Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile ...surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.
This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.
The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.
Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
After neoadjuvant chemoradiotherapy (nCRT) plus surgery for oesophageal cancer, 29 per cent of patients have a pathologically complete response in the resection specimen. Active ...surveillance after nCRT (instead of standard oesophagectomy) may improve health‐related quality of life (HRQoL), but patients need to undergo frequent diagnostic tests and it is unknown whether survival is worse than that after standard oesophagectomy. Factors that influence patients' preferences, and trade‐offs that patients are willing to make in their choice between surgery and active surveillance were investigated here.
Methods
A prospective discrete‐choice experiment was conducted. Patients with oesophageal cancer completed questionnaires 4–6 weeks after nCRT, before surgery. Patients' preferences were quantified using scenarios based on five aspects: 5‐year overall survival, short‐term HRQoL, long‐term HRQoL, the risk that oesophagectomy is still necessary, and the frequency of clinical examinations using endoscopy and PET–CT. Panel latent class analysis was used.
Results
Some 100 of 104 patients (96·2 per cent) responded. All aspects, except the frequency of clinical examinations, influenced patients' preferences. Five‐year overall survival, the chance that oesophagectomy is still necessary and long‐term HRQoL were the most important attributes. On average, based on calculation of the indifference point between standard surgery and active surveillance, patients were willing to trade off 16 per cent 5‐year overall survival to reduce the risk that oesophagectomy is necessary from 100 per cent (standard surgery) to 35 per cent (active surveillance).
Conclusion
Patients are willing to trade off substantial 5‐year survival to achieve a reduction in the risk that oesophagectomy is necessary.
Organ preservation preferred
We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected ...males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a “molar tooth sign,” which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of
OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified.
OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the
LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in
OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant
OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in
OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for
OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.
IMPORTANCE: Postoperative pancreatic fistula is a potentially life-threatening complication after pancreatoduodenectomy. Evidence for best management is lacking. OBJECTIVE: To evaluate the clinical ...outcome of patients undergoing catheter drainage compared with relaparotomy as primary treatment for pancreatic fistula after pancreatoduodenectomy. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, retrospective, propensity-matched cohort study was conducted in 9 centers of the Dutch Pancreatic Cancer Group from January 1, 2005, to September 30, 2013. From a cohort of 2196 consecutive patients who underwent pancreatoduodenectomy, 309 patients with severe pancreatic fistula were included. Propensity score matching (based on sex, age, comorbidity, disease severity, and previous reinterventions) was used to minimize selection bias. Data analysis was performed from January to July 2016. EXPOSURES: First intervention for pancreatic fistula: catheter drainage or relaparotomy. MAIN OUTCOMES AND MEASURES: Primary end point was in-hospital mortality; secondary end points included new-onset organ failure. RESULTS: Of the 309 patients included in the analysis, 209 (67.6%) were men, and mean (SD) age was 64.6 (10.1) years. Overall in-hospital mortality was 17.8% (55 patients): 227 patients (73.5%) underwent primary catheter drainage and 82 patients (26.5%) underwent primary relaparotomy. Primary catheter drainage was successful (ie, survival without relaparotomy) in 175 patients (77.1%). With propensity score matching, 64 patients undergoing primary relaparotomy were matched to 64 patients undergoing primary catheter drainage. Mortality was lower after catheter drainage (14.1% vs 35.9%; P = .007; risk ratio, 0.39; 95% CI, 0.20-0.76). The rate of new-onset single-organ failure (4.7% vs 20.3%; P = .007; risk ratio, 0.15; 95% CI, 0.03-0.60) and new-onset multiple-organ failure (15.6% vs 39.1%; P = .008; risk ratio, 0.40; 95% CI, 0.20-0.77) were also lower after primary catheter drainage. CONCLUSIONS AND RELEVANCE: In this propensity-matched cohort, catheter drainage as first intervention for severe pancreatic fistula after pancreatoduodenectomy was associated with a better clinical outcome, including lower mortality, compared with primary relaparotomy.
Active surveillance may be a safe and effective treatment in oesophageal cancer patients with a clinically complete response after neoadjuvant chemoradiotherapy (nCRT). In the NOSANO‐study we gained ...insight in patients' motive to opt for either an experimental treatment called active surveillance or for standard immediate surgery. Both qualitative and quantitative analyses methods were used. Forty patients were interviewed about their treatment preference, 3 months after completion of nCRT (T1). Data were recorded, transcribed verbatim and analysed according to the principles of grounded theory. In addition, at T1 and T2 (12 months after completion of nCRT) questionnaires on health‐related quality of life, coping, anxiety and decisional regret (only T2) were administered. Interview data analyses resulted in a conceptual model with ‘dealing with threat of cancer’ as the central theme. Patients preferring active surveillance tend to cope with this threat by confiding in their bodies and good outcomes. Their mind‐set is one of ‘enjoy life now’. Patients preferring surgery tend to cope by minimizing uncertainty and eliminating the source of cancer. Their mind‐set is one of ‘don't give up, act now’. Furthermore, questionnaire results showed that patients with a preference for standard surgery had a lower quality of life. Patient preferences are individualized and thus difficult to predict. Our model can help healthcare professionals to determine patient preferences for treatment. Coping style and mind‐set seem to be determining factors here.
What's new?
Active surveillance has become an alternative to standard surgery for oesophageal cancer patients with a clinically complete response after neoadjuvant chemoradiotherapy. This is the first study to explore the personal motivations for patients to opt for active surveillance or standard surgery. The results show that patients with a strong preference for active surveillance tend to cope with the threat of cancer by having faith in their bodies and good outcomes; patients with a strong preference for standard surgery tend to cope by minimizing the uncertainty. The model could support doctors and patients in reaching a well‐informed and personalized treatment decision.
Untargeted liquid chromatography–mass spectrometry (LC–MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The ...long-standing “grand challenge” in the utilization of this approach is metabolite identificationconfidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC–MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of α-aminoadipic semialdehyde (α-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While α-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics–IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.
Microtubules are a vital component of the cell's cytoskeleton and their organization is crucial for healthy cell functioning. The use of label-free SH imaging of microtubules remains limited, as ...sensitive detection is required and the true molecular origin and main determinants required to generate SH from microtubules are not fully understood. Using advanced correlative imaging techniques, we identified the determinants of the microtubule-dependent SH signal. Microtubule polarity, number and organization determine SH signal intensity in biological samples. At the molecular level, we show that the GTP-bound tubulin dimer conformation is fundamental for microtubules to generate detectable SH signals. We show that SH imaging can be used to study the effects of microtubule-targeting drugs and proteins and to detect changes in tubulin conformations during neuronal maturation. Our data provide a means to interpret and use SH imaging to monitor changes in the microtubule network in a label-free manner.
Carbon nanotube yarns are micron-scale fibers comprised by tens of thousands of carbon nanotubes in their cross section and exhibiting piezoresistive characteristics that can be tapped to sense ...strain. This paper presents the details of novel foil strain gauge sensor configurations comprising carbon nanotube yarn as the piezoresistive sensing element. The foil strain gauge sensors are designed using the results of parametric studies that maximize the sensitivity of the sensors to mechanical loading. The fabrication details of the strain gauge sensors that exhibit the highest sensitivity, based on the modeling results, are described including the materials and procedures used in the first prototypes. Details of the calibration of the foil strain gauge sensors are also provided and discussed in the context of their electromechanical characterization when bonded to metallic specimens. This characterization included studying their response under monotonic and cyclic mechanical loading. It was shown that these foil strain gauge sensors comprising carbon nanotube yarn are sensitive enough to capture strain and can replicate the loading and unloading cycles. It was also observed that the loading rate affects their piezoresistive response and that the gauge factors were all above one order of magnitude higher than those of typical metallic foil strain gauges. Based on these calibration results on the initial sensor configurations, new foil strain gauge configurations will be designed and fabricated, to increase the strain gauge factors even more.
In this article we combine the well-known Ptychographical Iterative Engine (PIE) with the Hybrid Input-Output (HIO) algorithm. The important insight is that the HIO feedback function should be kept ...strictly separate from the reconstructed object, which is done by introducing a separate feedback function per probe position. We have also combined HIO with floating PIE (fPIE) and extended PIE (ePIE). Simulations indicate that the combined algorithm performs significantly better in many situations. Although we have limited our research to a combination with HIO, the same insight can be used to combine ptychographical algorithms with any phase retrieval algorithm that uses a feedback function.
•Ptychographical phase retrieval algorithms PIE, fPIE, and ePIE are improved with HIO.•Using a separate feedback functions may be applied to other algorithms like RAAR.•The algorithm does not require many or small probes, and may converge faster.•Additional algorithms are proposed to deal with the presence of shot noise.
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