Histopathological aspects of resected non-small cell lung cancer, with emphasis on spread through air spaces and collapsed adenocarcinoma in situ

This thesis investigates three aspects in lung resections with non-small cell carcinoma that are relevant for diagnosis, prognosis, and staging. Firstly, the pathological response after neoadjuvant therapy. Secondly, research on the so-called "STAS" with the hypothesis that this phenomenon may be an artifact rather than a biological phenomenon. Thirdly, attempts were made to refine diagnostic tools that can help distinguish invasion from non-invasion in non-mucinous adenocarcinoma. In chapter 2 of part I, the histological changes after neoadjuvant therapy are described in patients with a sulcus superior tumor who underwent chemoradiation followed by surgical resection. In chapter 3, additional morphological prognostic characteristics of tumors were sought. Importantly, low MIB-1 expression was associated with improved survival and disease-free survival, while negative PD-L1 expression also predicted better survival. Chapter 4 presents the results of a national study on T3N0 NSCLC, which includes various tumor categories, including those with parietal pleural invasion or a diameter greater than 7 cm. The study in Chapter 4 had two objectives: to assess the validity of the shift from pT3 to pT4 in the Dutch population and to investigate whether the inclusion of additional morphological factors could improve staging accuracy. Part II focuses on the phenomenon of Spread Through Air Spaces (STAS). This has been described as a new way of metastases since the 2015 WHO classification, but it may be an artifact. Chapter 5 describes various histopathological artifacts related to tissue treatment after removal and upon receipt at the pathology department. Additionally, spreading of tumor tissue by a knife during the cutting of the resection specimen is described as a possible explanation for the presence of loose tumor cells or cell clusters in alveolar spaces away from the tumor's border. In Chapter 6, a prospective multicenter study is described that suggests that STAS is an inducible phenomenon. In 44 resection specimens, the number of loose tumor cells and/or cell clusters was counted in four sections taken through the tumor without cleaning the preparation knife. The number of loose cells and/or clusters increased from the first section that was cut without going through the tumor to the last section where the knife had been used twice through the tumor. Based on this study, it was concluded that it is highly likely that STAS is an inducible artifact. Chapter 7 is a critical evaluation of the STAS phenomenon. In Chapter 10, another possible artifact is investigated, namely the presence of individual tumor cells and tumor cell clusters, as well as macrophages in branches of the pulmonary artery in histological sections of lung resection specimens. Chapter 11 contains the most recent arguments together about STAS as an artifact in the CON part of a Pro-Con editorial. In Part III, the focus is on iatrogenic and biological collapse as a possible pitfall in the assessment of invasion in small adenocarcinomas. Chapter 12 describes the importance of elastin in pulmonary pathology. Chapter 13 discusses a proof-of-principle study that investigated whether consideration of surgical collapse leads to a more frequent diagnosis of AIS. Chapter 14 describes the morphological features of iatrogenic and biological collapsed AIS, where lessons are learned from a mathematical model, and cytokeratin 7 and elastin stains are used to assess invasiveness. Chapter 15 concerns the largest international interobserver study with pathologists ever, in which the presence of iatrogenic and biological collapse in the assessment of invasion of lung adenocarcinoma using elastin and cytokeratin 7 staining to diagnose (collapsed) AIS more reliably and reduce variation between assessors of invasive patterns in small pulmonary adenocarcinomas was investigated. Chapter 16 provides strong arguments for abandoning the diameter limit of 3 cm for AIS

Structure of surface vortex sheet between two rotating 3He superfluids

We study a two-phase sample of superfluid 3He where vorticity exists in one phase (3He-A) but cannot penetrate across the interfacial boundary to a second coherent phase (3He-B). We calculate the bending of the vorticity into a surface vortex sheet on the interface and solve the internal structure of this new type of vortex sheet. The compression of the vorticity from three to two dimensions enforces a structure which is made up of half-quantum units, independently of the structure of the source vorticity in the bulk. These results are consistent with our NMR measurements.Comment: 4 pages, 4 figure

Onset of turbulence in superfluid 3He-B and its dependence on vortex injection in applied flow

Vortex dynamics in 3He-B is divided by the temperature dependent damping into a high-temperature regime, where the number of vortices is conserved, and a low-temperature regime, where rapid vortex multiplication takes place in a turbulent burst. We investigate experimentally the hydrodynamic transition between these two regimes by injecting seed vortex loops into vortex-free rotating flow. The onset temperature of turbulence is dominated by the roughly exponential temperature dependence of vortex friction, but its exact value is found to depend on the injection method.Comment: To be published in the proceedings of the 24th International Conference on Low Temperature Physics - LT24, in Conference Proceedings of the American Institute of Physic

Transition to superfluid turbulence governed by an intrinsic parameter

Hydrodynamic flow in both classical and quantum fluids can be either laminar or turbulent. To describe the latter, vortices in turbulent flow are modelled with stable vortex filaments. While this is an idealization in classical fluids, vortices are real topologically stable quantized objects in superfluids. Thus superfluid turbulence is thought to hold the key to new understanding on turbulence in general. The fermion superfluid 3He offers further possibilities owing to a large variation in its hydrodynamic characteristics over the experimentally accessible temperatures. While studying the hydrodynamics of the B phase of superfluid 3He, we discovered a sharp transition at 0.60Tc between two regimes, with regular behaviour at high-temperatures and turbulence at low-temperatures. Unlike in classical fluids, this transition is insensitive to velocity and occurs at a temperature where the dissipative vortex damping drops below a critical limit. This discovery resolves the conflict between existing high- and low-temperature measurements in 3He-B: At high temperatures in rotating flow a vortex loop injected into superflow has been observed to expand monotonically to a single rectilinear vortex line, while at very low temperatures a tangled network of quantized vortex lines can be generated in a quiescent bath with a vibrating wire. The solution of this conflict reveals a new intrinsic criterion for the existence of superfluid turbulence.Comment: Revtex file; 5 pages, 2 figure

Dry demagnetization cryostat for sub-millikelvin helium experiments: Refrigeration and thermometry

We demonstrate successful “dry” refrigeration of quantum fluids down to T = 0.16 mK by using copper nuclear demagnetization stage that is pre-cooled by a pulse-tube-based dilution refrigerator. This type of refrigeration delivers a flexible and simple sub-mK solution to a variety of needs including experiments with superfluid 3He. Our central design principle was to eliminate relative vibrations between the high-field magnet and the nuclear refrigeration stage, which resulted in the minimum heat leak of Q = 4.4 nW obtained in field of 35 mT. For thermometry, we employed a quartz tuning fork immersed into liquid 3He. We show that the fork oscillator can be considered as self-calibrating in superfluid 3He at the crossover point from hydrodynamic into ballistic quasiparticle regime.Peer reviewe