Guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of nonmetastatic muscle-invasive bladder cancer (MIBC). NAC is, however, underutilized in practice because of its associated ...limited overall survival (OS) benefit and significant treatment-related toxicity. We hypothesized that the absence of circulating tumour cells (CTCs) identifies MIBC patients with such a favourable prognosis that NAC may be withheld.
The CirGuidance study was an open-label, multicentre trial that included patients with clinical stage T2-T4aN0-N1M0 MIBC, scheduled for radical cystectomy. CTC-negative patients (no CTCs detectable using the CELLSEARCH system) underwent radical surgery without NAC; CTC-positive patients (≥1 detectable CTCs) were advised to receive NAC, followed by radical surgery. The primary endpoint was the 2-year OS in the CTC-negative group with a prespecified criterion for trial success of ≥75% (95% confidence interval (CI) ±5%).
A total of 273 patients were enrolled. Median age was 69 years; median follow-up was 36 months. The primary endpoint of 2-year OS in the CTC-negative group was 69.5% (N = 203; 95% CI 62.6%-75.5%). Two-year OS was 58.2% in the CTC-positive group (N = 70; 95% CI 45.5%-68.9%). CTC-positive patients had a higher rate of cancer-related mortality hazard ratio (HR) 1.61, 95% CI 1.05-2.45, P = 0.03 and disease relapse (HR 1.87, 95% CI 1.28-2.73, P = 0.001) than CTC-negative patients. Explorative analyses suggested that CTC-positive patients who had received NAC (n = 22) survived longer than CTC-positive patients who had not (n = 48).
The absence of CTCs in MIBC patients was associated with improved cancer-related mortality and a lower risk of disease relapse after cystectomy; however, their absence alone does not justify to withhold NAC. Exploratory analyses suggested that CTC-positive MIBC patients might derive more benefit from NAC.
Netherlands Trial Register NL3954; https://www.trialregister.nl/trial/3954
•Two-year OS in CTC-negative MIBC patients did not meet the criterion for trial success.•CTCs are prognostic for cancer-related mortality and relapse-free survival in MIBC.•CTC-positive MIBC patients survived longer when receiving NAC in explorative analyses.•The absence of CTCs alone is insufficient to withhold NAC in MIBC patients.
Small island developing states are among the most vulnerable areas to the impact of natural hazards and climate change. Flooding due to storm surges and extreme waves, coastal erosion, and ...salinization of freshwater lenses are already a serious threat and could lead to irreversible consequences in the coming decades. Reef flat mining is one of the most common practices to source the required material for the implementation of coastal protection measures, but concerns remain that partial removal of the protective reef could increase wave loading on the islands. However, the available data and knowledge on the effects of these mining pits are currently very limited. This study provides new insights on the effects that pits may have on nearshore hydrodynamics and wave runup. Results are based on a large numerical data set of fringing reefs, derived using the validated XBeach nonhydrostatic+ process‐based model. Model results indicate that excavation pits cause a decrease in infragravity wave energy around the fundamental mode of the reef, which is partly caused by reduced wave transmission. Additionally, changes in sea and swell wave energy are attributed to reduced transmission, a decrease in wave dissipation, and (triad) wave–wave interaction. Furthermore, in 13% of all modeled cases, an increase in wave runup is observed, mainly due to more sea and swell wave energy reaching the shoreline. This probability is lowest for narrow pits relative to the reef flat width or pits located further from shore.
Plain Language Summary
Many small island states are among the most vulnerable areas to the impacts of climate change. Additionally, flooding due to storms, coastal erosion, and loss of freshwater supply already form a serious threat. Mining of dead coral sediments from the reef flat is a common practice to source material for coastal protection works. This could potentially lead to higher waves at the coastline through the partial removal of the reef, which breaks large waves. However, the knowledge on the effects of these mining pits is currently very limited. The present study provides improved explanations on the effects that a pit may have on waves and assesses the resulting risk of flooding it poses on these islands. The results are obtained by simulating a large set of different reefs and wave conditions using a numerical model named XBeach. These show that the effect of a pit can vary significantly, but in general, a pit causes lower waves near the shoreline. At some cases, larger waves at the shoreline were found, thereby increasing the risk of flooding. This risk is the lowest for pits that are located further from the coastline, or those that have narrow width relative to the reef width.
Key Points
Coral Reef mining pits cause a variation in the nearshore hydrodynamics and wave runup during extreme events
Pits generally cause a decrease in nearshore wave height and extreme runup mainly due to lower infragravity wave energy
Pits with a relatively narrow cross‐shore width or with a location further from shore are least likely to cause an increase in runup
Summary
The Laryngeal Tube S™ and the LMA‐ProSeal® are supraglottic instruments with an improved airway seal and a drainage tube to protect against regurgitation and to facilitate passage of a ...gastric tube. We compared the feasibility of these two instruments in a randomised, controlled clinical trial. One hundred and sixty patients were randomly allocated to undergo insertion of a Laryngeal Tube S (n = 82) or an LMA‐ProSeal (n = 78). All insertions were carried out by first‐month anaesthesia residents. Success rates were not significantly different: Laryngeal Tube S 89%, LMA‐ProSeal 95%. There was also no significant difference in leak pressure or insertion time. Insertion time decreased significantly when we compared the first with the last 10 insertions. Gastric tube placement was successful in all patients in the Laryngeal Tube S group, but failed in 12 patients in the LMA‐ProSeal group (p < 0.001). Dysphagia was reported by 22% of Laryngeal Tube S group and 3% of LMA‐ProSeal group (p = 0.001). These findings demonstrate the applicability of the devices and a learning effect in the hands of anaesthesia residents with limited experience.
Detection of tumor cells in blood and bone marrow is increasingly used for the staging of patients with breast cancer and to evaluate the presence of tumor cells in peripheral blood progenitor cell ...collections to be used after high-dose therapy. We evaluated the sensitivity and specificity of three different methods for detection of tumor cells among non-tumor tissue. An immunocytochemical assay using antibodies directed against epitopes of the cytokeratin-19 (CK19) protein and two RNA-based methods: reverse transcriptase polymerase chain reaction (RT-PCR) and Nucleic Acid Sequence-Based Amplification (NASBA) for the same target gene were tested. With all the three methods, false-positive results were observed when peripheral blood mononuclear cells (PBMC) of healthy volunteers were tested. There was no concordance between the RNA-based assays and the immunocytochemical assay. The false-positive results in the RNA-based assays may be due to 'illegitimate expression' of epithelial genes in normal PBMC. The false-positive results in the immunocytochemical assay resulted from background staining of monocytes and granulocytes. This study demonstrates that CK19 is not a suitable target to detect the presence of breast tumor tells in PBMC. To reliably detect circulating tumor cells with RNA methods, the selection of suitable target genes is required, which are highly expressed in tumors but not at all in normal cells of blood and bone marrow. Genes with such characteristics may be identifiable with novel differential display techniques.
In patients with chronic myeloid leukemia (CML) who do not reach a (near) complete cytogenetic response, the disease progresses over several years from an indolent, chronic phase into a rapidly fatal ...blast crisis. Events that are responsible for this transformation process are largely unknown. To identify changes in gene expression that occurred during the course of the disease, we performed cDNA subtraction on sequentially stored peripheral blood mononuclear cell pellets, collected throughout the course of disease of a single CML patient. In total, 32 differentially expressed sequences were identified, of which 27 corresponded to known genes. On quantitative PCR, eight of these genes, YWHAZ, GAS2, IL8, IL6, PBEF1, CCL4, SAT and MMRN, showed comparable differential expression in additional CML patient samples. This set of genes can be considered as a starting point for further research on causes of disease transformation in CML and may lead to new targets in the treatment of resistant CML.
Purpose
For many malignancies, considerable divergence between the efficacy found in clinical trials and effectiveness in routine practice have been reported (efficacy–effectiveness gap). The purpose ...of this study was to evaluate the efficacy–effectiveness gap in palliative first-line (1L) chemotherapy treatment (CTx) for urothelial carcinoma of the bladder.
Methods
From seven Dutch teaching hospitals, all patients diagnosed with unresectable stage III (cT2-4aN1-3M0) and IV (cT4b and/or cM1) disease, who received 1L-CTx (for both primary as recurrent disease after radical cystectomy) between 2008 and 2016, were captured. Results were compared with data from seven randomised trials that investigated 1L gemcitabine + cisplatin (GemCis) and/or gemcitabine + carboplatin (GemCarbo).
Results
Of the 835 included patients, 191 received 1L-CTx. Median overall survival (mOS) of GemCis patients (
N
= 88) was 10.4 months 95% CI 7.9–13.0, which was shorter compared to clinical trial findings (range mOS: 12.7–14.3 months) despite comparable clinical characteristics. The mOS of GemCarbo patients (
N
= 92) was 9.3 months 95% CI 7.5–11.1. Patients who received GemCarbo had worse prognostic characteristics (higher age, impaired renal function and worse performance status (all
P
-values < 0.001)) compared to GemCis patients, but were equal in occurrence of dose reductions (24.4% vs. 29.5%,
P
-value = 0.453), early termination (55.7% vs. 54.1%,
P
-value = 0.839), clinical best response (
P
-value = 0.733), and toxicity (68.1% vs. 63.3%,
P
-value = 0.743). In multivariable regression, GemCis was not superior to GemCarbo (HR 0.90 95% CI 0.55–1.47,
P
-value = 0.674).
Conclusion
There seems to be an efficacy–effectiveness gap in 1L GemCis treatment, despite patients having similar baseline characteristics. Early termination of treatment occurred more often and dose reduction less often compared to clinical trials, hinting towards abandonment of treatment in case of adverse events. Patients treated with 1L GemCis did not have superior survival compared to GemCarbo patients, even though GemCarbo patients had worse baseline characteristics.
Purpose
Population-based studies on treatment patterns in oncology and corresponding clinical outcomes can help identify strategies towards optimal value for patients. This study was performed to ...describe the variation in treatment patterns and major oncological outcomes for muscle-invasive or metastatic bladder cancer (MIBC/mBC) patients in the Netherlands.
Methods
Patients diagnosed with cT2-4aN0-3M0-1 disease between 2008 and 2016 in seven large teaching hospitals in the Netherlands were included. Baseline characteristics, disease stage, intended and definitive treatment, and oncological outcomes were collected. Patients were categorized based on cTNM-stage: (1) cT2-4aN0M0, (2) cT2-4aN1-3M0 and (3) cT4b and/or M1.
Results
The total study population comprised 1853 patients, of which 1303 patients were diagnosed with cT2-4aN0M0 disease. Overall, curative treatment was intended in 81% (range 74–85%,
P
value = 0.132). Radical cystectomy (RC) and curative radiotherapy (RTx) ranged between hospitals from 42 to 66% and 13 to 27%, respectively (
P
value < 0.001). For 334 patients staged cT4b and/or M1, frequencies for palliative therapy and best supportive care (no anti-cancer therapy) ranged between hospitals from 20 to 54% and 44 to 71%, respectively (
P
value < 0.001). There was no association between hospital site and overall survival (OS) in a univariable and multivariable Cox regression for survival analysis (after adjusting for age and cT-stage), for all three cTNM-groups. Neoadjuvant or induction chemotherapy (NAIC) utilization rates before RC ranged from 8 to 38% (
P
value < 0.001).
Conclusions
There is large inter-hospital variation in treatment intent in MIBC/mBC patients. This variation does not seem to translate to differences in overall survival rates. There is an ongoing trend of increased use of RC. Utilisation of NAIC is relatively low considering European guideline recommendations.
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