Purpose
Due to the tissue preserving approach of focal therapy (FT), local cancer relapse can occur. Uncertainty exists regarding triggers and outcome of salvage strategies.
Methods
Patients with ...biopsy-proven prostate cancer (PCa) after FT for localized PCa from 2011 to 2020 at eight tertiary referral hospitals in Germany that underwent salvage radical prostatectomy (S-RP), salvage radiotherapy (S-RT) or active surveillance (AS) were reported. Prostate specific antigen (PSA) changes, suspicious lesions on mpMRI and histopathological findings on biopsy were analyzed. A multivariable regression model was created for adverse pathological findings (APF) at S-RP specimen. Kaplan–Meier curves were generated to determine oncological outcomes.
Results
A total of 90 men were included. Cancer relapse after FT was detected at a median of 12 months (IQR 9–16). Of 50 men initially under AS 13 received S-RP or S-RT. In total, 44 men underwent S-RP and 13 S-RT. At cancer relapse 17 men (38.6%) in the S-RP group S-RT
n
= 4 (30.8%); AS
n
= 3 (6%) had ISUP > 2. APF (pT ≥ 3, ISUP ≥ 3, pN + or R1) were observed in 23 men (52.3%). A higher ISUP on biopsy was associated with APF
p
= 0.006 (HR 2.32, 97.5% CI 1.35–4.59) on univariable analysis. Progression-free survival was 80.4% after S-RP and 100% after S-RT at 3 years. Secondary therapy-free survival was 41.7% at 3 years in men undergoing AS. Metastasis-free survival was 80% at 5 years for the whole cohort.
Conclusion
With early detection of cancer relapse after FT S-RP and S-RT provide sufficient oncologic control at short to intermediate follow-up. After AS, a high secondary-therapy rate was observed.
Tissue-resident memory T cells have critical roles in long-term pathogen and tumor immune surveillance in the liver. We investigate the role of autophagy in equipping human memory T cells to acquire ...tissue residence and maintain functionality in the immunosuppressive liver environment. By performing ex vivo staining of freshly isolated cells from human liver tissue, we find that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells. CD8+ T cells with increased autophagy are those best able to proliferate and mediate cytotoxicity and cytokine production. Conversely, blocking autophagy induction results in the accumulation of depolarized mitochondria, a feature of exhausted T cells. Primary hepatic stellate cells or the prototypic hepatic cytokine interleukin (IL)-15 induce autophagy in parallel with tissue-homing/retention markers. Inhibition of T cell autophagy abrogates tissue-residence programming. Thus, upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.
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•An increased rate of basal autophagy is a hallmark of liver-resident CD8+ T cells•Enhanced T cell autophagy can be imprinted by IL-15 or hepatic stellate cells•Autophagy induction is required for tissue-residence programming in vitro•Enhanced autophagy maintains TRM mitochondrial fitness in the liver
Swadling et al. show that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells and that in vitro TRM programming requires autophagy induction. Upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.
To evaluate the safety and tolerability of intravitreal ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2), in patients with primary open angle ...glaucoma (POAG) undergoing trabeculectomy (TE; glaucoma filtration surgery).
In this prospective phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC) received a single intravitreal injection of ISTH0036 at the end of surgery in escalating total doses of 6.75 μg, 22.5 μg, 67.5 μg or 225 μg, resulting in calculated intraocular ISTH0036 concentrations in the vitreous humor of approximately 0.3 μM, 1 μM, 3 μM or 10 μM after injection, respectively. Outcomes assessed included: type and frequency of adverse events (AEs), intraocular pressure (IOP), numbers of interventions post trabeculectomy, bleb survival, visual acuity, visual field, electroretinogram (ERG), slit lamp biomicroscopy and optic disc assessment.
In total, 12 patients were treated in the 4 dose groups. Main ocular AEs observed were corneal erosion, corneal epithelium defect, or too high or too low IOP, among others. No AE was reported to be related to ISTH0036. All other safety-related analyses did not reveal any toxicities of concern, either. The mean medicated preoperative IOP at decision time-point for surgery was 27.3 mmHg +/- 12.6 mmHg (SD). Mean IOP (±SD) for dose levels 1, 2, 3, and 4 were at Day 43 9.8 mmHg ± 1.0 mmHg, 11.3 mmHg ± 6.7 mmHg, 5.5 mmHg ± 3.0 mmHg and 7.5 mmHg ± 2.3 mmHg SD; and at Day 85 9.7 mmHg ± 3.3 mmHg, 14.2 mmHg ± 6.5 mmHg, 5.8 mmHg ± 1.8 mmHg and 7.8 mmHg ± 0.6 mmHg, respectively. In contrast to IOP values for dose levels 1 and 2, IOP values for dose levels 3 and 4 persistently remained below 10 mmHg throughout the observation period.
This first-in-human trial demonstrates that intravitreal injection of ISTH0036 at the end of TE is safe. Regarding IOP control, single-dose ISTH0036 administration of 67.5 μg or 225 μg at the time of TE resulted in IOP values persistently < 10 mmHg over the three month postoperative observation period.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Gram-negative pathogen Pseudomonas aeruginosa causes severe infections mainly in immunocompromised or cystic fibrosis patients and is able to resist antimicrobial treatments. The extracellular ...lectin LecB plays a key role in bacterial adhesion to the host and biofilm formation. For the inhibition of LecB, we designed and synthesized a set of fucosyl amides, sulfonamides, and thiourea derivatives. Then, we analyzed their binding to LecB in competitive and direct binding assays. We identified β-fucosyl amides as unprecedented high-affinity ligands in the two-digit nanomolar range. X-ray crystallography of one α- and one β-anomer of N-fucosyl amides in complex with LecB revealed the interactions responsible for the high affinity of the β-anomer at atomic level. Further, the molecules showed good stability in murine and human blood plasma and hepatic metabolism, providing a basis for future development into antibacterial drugs.
There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such ...variation.
This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15–99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs).
Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85–99 years had 20-times lower odds of chemotherapy use than those aged 65–74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI –15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85–99 years had slightly shorter median time to first chemotherapy compared with those aged 65–74 years, consistently between jurisdictions (–3·7 days, 95% PI –7·6 to 0·1).
Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established.
International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).
Purpose: To determine oncological and functional outcomes and side effects after focal therapy of prostate cancer (PCa) with high-intensity focused ultrasound (HIFU). Methods: This retrospective ...single-center study included 57 consecutive patients with localised PCa. Aged 18–80 with ≤2 suspicious lesions on mpMRI (PIRADS ≥ 3), PSA of ≤15 ng/mL, and an ISUP GG of ≤2. HIFU was performed between November 2014 and September 2018. All men had an MRI/US fusion-guided targeted biopsy (TB) combined with a TRUS-guided 10-core systematic biopsy (SB) prior to focal therapy. HIFU treatment was performed as focal, partial, or hemiablative, depending on the prior histopathology. Follow-up included Questionnaires (IIEF-5, ICIQ, and IPSS), prostate-specific antigen (PSA) measurement, follow-up mpMRI, and follow-up biopsies. Results: The median age of the cohort was 72 years (IQR 64–76), and the median PSA value before HIFU was 7.3 ng/mL (IQR 5.75–10.39 ng/mL). The median follow-up was 27.5 (IQR 23–41) months. At the time of the follow-up, the median PSA value was 2.5 ng/mL (IQR 0.94–4.96 ng/mL), which shows a significant decrease (p < 0.001). In 17 (29.8%) men, mpMRI revealed a suspicious lesion, and 19 (33.3%) men had a positive biopsy result. Only IIEF values significantly decreased from 16 (IQR 10.75–20.25) to 11.5 (IQR 4.5–17) (p < 0.001). The rate of post-HIFU complications was low, at 19.3% (11 patients). The limitation of this study is the lack of long-term follow-up. Conclusions: HIFU as a therapy option for nonmetastatic, significant prostate cancer is effective in the short term for carefully selected patients and shows a low risk of adverse events and side effects.
OnabotulinumtoxinA (Botox) has been approved in Germany since 2013 for the second-line treatment of idiopathic overactive bladder in the form of a detrusor injection (OnabotA DI) after failure of ...anticholinergic therapy. Until 2018, however, its application lagged far behind the demand due to billing hurdles. Since the beginning of 2018, there has been an EBM (German Uniform Evaluation Standard) approval number in Germany for the transurethral application of Botox in urology.
The aim of a survey performed in 2019 among course participants of regular injection workshops (WS-P) in our institution was to evaluate whether billability has changed user behaviour in Germany in line with the demand. A similar survey was carried out in 2021 to show the developments over the past two years.
In 2019, 88 consecutive participants in a user workshop that had been held regularly since 2013 were asked about their OnabotA DI practice anonymously via questionnaire. The survey was repeated in 2021 in an anonymous online survey of 55 course participants in order to evaluate changes in user behaviour over the past two years.
Evaluation 2019: Response rate 35/88 of the questionnaires (39.8%); a large majority (82%) of the WS-P attended the workshop AFTER the establishment of the EBM code. Only 54.5% of the WS-P performed two or more (12% more than 10) OnabotA DIs per quarter after the workshop. Most users (85%) always or predominantly performed the procedure on an outpatient basis, 63% always or predominantly under local anesthesia. The majority (84%) administered no or only a perioperative antibiotic treatment, 13% for one week. 89% stated that at least 70% of their patients had no or only mild symptoms under the LA. In the 2021 evaluation, the users tended to perform the procedure more often on an outpatient basis and in LA, and more often without any antibiotics.
The results of our user survey indicate that the implementation of the OnabotA DI has gained significant impetus since the EBM approval in Germany in January 2018. In most cases, the procedure can be performed easily on an outpatient basis under local anesthesia.
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