Src family kinases (SFKs) have been implicated in resistance to both radiation and epidermal growth factor receptor (EGFR) inhibition. Therefore, we investigated whether inhibition of SFK through ...dasatinib (DSB) can enhance the effect of radiotherapy in two
in vivo
human head and neck squamous cell carcinoma (HNSCC) models. Response to DSB and/or radiotherapy was assessed with tumor growth delay assays in two HNSCC xenograft models, SCCNij153 and SCCNij202. Effects on EGFR signaling were evaluated with Western blot analysis, and effects on DNA repair, hypoxia, and proliferation were investigated with immunohistochemistry. DSB and radiotherapy induced a significant growth delay in both HNSCC xenograft models, although to a lesser extent in SCCNij202. DSB did not inhibit phosphorylated protein kinase B (pAKT) or phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) but did inhibit (phosphorylated) DNA-dependent protein kinase. Moreover, DSB reduced repair of radiation-induced DNA double-strand breaks as shown by an increase of p53-binding protein 1 (53BP1) staining 24 hours after radiation. This effect on DNA repair was only observed in the cell compartment where phosphorylated SFK (pSFK) was expressed: for SCCNij153 tumors in both normoxic and hypoxic areas and for SCCNij202 tumors only in hypoxic areas. No consistent effects of DSB on hypoxia or proliferation were observed. In conclusion, DSB enhances the effect of radiotherapy
in vivo
by inhibition of radiation-induced DNA repair and is a promising way to improve outcome in HNSCC patients.
BackgroundSinonasal teratocarcinosarcoma is a rare, aggressive malignancy located almost exclusively in the nasal cavity, paranasal sinuses, or anterior skull base. Histopathological diagnosis can be ...challenging due to the heterogeneous composition.MethodsRetrospective analysis of 3 patients with sinonasal teratocarcinosarcoma diagnosed and treated at the University Medical Center Utrecht was conducted.ResultsPatients presented with nasal obstruction, epistaxis, headaches, or behavioral changes. All three patients had locally advanced disease, and one had lymph node metastases. Two patients underwent surgery followed by radiotherapy, and one underwent neoadjuvant chemotherapy followed by surgery. The follow-up duration ranged from 3 to 32 months. All three patients died due to progression of their disease.ConclusionSinonasal teratocarcinosarcoma is characterized by rapid, aggressive local expansion. The prognosis is poor due to a high risk of metastases and locally recurrent disease. Multimodality treatment consisting of surgery, followed by (chemo)-radiotherapy, is essential for optimizing outcomes. Neoadjuvant therapy offers a promising treatment option.
Introduction
Management options for women with placenta accreta spectrum (PAS) comprise termination of pregnancy before the viable gestational age, leaving the placenta in situ for subsequent ...reabsorption of the placenta or delayed hysterectomy, manual removal of placenta after vaginal delivery or during cesarean section, focal resection of the affected uterine wall, and peripartum hysterectomy. The aim of this observational study was to describe actual clinical management and outcomes in PAS in a large international cohort.
Material and methods
Data from women in 15 referral centers of the International Society of PAS (IS‐PAS) were analyzed and correlated with the clinical classification of the IS‐PAS: From Grade 1 (no PAS) to Grade 6 (invasion into pelvic organs other than the bladder). PAS was usually diagnosed antenatally and the operators performing ultrasound rated the likelihood of PAS on a Likert scale of 1 to 10.
Results
In total, 442 women were registered in the database. No maternal deaths occurred. Mean blood loss was 2600 mL (range 150‐20 000 mL). Placenta previa was present in 375 (84.8%) women and there was a history of a previous cesarean in 329 (74.4%) women. The PAS likelihood score was strongly correlated with the PAS grade (P < .001). The mode of delivery in the majority of women (n = 252, 57.0%) was cesarean hysterectomy, with a repeat laparotomy in 20 (7.9%) due to complications. In 48 women (10.8%), the placenta was intentionally left in situ, of those, 20 (41.7%) had a delayed hysterectomy. In 26 women (5.9%), focal resection was performed. Termination of pregnancy was performed in 9 (2.0%), of whom 5 had fetal abnormalities. The placenta could be removed in 90 women (20.4%) at cesarean, and in 17 (3.9%) after vaginal delivery indicating mild or no PAS. In 34 women (7.7%) with an antenatal diagnosis of PAS, the placenta spontaneously separated (false positives). We found lower blood loss (P < .002) in 2018‐2019 compared with 2009‐2017, suggesting a positive learning curve.
Conclusions
In referral centers, the most common management for severe PAS was cesarean hysterectomy, followed by leaving the placenta in situ and focal resection. Prenatal diagnosis correlated with clinical PAS grade. No maternal deaths occurred.
Background
Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.
Objectives
By studying the fibrin network structure of coronavirus ...disease 2019 (COVID‐19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID‐19 related thrombosis.
Patients/Methods
In this case‐control study, we collected plasma samples from intensive care unit (ICU) patients with COVID‐19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID‐19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis.
Results
COVID‐19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID‐19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID‐19 ICU patients with thrombosis (n = 19) than in COVID‐19 ICU patients without thrombosis (n = 18).
Conclusions
Our results suggest that severe COVID‐19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID‐19 patients, they may not explain the increased thrombosis risk.
Objective:
To present short-term outcomes of liver surgery in patients with initially unresectable colorectal liver metastases (CRLM) downsized by chemotherapy plus targeted agents.
Background:
The ...increase of complex hepatic resections of CRLM, technical innovations pushing boundaries of respectability, and use of intensified induction systemic regimens warrant for safety data in a homogeneous multicenter prospective cohort.
Methods:
Patients with initially unresectable CRLM, who underwent complete resection after induction systemic regimens with doublet or triplet chemotherapy, both plus targeted therapy, were selected from the ongoing phase III CAIRO5 study (NCT02162563). Short-term outcomes and risk factors for severe postoperative morbidity (Clavien Dindo grade ≥ 3) were analyzed using logistic regression analysis.
Results:
A total of 173 patients underwent resection of CRLM after induction systemic therapy. The median number of metastases was 9 and 161 (93%) patients had bilobar disease. Thirty-six (20.8%) 2-stage resections and 88 (51%) major resections (>3 liver segments) were performed. Severe postoperative morbidity and 90-day mortality was 15.6% and 2.9%, respectively. After multivariable analysis, blood transfusion (odds ratio OR 2.9 95% confidence interval (CI) 1.1–6.4,
P =
0.03), major resection (OR 2.9 95% CI 1.1–7.5,
P =
0.03), and triplet chemotherapy (OR 2.6 95% CI 1.1–7.5,
P =
0.03) were independently correlated with severe postoperative complications. No association was found between number of cycles of systemic therapy and severe complications (
r
= −0.038
, P
= 0.31).
Conclusion:
In patients with initially unresectable CRLM undergoing modern induction systemic therapy and extensive liver surgery, severe postoperative morbidity and 90-day mortality were 15.6% and 2.7%, respectively. Triplet chemotherapy, blood transfusion, and major resections were associated with severe postoperative morbidity.
Background and purpose
Yawning is a stereotypical complex muscular movement and is commonly executed by most vertebrates. In seconds, the entire airway is fully dilated and surrounding muscles are ...powerfully stretched, most prominently around the pharynx. To date, yawning has been rarely studied, and as of yet there is no consensus on its main function.
Material and methods
To investigate a mechanical airway function for yawning, a literature search was conducted to relate the frequency of yawning and obstructive airway conditions.
Results
The results show that changes in obstructive airway conditions and alteration of the frequency of yawning are temporally related.
Interpretation
These relationships, however, cannot be interpreted as causal, nor can they be extrapolated to explain the function of yawning. Yet airway management and yawning share many physiological characteristics. We therefore propose a novel hypotheses: yawning plays a significant role in airway physiology by muscle repositioning and widening the airway lumen, thereby securing long-term oxygenation.
Hypoxic tumor cells are resistant to radiotherapy and various chemotherapeutic agents. The pretherapeutic assessment of intratumoral hypoxia may allow selection of patients for intensified treatment ...regimens. Carbonic anhydrase IX (CAIX) is an endogenous hypoxia-related protein involved in pH regulation and is upregulated in many tumor types. Radionuclide imaging using a monoclonal antibody against CAIX, such as cG250, may allow noninvasive PET of hypoxia in these tumor types. The aims of this study were to investigate whether (89)Zr-labeled cG250-F(ab')(2) allowed visualization of tumor hypoxia using small-animal PET and whether the tracer showed spatial correlation to the microscopic distribution of CAIX-expressing cells in a human head and neck xenograft tumor model.
Athymic mice with subcutaneous human head and neck carcinoma xenografts (SCCNij3) were imaged with small-animal PET after injection of (89)Zr-cG250-F(ab')(2). PET images were parameterized in terms of standardized uptake values (SUVs). After injection with the nitroimidazole hypoxia marker pimonidazole and the perfusion marker Hoechst 33342, the animals were sacrificed, tumors excised, and CAIX- and pimonidazole-marked hypoxia and blood perfusion were analyzed immunohistochemically. (89)Zr-cG250-F(ab')(2) tumor uptake was analyzed by ex vivo activity counting and by autoradiography of tumor sections.
As early as 4 h after administration, accumulation of (89)Zr-cG250-F(ab')(2) in the tumor had occurred and tumors were clearly visualized by PET, with reduced uptake by 24 h after injection. Pixel-by-pixel analysis showed a significant positive spatial correlation between CAIX expression and (89)Zr-cG250-F(ab')(2) localization (r = 0.57-0.74; P < 0.0001). Also, significant correlations were found between pimonidazole staining intensity and (89)Zr-cG250-F(ab')(2) activity concentration, although less strong (r = 0.46-0.68; P < 0.0001). Tumor maximum SUV correlated significantly with tumor uptake determined ex vivo (r = 0.93; P = 0.0067), as did fractions of CAIX and pimonidazole in tumor sections (r = 0.75; P = 0.03 and r = 0.78; P = 0.02, respectively).
(89)Zr-labeled cG250-F(ab')(2) small-animal PET showed rapid accumulation in a head and neck xenograft tumor model with good correlation to CAIX expression on a microscopic level.
Abstract
Background
Asylum seekers (AS) and undocumented migrants (UM) are at risk of adverse pregnancy outcomes due to adverse health determinants and compromised maternal healthcare access and ...service quality. Considering recent migratory patterns and the absence of a robust overview, a systematic review was conducted on maternal and perinatal outcomes in AS and UM in Europe.
Methods
Systematic literature searches were performed in MEDLINE and EMBASE (until 1 May 2017), complemented by a grey literature search (until 1 June 2017). Primary research articles reporting on any maternal or perinatal outcome, published between 2007 and 2017 in English/Dutch were eligible for inclusion. Review protocols were registered on Prospero: CRD42017062375 and CRD42017062477. Due to heterogeneity in study populations and outcomes, results were synthesized narratively.
Results
Of 4652 peer-reviewed articles and 145 grey literature sources screened, 11 were included from 4 European countries. Several studies reported adverse outcomes including higher maternal mortality (AS), severe acute maternal morbidity (AS), preterm birth (UM) and low birthweight (UM). Risk of bias was generally acceptable, although the limited number and quality of some studies preclude definite conclusions.
Conclusion
Limited evidence is available on pregnancy outcomes in AS and UM in Europe. The adverse outcomes reported imply that removing barriers to high-quality maternal care should be a priority. More research focussing on migrant subpopulations, considering potential risk factors such as ethnicity and legal status, is needed to guide policy and optimize care.
Large inter-surgeon variability exists in technical anatomical resectability assessment of colorectal cancer liver-only metastases (CRLM) following induction systemic therapy. We evaluated the role ...of tumour biological factors in predicting resectability and (early) recurrence after surgery for initially unresectable CRLM.
482 patients with initially unresectable CRLM from the phase 3 CAIRO5 trial were selected, with two-monthly resectability assessments by a liver expert panel. If no consensus existed among panel surgeons (i.e. same vote for (un)resectability of CRLM), conclusion was based on majority. The association of tumour biological (sidedness, synchronous CRLM, carcinoembryonic antigen and RAS/BRAFV600E mutation status) and technical anatomical factors with consensus among panel surgeons, secondary resectability and early recurrence (<6 months) without curative-intent repeat local treatment was analysed by uni- and pre-specified multivariable logistic regression.
After systemic treatment, 240 (50%) patients received complete local treatment of CRLM of which 75 (31%) patients experienced early recurrence without repeat local treatment. Higher number of CRLM (odds ratio 1.09 95% confidence interval 1.03–1.15) and age (odds ratio 1.03 95% confidence interval 1.00–1.07) were independently associated with early recurrence without repeat local treatment. In 138 (52%) patients, no consensus among panel surgeons was present prior to local treatment. Postoperative outcomes in patients with and without consensus were comparable.
Almost a third of patients selected by an expert panel for secondary CRLM surgery following induction systemic treatment experience an early recurrence only amenable to palliative treatment. Number of CRLM and age, but no tumour biological factors are predictive, suggesting that until there are better biomarkers; resectability assessment remains primarily a technical anatomical decision.
•Role of tumour biological factors in resectability assessment of colorectal cancer liver-only metastases was evaluated.•31% of locally treated patients had early recurrence without repeat local treatment.•Number of colorectal cancer liver-only metastases and age are predictive for early recurrence without repeat local treatment.•Resectability assessment remains primarily a technical anatomical decision.
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