Final results of the PräVAC trial: prevention of wound complications following inguinal lymph node dissection in patients with penile cancer using epidermal vacuum-assisted wound closure.

PURPOSE: Inguinal lymphadenectomy in penile cancer is associated with a high rate of wound complications. The aim of this trial was to prospectively analyze the effect of an epidermal vacuum wound dressing on lymphorrhea, complications and reintervention in patients with inguinal lymphadenectomy for penile cancer. PATIENTS AND METHODS: Prospective, multicenter, randomized, investigator-initiated study in two German university hospitals (2013-2017). Thirty-one patients with penile cancer and indication for bilateral inguinal lymph node dissection were included and randomized to conventional wound care on one side (CONV) versus epidermal vacuum wound dressing (VAC) on the other side. RESULTS: A smaller cumulative drainage fluid volume until day 14 (CDF) compared to contralateral side was observed in 15 patients (CONV) vs. 16 patients (VAC), with a median CDF 230 ml (CONV) vs. 415 ml (VAC) and a median maximum daily fluid volume (MDFV) of 80 ml (CONV) vs. 110 ml (VAC). Median time of indwelling drainage: 7 days (CONV) vs. 8 days (VAC). All grade surgery-related complications were seen in 74% patients (CONV) vs. 74% patients (VAC); grade 3 complications in 3 patients (CONV) vs. 6 patients (VAC). Prolonged hospital stay occurred in 32% patients (CONV) vs. 48% patients (VAC); median hospital stay was 11.5 days. Reintervention due to complications occurred in 45% patients (CONV) vs. 42% patients (VAC). CONCLUSIONS: In this prospective, randomized trial we could not observe a significant difference between epidermal vacuum treatment and conventional wound care.

Prognostic value of computed tomography before radical cystectomy in patients with invasive bladder cancer: imaging predicts survival.

PURPOSE: Computed tomography (CT) is current standard-of-care for preoperative staging in patients with invasive bladder cancer before radical cystectomy (RC). There are only sparse data on the association between preoperative CT findings and postoperative survival of patients. METHODS: We retrospectively evaluated preoperative CTs of 206 patients with invasive bladder cancer undergoing RC in an academic tertiary referral center. CTs were analyzed retrospectively for relative bladder wall thickness (BWT) and size of lymph nodes (LN). Associations between CT findings and risk of death from any cause (AC) as well as risk of death from bladder cancer (BC) were assessed by Kaplan-Meier estimates, cumulative incidence curves and multivariable Cox regression analysis. RESULTS: The median follow-up was 40 months. Increased BWT was significantly correlated with higher risk of death (AC: HR 1.68; p = 0.043; BC: HR 2.00; p = 0.027), as well as LN with a size of 6-10 mm (AC: HR 2.13; p = 0.002; BC: HR 2.77; p = 0.002) and >10 mm (AC: HR 2.47; p = 0.018; BC: HR 3.66; p = 0.007) when compared to LN ≤ 5 mm. CONCLUSION: Our data showed a significant correlation of bladder wall thickness and LN size with the risk of death. Also lymph nodes >5 mm but ≤ 10 mm (resp. ≤ 8 mm)-usually considered non-pathologic-were associated with a significantly worse prognosis. This information can be used to counsel patients preoperatively. It might also be useful for a risk-adapted approach in regard to neoadjuvant chemotherapy.

Clinical prognosticators of survival in patients with urothelial carcinoma of the bladder and lymph node metastases after cystectomy with curative intent.

INTRODUCTION: Patients with lymph node-positive urothelial carcinoma of the bladder generally have a poor prognosis. Nevertheless, long-term survival in up to 30% of patients is reported. In the absence of established prognostic molecular markers, an assessment of the prognosis with clinical parameters is mandatory. PATIENTS AND METHODS: All patients from one high-volume center with a curatively intended cystectomy for lymph node-positive urothelial carcinoma were evaluated. Patients' overall and cancer-specific survival were correlated with clinicopathological parameters. Pathological lymph node staging was performed with both the 2002 and 2010 TNM classification of the AJCC. RESULTS: Lack of a perioperative chemotherapy (p < 0.001), higher numbers of positive nodes (p = 0.002), a higher lymph node density (p = 0.003), a higher pathological T stage (p = 0.006) and urinary diversion with an ileal conduit compared to an ileal neobladder (p = 0.023) were prognostic of a shorter overall survival while the number of removed lymph nodes showed no significant association with survival. Both with the 2002 and 2010 TNM classifications patients staged pN1 had a longer overall survival and time to cancer-specific death in comparison to patients with more extensive lymph node disease. According to the 2002 classification, there was a significant survival difference between patients with lymph node metastases in regional and distant lymph nodes. DISCUSSION: Patients with a low lymph node density and an early pT stage present with the best prognosis among LN positive patients. The value of perioperative chemotherapy is emphasized. Which lymph node metastases are to be considered regional or distant remains a matter of debate.

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.

BACKGROUND: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. METHODS: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. RESULTS: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01). CONCLUSION: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients.

Successful use of Rectal Pregabalin for the Treatment of Chemotherapy-Induced Neuropathic Pain-a Case Report.

INTRODUCTION: A 65-year-old female patient could no longer take oral food or medications due to a duodenal occlusion associated with metastatic urothelial carcinoma. Her pre-existing chemotherapy-induced polyneuropathy had been well treated with pregabalin orally. METHODS: Since only preparations for oral use of pregabalin are available, pregabalin suppositories were compounded by the hospital pharmacy for rectal use in this patient. RESULTS: With the rectal administration, the treatment was successfully continued; we measured a good increase in serum levels and the symptoms improved significantly. DISCUSSION: Cancer patients often need to be treated with co-analgesics. At the end of life, treatment often cannot be continued due to lack of other than oral administration. Our case adds to the low evidence of pregabalin administered rectally.

Virus variant-specific clinical performance of SARS coronavirus two rapid antigen tests in point-of-care use, from November 2020 to January 2022.

OBJECTIVES: Antigen rapid diagnostic tests (RDTs) for SARS coronavirus 2 (SARS-CoV-2) are quick, widely available, and inexpensive. Consequently, RDTs have been established as an alternative and additional diagnostic strategy to quantitative reverse transcription polymerase chain reaction (RT-qPCR). However, reliable clinical and large-scale performance data specific to a SARS-CoV-2 virus variant of concern (VOC) are limited, especially for the Omicron VOC. The aim of this study was to compare RDT performance among different VOCs. METHODS: This single-centre prospective performance assessment compared RDTs from three manufacturers (NADAL, Panbio, MEDsan) with RT-qPCR including deduced standardized viral load from oropharyngeal swabs for detection of SARS-CoV-2 in a clinical point-of-care setting from November 2020 to January 2022. RESULTS: Among 35 479 RDT/RT-qPCR tandems taken from 26 940 individuals, 164 of the 426 SARS-CoV-2 positive samples tested true positive with an RDT corresponding to an RDT sensitivity of 38.50% (95% CI, 34.00-43.20%), with an overall specificity of 99.67% (95% CI, 99.60-99.72%). RDT sensitivity depended on viral load, with decreasing sensitivity accompanied by descending viral load. VOC-dependent sensitivity assessment showed a sensitivity of 42.86% (95% CI, 32.82-53.52%) for the wild-type SARS-CoV-2, 43.42% (95% CI, 32.86-54.61%) for the Alpha VOC, 37.67% (95% CI, 30.22-45.75%) for the Delta VOC, and 33.67% (95% CI, 25.09-43.49%) for the Omicron VOC. Sensitivity in samples with high viral loads of ≥106 SARS-CoV-2 RNA copies per mL was significantly lower in the Omicron VOC (50.00%; 95% CI, 36.12-63.88%) than in the wild-type SARS-CoV-2 (79.31%; 95% CI, 61.61-90.15%; p 0.015). DISCUSSION: RDT sensitivity for detection of the Omicron VOC is reduced in individuals infected with a high viral load, which curtails the effectiveness of RDTs. This aspect furthert: limits the use of RDTs, although RDTs are still an irreplaceable diagnostic tool for rapid, economic point-of-care and extensive SARS-CoV-2 screening.

Changing Threshold-Based Segmentation Has No Relevant Impact on Semi-Quantification in the Context of Structured Reporting for PSMA-PET/CT.

Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with 18F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUVmax, SUVpeak, SUVmean) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUVmax was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories (p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUVmax and SUVpeak compared to the entire PSMA-RADS-4 or -5 cohort (p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort (p < 0.0001), but not to the PSMA-RADS-4 cohort (SUVmax, p = 0.07; SUVpeak, p = 0.08). SUVmean (p = 0.30) and TL-PSMA (p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT (p = 0.0066), which was driven by lymph nodes (p = 0.0239), but not bone lesions (p = 0.15). SUVmax was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in 18F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUVmean and TL-PSMA in contrast to PSMA-TV.

Inhibition of Aurora kinase B is important for biologic activity of the dual inhibitors of BCR-ABL and Aurora kinases R763/AS703569 and PHA-739358 in BCR-ABL transformed cells.

ABL tyrosine kinase inhibitors (TKI) like Imatinib, Dasatinib and Nilotinib are the gold standard in conventional treatment of CML. However, the emergence of resistance remains a major problem. Alternative therapeutic strategies of ABL TKI-resistant CML are urgently needed. We asked whether dual inhibition of BCR-ABL and Aurora kinases A-C could overcome resistance mediated by ABL kinase mutations. We therefore tested the dual ABL and Aurora kinase inhibitors PHA-739358 and R763/AS703569 in Ba/F3- cells ectopically expressing wild type (wt) or TKI-resistant BCR-ABL mutants. We show that both compounds exhibited strong anti-proliferative and pro-apoptotic activity in ABL TKI resistant cell lines including cells expressing the strongly resistant T315I mutation. Cell cycle analysis indicated polyploidisation, a consequence of continued cell cycle progression in the absence of cell division by Aurora kinase inhibition. Experiments using drug resistant variants of Aurora B indicated that PHA-739358 acts on both, BCR-ABL and Aurora Kinase B, whereas Aurora kinase B inhibition might be sufficient for the anti-proliferative activity observed with R763/AS703569. Taken together, our data demonstrate that dual ABL and Aurora kinase inhibition might be used to overcome ABL TKI resistant CML.

Enzymatically degradable poly(ethylene glycol) based hydrogels for adipose tissue engineering.

Adipose tissue engineering requires biomaterials that promote the differentiation of seeded adipocytes. Here, we report on the development and characterization of in situ forming, poly(ethylene glycol) (PEG) based hydrogels for soft tissue augmentation. Branched PEG-amines were modified with collagenase-sensitive peptides and cross-linked with branched PEG-succinimidyl propionates without the use of free-radical initiators (enzymatically degradable hydrogels). Alanine-modified PEG-amines were used for the preparation of non-degradable gels. Depending on the used polymer concentration, the strength of degradable gels after swelling ranged from 1708 to 7412 Pa; the strength of non-degradable hydrogels varied between 1496 and 7686 Pa. Enzyme mediated gel degradation occurred within 10, 16, and 19 days (5%, 10%, and 15% initial polymer content). To evaluate their suitability as scaffold materials for adipose tissue engineering, the hydrogels were functionalized with the laminin-derived adhesion peptide YIGSR, and seeded with 3T3-L1 preadipocytes. Compared to a standard two-dimensional cell culture model, the developed hydrogels significantly enhanced the intracellular triglyceride accumulation of encapsulated adipocytes. Functionalization with YIGSR further enhanced lipid synthesis within differentiating adipocytes. Long-term studies suggested that enzymatically degradable hydrogels furthermore promote the formation of coherent adipose tissue-like structures featuring many mature unilocular fat cells.

In vivo development and long-term survival of engineered adipose tissue depend on in vitro precultivation strategy.

One strategy of adipose tissue engineering is to transplant adipocytes or adipocyte precursor cells in combination with polymeric materials. However, a satisfying formation of fat tissue and its long-term survival still remain major problems. There is increasing evidence that treatment of the cells prior to implantation plays a critical role in the success of adipose tissue growth. In a previous study, we established a model system based on 3T3-L1 cells that allows for reproducible engineering of mature, coherent adipose tissues in vitro. We utilized this model system in the current study and systematically investigated the long-term in vivo development of cellular constructs with varying stages of adipogenic development at the time point of implantation. Blank polyglycolic acid fiber meshes, scaffolds seeded with uninduced 3T3-L1 preadipocytes, and cell-polymer constructs precultivated under adipogenic conditions for 2, 9, or 35 days were implanted subcutaneously into nude mice. Histological analysis revealed that no fat formation occurred in constructs without adipogenic precultivation. Implantation of mature fat pads (35 days) resulted in adiponecrosis within the constructs. In contrast, implants with an immature phenotype at the time point of implantation (2 and 9 days) gave rise to vascularized, mature adipose tissue in vivo. Further, these engineered adipose tissues showed long-term survival in vivo over the whole investigation period of 24 weeks. The results of this study can contribute to the development of future clinical approaches as they give clear evidence which precultivation strategy promotes successful development and long-term survival of engineered adipose tissue.