Familial Papillary Thyroid Carcinoma: Genetics, Criteria for Diagnosis, Clinical Features, and Surgical Treatment

Hereditable predisposition to papillary thyroid carcinoma (PTC) and multinodular goiter (MNG) without evidence of an association with other malignancies as a distinct entity was recognized only recently. A meta-review of the literature on familial PTC (FPTC) was undertaken, and characteristics of families with frequent occurrence of PTC or MNG (or both) were summarized. A database on thyroid cancer patients maintained in our institution was searched for potential FPTC families. Clinical examinations were performed in 6 of 12 Hannover kindreds identified, and blood samples of all family members were collected for genetic analyses. Clinical presentations and histopathologic features of the FPTC cases were compiled. Based on the FPTC meta-review and own experience, predictive criteria to identify families at risk were developed: Exclusion criteria were previous radiation exposure and coincidence with neoplasia syndromes. Primary criteria for susceptibility to FPTC are (1) PTC in two or more first-degree relatives and (2) MNG in at least three first- or second-degree relatives of a PTC patient. Secondary criteria are diagnosis in a patient younger than 33 years, multifocal or bilateral PTC, organ-exceeding tumor growth (T4), metastasis (N1, M1), and familial accumulation of adolescent-onset thyroid disease. A hereditary predisposition to PTC is considered if both primary criteria or one primary criterion plus three secondary criteria are present. Family history-taking is recommended for all PTC patients to identify FPTC kindreds at risk. Blood relatives of FPTC index patients who harbor MNG should undergo thorough and regular clinical screening. Suspicious lesions should prompt early surgical intervention.     

Immuntherapeutische Behandlung therapierefraktärer und rezidivierter akuter lymphatischer Leukämien im Kindes- und Jugendalter

Acute lymphoblastic leukemia (ALL) represents the most frequent malignant disease in childhood and adolescence and offers a good prognosis with approximately 80% survival in first remission after polychemotherapy and radiotherapy. In addition,many children with relapsed or refractory ALL will still be cured by allogeneic hematopoietic stem cell transplantation (alloHSCT).However, therapeutic options are limited with a very poor prognosis in case of another relapse after alloHSCT.Here,immunotherapy strategies offer a promising alternative to another chemotherapy or second alloHSCT, which are mainly palliative and accompanied by high morbidity and mortality. Immunotherapy strategies aim at an improvement of the graft-versus-leukemia (GvL) effect.The therapeutic GvL effect is usually associated with graft-versus-host disease (GvHD).The definition of patients subgroups with an increased risk for relapse after alloHSCT gains growing importance for immunotherapy strategies.Promising approaches for separation of GvL-effect and GvHD after donor lymphocyte infusions, e.g. T-cell suicide gene therapy, will be described. Finally, vaccination strategies for ALL exist.     

Heterogeneous iodine-organic chemistry fast-tracks marine new particle formation

The gas-phase formation of new particles less than 1 nm in size and their subsequent growth significantly alters the availability of cloud condensation nuclei (CCN, >30–50 nm), leading to impacts on cloud reflectance and the global radiative budget. However, this growth cannot be accounted for by condensation of typical species driving the initial nucleation. Here, we present evidence that nucleated iodine oxide clusters provide unique sites for the accelerated growth of organic vapors to overcome the coagulation sink. Heterogeneous reactions form low-volatility organic acids and alkylaminium salts in the particle phase, while further oligomerization of small α-dicarbonyls (e.g., glyoxal) drives the particle growth. This identified heterogeneous mechanism explains the occurrence of particle production events at organic vapor concentrations almost an order of magnitude lower than those required for growth via condensation alone. A notable fraction of iodine associated with these growing particles is recycled back into the gas phase, suggesting an effective transport mechanism for iodine to remote regions, acting as a “catalyst” for nucleation and subsequent new particle production in marine air.

Marine aerosol formation contributes significantly to the global radiative budget given the high susceptibility of marine stratiform cloud radiative properties to changes in cloud condensation nuclei (CCN) availability. Atmospheric new-particle-formation is thought to involve nucleation of sulfuric acid with water, ammonia, or amines followed by condensation/growth in the presence of organic vapors (1, 2). Unique in the marine boundary layer (MBL), new particle formation involves sequential addition of HIO₃ or clustering of iodine oxides (I_xO_y) (3, 4). In specific source regions such as coastal zones, seaweed beds, or snowpack/pack-ice, iodine oxide nucleation can be a driving force for nucleation (5–7). Over Arctic waters, nonetheless, one study finds insufficient iodic acid vapors to grow nucleated particles to CCN sizes (8), whereas another study finds that both nucleation and growth are almost exclusively driven by iodic acid (9). Over the open ocean, the supply of iodine oxides has been thought to be limited; however, recent measurements suggest that significant reactive iodine chemistry can occur in these regions (10). Moreover, observational evidence exists for open ocean particle formation and growth, especially when oceanic productivity is high (11, 12). An increase in atmospheric iodine levels in the North Atlantic since the mid-20th century has been shown to be driven by growth of anthropogenic ozone and enhanced subice phytoplankton production (13). While the reported IO concentration (0.4–3.1 ppt) in the remote MBL (10, 14, 15) is likely sufficient for formation of prenucleation clusters (∼1 nm), growth of these initial clusters requires the presence of other condensable vapors (16). Since preexisting aerosol particles act as a strong sink for the nucleated clusters, thus inhibiting atmospheric aerosol and CCN formation (17, 18), this early growth phase is essential for their survival. Whereas sulfuric acid vapor is also involved in nucleation, its level in remote open ocean is generally too low (10⁵ molecules cm⁻³) to support subsequent particle growth, leaving organic vapors as the most plausible alternative for particle growth.In the marine atmosphere, condensing organics must originate from the oxidation of marine volatile organic compounds (VOCs), which predominantly comprise C₁–C₅ VOCs (e.g., isoprene) released from phytoplankton. Principal high volatility oxidation products consist of intermediate oxidized organics (IOOs), such as polyhydric alcohols (e.g., tetrols) or polyfunctional carbonyls (e.g., glyoxal) (19–22). Nonetheless, growth of available prenucleation clusters/nanometer particles requires condensing organic molecules of low effective volatilities (i.e., saturation mass concentration, C* < ∼10⁻³ μg m⁻³); otherwise, preferential condensation of the organic mass to larger-diameter particles would occur (23, 24). Formation of such extremely low-volatility organic compounds (ELVOCs) from gas-phase reaction is well established for monoterpene oxidation products (25, 26).A potential pathway for formation of low-volatility organics could also result from particle-phase chemical reactions induced by iodine oxides in the early stages of marine particle formation. When the underlying chemistry is sufficiently fast, kinetic condensation occurs, resulting in particles with diameters smaller than about 50 nm growing at the same rate (e.g., nm h⁻¹) (24). If, however, particle-phase chemistry is preferentially favored in the smallest particles (i.e., stemming from the higher relative concentration of iodine oxides in freshly formed marine particles), growth of the nucleated particles could proceed more rapidly, as compared to that in which gas-phase chemistry is the source of the low-volatility compounds (23).In this paper, we present experimental results from field measurements as well as laboratory studies of nanometer particle growth and derive a plausible chemical mechanism from the results that can explain the observations of ultrafine particle growth in the marine atmosphere. The results suggest that both iodine and condensed organics contribute to particle growth from a nascent nucleation mode into an ultrafine particle mode. Moreover, laboratory studies of the growth of seed iodine oxide particles (IOP) via heterogeneous reactions with organic vapors suggest a hitherto unrecognized mechanism that fast-tracks the growth of nucleation mode clusters into survivable aerosol particles. In this process, a notable fraction of the iodine associated with these growing particles is recycled back to the gas phase, suggesting a transport mechanism for iodine to remote regions.     

Is faster better? Impact of operative time on postoperative outcomes after VATS anatomical pulmonary resection

BackgroundVideo-assisted thoracic surgery (VATS) is now the preferred approach for standard anatomical pulmonary resections. This study evaluates the impact of operative time (OT) on post-operative outcomes after VATS anatomical pulmonary resection for non-small cell lung cancer (NSCLC).MethodsWe retrospectively reviewed all consecutive patients undergoing VATS lobectomy or segmentectomy for NSCLC between November 2010 and December 2019. Postoperative outcomes were compared between short (<150 minutes) and long (≥150 minutes) OT groups. A multivariable analysis was performed to identify predictors of long OT and overall post-operative complications.ResultsA total of 670 patients underwent lobectomy (n=496, 74%) or segmentectomy (n=174, 26%) for NSCLC. Mediastinal lymph node dissection was performed in 621 patients (92.7%). The median OT was 141 minutes (SD: 47 minutes) and 387 patients (57.8%) were operated within 150 minutes. Neoadjuvant chemotherapy was given in 25 patients (3.7%). Conversion thoracotomy was realized in 40 patients (6%). Shorter OT was significantly associated with decreased post-operative overall complication rate (30% vs. 41%; P=0.003), shorter median length of drainage (3 vs. 4 days; P<0.001) and shorter median length of hospital stay (6 vs. 7 days; P<0.001). On multivariable analysis, long OT (≥150 minutes) (OR 1.64, P=0.006), ASA score >2 (OR 1.87, P=0.001), FEV₁ <80% (OR 1.47, P=0.046) and DLCO <80% (OR 1.5, P=0.045) were significantly associated with postoperative complications. Two predictors of long OT were identified: neoadjuvant chemotherapy (OR 3.11, P=0.01) and lobectomy (OR 1.5, P=0.032).ConclusionsA prolonged OT is significantly associated with postoperative complications in our collective of patients undergoing VATS anatomical pulmonary resection.     

TP53 mutation and survival in aggressive B cell lymphoma

TP53 is mutated in 20–25% of aggressive B‐cell lymphoma (B‐NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B‐NHL, we investigated TP53 gene mutations within the RICOVER‐60 trial. Of 1,222 elderly patients (aged 61–80 years) enrolled in the study and randomized to six or eight cycles of CHOP‐14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index‐Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B‐symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event‐free (EFS), progression‐free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI‐factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.     

Material differentiation by dual energy CT: initial experience

The aim of this study was to assess the feasibility of a differentiation of iodine from other materials and of different body tissues using dual energy CT. Ten patients were scanned on a SOMATOM Definition Dual Source CT (DSCT; Siemens, Forchheim, Germany) system in dual energy mode at tube voltages of 140 and 80 kVp and a ratio of 1:3 between tube currents. Weighted CT Dose Index ranged between 7 and 8 mGy, remaining markedly below reference dose values for the respective body regions. Image post-processing with three-material decomposition was applied to differentiate iodine or collagen from other tissue. The results showed that a differentiation and depiction of contrast material distribution is possible in the brain, the lung, the liver and the kidneys with or without the underlying tissue of the organ. In angiographies, bone structures can be removed from the dataset to ease the evaluation of the vessels. The differentiation of collagen makes it possible to depict tendons and ligaments. Dual energy CT offers a more specific tissue characterization in CT and can improve the assessment of vascular disease. Further studies are required to draw conclusions on the diagnostic value of the individual applications.     

The entire dural sinus tree is compressed in patients with idiopathic intracranial hypertension: a longitudinal, volumetric magnetic resonance imaging study

Introduction  

The objective of this study was to explore the volumetric alterations of dural sinuses in patients with idiopathic intracranial hypertension (IIH).