First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

Efficacy of model-based iterative reconstruction technique in non-enhanced CT of the renal tracts for ureteric calculi.

The purpose of this study was to assess the efficacy of model-based iterative reconstruction (MBIR), statistical iterative reconstruction (SIR), and filtered back projection (FBP) image reconstruction algorithms in the delineation of ureters and overall image quality on non-enhanced computed tomography of the renal tracts (NECT-KUB). This was a prospective study of 40 adult patients who underwent NECT-KUB for investigation of ureteric colic. Images were reconstructed using FBP, SIR, and MBIR techniques and individually and randomly assessed by two blinded radiologists. Parameters measured were overall image quality, presence of ureteric calculus, presence of hydronephrosis or hydroureters, image quality of each ureteric segment, total length of ureters unable to be visualized, attenuation values of image noise, and retroperitoneal fat content for each patient. There were no diagnostic discrepancies between image reconstruction modalities for urolithiasis. Overall image qualities and for each ureteric segment were superior using MBIR (67.5 % rated as 'Good to Excellent' vs. 25 % in SIR and 2.5 % in FBP). The lengths of non-visualized ureteric segments were shortest using MBIR (55.0 % measured 'less than 5 cm' vs. ASIR 33.8 % and FBP 10 %). MBIR was able to reduce overall image noise by up to 49.36 % over SIR and 71.02 % over FBP. MBIR technique improves overall image quality and visualization of ureters over FBP and SIR.

Synovial haemangioma of the knee joint: an unusual cause of knee pain in a 14-month old girl.

We report a histologically proven case of synovial haemangioma of the knee in a 14-month old girl who presented to the emergency department with an acute 1-day history of refusing to weight-bear on the right leg and a preceding 3-week history of a right knee lump. Physical examination revealed a non-tender, soft lump over the lateral infrapatellar region. Radiographs revealed a poorly defined soft tissue density over the infrapatellar fat pad and a suprapatellar joint effusion. Ultrasound was used to confirm the presence of a vascular soft tissue mass compatible with a synovial haemangioma within the infrapatellar fat pad which showed both intra-articular and extra-articular extension. There was good correlation of the ultrasound findings with magnetic resonance imaging (MRI), highlighting the potential clinical utility of ultrasound as an alternative imaging modality in establishing the pre-operative diagnosis and extent of a synovial haemangioma about the knee joint.

Extrapancreatic findings of IgG4-related disease.

IgG4-related disease is a systemic fibro-inflammatory condition, which includes autoimmune pancreatitis as part of the disease spectrum. Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis. Recognizing the wide spectrum of extrapancreatic manifestations of IgG4-related disease coupled with a high clinical index of suspicion will allow for an accurate and timely diagnosis to be made, thus avoiding unnecessary invasive procedures and ensuring that early effective corticosteroid therapy is commenced. This review aims to serve as a concise reference tool for both clinicians and radiologists in the diagnosis of extrapancreatic IgG4-related disease.

A physicochemical investigation of membrane fouling in cold microfiltration of skim milk.

The main challenge in microfiltration (MF) is membrane fouling, which leads to a significant decline in permeate flux and a change in membrane selectivity over time. This work aims to elucidate the mechanisms of membrane fouling in cold MF of skim milk by identifying and quantifying the proteins and minerals involved in external and internal membrane fouling. Microfiltration was conducted using a 1.4-µm ceramic membrane, at a temperature of 6±1°C, cross-flow velocity of 6m/s, and transmembrane pressure of 159kPa, for 90min. Internal and external foulants were extracted from a ceramic membrane both after a brief contact between the membrane and skim milk, to evaluate instantaneous adsorption of foulants, and after MF. Four foulant streams were collected: weakly attached external foulants, weakly attached internal foulants, strongly attached external foulants, and strongly attached internal foulants. Liquid chromatography coupled with tandem mass spectrometry analysis showed that all major milk proteins were present in all foulant streams. Proteins did appear to be the major cause of membrane fouling. Proteomics analysis of the foulants indicated elevated levels of serum proteins as compared with milk in the foulant fractions collected from the adsorption study. Caseins were preferentially introduced into the fouling layer during MF, when transmembrane pressure was applied, as confirmed both by proteomics and mineral analyses. The knowledge generated in this study advances the understanding of fouling mechanisms in cold MF of skim milk and can be used to identify solutions for minimizing membrane fouling and increasing the efficiency of milk MF.

Emphysematous cystitis: an incidental finding with varying outcomes.

Emphysematous cystitis (EC) is a rare severe urinary tract infection characterised by pockets of air in and around the urinary bladder wall caused by gas-forming organisms. Common predisposing factors are chronic infection, immunosuppression, diabetes and neurogenic bladder. The presentation may vary from mild illness to severe life-threatening cystitis. We report two cases of incidental detection of EC diagnosed on imaging for the evaluation of unrelated symptoms. Although asymptomatic, this lethal disease still warrants prompt recognition and treatment with broad-spectrum antibiotics and urinary bladder drainage to prevent severe morbidity and mortality.

Service evaluation of radiographer-led vetting and protocoling of Computed Tomography (CT) scan requests in a Singapore public healthcare institution.

INTRODUCTION: A service improvement project involving the vetting and protocoling of Computed Tomography (CT) scan requests by qualified CT radiographers was initiated in 2018. AIM: This study provides a comprehensive evaluation of how a radiographer-led initiative aims to ensure that the CT scan requests received by the Radiology department are clinically appropriate, which in turn will reduce interruptions to the interpretation and reporting of imaging examinations by radiologists, who might otherwise be required to attend to clinically inappropriate and wrongly protocolled CT scan requests. METHOD: Outpatient CT scan requests received from July to October 2021 were vetted and protocolled by a qualified CT-trained radiographer for parameters which included the appropriateness of the clinical indication, adequacy of patient preparation for the scan, as well as the suitability of the requested examination protocol pertaining to the need for contrast media, multiple contrast-enhanced imaging phases, and the appropriateness of the scan range. RESULTS: Poor patient preparation and insufficient or inaccurate clinical indications were the most common findings during the vetting process (71%). Out of the 64 CT scan requests with protocol errors, 77% were attributed to contrast media type errors. The odds of incorrect CT scan requests increased with the requesting clinician's rank, while there was no such significant correlation with the clinical specialty of the requesting clinician or the CT scan type. CONCLUSION: The meticulous vetting of imaging requests helps to ensure that limited imaging hardware resources are allocated to more clinically appropriate cases, correct protocols are applied to requested imaging scans, and that patients undergoing imaging are adequately prepared, thereby enhancing overall patient care. IMPLICATIONS FOR PRACTICE: Vetting of imaging requests by radiographers, who are capable to make appropriate clinical decisions related to their enhanced level of practice ensures patient safety and optimisation of Radiology resources.

Recommendations for the use of next-generation sequencing in patients with metastatic cancer in the Asia-Pacific region: a report from the APODDC working group.

INTRODUCTION: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers. METHODS: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration. RESULTS: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC. CONCLUSION: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.

Laryngeal dysplasia: a 10-year review of rates of progression to invasive carcinoma and treatment-specific outcomes in a regional ENT department in Northern Ireland.

BACKGROUND: Laryngeal dysplasia represents a complex pre-malignant condition characterised by a spectrum of mucosal changes, with a reported malignant transformation rate from dysplasia to invasive carcinoma of 14.0 per cent. OBJECTIVE: To identify whether increasing glottic dysplasia severity is associated with higher local malignant transformation rates or adverse clinical outcomes. METHODS: This retrospective cohort study identified 125 patients with any histopathological grade of glottic dysplasia over a 10-year period who were followed up for a standardised 10-year period. RESULTS: The malignant transformation rate was 21.8 per cent over 10 years, demonstrating a statistically significant greater risk with increasing dysplasia severity. The mean time to transformation was 52 months, with time to transformation statistically associated with increasing dysplasia severity. Rapid progression to carcinoma within 12 months occurred in 40 per cent of cases, and 58 per cent of subsequently diagnosed laryngeal squamous cell carcinomas were tumour stage T1. CONCLUSION: Laryngeal dysplasia carries a significant malignant potential, appearing greatest within 12 months of diagnosis and with increasing severity of dysplasia.

Short-term Total Hepatic Vascular Exclusion in Difficult Caudate Lobe Dissection in Living-donor Liver Transplantation Recipients.

BACKGROUND: Recipient hepatectomy can be complicated by severe bleeding during caudate lobe dissection in living-donor liver transplantation (LDLT), especially when the inferior vena cava is encased or with dense adhesions from prior interventions. Total hepatic vascular exclusion (TVE) including total hepatic inflow (Pringle maneuver) and occlusion of supra- and infra-hepatic inferior vena cava during the partial hepatectomy has been studied well, but it has not been mentioned regarding recipient hepatectomy in LDLT. The aim of this study is to evaluate hemodynamic impact and surgical outcome by using the technique of TVE in LDLT. METHODS: From April 2010 to June 2010, 30 consecutive LDLT recipients at Kaohsiung Chang Gung Memorial Hospital with TVE (TVE group, n = 14) or without TVE (non-TVE group, n = 16) for the caudate lobe dissection were analyzed retrospectively. RESULTS: The TVE group had a mean decrease in systolic blood pressure and cardiac index of 21% and 41% during caudate dissection in recipient hepatectomy, respectively. The TVE group had shorter time for caudate mobilization and less blood loss compared with the non-TVE group (3904 mL vs. 5650 mL, P = .461). Two patients in the non-TVE group were shifted to TVE as a salvage procedure to control bleeding. Three patients in the non-TVE group underwent relaparotomy for homeostasis. CONCLUSIONS: Short-term TVE is a technically feasible procedure and should be considered during recipient hepatectomy with difficult caudate lobe dissection in LDLT to create a bloodless surgical field. Most patients tolerated the TVE without hemodynamic impact under anesthetic management.

Identification and partial purification of GTPase-activating proteins from yeast and mammalian cells that preferentially act on Ypt1/Rab1 proteins.

Two GTPase-activating proteins of apparent molecular mass of 100 kDa and 30 kDa have been partially purified from porcine liver cytosol using mammalian Ypt1/Rab1 protein as substrate. Both proteins act most efficiently on Ypt1/Rab1p, but are inactive with H-Ras p21. From the budding yeast Saccharomyces cerevisiae, a cytosolic 40 kDa yptGAP was partially purified. It accelerates the intrinsic GTPase activity of wild-type Ypt1p but not of H-Ras p21 or a mutant ypt1p with an amino acid substitution of the effector domain which renders the protein functionally inactive in yeast cells.

Fibroblast mitogens in swine milk include an epidermal growth factor-related peptide.

Mammary secretions obtained from lactating sows can support in vitro growth of mammalian cells when added to Dulbecco's Modified Eagle Medium. In order to identify the growth factors present within, sow milk was fractionated and fractions having mitogenic activity were identified by their ability to stimulate DNA synthesis in density-arrested, quiescent (murine) AKR-2B fibroblasts. A prominent mitogenic activity (peak III) was observed in the 3,000-5,000 Mr range. This activity was partially purified by (1) preparative Sephadex G-200 chromatography, (2) gel-filtration in Sephadex G-50 columns and (3) DEAE-cellulose anion exchange chromatography. The last step resolved peak III activity into at least two distinct components. One component was highly-purified by use of reverse-phase high-performance liquid chromatography (RP-HPLC). This activity was identified as an epidermal growth factor (EGF)-related peptide based on its inactivation by polyclonal antibody (IgG fraction) specific for murine EGF (mEGF) and proteolytic agents. The other component is unrelated to EGF. Using cloned mEGF cDNA as a probe, the presence of EGF-related mRNA in lactating mammary tissues and newborn pig small intestine was also demonstrated. These factors may contribute to the preferential growth of gastrointestinal tissues in neonatal pigs.

Lymphographic abnormalities in patients with Brugia malayi filariasis and "idiopathic tropical eosinophilia".

Peripheral lymphography was carried out in 17 patients with elephantiasis and microfilaremia (Brugia malayi) and the findings compared to ten patients with "idiopathic tropical eosinophilia." There were extensive changes in peripheral lymphatic and regional nodal architecture in each group suggesting that "occult filariasis" is the cause of idiopathic tropical eosinophilia.

CT features of parotid gland oncocytomas: a study of 10 cases and literature review.

Oncocytomas of the salivary glands are rare benign epithelial tumors which occur most commonly in the parotid gland. The aim of our study was to characterize the clinical-radiologic-pathologic spectrum of parotid oncocytomas in a series of 10 cases seen in our institution between January 2003 and November 2008. The CT features of parotid oncocytomas in the largest imaging series of this rare but important benign lesion include a well-defined enhancing tumor with a "deformable" appearance when large, and a non-enhancing curvilinear cleft or cystic component. These CT findings are potentially helpful in distinguishing these benign lesions from other parotid tumors in clinical scenarios that preclude surgical resection or when biopsy results are non-diagnostic. Further studies are advocated to validate the specificity and positive predictive value of these imaging features.

Obturator hernia: diagnosis and treatment in the modern era.

INTRODUCTION: Obturator hernia is a rare variety of abdominal hernia that nonetheless is a significant cause of morbidity and mortality, especially in the elderly age group. This article aimed to review the diagnosis and management of obturator hernia by describing the anatomy, clinical presentation, predisposing factors, diagnostic modalities and management in the modern era. METHODS: We managed six cases of obturator hernia between 2003 and 2006. Five out of six cases were diagnosed by a preoperative computed tomography (CT) and the sixth case was diagnosed by ultrasonography. All except one were managed by an exploratory laparotomy and repair of the hernia, and one was treated with laparoscopic repair. RESULTS: Correct preoperative diagnosis was made in five out of five (100 percent) patients by clinical signs and CT of the abdomen and pelvis, and the sixth patient was operated on the basis of an ultrasonographical diagnosis and strong clinical suspicion. CONCLUSION: We conclude that the rapid evaluation by CT of the abdomen and pelvis and surgical intervention are possible, thereby reducing the morbidity and mortality of patients with obturator hernia. An algorithm for the management of obturator hernia is proposed.

Profile changes following orthodontic correction of bimaxillary protrusion with a preadjusted edgewise appliance.

This study aimed to determine the changes in soft tissue and skeletal profiles following orthodontic correction of bimaxillary protrusion in 50 Chinese adult patients. Treatment involved extractions of four premolars and use of the preadjusted edgewise appliance. The average treatment time was 2.2 years. Cephalometric analysis was carried out on pretreatment and posttreatment cephalograms. The result of treatment was a more harmonious soft tissue profile; with a less acute nasolabial angle (following a 10.55-degree change), 2.75- and 2.09-mm reductions in upper and lower lip protrusions, respectively, and a 3.41-mm decrease in interlabial gap. Effects on dental relationships included a 0.90-mm reduction in incisal show, a reduction of overbite, and an improvement in the inclination of maxillary and mandibular incisors. Therefore, orthodontic correction of bimaxillary protrusion achieved favorable soft tissue changes without causing undesirable effects on the underlying hard tissues.

A yeast GTPase-activating protein that interacts specifically with a member of the Ypt/Rab family.

Members of the Ras superfamily of GTP-binding proteins are involved in a variety of cellular processes, including signal transduction, cytoskeletal organization and protein transport. GTP-binding proteins of the Ypt/Rab family direct vesicular protein transport in the secretory and endocytic pathways in the yeast Saccharomyces cerevisiae (Ypt proteins) and in mammalian systems (Rab proteins). The cellular activity of monomeric GTP-binding proteins is influenced by proteins that regulate GDP/GTP exchange and GTP hydrolysis. GTPase-activating proteins (GAPs) can increase the slow intrinsic GTPase activity of GTP-binding proteins by several orders of magnitude. As GAPs modulate the activity of GTP-binding proteins, they are thought to give a biochemical handle on the functioning of Ypt/Rab proteins in transport vesicle budding and docking or fusion at donor and acceptor membranes. We report here the first cloned GTPase-activating protein for the Ypt/Rab protein family. The gene, GYP6 (GAP of Ypt6 protein), encodes a protein of 458 amino acids which is highly specific for the Ypt6 protein and shows little or no cross-reactivity with other Ypt/Rab family members or with H-Ras p21.

Mutational analysis of the putative effector domain of the GTP-binding Ypt1 protein in yeast suggests specific regulation by a novel GAP activity.

Ypt1p of Saccharomyces cerevisiae is a ras-related GTP-binding protein that fulfils an essential function in intracellular protein transport between the endoplasmic reticulum (ER) and the Golgi complex. Ypt proteins from yeasts and mammals that share an identical sequence in the region analogous to the ras effector domain are functionally interchangeable. We analyzed the function of the putative effector domain of yeast Ypt1p (amino acids 37-45) using site-directed mutagenesis and gene replacement. Four out of six point mutations leading to single amino acid substitutions (Y37F, S39A, T40S and V43E) did not cause any particular phenotype. ypt1(I41M) mutants were inviable whereas ypt1(D44N) mutant cells were temperature sensitive at 37 degrees C and accumulated core-glycosylated invertase at the nonpermissive temperature. This mutant also accumulated ER and small vesicles both at 25 degrees C and 37 degrees C. From porcine liver we identified and partially purified a GTPase-activating protein (yptGAP) that is similarly active with mouse ypt1p/rab1p and yeast Ypt1p but is inactive with H-ras protein as a substrate. Although none of the yeast ypt1 mutant proteins were significantly impaired in their ability to bind GTP, purified ypt1(D44N)p responded only partially and ypt1(I41M)p did not respond at all, to yptGAP. Thus we suggest that analogous to rasGAP/H-ras p21 interaction in mammalian cells, yptGAP is an intracellular target of Ypt1p, interacting with the effector domain and regulating its GTPase activity, and that this interaction is required for the functioning of yeast Ypt1p in intracellular protein transport.