Pudexacianinium (ASP5354) chloride for ureter visualization in participants undergoing laparoscopic, minimally invasive colorectal surgery

Ureteral injury is a known complication of pelvic surgeries, including gynecological, urologic, colorectal, and vascular surgeries. This can occur by transvaginal, laparoscopic, or transabdominal approach [1,2]. Gynecological surgery remains by far the most common means of injury (75%), followed by colorectal surgeries (14%) [3-5], with reports of ureteral injury during gynecologic surgery from 0.35% to 1.5% [4,6]. Total abdominal and laparoscopic hysterectomies are the most common procedures where ureteral injury occurs [1,5]. Injury occurs most often at the level where the ureter courses under the uterine vessels, followed by the ureterovesical junction and the base of the infundibulopelvic ligament [4,7,8]. Many ureteral injuries occur during uncomplicated, routine surgery [8,9]. An abnormal connection between the ureter and vagina, or ureterovaginal fistula, allows for a conduit through which urine can continually leak. This is specific to the combination of ureteral injury and hysterectomy where the urine finds its way to the freshly closed vaginal cuff. Genitourinary fistula formation remains one of the most feared complications of pelvic surgery, with lasting emotional damage, risk for infections, infertility, reoperation, and increased hospital stay [5,10]. Our objective is to present the difficulties encountered in management of our cases and how to rectify them.

BackgroundOne of the potential benefits of surgical audit is improved hospital cost-efficiencies arising from lower resource consumption associated with fewer adverse events. The aim of this study was to estimate the potential cost-savings for Australian hospitals from improved surgical performance for colorectal surgery attributed to a surgical self-audit program.MethodsWe used a mathematical decision-model to investigate cost differences in usual practice versus surgical audit and synthesized published hospital cost data with epidemiological evidence of adverse surgical events in Australia and New Zealand. A systematic literature review was undertaken to assess post-operative outcomes from colorectal surgery and effectiveness of surgical audit. Results were subjected to both one-way and probabilistic sensitivity analyses to address uncertainty in model parameters.ResultsIf surgical self-audit facilitated the reduction of adverse surgical events by half those currently reported for colorectal cancer surgery, the potential cost-savings to hospitals is AU$48,720 (95% CI: $18,080-$89,260) for each surgeon treating 20 cases per year. A smaller 25% reduction in adverse events produced cost-savings of AU$24,960 per surgeon (95%CI: $1,980-$62,980). Potential hospital savings for all operative colorectal cancer cases was estimated at AU$30.3 million each year.ConclusionsSurgical self-audit has the potential to create substantial hospital cost-savings for colorectal cancer surgery in Australia when considering the widespread incidence of this disease. The study is limited by the current availability and quality of data estimates abstracted from the published literature. Further evidence on the effectiveness of self-audit is required to substantiate these findings.

Steep ramp test protocol for preoperative risk assessment and short-term high-intensity interval training to evaluate, improve, and monitor cardiorespiratory fitness in surgical oncology.

Background:Imatinib generics were introduced to Poland in December 2013 and reimbursement of branded imatinib was stopped in July 2014. The Polish Adult Leukemia Group (PALG) Imatinib Generics Registry was established to provide clinical data on efficacy and safety of imatinib generics in a large cohort of patients with chronic myeloid leukemia (CML).Aims:To evaluate and compare safety of branded imatinb (Glivec) and its two generics – Nibix and Telux in a cohort of patients of CML treated in a single‐centre in Poland.Methods:91 patients were treated with Glivec with mean time of observation of 5.7 years. All patients were switched to Nibix in 2014. The mean time of Nibix therapy was 14 months. 78 patients were subsequently switched to Telux with mean time of observation of 13 months. 70 patients were switched back to Nibix in 2017 with mean time of observation of 12 months. The changes of imatinib generics brands were dictated by reimbursement policy of the National Health Fund. We evaluated type and rate of hematologic adverse events (AEs) of grade 3 and 4 according to CTCAE criteria as well as type and rate of non‐hematologic AEs of all grades. Time of AEs occurrence and the rate of treatment discontinuation were also analyzed.Results:None of the patients experienced G3/G4 hematologic toxicity after switching from Glivec to Nibix or Telux. 22 out of 91 (24.1%) patients experienced non‐hematologic toxicity after switching to Nibix. The most common type of toxicity was palpebral/facial edema (20.5% of all toxicity cases). 17 out of 38 (44.7%) patients who had non‐hematologic AEs on Glivec reported AEs also during the first Nibix therapy. 5 out of 53 (9.4%) patients who did not report Glivec intolerance had AEs on Nibix. Most frequent new AEs on Nibix were peripheral edema and muscle cramps. 7 patients (7,7%) discontinued Nibix due to intolerance. 35.9% (28 out of 78) of patients reported AEs after switching therapy from Nibix to Telux. The most common type of toxicity was dyspepsia (18.4 % of all toxicity cases). Seven out of 10 (70%) patients who reported AEs both on Glivec and Nibix experienced AEs also while on Telux. Eight out of 40 (20%) patients who had not reported neither Glivec nor Nibix intolerance had AEs during Telux therapy. Most frequent new AEs on Telux were nausea/dyspepsia and vomiting. Eight out of 78 patients (10.2%) discontinued Telux due to intolerance. 37.1% (26 out of 70) of patients reported AEs after switching therapy to Nibix for the second time. The most common type of toxicity was palpebral/facial edema and muscle cramps. 3 out of 70 (4.3%) patients experienced AEs for the first time while on second Nibix therapy. Two patients (2.8%) discontinued Nibix due to intolerance. The vast majority of observed non‐hematologic AEs were of grade 1 or 2 (53.8% and 31%, 36.8% and 52.6%, 79.5 and 15.4% on Nibix, Telux and Nibix again, respectively). Most cases of toxicity occurred within the first three months of treatment (79.5%, 86.8%, 100% on Nibix, Telux and Nibix again, respectively) and resolved during further treatment.Summary/Conclusion:The safety of Nibix and Telux is comparable to that of the original drug. The majority of observed non‐hematologic AEs were mild or moderate and the rate of treatment discontinuation due to intolerance was approximately 10% or less. Hematologic AEs of grade 3 and 4 did not reoccur after switching Glivec to generic drug. Telux caused more cases of gastrointestinal‐related AEs than Glivec or Nibix. Patients who experienced non‐hematologic AEs on Glivec or first generic had higher risk of AEs during further therapy.

Background: Urological trauma is a dreaded complication of gynecological or obstetrical surgery and its incidence is poorly documented in resource limited settings can cause a major health problem. The objective of this study is to determine the clinical, therapeutic and evolutionary aspects of iatrogenic urological lesions in a low- and middle-income country (LMIC). Methods: A retrospective, descriptive study conducted for 5 years at the obstetrics and gynecology department of the university hospital of Cocody. It concerned all gynecological surgery performed in the department. All Urinary Tract Injuries (UTI) during surgery were recorded. UTI occurring outside this scenario were excluded. The socio-demographic features, clinical data, intraoperative UTI features, and treatment outcome parameters were studied. Statistical analysis was carried out using Epi Info 3.5.1 2008 software. Results: We recorded 46 cases of UTI (4.0%) including bladder (n = 33 or 71.7%), ureter (n = 8 or 17.4%) and both bladder and ureteral lesions (n = 5 or 10.9%). The average age of patients was 29 years. The UTI were suspected during the initial surgery by hematuria (52.2%), or intraoperative visualization (23.07%). Postoperative diagnosis of UTI was made in patients presenting with signs of peritonitis (3.84%). The UTI were immediately repaired (96.16%) by simple suturing of bladder or cystorraphy (84.64%), ureter: or ureterorraphy (4.3%), ureterostomy (4.3%) and removal of ureteral strictures (4.3%). Postoperative complications (15.36%) included urogenital fistulae (50%), urinary tract infection (25%) and acute peritonitis (25%). The average length of stay in the urology department was 45 ± 5 days. No maternal deaths were reported. Conclusions: Urologic complications associated with gynecologic procedures are sometimes unavoidable but can be reduced by complying with standard surgical guidelines. Bladder trauma were the most common iatrogenic lesions, however ureteral injuries are feared because of their more complex treatment. Treatment strategies should be dependent on location and length of injury, and surgical possibilities.

Haematopoietic gene therapy of non-conditioned patients with Fanconi anaemia-A: results from open-label phase 1/2 (FANCOLEN-1) and long-term clinical trials

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study

Laparoscopic surgery is increasingly being performed for benign and malignant colorectal disease. This study examines the short-term results in a consecutive series of laparoscopic colorectal procedures performed over 2 years. A prospective database was established for all elective patients undergoing laparoscopic colorectal surgery by one surgeon. The main outcome measures assessed were operative duration, conversion rate, length of hospital stay, morbidity and mortality and lymph node harvest. Two hundred and thirty-one consecutive patients were referred for elective colorectal surgery, with 18 patients excluded from laparoscopic surgery. Thirteen patients had nonresective laparoscopic colorectal procedures for endometriosis and have been excluded from the series. Of 200 patients who underwent a laparoscopic colorectal procedure, 114 (57%) were female, the median age was 67 years (inter-quartile range (IQR) 57-76), and there were 116 malignancies. The most common operations were anterior resection and sigmoid colectomy (n = 82), right hemicolectomy (n = 62) and left hemicolectomy (n = 12). The median operating time was 120 min (IQR 90-150) and 10 patients (5%) required conversion to open surgery. The median lymph node harvest in malignancies was 21 nodes (IQR 15-30) and no positive resection margins were found. There were two deaths and 29 significant complications (14.5%), with seven patients requiring re-operations because of postoperative complications. The median postoperative hospital stay was 4 days (IQR 3-6) and 13 patients (6.5%) were re-admitted within 30 days of hospital discharge. Laparoscopic colorectal surgery is possible for most benign and malignant conditions, with low conversion and complication rates, as well as short hospital stay.

Single stage risk-reducing breast and gynecologic surgery for hereditary predisposition to breast and ovarian cancer

BackgroundSystemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This study aimed to provide the complete efficacy and safety profiles and ranking of systemic therapies for the treatment of unresectable advanced or metastatic CRC.MethodsWe searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until June 30, 2021, and also the bibliographies of relevant studies. Randomized controlled trials comparing two or more treatments, namely, at least capecitabine, 5-fluorouracil, leucovorin, irinotecan, bevacizumab, cetuximab, oxaliplatin, or panitumumab were investigated. A network meta-analysis using the Bayesian approach was performed to compare the efficacy and safety of treatments. The surface under the cumulative ranking curve (SUCRA) was calculated for the probability of each treatment as the most effective. The overall response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) grade ≥3, and serious adverse events (SAEs) were evaluated.ResultsOne hundred two publications with 36,147 participants were assigned to 39 different treatments. Among 11 treatments with full information on six outcomes, FOLFIRI/FOLFOX/FOLFOXIRI + bevacizumab significantly improved both the ORR and DCR, compared to FOLFIRI. Although FOLFOX and FOLFIRI/FOLFOX + cetuximab significantly prolonged both OS and PFS, treatments were comparable in terms of AEs grade ≥3 and SAEs. The top highest SUCRA values were observed in the FOLFOXIRI + panitumumab group for ORR (96%) and DCR (99%), FOLFIRI + bevacizumab + panitumumab group for OS (62%) and PFS (54%), and FOLFOXIRI + bevacizumab group for AEs grade ≥3 (59%) and SAEs (59%) outcomes.ConclusionsThese findings suggest an available range of systemic treatment therapies with different efficacy and safety profiles with patients. Further investigations of the side effects and mutation status are required to confirm our findings.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42019127772

BackgroundImmune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies of alternatives...

Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study

BackgroundMB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally.Methods and findingsThe clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively).The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys.Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 μg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 μg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 μg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 μg/mL); HSV8-N concentrations ranged from 80 to 601 μg/mL, well above the IC50 of 0.1 μg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation.ConclusionsSingle and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception.Trial registrationClinicalTrials.gov NCT02579083.

PurposeSymptomatic adverse event (AE) monitoring is essential in cancer clinical trials to assess patient safety, as well as inform decisions related to treatment and continued trial participation. As prior research has demonstrated that conventional concordance metrics (e.g., intraclass correlation) may not capture nuanced aspects of the association between clinician and patient-graded AEs, we aimed to characterize differences in AE grading thresholds between doctors (MDs), registered nurses (RNs), and patients using the Bayesian Graded Item Response Model (GRM).MethodsFrom the medical charts of 393 patients aged 26–91 (M = 62.39; 43% male) receiving chemotherapy, we retrospectively extracted MD, RN and patient AE ratings. Patients reported using previously developed Common Terminology Criteria for Adverse Events (CTCAE) patient-language adaptations called STAR (Symptom Tracking and Reporting). A GRM was fitted to calculate the latent grading thresholds between MDs, RNs and patients.ResultsClinicians have overall higher average grading thresholds than patients when assessing diarrhea, dyspnea, nausea and vomiting. However, RNs have lower grading thresholds than patients and MDs when assessing constipation. The GRM shows higher variability in patients’ AE grading thresholds than those obtained from clinicians.ConclusionsThe present study provides evidence to support the notion that patients report some AEs that clinicians might not consider noteworthy until they are more severe. The availability of GRM methodology could serve to enhance clinical understanding of the patient symptomatic experience and facilitate discussion where AE grading discrepancies exist. Future work should focus on capturing explicit AE grading decision criteria from MDs, RNs, and patients.

Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations — Part I