Sendai virus persistence questions the transient naive reprogramming method for iPSC generation.

Since the revolutionary discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka, the comparison between iPSCs and embryonic stem cells (ESCs) has revealed significant differences in their epigenetic states and developmental potential. A recent compelling study published in Nature by Buckberry et al.1 demonstrated that a transient-naive-treatment (TNT) could facilitate epigenetic reprogramming and improve the developmental potential of human iPSCs (hiPSCs). However, the study characterized bulk hiPSCs instead of isolating clonal lines and overlooked the persistent expression of Sendai virus carrying exogenous Yamanaka factors. Our analyses revealed that Sendai genes were expressed in most control PSC samples, including hESCs, which were not intentionally infected. The highest levels of Sendai expression were detected in samples continuously treated with naive media, where it led to overexpression of exogenous MYC, SOX2, and KLF4, altering both the expression levels and ratios of reprogramming factors. Our findings call for further research to verify the effectiveness of the TNT method in the context of delivery methods that ensure prompt elimination of exogenous factors, leading to the generation of bona fide transgene-independent iPSCs.

Interplay of Andreev Reflection and Coulomb Blockade in Hybrid Superconducting Single-Electron Transistors.

We study the interplay between Coulomb blockade and superconductivity in a tunable superconductor-superconductor-normal-metal single-electron transistor. The device is realized by connecting the superconducting island via an oxide barrier to the normal-metal lead and with a break junction to the superconducting lead. The latter enables Cooper pair transport and (multiple) Andreev reflection. We show that these processes are relevant also far above the superconducting gap and that signatures of Coulomb blockade may reoccur at high bias while they are absent for small bias in the strong-coupling regime. Our experimental findings agree with simulations using a rate equation approach in combination with the full counting statistics of multiple Andreev reflection.

R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial.

BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m2 on day 1 and 9, cyclophosphamide 800 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2-5, vincristine 1·5 mg/m2 on days 1 and 8, doxorubicin 40 mg/m2 on day 1, and methotrexate 3000 mg/m2 on day 10; R-IVAC: rituximab 375 mg/m2 on days 3 and 7, iphosphamide 1500 mg/m2 on days 1-5, etoposide 60 mg/m2 on days 1-5, and cytarabin 2000 mg/m2 on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m2 on days 1-4, prednisolone 120 mg/m2 on days 1-5, vincristine 0·4 mg/m2 on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m2 on day 5, dose-adjusted doxorubicin 10-24·8 mg/m2 on days 1-4, rituximab 375 mg/m2 on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27. FINDINGS: Due to a slow accrual, the study was closed prematurely on Nov 15, 2021. Between Aug 4, 2014, and Sept 17, 2021, 89 patients were enrolled and randomly assigned to receive R-CODOX-M/R-IVAC (n=46) or DA-EPOCH-R (n=43). Five patients were excluded after random assignment (three in the R-CODOX-M/R-IVAC group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and two CNS involvement] and two in the DA-EPOCH-R group [one diagnosis other than Burkitt lymphoma at study entry according to local pathology and one CNS involvement]. 84 remaining patients were included in the modified intention-to-treat analysis. 73 (87%) of 84 patients were male, 76 (90%) presented with stage III or IV disease, and nine (11%) had HIV-positive Burkitt lymphoma. Median patient age was 52 years (IQR 37-64). With a median follow-up of 28·5 months (IQR 13·2-43·7), 2-year progression-free survival was 76% (95% CI 60-86%) in the R-CODOX-M/R-IVAC group and 70% (54-82%) in the DA-EPOCH-R group (hazard ratio 1·42, 95% CI 0·63-3·18; p=0·40). There were two deaths in the R-CODOX-M/R-IVAC group (one infection [treatment related] and one due to disease progression [not treatment related]) and one death in the DA-EPOCH-R group (COVID-19 infection [treatment related]). In the R-CODOX-M/R-IVAC group, four patients went off-protocol because of toxic effects, versus none in the DA-EPOCH-R group. Patients treated with R-CODOX-M/R-IVAC had more infectious adverse events (24 [56%] of 43 patients had at least one grade 3-5 infection vs 14 [34%] of 41 patients in the DA-EPOCH-R group). INTERPRETATION: The trial stopped early, but the available data suggest that while DA-EPOCH-R did not result in superior progression-free survival compared with R-CODOX-M/R-IVAC, it was associated with fewer toxic effects and need for supportive care. DA-EPOCH-R appears to be an additional valid therapeutic option for patients with high-risk Burkitt lymphoma without CNS involvement. FUNDING: The Dutch Cancer Society and the Schumacher-Kramer Foundation.

Virtual Reality for Anxiety Reduction in Women Undergoing Colposcopy: A Randomized Controlled Trial.

OBJECTIVE: To test whether headset-delivered virtual reality (VR) content affects satisfaction and/or anxiety in women with cervical squamous intraepithelial lesions undergoing colposcopy and colposcopically guided cervical biopsy. METHODS: In this single-center, randomized trial, the authors measured overall satisfaction (100-mm visual analog scale) and situation-specific anxiety (STAI-S) in 247 women with suspected cervical squamous intraepithelial lesions wearing either no VR headset (arm 1, control) or a VR headset before (arm 2) or before and during colposcopy (arm 3). Secondary endpoints were pain, discomfort, and anxiety during colposcopy, heart rate, and 72-hour follow-up parameters: overall satisfaction, bleeding severity, bleeding duration, pain, and use of analgesics. Analysis was by intention to treat. RESULTS: Median values for overall satisfaction were 100 (interquartile range, 90-100) in controls (n = 83), 100 (95-100) in arm 2 (n = 82), and 100 (95-100) in arm 3 (n = 82), respectively ( p = .92). The median Δ of situational anxiety (baseline vs after colposcopy) was -8 (-13 to -3), -8 (-16.5 to -4), and -10 (-20.5 to -4.5), respectively ( p = .09). The secondary endpoints pain during colposcopy (20 [10-50] vs 20 [10-40] vs 30 [10-50]; p = .65), discomfort during colposcopy (30 [10-50] vs 30 [10-50] vs 20 [10-50]; p = .46), and anxiety during colposcopy (20 [0-50] vs 10 [0-40] vs 10 [0-30]; p = .44), were not different between arms. Follow-up data showed no improvement in the 2 VR arms compared with controls (overall satisfaction, p = .37; bleeding severity, p = .09; pain level, p = .89; duration of pain; p = .23; and use of analgesics; p = .39). Per-protocol analysis did not change the results. CONCLUSIONS: A VR headset showing a 360-degree surround vision film has no effect on satisfaction or anxiety in women undergoing colposcopy.

A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m2 iv, on day one of a 28 days-cycle until progression. The Kaplan-Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects.Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

Diode effect in Josephson junctions with a single magnetic atom.

Current flow in electronic devices can be asymmetric with bias direction, a phenomenon underlying the utility of diodes1 and known as non-reciprocal charge transport2. The promise of dissipationless electronics has recently stimulated the quest for superconducting diodes, and non-reciprocal superconducting devices have been realized in various non-centrosymmetric systems3-10. Here we investigate the ultimate limits of miniaturization by creating atomic-scale Pb-Pb Josephson junctions in a scanning tunnelling microscope. Pristine junctions stabilized by a single Pb atom exhibit hysteretic behaviour, confirming the high quality of the junctions, but no asymmetry between the bias directions. Non-reciprocal supercurrents emerge when inserting a single magnetic atom into the junction, with the preferred direction depending on the atomic species. Aided by theoretical modelling, we trace the non-reciprocity to quasiparticle currents flowing by means of electron-hole asymmetric Yu-Shiba-Rusinov states inside the superconducting energy gap and identify a new mechanism for diode behaviour in Josephson junctions. Our results open new avenues for creating atomic-scale Josephson diodes and tuning their properties through single-atom manipulation.

Eribulin as first-line treatment in older patients with advanced breast cancer: A multicenter phase II trial [SAKK 25/14].

INTRODUCTION: Standard-dose eribulin mesylate (1.4 mg/m2 d1 + 8) achieves clinical benefit rates of 26%-52% in patients with metastatic breast cancer (mBC). <10% of patients in the registration trial were ≥ 70 years old; dose reductions were common in these older patients. MATERIALS AND METHODS: This single-arm phase II trial explored the efficacy of reduced starting dosing of first-line eribulin at 1 mg/m2 d1 + 8 q3 weeks in patients with mBC aged ≥70 years. The primary endpoint was a disease control rate (DCR) ≥55%. The secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and patient-reported neurotoxicity. RESULTS: Overall, 77 patients were accrued; their median age was 76 years and Eastern Cooperative Oncology Group performance status was 0-1 in 90%. The DCR was 40% (90% confidence interval [CI]: 31-50); therefore, the primary endpoint was not reached. The overall response rate was 22% (95%CI: 13-33), median PFS 5.4 months (95%CI: 4.5-7.7), and median OS 16.1 months (95%CI: 13.5-26.9). Dose modifications were necessary in 35% of patients. In nine patients, more than fifteen cycles were given; 48 patients (62%) experienced at least one grade 3 toxicity. Median patient-reported neurotoxicity scores remained stable for at least fifteen cycles. The main reason for treatment discontinuation was disease progression (57%). DISCUSSION: We report the first prospective data on first-line eribulin in older patients. The reduced starting dose of 1.1 mg/m2 was safe, with prolonged treatment and DC achieved in a considerable proportion of patients (but less than the 55% assumed), without cumulative neurotoxicity. The reduced dose was apparently within the range of the minimal effective dose, as shown by the efficacy lack in patients requiring further dose reductions. Thus, our results do not support the approach of a reduced starting dose for older patients.

An epitaxial graphene platform for zero-energy edge state nanoelectronics.

Graphene's original promise to succeed silicon faltered due to pervasive edge disorder in lithographically patterned deposited graphene and the lack of a new electronics paradigm. Here we demonstrate that the annealed edges in conventionally patterned graphene epitaxially grown on a silicon carbide substrate (epigraphene) are stabilized by the substrate and support a protected edge state. The edge state has a mean free path that is greater than 50 microns, 5000 times greater than the bulk states and involves a theoretically unexpected Majorana-like zero-energy non-degenerate quasiparticle that does not produce a Hall voltage. In seamless integrated structures, the edge state forms a zero-energy one-dimensional ballistic network with essentially dissipationless nodes at ribbon-ribbon junctions. Seamless device structures offer a variety of switching possibilities including quantum coherent devices at low temperatures. This makes epigraphene a technologically viable graphene nanoelectronics platform that has the potential to succeed silicon nanoelectronics.

Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Innovative Diagnostic and Therapeutic Interventions in Cervical Dysplasia: A Systematic Review of Controlled Trials.

Cervical dysplasia is a common precancerous lesion affecting 1% to 2% of women worldwide. Significant progress in the diagnosis and treatment of cervical dysplasia have been made in the last decade. We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled clinical trials reporting on the efficacy and safety of diagnostic and therapeutic interventions for cervical dysplasia. Data were analyzed according to PRISMA guidelines. In total, 33 studies reporting on 5935 women were identified. We recommend intravenous or intracervical lidocaine for pain reduction during colposcopically-directed cervical biopsies but not topical lidocaine, music, or video colposcopy. Monsel's solution might be used to control bleeding after cervical biopsies. The acetic acid test should be scored 1 min after the application of acetic acid and should be followed by Lugol's iodine test for an optimal yield of LSIL/HSIL. LEEP/LLETZ remains the standard and techniques such as SWETZ, C-LETZ, and TCBEE are not superior. LEEP/LLETZ should be performed under local anesthesia and with direct colposcopic vision. Cryotherapy and thermoablation might be used in women with LSIL, especially in women with HIV infection, but LEEP/LLETZ remains the standard for HSIL. Topical imiquimod remains an experimental procedure. In conclusion, significant progress has been made in the last decade regarding both diagnostic interventions as well as therapeutic interventions for women with cervical dysplasia. Based on >30 controlled clinical trials, we were able to formulate specific and evidence-based recommendations.

Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.

Imaging tunable quantum Hall broken-symmetry orders in graphene.

ABSTARCT: When electrons populate a flat band their kinetic energy becomes negligible, forcing them to organize in exotic many-body states to minimize their Coulomb energy1-5. The zeroth Landau level of graphene under a magnetic field is a particularly interesting strongly interacting flat band because interelectron interactions are predicted to induce a rich variety of broken-symmetry states with distinct topological and lattice-scale orders6-11. Evidence for these states stems mostly from indirect transport experiments that suggest that broken-symmetry states are tunable by boosting the Zeeman energy12 or by dielectric screening of the Coulomb interaction13. However, confirming the existence of these ground states requires a direct visualization of their lattice-scale orders14. Here we image three distinct broken-symmetry phases in graphene using scanning tunnelling spectroscopy. We explore the phase diagram by tuning the screening of the Coulomb interaction by a low- or high-dielectric-constant environment, and with a magnetic field. In the unscreened case, we find a Kekulé bond order, consistent with observations of an insulating state undergoing a magnetic-field driven Kosterlitz-Thouless transition15,16. Under dielectric screening, a sublattice-unpolarized ground state13 emerges at low magnetic fields, and transits to a charge-density-wave order with partial sublattice polarization at higher magnetic fields. The Kekulé and charge-density-wave orders furthermore coexist with additional, secondary lattice-scale orders that enrich the phase diagram beyond current theory predictions6-10. This screening-induced tunability of broken-symmetry orders may prove valuable to uncover correlated phases of matter in other quantum materials.

Targeted modifications of monolithic multiterminal superconducting weak-links.

In a multi-branch metallic interconnect we demonstrate the possibility to induce targeted modifications of the material properties by properly selecting the intensity and polarity of the applied current. We illustrate this effect in Y-shape multiterminal devices made of Nb on sapphire for which we show that the superconducting critical current can be lowered in a controlled manner at a preselected junction. We further observe the gradual appearance of Fraunhofer-like critical current oscillations with magnetic field which indicates the gradual modification of a superconducting weak link. This method permits progressive modifications of a hand-picked junction without affecting the neighboring terminals. The proposed approach has the benefit of being inexpensive and requiring conventional electronics. This technique represents a major step toward all-electric control of multiterminal Josephson junctions.

Quantum Confinement Suppressing Electronic Heat Flow below the Wiedemann-Franz Law.

The Wiedemann-Franz law states that the charge conductance and the electronic contribution to the heat conductance are proportional. This sets stringent constraints on efficiency bounds for thermoelectric applications, which seek a large charge conduction in response to a small heat flow. We present experiments based on a quantum dot formed inside a semiconducting InAs nanowire transistor, in which the heat conduction can be tuned significantly below the Wiedemann-Franz prediction. Comparison with scattering theory shows that this is caused by quantum confinement and the resulting energy-selective transport properties of the quantum dot. Our results open up perspectives for tailoring independently the heat and electrical conduction properties in semiconductor nanostructures.

Endometrial hyperplasia as a risk factor of endometrial cancer.

Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.

A community-based approach to image analysis of cells, tissues and tumors.

Emerging multiplexed imaging platforms provide an unprecedented view of an increasing number of molecular markers at subcellular resolution and the dynamic evolution of tumor cellular composition. As such, they are capable of elucidating cell-to-cell interactions within the tumor microenvironment that impact clinical outcome and therapeutic response. However, the rapid development of these platforms has far outpaced the computational methods for processing and analyzing the data they generate. While being technologically disparate, all imaging assays share many computational requirements for post-collection data processing. As such, our Image Analysis Working Group (IAWG), composed of researchers in the Cancer Systems Biology Consortium (CSBC) and the Physical Sciences - Oncology Network (PS-ON), convened a workshop on "Computational Challenges Shared by Diverse Imaging Platforms" to characterize these common issues and a follow-up hackathon to implement solutions for a selected subset of them. Here, we delineate these areas that reflect major axes of research within the field, including image registration, segmentation of cells and subcellular structures, and identification of cell types from their morphology. We further describe the logistical organization of these events, believing our lessons learned can aid others in uniting the imaging community around self-identified topics of mutual interest, in designing and implementing operational procedures to address those topics and in mitigating issues inherent in image analysis (e.g., sharing exemplar images of large datasets and disseminating baseline solutions to hackathon challenges through open-source code repositories).

Clinical Outcome for Patients Managed with Low-Dose Cisplatin and Doxorubicin Delivered as Pressurized Intraperitoneal Aerosol Chemotherapy for Unresectable Peritoneal Metastases of Gastric Cancer.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to manage gastric cancer peritoneal metastasis (GCPM). METHODS: This study analyzed a prospective database of GCPM patients treated with cisplatin and doxorubicin PIPAC (PIPAC-C/D). The outcome criteria were adverse events, pathologic response [peritoneal regression grading score (PRGS)], and overall survival (OS). RESULTS: The PIPAC-C/D procedure was scheduled for 144 patients with a median age of 57 years (range 22-88 years). Access to the abdominal cavity for the first PIPAC failed in 11 patients (7.7 %). A total of 296 procedures were performed for 131 patients. Of the 144 patients, 52 (36.1%) underwent one PIPAC, 32 (22.2%) underwent two PIPACs, 24 (16.7%) underwent three PIPACs, and 21 (14.6%) underwent four or more PIPACs. The overall morbidity/mortality was grade 1 for 22 patients (15.3%), grade 2 for 32 patients (22.2%), grade 3 for 7 patients (4.9%), grade 4 for no patients (0%), and grade 5 for 2 patients (1.4%). Of the 37 patients who had three or more PIPACs eligible for histopathologic response analysis, 27 (73%) had major or complete regression (PRGS 1/2). A median OS of 11 months (range 0-61 months) for the total study population and 16 months (range 2-61 months) for the patients with three or more PIPACs was observed. For 10 patients (7%) who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, the median OS was 15 months (minimum, 4 months; maximum, 27 months). Multivariate analysis showed three or more PIPACs to be an independent prognostic factor for improved OS (hazard ratio, 0.36; p < 0.0001). CONCLUSIONS: Repetitive PIPAC-C/D ± systemic chemotherapy is associated with low morbidity and mortality rates. Prospective randomized trials are needed to confirm whether three or more PIPAC-C/Ds improve clinical outcome.

Video colposcopy versus headlight for large loop excision of the transformation zone (LLETZ): a randomised trial.

PURPOSE: To compare resected cone mass and resection margin status when performing Large Loop Excision of the Transformation Zone (LLETZ) using video colposcopy (LLETZ-VC) versus a headlight (LLETZ-HL) in women with cervical dysplasia. METHODS: Prospective, randomised trial (monocentric) at a specialised cervical dysplasia unit in a University Hospital. Women with a biopsy-proven CIN2 + or persisting CIN1 or diagnostic LLETZ were recruited and randomised. LLETZ was performed either under video colposcopic vision or using a standard surgical headlight. The primary endpoint was resected cone mass. Secondary endpoints were the rate of involved margins, fragmentation of the specimen, procedure time, time to complete haemostasis (TCH), blood loss, pain, intra- and postoperative complications, and surgeon preference. RESULTS: LLETZ-VC and LLETZ-HL (109 women each) had comparable cone masses (1.57 [0.98-2.37] vs. 1.67 [1.15-2.46] grams; P = 0.454). TCH was significantly shorter in the LLETZ-VC arm (60 [41-95.2] vs. 90 [47.2-130.2] seconds; P = 0.008). There was no statistically significant difference in involved resection margins (6/87 [6.5%] vs. 16/101 [13.7%], P = 0.068) and postoperative complications (13/82 [13.7%] vs. 22/72 [23.4%], P = 0.085). Patient-reported outcomes favoured LLETZ-VC with a lower use of analgesics (6/80 [7.0%] vs. 17/87 [16.3%]; P = 0.049). However, LLETZ-VC was more difficult to perform with significantly lower ratings for handling (7 [5-9] vs. 9 [8-10]; P < 0.001) and general satisfaction (7.5 [5-9] vs. 10 [8-10]; P < 0.001). CONCLUSION: Intraoperative video colposcopy for LLETZ has minimal benefits at the cost of surgeons' satisfaction. CLINICAL TRIAL REGISTRATION: NCT04326049 (ClinicalTrials.gov).

Sequential Application of Lugol's Iodine Test after Acetic Acid for Detecting Cervical Dysplasia: A Prospective Cohort Study.

Applying Lugol's iodine solution to the cervix followed by colposcopic assessment is an established standard test to identify low grade/high grade squamous intraepithelial lesions (LSIL/HSIL). Here, we assessed the performance of Lugol's iodine test during colposcopy using a standardized protocol with 5% acetic acid followed by 5% Lugol's iodine solution and recording the most severe acetowhite (MSAWL) and iodine-negative (MSINL) lesions in a prospective cohort of consecutive women referred to our specialized colposcopy unit. The primary study endpoint was the sensitivity/specificity of MSINL for the detection of LSIL/HSIL. Secondary endpoints were the time to first appearance of the MSINL, MSINL staining intensity, and fading of MSINL. Three hundred and twenty women were included. The sensitivity and specificity of MSINL for the detection of LSIL/HSIL was 81.4 (95%-confidence interval (CI) 77.3-85.0)% and 29.5 (24.2-35.5)%, respectively. Ninety-six MSINL were identified exclusively by Lugol's iodine test (no pathology, n = 46; LSIL, n = 29; HSIL, n = 21) (number needed to biopsy to identify one additional LSIL/HSIL = 1.9). In 17/320 (5.3%) patients, the clinical management was changed based on the result of Lugol's iodine test. Video analysis showed an instant appearance of the MSINL within 10 s in 100% of cases. Intensity of MSINL significantly correlated with the presence/absence of LSIL/HSIL (Spearman rank order correlation; p < 0.0001). Fading of iodine-induced staining intensity over time was not observed. Thus, Lugol's iodine showed moderate sensitivity and poor specificity, but changed clinical management in 5% of cases when used in addition to acetic acid.

Risk Factors for Retinopathy of Prematurity in the Netherlands: A Comparison of Two Cohorts.

INTRODUCTION: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP. METHODS: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied. RESULTS: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage ≥3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54-0.66) and increased for small for GA (SGA) (1.73, 1.11-2.62), mechanical ventilation >7 days (2.13, 1.35-3.37) and postnatal corticosteroids (2.57, 1.44-4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27-0.50), SGA (OR 5.65 and CI 2.17-14.92), postnatal corticosteroids (OR 3.81 and CI 1.72-8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29-24.48). CONCLUSION: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline.