Swallowing after Oral Oncological Treatment: A Five-Year Prospective Study.

BACKGROUND: Swallowing rehabilitation in curative treated patients with oral cancer is still a challenge. Different factors may influence these patients' swallowing function. The aim of this study was to identify factors associated with swallowing function up to 5 years after cancer treatment. METHODS: Swallowing duration and frequency of 5 mL water and 15 mL applesauce were measured in 123 patients treated for oral cancer. Mixed model analyses were performed to identify associated factors. RESULTS: Age influenced all measured swallowing outcomes. Assessment moment, gender, tumor location, maximum tongue force, and tactile sensory function of the tongue were associated with both water and applesauce swallowing duration, tumor classification was associated with water swallowing duration, and alcohol consumption was associated with applesauce swallowing duration. Assessment moment, cancer treatment, maximum tongue force, and tactile sensory function of the tongue were associated with water and applesauce swallowing frequency. CONCLUSION: Patients who are older at diagnosis, women, and patients who regularly consume alcohol before their treatment may have poorer swallow functioning after curative oral cancer treatment. Patients that fit these criteria should have their swallowing evaluated during clinical follow-ups and sent to swallowing therapy when needed. During this therapy, optimizing tongue function needs attention to maintain an optimal swallowing function.

RNA Biomarkers as a Response Measure for Survival in Patients with Metastatic Castration-Resistant Prostate Cancer.

Treatment evaluation in metastatic castration-resistant prostate cancer is challenging. There is an urgent need for biomarkers to discriminate short-term survivors from long-term survivors, shortly after treatment initiation. Thereto, the added value of early RNA biomarkers on predicting progression-free survival (PFS) and overall survival (OS) were explored. The RNA biomarkers: KLK3 mRNA, miR-375, miR-3687, and NAALADL2-AS2 were measured in 93 patients with mCRPC, before and 1 month after start of first-line abiraterone acetate or enzalutamide treatment, in two prospective clinical trials. The added value of the biomarkers to standard clinical parameters in predicting PFS and OS was tested by Harell's C-index. To test whether the biomarkers were independent markers of PFS and OS, multivariate Cox regression was used. The best prediction model for PFS and OS was formed by adding miR-375 and KLK3 (at baseline and 1 month) to standard clinical parameters. Baseline miR-375 and detectable KLK3 after 1 month of therapy were independently related to shorter PFS, which was not observed for OS. In conclusion, the addition of KLK3 and miR-375 (at baseline and 1 month) to standard clinical parameters resulted in the best prediction model for survival assessment.

Anti-thymocyte globulin with CsA and MMF as GVHD prophylaxis in nonmyeloablative HLA-mismatched allogeneic HCT.

Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting.

Depression and related factors after oral oncological treatment: a 5-year prospective cohort study.

PURPOSES: Being diagnosed with oral cancer is a life-threatening life event. It often induces social, emotional and psychological consequences and may cause depressive disorders. The primary aim of this study was to identify and quantify the personal and clinical characteristics involved in depression for patients who have been treated for oral cavity malignancies, with a 5-year follow-up period after treatment. The secondary aim of this study was to identify the clinical factors that increase a patient's risk of experiencing depression 5 years after treatment. METHODS: Patients with primary oral cancer were assessed for up to 5 years after primary treatment. A mixed-model analysis was performed, with depression measured by the Center for Epidemiologic Studies Depression Scale as outcome measure. RESULTS: A total of 141 patients were included in the study. Factors associated with depression were gender, tumour location and having an emotion-oriented coping style. The occurrence of depression within 5 years after treatment could be reliably predicted by a patient's gender, the location of their tumour and the extent to which they had an emotion-oriented coping style. CONCLUSIONS: This study revealed that being female, having a maxillary tumour and having an emotion-oriented coping style are associated with higher levels of depressive symptoms in patients treated for oral cancer up to 5 years post-treatment. A substantial proportion of the patients with oral cancer experienced high levels of depression both before and after their treatment, suggesting that adequate diagnostics and care are needed to try to prevent severe depression in these patients.

Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)-study protocol for a multicenter randomized double-blind placebo-controlled trial.

BACKGROUND: Since decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population. METHODS/DESIGN: A multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day - 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity. DISCUSSION: The AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis. TRIAL REGISTRATION: Clinicaltrials.gov NCT04099901 . Registered on September 23, 2019. EudraCT: 2018-005046-10.

Recovery after traumatic thoracic- and lumbar spinal cord injury: the neurological level of injury matters.

STUDY DESIGN: Multicenter prospective cohort. OBJECTIVE: To discern neurological- and functional recovery in patients with a traumatic thoracic spinal cord injury (TSCI), conus medullaris syndrome (CMS), and cauda equina syndrome (CES). SETTING: Specialized spinal cord injury centers in Europe. METHOD: Lower extremity motor score (LEMS) and spinal cord independent measure (SCIM) scores from patients with traumatic TSCI, CMS, and CES were extracted from the EMSCI database. Scores from admittance and during rehabilitation at 1, 3, 6, and 12 months were compared. Linear mixed models were used to statistically analyse differences in outcome, which were corrected for the ASIA Impairment Scale (AIS) in the acute phase. RESULTS: Data from 1573 individuals were analysed. Except for the LEMS in patients with a CES AIS A, LEMS, and SCIM significantly improved over time for patients with a TSCI, CMS, and CES. Irrespectively of the AIS score, recovery in 12 months after trauma as measured by the LEMS showed a statistically significant difference between patients with a TSCI, CMS, and CES. Analysis of SCIM score showed no difference between patients with TSCI, CMS, or CES. CONCLUSION: Difference in recovery between patients with a traumatic paraplegia is based on neurological (motor) recovery. Regardless the ceiling effect in CES patients, patients with a mixed upper and lower motor neuron syndrome (CMS) showed a better recovery compared with patients with a upper motor neuron syndrome (TSCI). These findings enable stratifications of patients with paraplegia according to the level and severity of SCI.

Tongue function and its influence on masticatory performance in patients treated for oral cancer: a five-year prospective study.

PURPOSE: The purpose of this study was to observe the impact of oral oncological treatment, including the recovery of several tongue functions (force, mobility, and sensory functions), and to determine the influence of these functions on masticatory performance. MATERIALS AND METHODS: Masticatory performance and tongue force, mobility, and sensory functions were determined in 123 patients with oral cavity cancer. The assessments were performed 4 weeks before treatment and 4 to 6 weeks, 6 months, 1 year, and 5 years after treatment. Generalized estimation equations and mixed model analyses were performed, correcting for previously identified factors in the same population. RESULTS: A significant deterioration in tongue mobility and sensory function was observed in patients with mandible and tongue and/or floor-of-mouth tumors. Better tongue force and sensory function (thermal and tactile) positively influenced masticatory performance, and this effect was stronger where fewer occlusal units were present. The effect of both the tongue force and maximum bite force was weaker in dentate patients in comparison with patients with full dentures. A web-based application was developed to enable readers to explore our results and provide insight into the coherence between the found factors in the mixed model. CONCLUSIONS: Tongue function deteriorates after oral oncological treatment, without statistically significant recovery. Adequate bite and tongue forces are especially important for patients with a poor prosthetic state. Patients with sensory tongue function deficits especially benefit from the presence of more occluding pairs.

A novel algorithm for better distinction of primary mucinous ovarian carcinomas and mucinous carcinomas metastatic to the ovary.

Primary mucinous ovarian carcinomas (MOC) are notoriously difficult to distinguish from mucinous carcinomas metastatic to the ovary (mMC). Studies performed on small cohorts reported algorithms based on tumor size and laterality to aid in distinguishing MOC from mMC. We evaluated and improved these by performing a large-scale, nationwide search in the Dutch Pathology Registry. All registered pathology reports fulfilling our search criteria concerning MOC in the Netherlands from 2000 to 2011 were collected. Age, histology, laterality, and size were extracted. An existing database covering the same timeline containing tumors metastatic to the ovary was used, extracting all mMC, age, size, laterality, and primary tumor location. Existing algorithms were applied to our cohort. Subsequently, an algorithm based on tumor histology, laterality, and a nomogram based on age and size was created for differentiating MOC and mMC. We identified 735 MOC and 1018 mMC. Patients with MOC were significantly younger and MOC were significantly larger and more often unilateral than mMC. Signet ring cell carcinomas were rarely primary. Our algorithm used signet ring cell histology, bilaterality, and a nomogram integrating patient age and tumor size to diagnose mMC. Sensitivity and specificity for mMC was 90.1% and 59.0%, respectively. Applying existing algorithms on our cohort yielded a far lower sensitivity. The algorithm described here using tumor histology, laterality, size, and patient age has higher sensitivity but lower specificity compared to earlier algorithms and aids in indicating tumor origin, but for conclusive diagnosis, careful integration of morphology, immunohistochemistry, and clinical and imaging data is recommended.

Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study.

BACKGROUND: Triazole resistance is an increasing problem in invasive aspergillosis (IA). Small case series show mortality rates of 50%-100% in patients infected with a triazole-resistant Aspergillus fumigatus, but a direct comparison with triazole-susceptible IA is lacking. METHODS: A 5-year retrospective cohort study (2011-2015) was conducted to compare mortality in patients with voriconazole-susceptible and voriconazole-resistant IA. Aspergillus fumigatus culture-positive patients were investigated to identify patients with proven, probable, and putative IA. Clinical characteristics, day 42 and day 90 mortality, triazole-resistance profiles, and antifungal treatments were investigated. RESULTS: Of 196 patients with IA, 37 (19%) harbored a voriconazole-resistant infection. Hematological malignancy was the underlying disease in 103 (53%) patients, and 154 (79%) patients were started on voriconazole. Compared with voriconazole-susceptible cases, voriconazole resistance was associated with an increase in overall mortality of 21% on day 42 (49% vs 28%; P = .017) and 25% on day 90 (62% vs 37%; P = .0038). In non-intensive care unit patients, a 19% lower survival rate was observed in voriconazole-resistant cases at day 42 (P = .045). The mortality in patients who received appropriate initial voriconazole therapy was 24% compared with 47% in those who received inappropriate therapy (P = .016), despite switching to appropriate antifungal therapy after a median of 10 days. CONCLUSIONS: Voriconazole resistance was associated with an excess overall mortality of 21% at day 42 and 25% at day 90 in patients with IA. A delay in the initiation of appropriate antifungal therapy was associated with increased overall mortality.

Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material.

Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma-based candidate secondary reference material (csRM) was modified into a serum-based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an isotope dilution mass spectrometry-based candidate reference method calibrated using the certified pRM. Results The inter-assay CV without harmonization was 42.1% and 52.8% in RR1 and RR2, respectively. In RR1, simulation of harmonization with sRM resulted in an inter-assay CV of 11.0%, whereas in RR2 calibration with the material resulted in an inter-assay CV of 19.1%. Both the sRM and pRM passed international homogeneity criteria and showed long-term stability. We assigned values to the low (0.95±0.11 nmol/L) and middle concentration (3.75±0.17 nmol/L) calibrators of the sRM. Conclusions Standardization of hepcidin is possible with our sRM, which value is assigned by a pRM. We propose the implementation of this material as an international calibrator for hepcidin.

Factors influencing neck and shoulder function after oral oncology treatment: a five-year prospective cohort study in 113 patients.

BACKGROUND: The aim of this study was to identify factors influencing shoulder and/or neck function in patients up to five years after treatment. MATERIALS AND METHODS: Lateral flexion of the neck, ipsilateral forward flexion, and abduction of the shoulder were measured. Potential factors were entered into a linear mixed model analysis to create a multivariate model for describing the results. RESULTS: Predicted neck and shoulder function was negatively influenced by higher age before intervention. Contralateral flexion of the neck was lower for patients undergoing surgery and radiotherapy compared to surgery. Ipsilateral flexion of the neck is influenced by a higher age at baseline. Ipsilateral shoulder abduction is lower for female gender, bone graft/flap reconstruction, and more extensive neck dissection. Ipsilateral forward flexion of the shoulder is lower for bone graft/flap reconstruction and better for patients with a T2 tumor in comparison to T3 and T4 tumors, as predicted. CONCLUSION: By our five-year follow-up outcomes of this study, neck and/or shoulder impairments can be found for high-risk patients by physiotherapists.

Masticatory function and related factors after oral oncological treatment: A 5-year prospective study.

BACKGROUND: Chewing ability is often compromised in patients with oral cancer. The aim of this study was to identify which factors affect masticatory performance in these patients. METHODS: Patients with primary oral cancer were assessed for up to 5 years after primary treatment. Healthy controls were assessed once. A mixed-model analysis was performed, with masticatory performance as outcome measure. RESULTS: A total of 123 patients were included in the study. Factors positively associated with masticatory performance were number of occlusal units (OU), having functional dentures, and maximum mouth opening (MMO). The impact of tumor location and maximum bite force (MBF) differed per assessment moment. Masticatory performance declined for up to 1 year but recovered at 5 years after treatment. CONCLUSION: Masticatory performance in patients treated for oral cancer is affected by MBF, MMO, number of OU, and dental status. These should be the focus of posttreatment therapy.

In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir.

AIMS: The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. METHODS: In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. RESULTS: The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (-8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was -0.9 (-12, 9.8) mm. CONCLUSION: The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements.

Early-onset preeclampsia is associated with perinatal mortality and severe neonatal morbidity.

OBJECTIVE: To evaluate neonatal outcomes of pregnancies complicated by early-onset preeclampsia (PE) and compare these outcomes to those of gestational age matched neonates born to mothers whose pregnancy was not complicated by early-onset PE. METHODS: We analyzed the outcome in 97 neonates born to mothers with early-onset PE (24-32 weeks amenorrhea at diagnosis) and compared it to that of 680 gestational age-matched neonates born between 25-36 weeks due to other etiologies and admitted to the Neonatal Intensive Care Unit (NICU) of a tertiary referral hospital in the Netherlands. We used Chi-square test, Wilcoxon test, and logistic regression analyses. RESULTS: Neonates born to PE mothers had a higher perinatal mortality (13% vs. 7%, p = 0.03) and infant mortality (16% vs. 9%, p= 0.03), a 20% lower birth weight (1150 vs. 1430 g, p<0.001), were more often SGA (22% vs. 9%, p < 0.001) and had more neonatal complications as compared to neonates born to mothers without PE. CONCLUSIONS: Overall adverse perinatal outcome is significantly worse in neonates born to mothers with early-onset PE. The effect of early-onset PE on perinatal mortality seems partially due to SGA. Whether these differences are due to uteroplacental factors or intrinsic neonatal factors remains to be elucidated.

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients.

MPA is an immunosuppressive agent used to prevent graft rejection after renal transplantation. MPA shows considerable inter- and intraindividual variability in exposure in children and has a defined therapeutic window, and TDM is applied to individualize therapy. We aimed to study the exposure to MPA measured as the AUC in pediatric renal transplant patients, to identify factors influencing exposure and to assess target attainment. Children transplanted between 1998 and 2014 in a single center were included. Two groups were identified: Group 1 (AUC <3 wk post-transplantation) and Group 2 (AUC >18 months post-transplantation). Therapeutic targets were set at: AUC0-12h of 30-60 mg h/L. A total of 39 children were included in Group 1 (median age 13.3 yr) vs. 14 in Group 2 (median age 13.4 yr). AUC0-12h was 29.7 mg h/L in Group 1 and 56.6 mg h/L in Group 2, despite a lower dosage in Group 2 (584 and 426 mg/m(2) , respectively). About 46% of patients reached the target AUC0-12h in Group 1. Time since transplantation and serum creatinine were significantly associated with MPA exposure (p < 0.001), explaining 36% of the variability. Individualization of the mycophenolate dose by more intense and more early TDM could improve target attainment.

Functional benefits of implants placed during ablative surgery: A 5-year prospective study on the prosthodontic rehabilitation of 56 edentulous oral cancer patients.

BACKGROUND: The timing of placement as well as the functional benefit of interforaminal implants in edentulous patients treated for oral cancer is unclear. METHODS: Fifty-six patients were recruited at 2 institutions. In 1 institution, interforaminal implants were placed during ablative surgery, the other institution used conventional prosthodontics with optional placement of implants postsurgery (postponed-placement). Masticatory performance, bite force, and subjective masticatory function were assessed before and 6 months, 1 year, and 5 years after surgery. RESULTS: Implant-retained overdentures (IODs) demonstrated the highest bite force and the least problems with solid food and food choice. Masticatory performance was equal for IODs and conventional dentures. After 5 years, IODs from patients in the during-ablative-surgery cohort tend to have higher bite force and masticatory performance than those from patients in the postponed-placement cohort. CONCLUSION: IODs produce the highest overall masticatory function. Implant placement during ablative surgery seems to be functionally beneficial. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2103-E2111, 2016.

Combination Therapy with Inolimomab and Etanercept for Severe Steroid-Refractory Acute Graft-versus-Host Disease.

Steroid-refractory acute graft-versus-host disease (aGVHD) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). A protocol on the management of aGVHD was introduced in our center that incorporated a prospective study on combination therapy with inolimomab (anti-IL-2Rα) and etanercept (anti-tumor necrosis factor-α) for steroid-refractory aGVHD. We evaluated the efficacy and safety in 21 consecutively treated patients. The patients had developed refractory aGVHD after SCT (n = 16) or donor lymphocyte infusion (n = 5), and aGVHD was classified as severe in all patients, mostly due to gastrointestinal involvement stages 2 to 4. No drug-related side effects were observed apart from the infections expected to occur in these severely immunocompromised patients. Overall response at day 28 of second-line therapy was 48% (10/21), with 6 and 4 patients achieving a complete and partial response, respectively. Eventually, 19 patients died (90%), with early mortality (<6 months) predominantly resulting from refractory aGVHD and secondary infections and late mortality resulting from relapse of the underlying disease. With a median follow-up of 55 days, the estimated rates of 6-month and 2-year overall survival were dismal, 29% and 10%, respectively. In conclusion, the combination of inolimomab and etanercept for steroid-refractory aGVHD failed to improve the dismal prognosis of severe steroid-refractory aGVHD.