Time toxicity associated with early phase clinical trial participation.

BACKGROUND: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. PATIENTS AND METHODS: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. RESULTS: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. CONCLUSIONS: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

The influence of surface coatings on the toxicity of silver nanoparticle in rainbow trout.

Silver nanoparticles (nAg) are often produced with different coatings that could influence bioavailability and toxicity in aquatic organisms. The purpose of this study was to examine the influence of 4 surface coatings of nAg of the same core size towards bioavailability and toxicity in juvenile rainbow trout (Oncorhynchus mykiss). Juveniles were exposed to 50 µg/L of 50 nm diameter nAg for 96 h at 15 °C with the following coatings: branched polyethylenimine (bPEI), citrate, polyvinylpyrrolidone (PVP) and silicate (Si). The data revealed that the coatings influenced hepatic Ag loadings in the following trend PVP > citrate > bPEI and Si with estimated bioavailability factors of 28, 18, 6 and 2 L/kg respectively. Hepatic Ag levels were significantly associated with DNA damage and inflammation as determined by arachidonate cyclooxygenase activity. The bPEI and citrate-coated nAg consistently produced the observed effects above in addition to increased mitochondrial electron transport activity and glutathione S-transferase activity. The absence of metallothionein and lipid peroxidation suggests that mechanisms other than the liberation of Ag+ were at play. In conclusion, surface coatings were shown to significantly influence bioavailability and toxic properties of nAg to rainbow trout juveniles.

Pelvic organ prolapse: An unusual cause of small bowel obstruction.

We present the rare case of a small bowel obstruction secondary to pelvic organ prolapse (POP). A 77-year-old female presented with four days of abdominal pain, nausea, and vomiting. She had a history of abdominal hysterectomy with bilateral salpingo-opherectomy and a mildly symptomatic cystocele. She was found to have an enterocele causing small bowel obstruction. The enterocele was manually reduced and subsequently managed non-operatively with a pessary. Prior case reports of small bowel obstructions secondary to POP required emergent surgical intervention. Post-menopausal women should be asked about symptoms or presence of pelvic organ prolapse and in the correct patient population, pelvic examination can be important for diagnosis and treatment of small bowel obstruction. If the enterocele is manually reduced non-operative management can be safe and effective.

The Risk of Post-operative Complications in Super-Super Obesity Compared to Super Obesity in Accredited Bariatric Surgery Centers.

BACKGROUND: The prevalence of super obesity (SO, BMI > 50.0 kg/m2) and super-super obesity (SSO, BMI > 60 kg/m2) is increasing. Current data are limited and discrepant on the relationship between SSO and post-bariatric surgery complication risk. We hypothesized there would be increased complications for both laparoscopic Roux-en-Y gastric bypass (LRYGB) and sleeve gastrectomy (LSG) in SSO compared to SO, but the relative risk (RR) would support the use of LSG in SSO patients. METHODS: Metabolic and Bariatric Surgery Accreditation and Quality Improvement 2016 data were queried for SO and SSO patients undergoing LRYGB or LSG. Thirty-day post-operative complications were calculated. Univariate analyses were performed with a χ2 or Student's t test. Comparisons between multiple groups were performed using a one-way ANOVA. Statistical significance was defined as p < 0.05. RESULTS: A total of 5723 patients with SSO and 24,940 with SO were included for analysis. Patients with SSO had more co-morbidities. Patients with SSO had a higher likelihood of complications compared to SO patients (15.2% vs 12.6%, p < 0.0005). SSO patients, and specifically SSO RYGB, were significantly more likely to experience an unplanned intubation, prolonged ventilation, and unplanned ICU admission. Compared to SO LRYGB, the RR for complications in SSO LRYGB and LGS were 1.19 and 0.76 respectively (p < 0.0005). DISCUSSION: We found SSO patients had increased 30-day post-operative complications after both LRYGB and LSG compared to SO patients. LSG may be the preferred procedure for this high-risk population.

Delivery of lethal dsRNAs in insect diets by branched amphiphilic peptide capsules.

Development of new and specific insect pest management methods is critical for overcoming pesticide resistance and collateral off-target killings. Gene silencing by feeding dsRNA to insects shows promise in this area. Here we described the use of a peptide nano-material, branched amphiphilic peptide capsules (BAPCs), that facilitates cellular uptake of dsRNA by insects through feeding. The insect diets included dsRNA with and without complexation with BAPCs. The selected insect species come from two different orders with different feeding mechanisms: Tribolium castaneum and Acyrthosiphon pisum. The gene transcripts tested (BiP and Armet) are part of the unfolded protein response (UPR) and suppressing their translation resulted in lethality. For Acyrthosiphon pisum, ingestion of BiP-dsRNA associated with BAPCs led to the premature death of the aphids (t1/2=4-5days) compared to ingestion of the same amounts of free BiP-dsRNA (t1/2=11-12days). Tribolium castaneum was effectively killed using a combination of BiP-dsRNA and Armet-dsRNA complexed with BAPCs; most dying as larvae or during eclosion (~75%). Feeding dsRNA alone resulted in fewer deaths (~30%). The results show that complexation of dsRNA with BAPCs enhanced the oral delivery of dsRNA over dsRNA alone.

Triple-Negative Breast Cancer: Who Should Receive Neoadjuvant Chemotherapy?

Progress in the treatment of triple-negative breast cancer remains an important challenge. Given the aggressive biology and high risk of distant recurrence, systemic chemotherapy is warranted in most patients. Neaodjuvant chemotherapy benefits patients with locally advanced disease by downsizing the tumor and increasing the probability of breast-conserving surgery. Clinical and pathologic responses provide important prognostic information, which makes neoadjuvant therapy an attractive approach for all patients with triple-negative breast cancer. Clinical research in the neoadjuvant setting is focused on improvement in pathologic complete response rates and outcomes of patients with residual disease.

Gene delivery and immunomodulatory effects of plasmid DNA associated with Branched Amphiphilic Peptide Capsules.

We recently reported on a new class of branched amphiphilic peptides that associate with double stranded DNA and promote in vitro transfection of eukaryotic cells. In the present study, we tested a different formulation in which plasmid DNA associates with the surface of preformed 20-30nm cationic capsules formed through the self-assembly of the two branched amphiphilic peptides. Under these conditions, the negatively charged DNA interacts with the cationic surface of the Branched Amphiphilic Peptide Capsules (BAPCs) through numerous electrostatic interactions generating peptide-DNA complexes with sizes ranging from 50 to 250nm. The BAPCs-DNA nanoparticles are capable of delivering plasmid DNA of different size into cells in culture, yielding high transfection rates and minimal cytotoxicity. Furthermore, BAPCs were tested for in vivo delivery of a DNA vaccine previously designed to activate immune responses and capable of controlling tumors induced by type 16 human papilloma virus (HPV-16). The BAPCs-DNA nanoparticles enhanced the vaccine-induced antitumor protection and promoted activation of murine dendritic cells without significant toxic effects. These results indicate that branched amphiphilic oligo-peptides nanoparticles represent a new and promising nonviral DNA/gene delivery approach endowing immunomodulatory properties for DNA vaccines.

Patient-reported outcomes in routine cancer clinical practice: a scoping review of use, impact on health outcomes, and implementation factors.

BACKGROUND: This review focused on the identification of patient-reported outcome measures (PROMs) used in routine cancer clinical practice, the impact on patient, provider, and system outcomes, and the implementation factors influencing uptake. METHODS: A scoping review of the published health literature was conducted using empirical databases, namely, Ovid Medline (2003 to September 2013), CINAHL (2003-2013) and PsycINFO (2003-2013). Scoping reviews are systematic literature reviews in a broad topic area that provide relevant and quantified results about the knowledge available on a particular topic and aim to rapidly map and synthesize the evidence to emphasize what is known. RESULTS: From a total of 2447 unique publications, 30 articles that met eligibility criteria were reviewed. PRO use appears to be acceptable to patients, enables earlier detection of symptoms and may improve communication between clinicians and patients. However, the impact of routine PROMs collection on health outcomes is less clear and high-quality research is still warranted. CONCLUSION: PROMs use in routine cancer clinical practice is growing with improvements on essential care processes shown but a number of implementation barriers must still be addressed. The lack of standardization in PROMs used in cancer organizations may make it difficult to use these data for quality monitoring in the future.

Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome.

Increased access to combination antiretroviral therapy in areas co-endemic for tuberculosis (TB) and HIV-1 infection is associated with an increased incidence of immune reconstitution inflammatory syndrome (TB-IRIS) whose cause is poorly understood. A case-control analysis of pro- and anti-inflammatory cytokines in TB-IRIS patients sampled at clinical presentation, and similar control patients with HIV-TB prescribed combined antiretroviral therapy who did not develop TB-IRIS. Peripheral blood mononuclear cells were cultured in the presence or absence of heat-killed Mycobacterium tuberculosis for 6 and 24 h. Stimulation with M. tuberculosis increased the abundance of many cytokine transcripts with interleukin (IL)-1ß, IL-5, IL-6, IL-10, IL-13, IL-17A, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF) being greater in stimulated TB-IRIS cultures. Analysis of the corresponding proteins in culture supernatants, revealed increased IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p40, IFN-γ, GM-CSF and TNF in TB-IRIS cultures. In serum, higher concentrations of TNF, IL-6, and IFN-γ were observed in TB-IRIS patients. Serum IL-6 and TNF decreased during prednisone therapy in TB-IRIS patients. These data suggest that cytokine release contributes to pathology in TB-IRIS. IL-6 and TNF were consistently elevated and decreased in serum during corticosteroid therapy. Specific blockade of these cytokines may be rational approach to immunomodulation in TB-IRIS.

Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk.

BACKGROUND AND AIMS: The risk of colorectal cancer is increased in ulcerative colitis (UC). Patients with UC have diverse colonoscopic appearances. Determining colonoscopic markers for cancer risk could allow patient risk stratification. PATIENTS AND METHODS: Following on from an earlier study which demonstrated a correlation between inflammation severity and neoplasia risk, a case control study was performed to look for colonoscopic markers of colorectal neoplasia risk in UC. Each patient with neoplasia detected between 1988 and 2002 was matched with two non-dysplastic colitic controls. Data were collected on post-inflammatory polyps, scarring, strictures, backwash ileitis, a shortened, tubular, or featureless colon, severe inflammation, and normal looking surveillance colonoscopies. RESULTS: Cases (n = 68) and controls (n = 136) were well matched. On univariate analysis, cases were significantly more likely to have post-inflammatory polyps (odds ratio (OR) 2.14 (95% confidence interval 1.24-3.70)), strictures (OR 4.22; 1.08-15.54), shortened colons (OR 10.0; 1.17-85.6), tubular colons (OR 2.03; 1.00-4.08), or segments of severe inflammation (OR 3.38; 1.41-10.13), and less likely to have had a macroscopically normal looking colonoscopy (OR 0.40; 0.21-0.74). After multivariate analysis, a macroscopically normal looking colonoscopy (OR 0.38; 0.19-0.73), post-inflammatory polyps (2.29; 1.28-4.11), and strictures (4.62; 1.03-20.8) remained significant. The five year risk of colorectal cancer following a normal looking colonoscopy was no different from that of matched general population controls. CONCLUSIONS: Macroscopic colonoscopic features help predict neoplasia risk in UC. Features of previous/ongoing inflammation signify an increased risk. A macroscopically normal looking colonoscopy returns the cancer risk to that of the general population: it should be possible to reduce surveillance frequency to five years in this cohort.

Macaque dendritic cells infected with SIV-recombinant canarypox ex vivo induce SIV-specific immune responses in vivo.

Dendritic cells (DCs) infected with recombinant avipox vectors express the introduced genes and activate antigen-specific T cells. DCs exhibit distinct differentiation-dependent immune functions. Moreover, immature DCs are readily infected by canarypox vectors, but undergo tumor necrosis factor (TNF)-alpha-dependent death, while fewer mature DCs get infected and resist dying. A pilot study was performed using the rhesus macaque system to explore whether immature and mature DCs infected with SIV-recombinant canarypox (vCP180) ex vivo could induce primary virus-specific immune responses in vivo. After subcutaneous (sc) reinjection, functional monocyte-derived DCs migrated to lymph nodes (LNs) within 1-2 days and primed T cells in vivo. This was observed by monitoring dye-labeled DCs in the draining LNs and tetanus toxoid (TT)-specific T cell responses after injection of TT-loaded DCs. DCs from simian immunodeficiency virus (SIV)-naïve rhesus macaques were infected with vCP180 (SIVmac142 gag, pol, and env genes), and sc reinjected into donor animals. Low-level SIV-specific T cell proliferation, but little if any interferon (IFN)-gamma production was detected. DCs pulsed with vCP180 in combination with TT and keyhole limpet hemocyanin (KLH) (to activate additional T cells and provide "helper" cytokines) induced SIV-, TT-, and KLH-specific T cell responses, including IFN-gamma responses not seen when vCP180-carrying DCs were used alone. Interleukin (IL)-10 and low-level antibody responses were also observed. This pilot study provides the proof of principle that sc injected ex vivo SIV-recombinant canarypox-infected DCs safely induce low-level SIV-specific immune responses in vivo.

Histological categorisation of fibrotic cancer stroma in advanced rectal cancer.

BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development--namely, that a desmoplastic reaction can favour either the host or the tumour--it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. METHODS: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. RESULTS: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.

Leg weakness is a complication of ilio-inguinal nerve block in children.

BACKGROUND: Ilio-inguinal nerve block is commonly used in children to provide analgesia after surgery in the groin. Several case reports and clinical studies have described leg weakness after this technique and suggest that it may caused by inadvertent femoral nerve block. No prospective studies describing the incidence of this complication have been published. METHODS: We carried out a prospective, observational study to find out how many children had leg weakness after ilio-inguinal nerve block. We studied 200 children having day-case surgery in the groin under a general anaesthetic with an ilio-inguinal nerve block. All children performed a simple leg-raising test with each leg before induction of general anaesthesia with a standardized ilio-inguinal nerve block on the side of surgery. When the child was awake and comfortable after surgery, they repeated the leg-raising test. RESULTS: Sixteen of 182 children (8.8%) had leg weakness after surgery on the side of the nerve block only, as detected by a leg-raising test. CONCLUSIONS: Leg weakness consistent with a femoral nerve block occurs after ilio-inguinal nerve block in approximately one in nine children.

The clinical course of fistulating Crohn's disease.

AIM: To determine the clinical characteristics, management and outcome of Crohn's fistulas from the time of first presentation. METHODS: Patients treated for fistulas 6 years previously were assessed for disease demographics, fistula characteristics and treatment from first presentation to final follow-up. RESULTS: Eighty-seven patients with active Crohn's fistulas were evaluated. The median age was 35 years and the median duration of Crohn's disease was 8 years at study entry. Disease was ileo-colonic or colonic in 85%, and 65% had rectal involvement. A single fistula was present in one-third and multiple fistulas in two-thirds; 65% of fistulas were perianal; 80% of fistulas were complex. After a median follow-up from the last treatment of 5.9 years, 68% of patients showed healing of all fistulas, 18% showed healing of some fistulas and 14% showed no healing of fistulas. The fistula site did not influence healing. Perianal and recto-vaginal fistulas took a median of 2.6 years to heal. Half of the complex fistulas required a stoma, resection or proctectomy. CONCLUSIONS: Healing is usually achieved. However, morbidity is great and healing is slow. Proctectomy is required in one-fifth of patients, and perineal healing is often slow. Defining the perianal fistula anatomy as complex or simple determines the likelihood of healing and the type of surgical approach required.

Salvage abdominal surgery in patients with a retained rectal stump after restorative proctocolectomy and stapled anastomosis.

BACKGROUND: The introduction of surgical stapling instruments has widened the use of restorative proctocolectomy. Too high a distal transection of the rectum can, however, produce a retained rectal stump, which may cause symptoms. A study of the operative and functional data in a consecutive series of patients undergoing salvage surgery for retained rectal stump was undertaken. METHODS: Twenty-five patients referred between January 1990 and September 2000 for pouch dysfunction were identified as having a retained rectal stump. Twenty-two underwent abdominoanal revision. The hospital notes were reviewed and function was assessed during outpatient visits, by postal questionnaire and by telephone interview. RESULTS: Median operating time was 225 (range 170-340) min and median hospital stay was 15 (range 8-48) days. There was no operative death. Five pouches were excised. Seventeen patients were available for functional assessment. Median follow-up was 22.5 (range 4-114) months. Median 24-h frequency before and after operation was 12 (range 4-20) and 6 (range 3-12) respectively, and median night-time frequency was 4 (range 0-8) and 0.5 (range 0-4) respectively. Fifteen patients reported marked subjective improvement in pouch function and quality of life. CONCLUSION: Major revisional surgery for symptomatic retained rectal stump after restorative proctocolectomy with stapled anastomosis was successful in 15 of 22 patients. These results are worse than the outcome following first-time restorative proctocolectomy with anastomosis constructed at the anal level. Pouch-rectal anastomosis should be avoided.

A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14.

A C-terminally modified ubiquitin (Ub) derivative, ubiquitin vinyl sulfone (UbVS), was synthesized as an active site-directed probe that irreversibly modifies a subset of Ub C-terminal hydrolases (UCHs) and Ub-specific processing proteases (UBPs). Specificity of UbVS for deubiquitylating enzymes (DUBs) is demonstrated not only by inhibition of [(125)I]UbVS labeling with N-ethylmaleimide and Ub aldehyde, but also by genetic analysis. [(125)I]UbVS modifies six of the 17 known and putative yeast deubiquitylating enzymes (Yuh1p, Ubp1p, Ubp2p, Ubp6p, Ubp12p and Ubp15p), as revealed by analysis of corresponding mutant strains. In mammalian cells, greater numbers of polypeptides are labeled, most of which are likely to be DUBs. Using [(125)I]UbVS as a probe, we report the association of an additional DUB with the mammalian 26S proteasome. In addition to the 37 kDa enzyme reported to be part of the 19S cap, we identified USP14, a mammalian homolog of yeast Ubp6p, as being bound to the proteasome. Remarkably, labeling of 26S-associated USP14 with [(125)I]UbVS is increased when proteasome function is impaired, suggesting functional coupling between the activities of USP14 and the proteasome.