doses recommended for further study.

The role of protein kinase C in the initial events of platelet activation by thrombin assessed with a selective inhibitor.

The role of protein kinase C (PKC) in platelet activation by thrombin was assessed using a PKC inhibitor Ro 31-7549/001 (R2) which, in vitro, shows more selectivity for PKC than other kinase inhibitors. During early (1.5 s) thrombin-induced platelet activation, when phosphorylation of 47 kDa protein (pleckstrin) and myosin light chain by PKC and myosin light chain kinase, respectively, are most readily differentiated, R2 suppressed phosphorylation of pleckstrin more effectively than myosin light chain. R2-inhibited dense granule secretion (measured 0-10 s using quenched-flow techniques) with a dose dependency similar to that for inhibition of pleckstrin phosphorylation, supporting a role for PKC in this process. R2, at 0.5 microM inhibited 47 kDa protein phosphorylation by more than 60%, but had only minimal effects on the kinetics (0-3s) of ADP-induced primary aggregation. At this same concentration, R2 potentiated the thrombin-induced rise in cytosolic calcium during early (0-15 s) activation as measured in the presence or absence of external calcium. These data support the hypothesis that activation of PKC during early platelet function helps regulate cytosolic calcium levels by limiting calcium release into the cytosol.

Activation of the vascular system: a main mediator of periodontal fiber remodeling in orthodontic tooth movement.

The behavior and role of blood vessels and blood-borne cells in the process of the remodeling of the periodontal ligament (PDL) incident to experimental tooth movement was studied in rats. Particular interest was focused on areas of tension and of pressure with frontal bone resorption but without overt hyalinization. An increase of vascular activity occurred in the above mentioned situations. Extensive breakdown of collagen was observed in pressure areas with frontal resorption and in areas of tension concomitant with vascular invasion. Two patterns of fiber and bone remodeling were seen in areas of tension: intense vascular activity within the periodontal membrane and intense vascular activity inside the alveolar bone. Macrophages occurred consistently near blood vessels both in areas of tension and in areas of resorption. These are multipotent cells that obviously influence the remodeling process.