Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning

The incidence of Epstein-Barr virus (EBV) viraemia and lymphoproliferative disease (LPD) was studied in a consecutive cohort of 128 paediatric patients undergoing stem cell transplantation (SCT) with reduced-intensity conditioning (RIC; n = 65) or conventional-intensity conditioning (CIC; n = 68). Following CIC, six of 68 (8%) developed viraemia; all remained asymptomatic. EBV viraemia (23 of 65 patients = 35%, P < 0.001) and LPD (10 of 65 = 15%, P < 0.001) were significantly more frequent following RIC. Of the 23 RIC patients who developed viraemia, eight remained asymptomatic, five had symptomatic viraemia (fever +/- rash), and 10 patients developed LPD, two of whom died. An absolute lymphocyte count of <0.3 x 10(9)/l at the time of onset of viraemia was strongly predictive of development of LPD (P < 0.05) in this group. The incidence of viraemia was significantly higher in patients receiving serotherapy with antithymocyte globulin (ATG; 15 of 43, 35%) than Campath (12 of 73, 16.4%, P < 0.05). Primary immunodeficiency and acute graft-versus-host disease were associated with EBV viraemia in univariate analysis, but were not independent risk factors. In conclusion, EBV viraemia and LPD appear to be significantly more common in children following RIC SCT, particularly with selective depletion of recipient T cells relative to B cells following the use of ATG. This probably reflects the profound immunosuppression following RIC SCT, together with the incomplete ablation of recipient-derived B cells.     

Computed tomography imaging of patients with obstructive sleep apnea

Objectives/Hypothesis: This study used computed tomography (CT) to identify anatomic features of the awake upper respiratory tract (URT) that correlate with severity of obstructive sleep apnea (OSA). Study Design: An IRB approved radiographic study of 80 patients with OSA and 56 patients from the general population. Methods: Awake, noncontrast CT was performed from the skull base to the thoracic inlet in patients with OSA. Cross‐sectional measurements of the retropalatal and retrolingual airways were made along with the size of the cervicomandibular ring and the percentage neck fat. The mandibular plane to hyoid distance, neck length, and laryngeal descent were also recorded. The posterior tongue fat content was estimated using the Hounsfield unit for radiodensity. The radiographic data were then compared with clinical information, including apnea‐hypopnea index (AHI), body mass index, and neck circumference using linear regression. Results: AHI increases with smaller retrolingual cross‐sectional airway (P = .0026) and increasing mandibular plane to hyoid distance (P = .0003) but not retropalatal airway or laryngeal descent. The posterior tongue is hypodense with higher fat content than other muscles of the head and neck. Conclusions: This study describes anatomic findings of the retrolingual airway in patients that correlate with OSA and can be measured on an upper airway CT. Patients with severe OSA (AHI ≥40) tend to have retrolingual airways less than 4% of the cross‐sectional area of the cervicomandibular ring. The retrolingual airspace is the major site of obstruction in severe OSA and should be carefully evaluated before surgical treatment is considered.     

Home sleep testing in the diagnosis and treatment of sleep disordered breathing

Sleep-disordered breathing is a growing public health concern and an integral part of head and neck surgery. Multichannel home sleep testing is a cost-effective, patient-friendly, scientifically valid technique of evaluating patients who present with symptoms of sleep-disordered breathing, typically snoring or daytime sleepiness. Home sleep tests can be dispensed from the physician's office. They have a 95% successful recording rate. Scoring can be autoscore or manual score. There are several protocols that can be followed based on diagnostic outcomes.     

Co-expression of Ki-67 and p53 protein in ameloblastoma and keratocystic odontogenic tumor

Abstract Objectives. The purpose of this study was to evaluate the cell proliferation and p53 protein expression in ameloblastomas (ABs), keratocystic odontogenic tumor (KCOT) and dentigerous cyst (DC). Method. The immunohistochemistry were carried out for Ki-67 and p53 protein expression by using MIB-1 clone and DO-7 clone, respectively, in ABs (n = 23), KCOT (n = 32), DC (n = 30), normal oral mucosa (NOM) (n = 12) and fetal oral mucosa (FOM) (n = 10). Results. Both the Ki-67 LI Labeling index (LI) and p53 LI was significantly higher in ABs than KCOT, DC, NOM and FOM. The Ki-67 LI and p53 LI was significantly higher in KCOT as compared to DC. Ki-67 LI and p53 LI was observed in descending order in ABs, KOCT, FOM, NOM and DC. There was significant correlation between Ki-67 expression and p53 expression in ABs, KCOT, DC and NOM. The densely stained p53 positive cells were noted higher in ABs than KCOT. The very few densely p53 positive cells were noted in DC, NOM and FOM. Conclusion. The results suggest that the p53 protein expression does not necessarily imply an association with malignant disease and/or p53 gene mutation, but a tendency to be expressed in an increasing quantitative and qualitative manner, as the biologic behavior of odontogenic cyst or tumors becomes more aggressive. p53 over-expression may promote cell proliferation in odontogenic lesions. Thus, it can be stipulated that Ki-67 and p53 protein expression can be used as a prognostic marker in odontogenic lesions.     

Comparison of Myofibroblasts Expression in Oral Squamous Cell Carcinoma,Verrucous Carcinoma,High Risk Epithelial Dysplasia,Low Risk Epithelial Dysplasia and Normal Oral Mucosa

The aim was to evaluate and compare the presence of myofibroblasts in oral squamous cell carcinoma (OSCC), verrucous carcinoma (VC), high-risk epithelial dysplasia (HRED), low-risk epithelial dysplasia (LRED), and normal oral mucosa (NOM). The study consisted of 37 OSCC, 15 VC, 15 HRED, 15 LRED and 15 NOM. α-smooth muscle actin (α-SMA) antibody was used to identify myofibroblasts. The α-SMA expression was not observed in NOM and LRED. The α-SMA was expressed in 97.29% of OSCC, 86.66% of VC, 46.66 % of HRED. The α-SMA expression was significantly higher in OSCC than VC (p = 0.023) and HRED (p < 0.000). The α-SMA expression was significantly higher in VC than HRED (p = 0.043). Myofibroblastic expression, as highlighted by α-SMA, is undetectable in NOM and LRED but increases as the disease progresses from potentially malignant disorders, as HRED to VC to invasive OSCC. Thus, proliferation of myofibroblasts may be used as a stromal marker of oral premalignancy and malignancy.     

Freeman-Sheldon Syndrome Presenting with Microstomia: A Case Report and Literature Review

Freeman-Sheldon syndrome (FSS), as first described by Freeman and Sheldon in 1938, is a morphologically well-defined syndrome that results in a dysmorphic status combining bone anomalies and joint contractures with characteristic facies. It is part of the nosologic group of pathologies currently known as distal arthrogryposis as reported by Hall et al. (Am J Med Genet 11:185–239, 1982 [1]). It is a rare disorder and its exact prevalence is unknown. Our objective is to report a case of FSS presenting with microstomia and add a brief review of the literature for similar cases.     

“We are part of a family”. Benefits and limitations of community ART groups (CAGs) in Thyolo,Malawi: a qualitative study

Introduction : In 2012 Community ART Groups (CAGs), a community‐based model of antiretroviral therapy (ART) delivery were piloted in Thyolo District, Malawi as a way to overcome patient barriers to accessing treatment, and to decrease healthcare workers’ workload. CAGs are self‐formed groups of patients on ART taking turns to collect ART refills for all group members from the health facility. We conducted a qualitative study to assess the benefits and challenges of CAGs from patients’ and healthcare workers’ (HCWs) perspectives. Methods : Data were collected by means of 15 focus group discussions, 15 individual in‐depth interviews, and participant observation in 2 health centres. The 94 study participants included CAG members, ART patients eligible for CAGs who remained in conventional care, former CAG members who returned to conventional care and HCWs responsible for providing HIV care. Patient participants were purposively selected from ART registers, taking into account age and gender. Narratives were audio‐recorded, transcribed, and translated from Chichewa to English. Data were analyzed through a thematic analysis. Results : Patients and HCWs spoke favourably about the practical benefits of CAGs. Patient benefits included a reduced frequency of clinic visits, resulting in reduced transportation costs and time savings. HCW benefits included a reduced workload. Additionally peer support was perceived as an added value of the groups allowing not only sharing of the logistical constraints of drugs refills, but also enhanced emotional support. Identified barriers to joining a CAG included a lack of information on CAGs, unwillingness to disclose one's HIV status, change of residence and conflicts among CAG members. Participants reported that HIV‐related stigma persists and CAGs were seen as an effective strategy to reduce exposure to discriminatory labelling by community members. Conclusions : In this setting, patients and HCWs perceived CAGs to be an acceptable model of ART delivery. Despite addressing important practical barriers to accessing ART, and providing peer support, CAGs were not well known by patients and had a limited impact on reducing HIV‐related stigma. The CAG model of ART delivery should be considered in similar settings. Further measures need to be devised and implemented to address HIV‐related stigma.     

Effects of Rovalpituzumab Tesirine on Ventricular Repolarization in Patients With Small‐Cell Lung Cancer

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova‐T) is an antibody‐drug conjugate that targets delta‐like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova‐T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova‐T in patients with previously treated extensive‐stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova‐T over 30 minutes, administered 6 weeks apart. Forty‐six patients received at least one dose of Rova‐T. At the geometric mean Rova‐T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia‐corrected QT (QTcF) interval; the upper limit of the 2‐sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova‐T administration. All patients experienced a treatment‐emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac‐related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova‐T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ There currently are no clinical data regarding the electrocardiographic (ECG) effects of rovalpituzumab tesirine (Rova‐T).

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study was conducted to address questions regarding cardiac safety of this agent during its clinical drug development cycle to meet the US Food and Drug Administration (FDA) requirements.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ This study confirmed that targeting delta‐like 3 using Rova‐T at the 0.3 mg/kg dose that was utilized in the phase II/III studies did not result in any clinically significant changes in the ECG throughout several time points.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ This knowledge will facilitate future development of tesirine‐containing antibody‐drug conjugates by ameliorating concerns of potential ECG effect, even if Rova‐T itself did not meet efficacy end points for drug approval.

Lung cancer is one of the most common and deadly cancers, with 228,000 new diagnoses per year and 143,000 deaths per year in the United States. ¹ Small cell lung cancer (SCLC) accounts for 10% to 15% of lung cancers ¹ and is a leading cause of cancer death worldwide. ² , ³ The prognosis of patients with SCLC is poor, with a 5‐year survival rate of < 5%. ⁴ , ⁵ SCLC is categorized into limited‐stage and extensive‐stage (ES) disease based on the extent of the disease, with ES disease accounting for 65% of cases. ⁶ Treatment options are limited for ES disease, with platinum doublet chemotherapy along with anti‐PD‐L1 checkpoint blockade (atezolizumab or durvalumab) as the preferred first‐line treatment. There are few effective therapies approved for second‐line treatment of ES SCLC ⁷ ; median overall survival in patients treated with topotecan is only 26 weeks. ⁸ Recent studies of single‐agent cytotoxic agents and immunotherapy have yielded only modest improvements. ⁷ The Notch‐family ligand delta‐like 3 (DLL3) is highly expressed on SCLC cells but not expressed in most normal tissue, making it a tractable drug target for SCLC. ⁹ Rovalpituzumab tesirine (Rova‐T) is a first‐in‐class antibody‐drug conjugate (ADC) that targets DLL3 to deliver a cytotoxic agent directly to SCLC cells. Rova‐T is composed of a monoclonal DLL3 antibody linked to a DNA‐intercalating payload (pyrrolobenzodiazepine (PBD)) via a protease‐cleavable linker. The safety and efficacy of Rova‐T were initially evaluated in 82 patients in the first‐in‐human phase I study SCRX16‐001 (74 patients with SCLC and 8 patients with large‐cell neuroendocrine carcinoma). Treatment‐related cardiac adverse events (AEs) were uncommon. ¹⁰ The change in Fredericia‐corrected QT interval (QTcF) remained below a 10‐msec increase relative to baseline at 30 minutes after the end of infusion, when maximum Rova‐T serum concentrations were observed (unpublished data). Effects on QTcF at later time points have not been evaluated. In the phase 2 TRINITY study of patients with DLL3‐expressing relapsed/refractory SCLC, 12% of patients had a confirmed objective response to Rova‐T, and a manageable safety profile was observed. ¹¹ Further development of Rova‐T has since been halted because two phase III studies showed a lack of clinical benefit of Rova‐T in the frontline maintenance and second‐line settings. ¹² , ¹³ Determining cardiovascular safety is a key part of drug characterization. A delay in cardiac repolarization results in an electrophysiological environment that may lead to development of potentially fatal cardiac arrythmias. Typically, a thorough QT/corrected QT (QTc) study is conducted after the initial clinical study to determine whether an investigational agent meets a threshold level of effect on cardiac repolarization as detected by QT/QTc prolongation. ¹⁴ The cytotoxic component of Rova‐T precluded a thorough conventional QT/QTc study, which usually includes a crossover with the therapeutic dose, a supratherapeutic dose, a placebo, and a positive control in healthy volunteers. Additionally, because patients with SCLC require active treatment, the use of a placebo and/or a positive control would not be ethical. ¹⁵ Therefore, an alternative, intensive QT/QTc study design was determined to be appropriate, with the primary objective of determining the effect of Rova‐T on QTcF in patients with SCLC during the first two cycles of Rova‐T administration.     

English Cross-Cultural Translation and Validation of the Neuromuscular Score: A System for Motor Function Classification in Patients With Neuromuscular Diseases

Objective

To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function.

Design

Validation survey.

Setting

Patients seen at a medical research center between June and September 2013.

Participants

Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy.

Interventions

Not applicable.

Main Outcome Measures

An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa.

Results

Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=−.944, P<.0001), ACTIVLIM (ρ=−.895, P<.0001), and hip abduction strength by myometry (ρ=−.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701–.914) but moderate for D2 (κ=.592; 95% CI, .412–.773) and D3 (κ=.485; 95% CI, .290–.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores.

Conclusions

Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases.