bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of 18F-Fluorodeoxyglucose PET/CT in restaging patients with small cell lung cancer: a systematic review
Authors: Quartuccio Natale , Salem Ahmed , Laudicella Riccardo , Spataro Alessandro , Chiaravalloti Agostino , Caobelli Federico , Cistaro Angelina , Alongi Pierpaolo , Evangelista Laura
Published: March 2021

Aim

18F-Fluorodeoxyglucose (FDG) PET imaging may play an important role in the restaging of patients with small-cell lung cancer (SCLC),, nevertheless, a systematic review of literature was still missing in this setting. The aim of this review was to summarize the evidence on literature regarding the utility of 18F-FDG PET imaging in restaging patients with SCLC.

Methods

A literature search was performed to retrieve original studies using 18F-FDG PET or 18F-FDG PET/computed tomography (CT) in a minimum of 10 patients with SCLC at restaging.

Results

The selected literature (17 studies) was discussed in four sections: detection rate, impact on management, prediction of prognosis and evaluation of the response to therapy. According to the literature, PET imaging may result in discordance with conventional imaging, mainly contrast-enhanced CT (ceCT), and detect additional lesions in a certain proportion of cases, leading to upstaging or downstaging. A variable level of disagreement between PET and conventional imaging has been reported also in the evaluation of response to therapy. A positive PET study is associated with shorter survival, especially in the presence of distant metastases. According to some studies, semiquantitative parameters are also inversely associated with overall survival and progression-free survival. Although the retrieved articles proved the utility of 18F-FDG PET imaging in each clinical setting, literature is still limited.

Conclusions

This review encourages the use of 18F-FDG PET imaging, especially in conjunction with ceCT in recurrent SCLC patients. Further level I evidence is needed to further assess the diagnostic and prognostic capability of 18F-FDG PET/ceCT findings in SCLC.
Renogram image characteristics and the reproducibility of differential renal function measurement
Authors: Brink Anita , Libhaber Elena , Levin Michael
Published: March 2021

Purpose

Patient factors such as age and glomerular filtration rate (GFR), have been implicated as causes for poor reproducibility of differential renal function (DRF) estimates on 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) renography. This study aims to investigate factors associated with the reproducibility of DRF measurements.

Methods

The association between age, GFR and imaged derived image characteristics and reproducibility of repeated DRF estimates calculated using the area under the curve method and the Rutland Patlak method was analysed for cohort 1 (n = 127). The association between these variables and reproducibility of DRF was tested with univariate linear regression. The univariate linear regression results were used to plan the multiple linear regression combinations.

The associations between variables identified and reproducibility of DRF values were then tested in a second cohort (n = 227).

Results

The R
2 values for goodness-to-fit for the multiple regression models ranged from 0.33 to 0.49 for cohort 1 and from 0.17 to 0.22 for cohort 2. Left kidney to background ratio (LKTBR) was significant in all the multiple linear regression combinations (P < 0.05). Right kidney to background ratio (RKTBR), right renal margins well defined, right renal margins poorly visualised, time visualisation right calyces and age were significant in most combinations. The reproducibility of DRF measurement was decreased when the kidney to background ratio (KTBR) was ≤2.

Conclusion

Only LKTBR, RKTBR, right renal margins well defined, time visualisation right calyces and age predicted reproducibility for the measurement of DRF on 99mTc-MAG3 renograms. The KTBR should be incorporated into the renal processing software as a quality control step. The DRF values should be interpreted with caution if the KTBR is ≤2.0.
Fuzzy logic-based moving average filters for reducing noise from Tc-99m-sestamibi parathyroid images
Authors: Pandey Anil Kumar , Kumar Navneet , Dhiman Shweta , Patel Chetan , Bal Chandrashekhar , Kumar Rakesh
Published: March 2021

Introduction

The objective of the study was to use fuzzy logic-based moving average filters for reducing noise from Tc-99m-sestamibi parathyroid images and to compare its performance with classical moving average filters.

Methods

Sixty-eight Tc-99m-sestamibi parathyroid images (33 image zoom 1.0, 35 images zoom 2.0) were filtered using symmetric triangular fuzzy filters with the moving average (TMAV), asymmetric triangular fuzzy filters with the moving average (ATMAV) and classical moving average filter (MAV) with moving average within a square window of dimension N × N pixels (N=3,5,7,9,11). The relative filtering performance was compared both objectively (using Brisque score) and subjectively [by two nuclear medicine physicians on a 4-point scale (1 = nondiagnostic; 2 = diagnostic; 3 = good; and 4 = excellent image quality)]. The nonparametric two-sample Kolmogorov–Smirnov test was applied to find the statistically significant difference between the quality of input and their corresponding filtered images.

Results

The Brisque score assigned to MAV filtered zoom 2.0 images (MAV_3, median = −0.61) were significantly smaller than that of their input images (median = 53.84, at P = 1) and fuzzy filtered images (TMAV_3, median = 0.44, at P = 0.89 and ATMAV_3, median =8.26, at P = 0.97). The sum of average subjective image quality score for input, MAV_3, TMAV_3, TMAV_5, ATMAV_3, and ATMAV_5 were 148, 221, 221.5, 198,171,253 and 237.5, respectively.

Conclusion

On the basis of subjective assessment, the performance of ATMAV_3 fuzzy filter was found to be better compared to the classical moving average filter in reducing noise from Tc-99m-sestambi parathyroid images.
Attenuation correction in CZT myocardial perfusion imaging comparison of supine-prone and low-dose CT-corrected supine acquisitions
Authors: Hahn Eva , Kammeier Annett , Burchert Wolfgang , Lindner Oliver
Published: March 2021

Aims

The study aimed to investigate whether additional prone imaging delivers comparable results to supine imaging with low-dose computed tomography (CT) attenuation correction (CTAC) in cadmium, zinc and telluride (CZT) myocardial perfusion imaging.

Methods and results

Thirty-four patients with an indication for myocardial perfusion imaging were studied with a CZT camera in the supine and then prone position. Furthermore, a low-dose CT was acquired. Three data sets were reconstructed and considered for analysis: (1) supine CZT, (2) supine CZT with CTAC and (3) supine CZT with additional prone CZT. Based on 17-segment polartomograms, we compared radiopharmaceutical uptake percentage, summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), total ischemic and scarred segments, and finally scan classification and clinical decision-making. SSS of supine/supine-CTAC/supine-prone was 341/229/253 (P < 0.05), SRS was 246/156/164 (P < 0.05) and SDS was 104/88/96 (ns), respectively. Total ischemic segments were 65/67/65 (ns) and total scarred segments 96/62/69 (P < 0.05), respectively. The frequency of normal scans was highest for supine-prone, followed by supine-CTAC and supine (41/35/24%, respectively). Supine imaging indicated 23% of patients for invasive coronary angiography, both supine-CTAC and supine-prone 18%. These two showed a significant intercorrelation.

Conclusion

Additional prone imaging and CTAC are mainly correct for the amount and extent of myocardial scars. Both methods increase the frequency of normal scans and show a significant agreement in clinical decision-making. Additional prone imaging appears as a useful alternative when a low-dose CT for attenuation correction is not available.
‘Enhancing’ red cell fate through epigenetic mechanisms
Authors: Rossmann Marlies P. , Zon Leonard I.
Published: March 2021

Purpose of review

Transcription of erythroid-specific genes is regulated by the three-dimensional (3D) structure and composition of chromatin, which dynamically changes during erythroid differentiation. Chromatin organization and dynamics are regulated by several epigenetic mechanisms involving DNA (de-)methylation, posttranslational modifications (PTMs) of histones, chromatin-associated structural proteins, and higher-order structural changes and interactions. This review addresses examples of recent developments in several areas delineating the interface of chromatin regulation and erythroid-specific lineage transcription.

Recent findings

We survey and discuss recent studies that focus on the erythroid chromatin landscape, erythroid enhancer-promotor interactions, super-enhancer functionality, the role of chromatin modifiers and epigenetic crosstalk, as well as the progress in mapping red blood cell (RBC) trait-associated genetic variants within cis-regulatory elements (CREs) identified in genome-wide association study (GWAS) efforts as a step toward determining their impact on erythroid-specific gene expression.

As one of the best characterized and accessible cell differentiation systems, erythropoiesis has been at the forefront of studies aiming to conceptualize how chromatin dynamics regulate transcription. New emerging technologies that bring a significantly enhanced spatial and temporal resolution of chromatin structure, and allow investigation of small cell numbers, have advanced our understanding of chromatin dynamics during erythroid differentiation in vivo.
Ultrasound: an emerging modality for the dysphagia assessment toolkit?
Authors: Allen Jodi E. , Clunie Gemma M. , Winiker Katharina
Published: March 2021

Purpose of review

Videofluoroscopy (VFSS) and fibreoptic endoscopic evaluation of swallowing (FEES) are established instrumental techniques to support differential diagnosis and treatment of oropharyngeal dysphagia. Whilst their value is undisputed, each tool is not without limitations. The COVID-19 pandemic has restricted access to VFSS and FEES leading clinicians to explore alternative or augmentative tools to support swallowing assessment.

Ultrasound (US) is an established tool for visualisation of head and neck anatomy, including structures implicated in swallowing. Although US has been utilised in swallowing research for many years, its application has not translated into common clinical practice. This review presents and debates the evidence for and against use of US for clinical swallowing assessment.

Recent findings

Evaluation of swallowing muscle morphometry and measurement of isolated swallowing kinematics are two primary uses of US in swallowing assessment that have been identified in the literature. Use of US to detect bolus flow, aspiration and residues is in its early stages and needs further research.

US shows promise as an adjunctive modality to support assessment of swallowing. With standardisation, these measurements may have potential for transition into clinical care. Reliability and validity testing and development of normative data are imperative to ensure its use as an evidence-based instrumentation.
Pioneering virtual otolaryngology specialist examinations in South Africa in the COVID-19 and post-COVID-19 era
Authors: Seedat Riaz Y.
Published: March 2021

Purpose of review

South Africa, and the African continent, have a shortage of ear, nose and throat (ENT) specialists. The coronavirus disease 2019 (COVID-19) pandemic not only had an adverse impact on specialist training, but also impacted the ability of trainees to undertake the final examinations in order to qualify as ENT specialists.

Recent findings

The response to the COVID-19 pandemic resulted in the postponement of the final examination of the Fellowship of the College of Otorhinolaryngologists of South Africa (FCORL (SA)). A virtual clinical examination was held via videoconferencing to assess clinical judgement, insight, reasoning and decision making.

The virtual clinical assessment allowed trainees to undertake the final examination despite the COVID-19 pandemic, ensuring that they could be added to the limited number of specialists in South Africa and the African continent.
How to improve outcome in nephron-sparing surgery: the impact of new techniques
Authors: Cignoli Daniele , Fallara Giuseppe , Larcher Alessandro , Rosiello Giuseppe , Montorsi Francesco , Capitanio Umberto
Published: March 2021

Purpose of review

Nephron-sparing partial nephrectomy is the state of the art for localized small renal mass and it is gaining attention also for more advanced cases. In the present narrative review, we discuss the new developments that have occurred in the advancement of this approach over the past few years.

Recent findings

Off-clamp, selective/superselective clamp and early-unclamping techniques are safe and feasible approaches, with potentially superior functional outcomes, and noninferior complications rate and oncological outcomes, when compared with main artery clamping. Renorrhaphy must preserve the physiological vascularization of residual parenchyma. Running sutures, particularly using barbed wires, shorten the operating and ischemia times. A further advantage could derive from avoiding a double-layer suture. Transperitoneal robot-assisted partial nephrectomy (RAPN) and retroperitoneal RAPN can be considered equivalent in terms of perioperative morbidity, functional and oncologic outcomes, regardless of tumor's location, thus the choice of the approach should be driven by the surgeon's expertise. Future improvements should be introduced by the single-port robotic surgery, which seems to be safe and feasibly also in an off-clamp manner.

Significant advances have recently been achieved in nephron-sparing surgery technique. However, future studies with standardized reporting of these new techniques are needed to assess the real impact of them on early and long-term functional outcomes.
The current landscape of salvage therapies for patients with bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer
Authors: Packiam Vignesh T. , Richards Jordan , Schmautz Maximilian , Heidenreich Axel , Boorjian Stephen A.
Published: March 2021

Purpose of review

Although radical cystectomy represents the gold standard treatment for patients with high-risk nonmuscle invasive bladder cancer (NMIBC) whose disease does not respond to bacillus Calmette-Guérin (BCG), many patients are unable or unwilling to undergo surgery. The need remains for effective bladder-preserving therapies. This review aims to describe existing treatments, contemporary research in this field and ongoing trials of salvage therapies for patients with BCG-unresponsive NMIBC.

Recent findings

Intravesical chemotherapy has been utilized frequently in this setting. Emerging data on combination regimens such as intravesical gemcitabine and docetaxel and intravesical cabazitaxel, gemcitabine and cisplatin are promising; nevertheless, larger, prospective trials are needed. Meanwhile, the intravenous checkpoint inhibitor pembrolizumab was recently FDA-approved for patients BCG-unresponsive NMIBC. Encouraging clinical trial results for intravesical nadofaragene firadenovec, oportuzumab monatox and ALT-803 + BCG have been released, while data from trials of other treatment strategies, including novel chemotherapy and drug delivery, augmented BCG immunotherapy, adenoviral and gene therapy, targeted therapy, and combination systemic immunotherapy with intravesical agents, are eagerly awaited.

Several novel salvage therapies offer promise for patients with BCG-unresponsive NMIBC. Patient selection, efficacy, safety, cost and ease of administration must be carefully considered to determine the optimal treatment approach.
Renal cell carcinoma pathology in 2021: ‘new need for renal cancer immune profiling’
Authors: Sobottka Bettina , Lorch Anja , Silina Karina , van den Broek Maries , Moch Holger
Published: March 2021

Purpose of review

The aim of this review is to outline characteristics of the renal cell carcinoma (RCC) tumor immune microenvironment (TIME), the potential impact of tumor intrinsic alterations on the TIME and the value of metastatic tissue assessment in this context.

Recent findings

According to the latest European Association of Urology, European Society for Medical Oncology and National Comprehensive Cancer Network guidelines immune checkpoint inhibition represents a new core treatment strategy in advanced clear cell RCC (ccRCC). Despite its success, the prognosis of many RCC patients remains unsatisfactory most likely because of resistance mechanisms within the TIME. Moreover, most studies assess the primary tumor even though the advanced metastatic disease is targeted. Overall, metastatic RCC has hardly been investigated. First insights into the complexity of the genomic and immune landscape in RCC were recently provided. The functional impact of tumor intrinsic alterations on the TIME has just been described potentially contributing to therapy response in RCC.

The complexity of the RCC TIME and its potential interdependence with tumor intrinsic alterations has only just been recognized. A deeper understanding of the TIME may reveal predictive and prognostic biomarkers long-awaited in RCC, improve RCC patient stratification and could possibly be most instructive if assessed in metastatic tissue.
Surgical intervention in patients with urothelial carcinoma of the bladder and lymph node metastasis
Authors: Abufaraj Mohammad , Al-Ani Abdallah , AlQudah Alex , Shariat Shahrokh F.
Published: March 2021

Purpose of review

To systematically review the most recent evidence on the role of surgery in patients with urothelial carcinoma of bladder and lymph node metastasis.

Recent findings

Patients with urothelial carcinoma of bladder and lymph node metastasis have a poor prognosis. The mainstay treatment for these patients is systemic chemotherapy. However, slowly growing body of literature suggests that multimodal therapy comprised of radical cystectomy, lymph node dissection, and perioperative chemotherapy is more effective than either chemotherapy or surgery alone. The timing of chemotherapy, whether preoperative or adjuvant chemotherapy, is still controversial, but the current evidence indicates that patients who achieve a major or complete response after induction chemotherapy appear to benefit from the surgical intervention in the form of radical cystectomy and pelvic lymph node dissection. The limit of lymph node dissection has to be determined.

Multimodal therapy is associated with better survival outcomes in bladder cancer patients with lymph node metastasis. The current guidelines recommend systemic chemotherapy as the mainstay of treatment for these patients, and there is no convincing evidence on the efficacy of surgical intervention in isolation. Nonetheless, studies comparing multiple treatment modalities demonstrated that surgical salvage therapy is beneficial only when combined with chemotherapy. The methodological limitations of the current literature preclude a robust conclusion of survival advantage. Further studies are needed to help improve imaging for detecting lymph node metastasis and novel strategies to enrich our multimodal therapeutic implementation.
Dual immune check point blockade or immune check point-tyrosine kinase inhibitor combination: as a first-line treatment in metastatic renal cell carcinoma?
Authors: Schmidinger Manuela , Resch Irene , Fajkovic Harun , Remzi Mesut , Shariat Shahrokh F. , Bedke Jens
Published: March 2021

Purpose of review

To discuss treatment decisions in the first-line setting of metastatic renal cell carcinoma (mRCC).

Recent findings

Immune check point inhibitor (ICI) combinations have replaced sunitinib as the standard of care in the first-line treatment of mRCC. Dual ICI treatment with nivolumab and ipilimumab was shown to significantly improve overall survival and objective response rates. Similarly, the ICI–tyrosine kinase inhibitor combinations pembrolizumab and axitinib and nivolumab and cabozantinib have demonstrated superiority in terms of overall survival, objective response rates and progression-free survival versus sunitinib. The lack of both comparative trials and predictive markers impedes individualized treatment decisions. Clinicians are left to make treatment choices based on clinical and biological factors. These factors may include differences in toxicity profiles, the rate of complete remission, a clinical situation that requires urgent tumor shrinkage, the presence of inflammation, histological or immune-histochemical features and others.

In the absence of comparative trials, clinical and biological factors may facilitate the choice between various treatment options in the first-line setting of mRCC. In addition, both the experience of the physician with a specific treatment together with patient's preferences and expectations of systemic therapy may be part of the decision-making process.
Salvage management of patients with relapsing testicular germ cell tumors
Authors: Heidenreich Axel , Pfister David , Paffenholz Pia
Published: March 2021

Purpose of review

This review aims to summarize the latest evidence of medical and surgical treatment options for patients with relapsing testicular germ cell tumors.

Recent findings

Depending on International Germ Cell Cancer Classification Group risk classification 10–50% of patients with metastatic TGCT develop relapse which needs further multimodality treatment. With regard to therapy, early relapses are stratified according to their prognostic risk profile which results in a 3-year overall survival between 6% in the very high to 77% in the very low risk group. Prognostic risk score dictates systemic therapy which might be second line chemotherapy (TIP, PEI) or high dose chemotherapy. Any residual masses following salvage chemotherapy need to be completely resected due the presence of viable cancer and/or teratoma in more than 50% of cases. Targeted therapy in men with druggable mutations is for individualized cases only. Patients with late relapses developing more than 2 years after first-line chemotherapy are best managed by surgery. Desperation surgery is reserved for those patients with rising markers during or immediately after chemotherapy and good risk factors such as rising alpha-fetoprotein, <3 metastatic sites and complete resectability. Multimodality treatment will result in long-term cure of 25% to 60%. Due to the complexity of treatment, chemotherapy as well as surgery should be performed in highly experienced centres only.

Multimodality treatment to salvage relapsing patients with metastatic testis cancer requires extensive experience for both systemic therapy and surgery. If done properly, it will result in moderate to high cure rates. Personalized therapeutic options are currently evaluated in clinical trials.
Allopurinol to Prevent Mercaptopurine Adverse Effects in Children and Young Adults With Acute Lymphoblastic Leukemia
Authors: Kamojjala Ruchika , Bostrom Bruce
Published: March 2021

Mercaptopurine (6MP) is used to treat acute lymphoblastic leukemia (ALL) and is metabolized by hypoxanthine guanine phosphoribosal transferase to form 6-thioguanine nucleotide (6TGN). It is also metabolized by thiopurine methyl-transferase to produce 6-methylmercaptopurine (6MMP). Elevated levels of 6MMP have been associated with toxic effects that may interfere with therapy. Allopurinol is known to inhibit thiopurine methyl-transferase which reduces red cell 6MMP and increases 6TGN. Allopurinol has been utilized successfully in adult and pediatric patients with inflammatory bowel disease who have experienced 6MMP related gastrointestinal toxicity. Between August 2015 and August 2018 we started 25 patients with ALL in maintenance on allopurinol in combination with a reduced dose of 6MP. They all had unacceptable side-effects from elevated 6MMP, including abdominal pain, nausea, vomiting, decreased appetite, hypoglycemia, fatigue, and liver toxicity. In addition many had a facial rash. All patients showed resolution of symptoms within a few weeks after starting allopurinol. The red cell levels of 6MMP rapidly declined in the first month. The red cell levels of 6TGN transiently increased in spite of the lower 6MP dose. There was no decrease in absolute neutrophil count or hemoglobin. Platelets decreased slightly not requiring therapy modification. Elevated bilirubin normalized, and alanine aminotransferase decreased significantly with most normalizing. All patients continued on allopurinol with reduced dose 6MP until completing therapy. Allopurinol, in conjunction with a reduced dose of 6MP, effectively resolves 6MMP related side-effects in ALL patients on maintenance chemotherapy. This approach may lead to increased adherence to oral 6MP during ALL maintenance in patients with 6MMP induced side-effects.
Analysing the Action Research Arm Test (ARAT): a cautionary tale from the RATULS trial
Authors: Wilson Nina , Howel Denise , Bosomworth Helen , Shaw Lisa , Rodgers Helen
Published: March 2021

Many studies of stroke rehabilitation use the Action Research Arm Test (ARAT) as an outcome, which measures upper limb function by scoring the ability to complete functional tasks. This report describes an issue encountered when analysing the ARAT subscales in a trial of upper limb therapies after stroke. The subscales of the ARAT at three months followed a ‘U-shaped’ distribution, and therefore, comparing means or medians was not appropriate. A simple alternative approach was chosen that dichotomised the subscales. When analysing the ARAT, the shape of the distributions must be checked in order to choose the most appropriate descriptive and inferential statistical techniques. In particular, if the data follows a ‘U-shaped’ distribution, a simple dichotomising or a more sophisticated approach is needed. These should also be considered for heavily skewed distributions, often arising from substantial floor or ceiling effects. Inappropriate analyses can lead to misleading conclusions.
Vulvar Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma
Authors: Morse Daniel C. , Park Katherine E. , Chitsazzadeh Vida , Li Shaoying , Young Ken , Gunther Jillian R. , Dabaja Bouthaina S. , Duvic Madeleine
Published: March 2021

Cutaneous T-cell lymphomas may present with a clinical course that is incongruent with the associated histologic findings. Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma classically presents as an abrupt eruption of disseminated ulcerated annular plaques with aggressive behavior and a poor prognosis. Herein we describe a vulvar primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma with a locally aggressive clinical course that was strikingly responsive to radiation therapy. As aggressive therapy involving systemic chemotherapy is indicated for primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, appropriate clinico-pathologic correlation is crucial for preventing potentially excessive or insufficient therapeutic intervention. Our case also highlights the pivotal role of both radiation therapy and infection control in the management of aggressive cutaneous vulvar lymphomas.
Neurotoxicity Biology and Management
Authors: Danish Husain , Santomasso Bianca D.
Published: March 2021

Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell–engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood–brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management.
Chimeric Antigen Receptor T Cells for B-Cell Lymphoma
Authors: Newcomb Richard , Jacobson Caron
Published: March 2021

Anti-CD19–directed chimeric antigen receptor (CAR) T-cell therapy yields durable remissions in up to 40% of patients with chemoresistant aggressive B-cell non-Hodgkin lymphoma (NHL), a group of patients expected only to survive on average 6 months. Although longer follow-up is needed to define durability, CD19 CAR T cells are demonstrating similar promise in other B-NHL subtypes such as mantle cell lymphoma and the indolent B-cell NHLs. This transformative therapy, however, remains hamstrung by its associated toxicities of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, as well as by mechanisms of resistance and relapse and accessibility. To address these limitations, studies are underway to investigate toxicity prevention and mitigation strategies and the development of safer CARs, combination strategies to overcome T-cell exhaustion and dual antigen targeting to combat antigen loss, and alternative cell sources to address cost and manufacturing inefficiencies and resolve issues surrounding T-cell fitness.
Using Adoptive Cellular Therapy for Localized Protein Secretion
Authors: Evans Alysa N. , Lin Heather K. , Hossian A. K. M. Nawshad , Rafiq Sarwish
Published: March 2021

Redirection of T cell cytotoxicity by the chimeric antigen receptor (CAR) structure may not be sufficient for optimal antitumor function in the patient tumor microenvironment. Comodifying CAR T cells to secrete different classes of proteins can be used to optimize CAR T cell function, overcome suppressive signals, and/or alter the tumor microenvironment milieu. These modifications aim to improve initial responses to therapy and enhance the durability of response. Furthermore, CAR T cells can deliver these molecules locally to the tumor microenvironment, avoiding systemic distribution. This approach has been tested in preclinical models using a variety of different classes of agonistic and antagonistic proteins, and clinical trials are currently underway to assess efficacy in patients.
Challenges and Solutions to Bringing Chimeric Antigen Receptor T-Cell Therapy to Myeloid Malignancies
Authors: Borot Florence , Mukherjee Siddhartha , Ali Abdullah Mahmood
Published: March 2021

Myeloid malignancies including myelodysplastic syndromes and acute myeloid leukemia are a group of clonal hematopoietic stem progenitor cell disorders mainly effecting the elderly. Chemotherapeutic approaches improved the outcome in majority of the patients, but it is generally associated with severe toxicities and relapse and does not benefit all the patients. With the success of adoptive cell therapies including chimeric antigen receptor T-cell therapy in treating certain B-cell malignancies, these therapeutic approaches are also being tested for myeloid malignancies, but the preclinical and limited clinical trial data suggest there are significant challenges. The principal hurdle to efficient targeted immunotherapy approaches is the lack of a unique targetable antigen on cancer cells leading to off-target effects including myelosuppression due to depletion of normal myeloid cells. Advanced age of the patients, comorbidities, immunosuppressive bone marrow microenvironment, and cytokine release syndrome are some other challenges that are not unique to myeloid malignancies but pose significant challenge for the successful adaptation of this approach for treatment. In this review, we highlight the challenges and solutions to adopt chimeric antigen receptor T-cell therapies to treat myeloid malignancies.
Improving and Maintaining Responses in Pediatric B–Cell Acute Lymphoblastic Leukemia Chimeric Antigen Receptor–T Cell Therapy
Authors: Arya Rahul , Barrett David M. , Grupp Stephan A. , Melenhorst Jan Joseph
Published: March 2021

Chimeric antigen receptor T therapy has heralded a new era in the treatment of acute lymphoblastic leukemia (ALL) and other hematologic malignancies. In this autologous immunotherapy, patient-derived T cells are genetically engineered and then infused back to kill the leukemia cells. The observed response rates in ALL are a testament to the success of this therapy. However, there have been instances where the patients either did not respond or relapsed after initial response. Emergence of resistance due to antigen loss and T-cell exhaustion has been observed. This poses a challenge in making this therapy successful for every ALL patient and warrants deeper understanding of emergence of resistance and potential approaches to overcome them. Here we discuss current perspectives and advances in this area.
Chimeric Antigen Receptor Design Today and Tomorrow
Authors: Boucher Justin C. , Davila Marco L.
Published: March 2021

The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This includes different antigen-binding domains such as antigen-ligand binding partners and variable lymphocyte receptors. Another recent advancement in CAR design is Boolean logic gates that can minimize on-target, off-tumor toxicities. Recent studies on the optimization of costimulatory signaling have also shown how CAR design can impact function. By using specific signaling pathways and transcription factors, CARs can impact T-cell gene expression to enhance function. By using these techniques, the promise of CAR T-cell therapies for solid tumors can be fulfilled.
Is Adoptive Cellular Therapy With Non–T-Cell Immune Effectors the Future?
Authors: Ali Alaa Kassim , Tarannum Mubin , Romee Rizwan
Published: March 2021

Success from checkpoint blockade and adoptive cell therapy has brought a new hope in cancer immunotherapy. Adoptive cell therapy involves the isolation of immune cells, ex vivo activation and/or expansion, and reinfusion into the patients, and their effect can be dramatically increased by the incorporation of chimeric antigen receptors specific to molecules expressed on tumor cells. Chimeric antigen receptor T cells have shown exciting results in the treatment of liquid malignancies; nevertheless, they suffer from limitations including severe adverse effects such as cytokine release syndrome and neurotoxicity seen in patients as well as a potential for causing graft-versus-host disease in an allogeneic setting. It is thus imperial to explore innate immune cells including natural killer cells, macrophages, natural killer T cells, and γδ T cells. Here, we provide a broad overview of the major innate immune cells and their potential for adoptive cell therapy and chimeric antigen receptor engineering.
A Naturalistic Study of Outcomes for Durable Remission in Patients With Bipolar Disorder
Authors: RAPPORT DANIEL , MCGRADY ANGELE , SAJU LINDA , LYNCH DENIS
Published: March 2021

Objective:

Bipolar disorder is a severe mental illness affecting emotional stability, physical health, and quality of life. In a previous study, we identified medications associated with remission in patients with bipolar disorder. The objective of the current study was to determine the status of the patients after 3 additional years, as well as the medications associated with remission.

Methods:

Data were extracted from clinical records. The criteria for remission in both the original study and the follow-up were 12 continuous months of euthymia, mild symptoms, and no clinical relapse. Active illness was defined as <12 months of remission. Statistical comparisons were made between the remitted and active illness groups on demographics and medication regimens.

Results:

The original study contained 121 patients, 52 of whom were available for follow-up. Of the 121 patients from the original study, 53 (43.8%) were remitted for at least 12 months. Follow-up data were available for 19 of those patients, 15 of whom continued in remission while 4 relapsed. Of the 68 patients who were still ill at the end of the first study, follow-up data were available for 33 patients, 18 of whom had achieved remission at the time of follow-up while 15 continued to be ill. Remitted patients were more likely to be receiving a mood stabilizer (P=0.022) or a combination of a mood stabilizer and an antidepressant (P=0.004).

Conclusions:

On the basis of our results, mood stabilizers and antidepressants were associated with remission in long-term follow-up. Remission may ultimately be possible for many patients who did not succeed initially.
Abrupt Late-onset Psychosis as a Presentation of Coronavirus 2019 Disease (COVID-19): A Longitudinal Case Report
Authors: PARKER CATHERINE , SLAN AARON , SHALEV DANIEL , CRITCHFIELD ADAM
Published: March 2021

Introduction:

Coronavirus Disease 2019 (COVID-19) is a pandemic infection caused by the Severe Acute Respiratory Syndrome 2 Coronavirus (SARS-2-CoV). Although most prominently associated with pulmonary manifestations, COVID-19 is increasingly implicated in neuropsychiatric complications, including delirium and psychosis. There is a potential causal link between COVID-19 infection and psychotic symptoms; however, case reports to date have been incomplete, as the patients described had known psychiatric histories or other plausible medical causes for altered mental status. We present a longitudinal case of COVID-19 psychosis in a patient who underwent comprehensive diagnostic evaluation. This case is a contribution to the inchoate characterization of neuropsychiatric manifestations of COVID-19 infection.

Case Report:

We present a case of late-onset psychosis in a middle-aged man with no psychiatric history who tested positive for COVID-19 on admission following a recently resolved upper respiratory illness. His acute presentation—characterized by delusions, hallucinations, and disorganized thought and behavior, for which he required inpatient medical admission and subsequent inpatient psychiatric hospitalization—was successfully treated. During his hospitalization, he underwent comprehensive medical and neurological workup (including neuroimaging; electroencephalography; and serum and cerebrospinal fluid testing) that was grossly unremarkable.

Discussion:

Despite myriad potential causes of the patient’s psychosis, this patient’s diagnostic workup was largely unrevealing, apart from his nasopharyngeal SARS-2-CoV reverse transcriptase polymerase chain reaction assay. As such, psychosis secondary to COVID-19 infection emerged as the presumptive diagnosis.
Suspected Recurrence of Symptomatic COVID-19: Management During Inpatient Psychiatric Treatment
Authors: ZHANG EMILY , LEQUESNE ELIZABETH , ROHS ANNE , FRANKLE W. Gordon
Published: March 2021

The widespread prevalence of coronavirus disease 2019 (COVID-19) means that inpatient psychiatric units will necessarily manage patients who have COVID-19 that is comorbid with acute psychiatric symptoms. We report a case of recurrence of respiratory symptoms and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) testing in a patient on an inpatient psychiatric unit occurring 42 days after the initial positive SARS-CoV-2 RT-PCR test, 38 days after initial symptom resolution, and 30 days after the first of 3 negative SARS-CoV-2 RT-PCR tests. Over the course of the admission, the patient was safely initiated on clozapine. Recent literature on COVID-19’s potential recurrence and neuropsychiatric effects is reviewed and implications for the management of COVID-19 on inpatient psychiatric units are discussed. In the era of COVID-19 and our still-developing understanding of this illness, psychiatrists’ role as advocates and collaborators in our patients’ physical health care has become even more critical.
Antimicrobial use in central nervous system infections
Authors: Ciummo Francesco , Srinivas Pavithra , Biedny Jessica
Published: March 2021

Purpose of review

Central nervous system (CNS) infections are associated with high rates of morbidity and mortality. The purpose of this review is to summarize current antimicrobial therapies, as well as, updates in the management of community-acquired meningitis and healthcare-associated meningitis and ventriculitis.

Recent findings

Due to the increasing rates of multidrug resistant and extensively-drug resistant organisms, available antimicrobials are limited. Novel treatment options include newer systemic antimicrobials and antimicrobials that have previously limited data in the management of CNS infections. Although limited by retrospective data, intrathecal (IT) and intraventricular (IVT) routes of administration offer the opportunity for antimicrobials that conventionally have minimal cerebrospinal fluid (CSF) penetration to achieve high CSF concentrations while minimizing systemic exposure.

Updates in the use of systemic, IT, and IVT antimicrobials offer promise as therapeutic options for CNS infections. Additional pharmacokinetic and prospective data are needed to confirm these findings.
Application of Local Flaps in Repairing Total and Near-Total Lower Lip Defects of Young Patients
Authors: Bo Qitao , Lu Junxu , Wang Yuanbo , Hu Yanuan , Tang Shoukai , Yang Biaobing
Published: March 2021

Background:

It has always been a great challenge for clinical doctors to reconstruct total and near-total lower lip defects. Compared with elderly patients, the repair operation in young patients is more difficult where free flaps are usually used for transfer. In order to obtain better postoperative results, the authors combined two kinds of local skin flaps for operation purpose, and evaluated their postoperative clinical effects.

Methods:

From April 2011 to May 2019, a total of 5 young patients with lower lip tumor or trauma were included in this study, with an average age of 30.4 years old. The lesion was all resected and resulted in a defect of 87% to total area of the lower lip, accompanied by a partial defect of the chin each. To repair the defect of the lower lip, the authors firstly used the modified Bernard flap. Then the authors designed the double Abbe flap to perform the operation according to the recovery of the patient 3 months later than the first operation. Finally, the outcomes of either operation were compared upon slit width, mouth opening height, aesthetics, and function of the patients, and statistically analyzed the results.

Results:

All patients underwent the repair of modified Bernard flaps and double Abbe flaps of with no hemodynamic disorder of the flaps and well-recovery. At 3 months after the operation, the average gap width of lip was 4.34 ± 0.24 cm, the average opening height was 3.18 ± 0.28 cm, the average aesthetic score was 7.98 ± 0.51 (full score of 10), and the average functional score was 11.4 ± 0.55 (full score of 12). The 5 patients showed no obvious scar but a good shape on the lower lip. The function of eating, pronunciation, expression of feelings and smiling change were close to normal. Three patients had mild numbness in the lower lip, while the other two had normal sensory function.

Conclusion:

Combined modified Bernard flap and double Abbe flaps can bring out promising reparative outcomes of near-total or total lower lip defects in lower lip in young patients with good aesthetic and functional recovery, which is recommended while considering surgical alternatives.
Osseointegrated Implants for Orbito-Facial Prostheses: Common Complications and Solutions
Authors: Sendul Selam Yekta , Yildiz Aysegul Mavi , Yildiz Ali Atakhan , Akbas Emine
Published: March 2021

Purpose:

To evaluate anatomical and functional results of osseointegration with magnetic coupling for oculofacial prosthetic rehabilitation after exenteration.

Methods:

This retrospective study included 11 consecutive patients who received orbital reconstruction and oculofacial prosthetic rehabilitation between September 2015 and October 2019. Patient demographics, surgical indications, previous treatment procedures, histopathologic features, and reconstructive procedures were recorded.

Results:

The mean age was 37.81 ± 23 years (range 5–78 years). The mean follow-up was 23.81 ± 12 months (range 10–48 months). The principal diagnoses were squamous cell carcinoma of the eyelids (n = 2/11), mucoepidermoid carcinoma of the maxillary sinus (n = 2/11), rhabdomyosarcoma (n = 1/11), mucormycosis (n = 1/11), neurofibromatosis (n = 1/11), basosquamous carcinoma (n = 1/11), malign melanoma (n = 1/11), primitive neuroectodermal tumor (n = 1/11), and retinoblastoma (n = 1/11). Six of the patients were repaired by primary closure. Procedures performed to reconstruct the orbital cavity included split-thickness skin graft (n = 2/11), temporalis muscle flap (n = 2/11), and frontalis muscle flap (n = 1/11). Nine of the 11 patients who received orbital implants were successfully rehabilitated by epithesis. Postoperative complications included implant loss (n = 4/11), periprosthetic local infection (n = 3/11), and soft tissue overgrowth around the orbital prosthesis (n = 2/11). All patients had Straumann bone level implant (Basel, Switzerland) osseointegrated titanium implants (3.5 mm) placed in a 2-stage procedure over a span of 3 to 4 months with subsequent successful prosthesis fitting.

Conclusion:

The reconstructive methods following orbital exenteration, should be customized according to the patients’ characteristics such as extension of the orbital defect, bone quality, and expectations to achieve satisfactory results.
Reproducible Major Mold for a Silicone Orbital Prosthesis Prototype
Authors: Nguyen Truc Thi Hoang , Eo Mi Young , Cho Yun Ju , Kim Soung Min
Published: March 2021

The implant-supported magnet-retained silicon orbital prosthesis (SOP) was reported as a reliable method to restore the health-related quality of life of patients who underwent facial resection and reconstruction surgery. Currently, fabrication usually requires a long production time and a high level of expertise. Moreover, due to the complex features of facial defects, accurate prosthesis requires many patient fittings.

The prosthesis was designed to repair a complex orbital defect. A reproducible major mold was used to make various silicone prototypes with differences in margin design, silicone shade, and artificial eye's details. The most suitable silicone prototype was chosen for the finalization of the SOP. The patient reported the satisfaction with the function, prosthesis retention, and esthetic restoration.

This clinical study showed that the new technique using a reproducible major mold can allow the fabrication of various prototypes, save time during fitting, and help in improving personalized fabrication of the SOP.
Schwannoma in the External Auditory Canal
Authors: Jeong Junhui , Oh Jangwon , Choi Hyun Seung
Published: March 2021

Schwannoma is a slow-growing, benign tumor originating from the Schwann cells of peripheral nerve sheaths. Schwannoma in the external auditory canal is rare but should be included in the possible diagnosis of a cystic mass. If schwannoma is suspected, computed tomography or magnetic resonance imaging should be performed to explore tumor size, location, possible extension, and origin before excision. The authors here present a large schwannoma that almost completely occluded the external auditory canal and was completely excised using a transcanal approach.