-
European Urology Oncology Jan 2024Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non-muscle-invasive...
BACKGROUND
Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non-muscle-invasive bladder cancer (NMIBC). The implementation of a quality performance indicator (QPI) programme in Scotland's National Health Service (NHS) aimed to improve cancer outcomes and reduce nationwide variance.
OBJECTIVE
To evaluate the effect of hospitals achieving benchmarks for two specific QPIs on time to recurrence and progression in NMIBC.
DESIGN, SETTING, AND PARTICIPANTS
QPIs for bladder cancer (BC) were enforced nationally in April 2014. NHS health boards collected prospective data on all new BC patients. Prospectively recorded surveillance data were pooled from 12 collaborating centres.
INTERVENTION
QPIs of interest were (1) hospitals achieving detrusor muscle (DM) sampling target at initial transurethral resection of bladder tumour (TURBT) and (2) use of single instillation of mitomycin C after TURBT (SI-MMC).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary and secondary endpoints were time to recurrence and progression, respectively. Kaplan-Meier and Cox multivariable regression analyses were performed.
KEY FINDINGS AND LIMITATIONS
Between April 1, 2014 and March 31, 2017, we diagnosed 3899 patients with new BC, of which 2688 were NMIBC . With a median follow up of 60.3 mo, hospitals achieving the DM sampling target had a 5.4% lower recurrence rate at 5 yr than hospitals not achieving this target (442/1136 [38.9%] vs 677/1528 [44.3%], 95% confidence interval [CI] = 1.6-9.2, p = 0.005). SI-MMC was associated with a 20.4% lower recurrence rate (634/1791 [35.4%] vs 469/840 [55.8%], 95% CI = 16.4-24.5, p < 0.001). On Cox multivariable regression, meeting the DM target and SI-MMC were associated with significant improvement in recurrence (hazard ratio [HR] 0.81, 95% CI = 0.73-0.91, p = 0.0002 and HR 0.66, 95% CI = 0.59-0.74, p < 0.004, respectively) as well as progression-free survival (HR 0.62, 95% CI = 0.45-0.84, p = 0.002 and HR 0.65, 95% CI = 0.49-0.87, p = 0.004, respectively). We did not have a national multicentre pre-QPI control.
CONCLUSIONS
Within a national QPI programme, meeting targets for sampling DM and SI-MMC in the real world were independently associated with delays to recurrence and progression in NMIBC patients.
PATIENT SUMMARY
Following the first 3 yr of implementing a novel quality performance indicator programme in Scotland, we evaluated compliance and outcomes in non-muscle-invasive bladder cancer. In 2688 patients followed up for 5 yr, we found that achieving targets for sampling detrusor muscle and the single instillation of mitomycin C during and after transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression.
PubMed: 38296735
DOI: 10.1016/j.euo.2024.01.012 -
Ophthalmology Science 2024Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic...
PURPOSE
Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery.
DESIGN
Preclinical study using a rabbit model of glaucoma filtration surgery.
SUBJECTS
Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes.
METHODS
Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring.
MAIN OUTCOME MEASURES
The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology.
RESULTS
Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, < 0.01). Bleb histology did not reveal any significant toxicity in verteporfin-treated eyes. There were no significant differences in inflammation or scarring across groups.
CONCLUSIONS
Although verteporfin remained inferior to MMC with regard to surgical survival, there was a trend toward increased survival compared with BSS control and it had an excellent safety profile. Further studies with variations in verteporfin dosage and/or application frequency are needed to assess whether this may be a useful adjunct to glaucoma surgery.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38261964
DOI: 10.1016/j.xops.2023.100448 -
International Journal of Molecular... Jan 2024The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified...
Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.
The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
Topics: Humans; Depressive Disorder, Major; Astrocytes; Depression; Mitochondria; Neurons; Fibroblasts; Caricaceae; Mitomycin
PubMed: 38256041
DOI: 10.3390/ijms25020963 -
Taiwan Journal of Ophthalmology 2023Primary congenital glaucoma (PCG) occurs worldwide and has a broad range of ocular manifestations. It poses a therapeutic challenge to the ophthalmologist. A proper... (Review)
Review
Primary congenital glaucoma (PCG) occurs worldwide and has a broad range of ocular manifestations. It poses a therapeutic challenge to the ophthalmologist. A proper diagnostic evaluation under anesthesia is advisable for all children who do not cooperate for an office examination. Medical therapy only serves as a supportive role, and surgical intervention remains the principal therapeutic modality. Angle incision surgery such as goniotomy or trabeculotomy ab externo is the preferred choice of surgery in the Caucasian population. Primary combined trabeculotomy-trabeculectomy with or without antifibrotic therapy is the preferred choice in certain regions such as India and the Middle East where the disease usually presents with severe forms of corneal edema along with megalocornea. In refractory cases, trabeculectomy with antifibrotic therapy or glaucoma drainage devices are available options in the armamentarium. Cycloablative procedures should be reserved for eyes with poor visual potential. Myopia is common among children with PCG, and appropriate optical refractive correction in the form of glasses or contact lenses should be provided. Amblyopia therapy should be instituted to ensure overall visual development in the early developmental years. Low-vision rehabilitation services should be provided to children with vision impairment. Long-term follow-up is mandatory and carers of children with PCG should be counseled and educated about this need. Regardless of the visual outcomes, clinicians should emphasize the need for education of these children during the clinic visit. The overall goal of the management should be to improve the overall quality of life of the children with PCG and their carers.
PubMed: 38249492
DOI: 10.4103/tjo.TJO-D-23-00104 -
Cells Jan 2024Cancer-specific CD8 cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for...
A Novel Protozoa Parasite-Derived Protein Adjuvant Is Effective in Immunization with Cancer Cells to Activate the Cancer-Specific Protective Immunity and Inhibit the Cancer Growth in a Murine Model of Colorectal Cancer.
Cancer-specific CD8 cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8 cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of , an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable (either treated with mitomycin C or irradiated by X-ray) MC38 CRC cells in combination with rGRA6Nt adjuvant and received a challenge implantation of replication-capable MC38 tumor cells, those mice markedly inhibited the growth of the implanted tumors in association with a two-fold increase in CD8 T cell density within the tumors. In addition, CD8 T cells of the immunized mice secreted significantly increased amounts of granzyme B, a key mediator of the cytotoxic activity of CD8 T cells, and IFN-γ in response to MC38 CRC cells in vitro when compared to the T cells from unimmunized mice. Notably, the protective effects of the immunization were specific to MC38 CRC cells, as the immunized mice did not exhibit a significantly inhibited growth of EL4 lymphoma tumors. These results indicate that rGRA6Nt is a novel and effective protein adjuvant when used in immunizations with non-replicable cancer cells to potently activate the protective immunity specifically against the cancer cells employed in the immunization.
Topics: Animals; Mice; Parasites; CD8-Positive T-Lymphocytes; Disease Models, Animal; Immunization; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Colorectal Neoplasms
PubMed: 38247803
DOI: 10.3390/cells13020111 -
Romanian Journal of Ophthalmology 2023To report outcomes in terms of efficacy and safety of patients affected with Primary Open Angle Glaucoma (POAG) and Vitreoretinal Disease, who have undergone Pars Plana... (Observational Study)
Observational Study
To report outcomes in terms of efficacy and safety of patients affected with Primary Open Angle Glaucoma (POAG) and Vitreoretinal Disease, who have undergone Pars Plana Vitrectomy (PPV) and ab-interno XEN gel 45 (Abbvie) implantations. This is a retrospective, observational, case series on five patients who underwent combined Pars Plana Vitrectomy and XEN gel Stent 45 implantation at "Careggi Hospital" Eye Clinic of Florence. Best-corrected visual acuity (BCVA) evaluation, intraocular pressure (IOP) measurements with Goldmann applanation tonometer (GAT), and several glaucoma medications were evaluated at the baseline and at one, three, six, and twelve months after surgery. Complications were recorded up to 1 year after surgery. 5 eyes in five patients were enrolled. IOP dropped from an average of 21,2 ± 3,3 mmHg preoperatively to 14,6 ± 1,1 mmHg at the end of the follow-up period (month 12), with a mean percentage reduction of 58%. One patient needed a needling procedure (20%). None needed reintervention. We did not register any case of hypotony (IOP < 6,5 mmHg), hypotony maculopathy and choroidal detachment. The postoperative number of anti-glaucomatous molecules was on average 0,2 ± 0,4. Our results suggested that combined Pars Plana Vitrectomy and XEN gel stent 45 implantation is safe and effective for patients affected by visually significant vitreoretinal diseases and POAG. AC = anterior chamber, BCVA = Best-corrected visual acuity, ERM = epiretinal membrane, FTMH = full-thickness macular holes, FU = fluorouracil, GAT = Goldmann applanation tonometer, IOP = intraocular pressure, MIGS = minimally invasive glaucoma surgery, MMC = mitomycin C, NVG = neovascular glaucoma, OCT = optical coherence tomography, POAG = Primary Open Angle Glaucoma, PPV = Pars Plana Vitrectomy, SD = standard deviation, TB = Trabeculectomy, VF = visual field, VMI = Vitreomacular Interface, VMA = vitreomacular adhesion, VMT = vitreomacular traction.
Topics: Humans; Glaucoma, Open-Angle; Vitrectomy; Glaucoma Drainage Implants; Glaucoma; Intraocular Pressure; Retinal Diseases; Retrospective Studies; Mitomycin; Stents; Treatment Outcome
PubMed: 38239415
DOI: 10.22336/rjo.2023.57 -
Romanian Journal of Ophthalmology 2023Head and neck cancers (HNCs) present a significant global health burden, especially in India, where oral cavity cancers, notably affecting the tongue, are prevalent. A...
Head and neck cancers (HNCs) present a significant global health burden, especially in India, where oral cavity cancers, notably affecting the tongue, are prevalent. A substantial portion of global HNCs (57.5%) is concentrated in Asia, India contributing with 30%. Despite advancements, challenges persist due to HNCs' invasive nature and metastatic potential. This study aims to explore the link between HNCs and ocular manifestations. A cross-sectional study was conducted at Bangalore Medical College and Research Institute involving 47 patients with diagnosed HNCs and ocular complaints. Clinical evaluations encompassed visual acuity, anterior and posterior segment examinations, and specialized investigations when necessary. A diverse range of malignancies were observed, with SCC maxilla and xeroderma pigmentosa, each accounting for 10.63% of cases. Ocular examinations unveiled visual acuity challenges, anterior segment findings like masses, exotropia, pigmented lesions, and varied fundus abnormalities. The anterior segment findings encompassed masses often accompanied by protrusion or relative afferent pupillary defect (RAPD). Additionally, exotropia, pigmented lesions, and other conditions were observed. Fundus examination revealed a spectrum of findings, including media haziness (10.63%), lack of view (17.02%), and pale discs (6.38%). Treatment plans were diverse, including excision biopsies (42.55%), exenteration procedures, Mitomycin-C applications, and referrals for chemotherapy and radiotherapy. The present study underscores the significance of ophthalmological assessment and investigations in patients with diagnosed HNCs, emphasizing the value of early detection and intervention. HNC = Head and Neck Cancer, OCT = Optical Coherence Tomography, WNL = Within Normal Limits, SCC = Squamous Cell Carcinoma, MRI = Magnetic Resonance Imaging, CT = Computed Tomography, RAPD = Relative Afferent Pupillary Defect, XP = Xeroderma Pigmentosa.
Topics: Humans; Cross-Sectional Studies; Tertiary Care Centers; Exotropia; India; Head and Neck Neoplasms; Pupil Disorders; Ichthyosis
PubMed: 38239414
DOI: 10.22336/rjo.2023.55 -
European Respiratory Review : An... Jan 2024Pulmonary veno-occlusive disease (PVOD), also known as "pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement", is a rare cause of... (Review)
Review
Pulmonary veno-occlusive disease (PVOD), also known as "pulmonary arterial hypertension (PAH) with overt features of venous/capillary involvement", is a rare cause of PAH characterised by substantial small pulmonary vein and capillary involvement, leading to increased pulmonary vascular resistance and right ventricular failure. Environmental risk factors have been associated with the development of PVOD, such as occupational exposure to organic solvents and chemotherapy, notably mitomycin. PVOD may also be associated with a mutation in the gene in heritable forms of disease. Distinguishing PVOD from PAH is critical for guiding appropriate management. Chest computed tomography typically displays interlobular septal thickening, ground-glass opacities and mediastinal lymphadenopathy. Life-threatening pulmonary oedema is a complication of pulmonary vasodilator therapy that can occur with any class of PAH drugs in PVOD. Early referral to a lung transplant centre is essential due to the poor response to therapy when compared with other forms of PAH. Histopathological analysis of lung explants reveals microvascular remodelling with typical fibrous veno-occlusive lesions. This review covers the main features distinguishing PVOD from PAH and two clinical cases that illustrate the challenges of PVOD management.
Topics: Humans; Pulmonary Veno-Occlusive Disease; Lung; Familial Primary Pulmonary Hypertension; Tomography, X-Ray Computed; Lung Transplantation; Pulmonary Arterial Hypertension; Protein Serine-Threonine Kinases
PubMed: 38232988
DOI: 10.1183/16000617.0156-2023 -
Cureus Dec 2023This case report presents a 66-year-old male with a complex medical history, including testicular cancer, chronic obstructive pulmonary disease, obstructive sleep apnea,...
This case report presents a 66-year-old male with a complex medical history, including testicular cancer, chronic obstructive pulmonary disease, obstructive sleep apnea, tobacco use disorder, erectile dysfunction, and obesity. The patient exhibited recurrent gross hematuria, leading to a comprehensive workup. Cystoscopy revealed a bladder tumor, prompting transurethral resection and mitomycin C instillation. Subsequent intravesical Bacillus Calmette-Guérin (BCG) therapy was initiated but resulted in severe sepsis during maintenance. Despite initial suspicion of BCG-induced sepsis, further evaluation suggested a reaction with chemical cystitis. Treatment involved brief antimicrobial therapy, and the patient's condition improved. This case highlights the challenges in managing BCG therapy complications, emphasizing the need for prompt intervention, careful monitoring, and consideration of risk factors. Patient education and vigilant follow-ups are crucial for addressing potential long-term effects.
PubMed: 38226105
DOI: 10.7759/cureus.50498 -
Nucleic Acids Research Mar 2024DNA damage represents a challenge for cells, as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or...
DNA damage represents a challenge for cells, as this damage must be eliminated to preserve cell viability and the transmission of genetic information. To reduce or eliminate unscheduled chemical modifications in genomic DNA, an extensive signaling network, known as the DNA damage response (DDR) pathway, ensures this repair. In this work, and by means of a proteomic analysis aimed at studying the STIM1 protein interactome, we have found that STIM1 is closely related to the protection from endogenous DNA damage, replicative stress, as well as to the response to interstrand crosslinks (ICLs). Here we show that STIM1 has a nuclear localization signal that mediates its translocation to the nucleus, and that this translocation and the association of STIM1 to chromatin increases in response to mitomycin-C (MMC), an ICL-inducing agent. Consequently, STIM1-deficient cell lines show higher levels of basal DNA damage, replicative stress, and increased sensitivity to MMC. We show that STIM1 normalizes FANCD2 protein levels in the nucleus, which explains the increased sensitivity of STIM1-KO cells to MMC. This study not only unveils a previously unknown nuclear function for the endoplasmic reticulum protein STIM1 but also expands our understanding of the genes involved in DNA repair.
Topics: Chromatin; DNA Damage; DNA Repair; Fanconi Anemia Complementation Group D2 Protein; Mitomycin; Proteomics; Stromal Interaction Molecule 1; Humans; Cell Nucleus; Neoplasm Proteins
PubMed: 38224453
DOI: 10.1093/nar/gkae001