Efficacy and safety of tirbanibulin 1% ointment in actinic keratoses: Data from two phase-III trials and the real-life clinical practice presented at the European Academy of Dermatology and Venereology Congress 2022.

BACKGROUND: The 31st European Academy of Dermatology and Venereology (EADV) Congress took place between 7th and 10th of September 2022 in Milan, Italy. OBJECTIVES: We report presented clinical data on the efficacy/effectiveness, safety and tolerability of tirbanibulin 1% ointment that has recently been licensed for actinic keratosis (AK) of the face or scalp in adults. METHODS: Summary of presentations given at the EADV Congress. RESULTS: Prof. Pellacani presented two post hoc analyses from two phase-III trials with AK patients (NCT03285477 [N = 351] and NCT03285490 [N = 351]): A descriptive analysis of medical history, concomitant medications, and safety results confirming a favourable profile for tirbanibulin showing that number of baseline AK lesions was not correlated to severity of local skin reactions. The latter analysis showed that cases of tirbanibulin application site pain or pruritus were few, and most were found to be mild. Prof. Kunstfeld reported six real-life clinical cases in Austria showing good tirbanibulin effectiveness, safety and tolerability for the treatment of new or recurring AK lesions. Results demonstrated that after 2- to 4-month follow-up, tirbanibulin was well tolerated and effective in AK patients. Presentations by Dr. Patel confirmed good outcomes and tolerability of tirbanibulin in Olsen grade 1-2 AK (N = 12) and porokeratosis patients (N = 4) treated once daily for 5 consecutive days in the United Kingdom. Furthermore, real-world experience in solid organ transplant recipients (N = 2) demonstrated effectiveness of tirbanibulin in skin field cancerization treatment. A symposium sponsored by Almirall was conducted during the congress in which Dr. Hadshiew and Dr. Lear brought together their clinical experience in Germany and the United Kingdom respectively. Interesting clinical cases of 5 consecutive days of tirbanibulin treatment compared to other treatments were discussed with attendees, as well as current treatment needs of AK patients. CONCLUSIONS: This article provides an overview of presentations and symposium discussions, summarizing key phase-III results and real-life clinical experience with tirbanibulin shared by dermatologists across Europe.

THE IMPACT OF SLEEP ON PHYSICAL AND MENTAL HEALTH: IMPORTANCE OF HEALTHY SLEEP HABITS.

Sleep is an important part of health, and when you go to sleep, how long you sleep, and how well you sleep all have a big impact on your health. Sleep may be required for regulating the body's metabolism, feelings, function, memory storage, brain recovery, and learning. Because of how important these processes are, sleep should be seen as just as important to health as what you eat and how much you exercise. Adults' sleep generally gets shorter and less restful, their sleep starts later and is more broken up, they have more sleep problems, and their rest-activity rhythms get weaker. In addition to receiving enough sleep (quality), healthy sleep habits also include maintaining a consistent sleep schedule. Ninety male college students with varying sleep schedules were analyzed for their physical and emotional well-being. By using factor analysis to categorize individuals' sleeping patterns across three dimensions regularity, quality, and quantity. We were able to develop sleep-habit measures. Clustering identified four distinct patterns of sleep behavior: good sleep was defined by regular, high-quality sleep despite being of comparatively brief duration; long sleep was predictable, fairly lengthy, but of minimal quality; short sleep was of excellent quality despite being short and irregular; and poor sleep was erratic, low-quality, and relatively long. The excellent sleepers also had reduced diastolic and systolic and a smaller means waist measurement. In addition, the poor sleepers had the lowest average MCS scores of all of the study groups. Poor sleepers also had the lowest mean scores on the Subjective Depression Scale (SDS). Issues involving glucose or lipid absorption were also more common in the short-term and long poor-sleep categories. Without restful sleep and a regular bedtime routine, it is impossible to maintain excellent mental and physical wellness, even if time and sleep are maintained constantly. Therefore, to produce suitable sleep recommendations for enhanced mental and physical health, we evaluated not only the quantity of sleep but also its consistency and high quality.

THE ROLE OF IMMUNOTHERAPY IN CANCER TREATMENT: CHECKPOINT INHIBITORS, CAR-T CELLS, AND VACCINES.

Immunotherapy causes cancer patients' immune systems to activate in search of and eliminate cancer cells. As a therapeutic area for cancer, it has expanded in importance and demonstrated promising results in treating many cancers. Checkpoint blockade (CPB) therapy may stimulate a suppressed immune response to provide long-lasting therapeutic results. However, the absence of a tumor-reactive immune infiltration is probably why response rates are still low. Using chimeric antigen receptor (CAR)-modified T cells to fight cancer may significantly impact immunology. This study explored using checkpoint inhibitors, car-T cells, and vaccines in immunotherapy to treat cancers. Drugs used for CPB aim to reduce immunological suppression, allowing for more effective CAR T cells and dendritic cell (DC) vaccines, providing some optimism that this may be increased, both of which have proven therapeutic efficacy in specific cancers. However, drug-induced side effects and the tumor microenvironment's propensity for immunosuppression mean treatment effectiveness is still inadequate. The outcomes of current preclinical tests suggest that novel therapies targeting lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin-domain containing-3 (TIM3), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1) could be used as adjuvant therapies to modify the tumor microenvironment.

Systematic review of medication related osteonecrosis of the jaw (MRONJ) in patients undergoing only antiangiogenic drug therapy: surgery or conservative therapy?

Osteonecrosis of the jaw is a severe adverse condition affecting patients exposed to specific types of medications. Previous studies have highlighted that osteonecrosis of the jaw is triggered by invasive dental procedures and can be very challenging to manage, especially in patients with cancer. The primary aim of this review was to analyse all available evidence on the management (surgical and/or conservative) of medication related osteonecrosis of the jaws (MRONJ) in patients with a history of antiangiogenic drugs therapy and who had not been previously exposed to any antiresorptive drug treatments. A multi-database search (PubMed, MEDLINE, EMBASE and CINAHL) was performed to identify related multi-language papers published from January 2003 until November 2020. Data were extracted from relevant papers and analysed according to the outcomes selected in this review. The search generated 28 studies eligible for the analysis. The total number of patients included in the analysis was 36. Sixteen patients were treated with anti-vascular endothelial growth factor drugs (anti-VEGF) while the remaining patients were administered a combination of antiangiogenic drugs. The most common MRONJ site was the mandible in 29 patients. MRONJ recurrence after treatment was only reported in six patients, the majority of which were treated conservatively. The data reviewed confirmed that an invasive procedure was the most common trigger of MRONJ with relatively high frequency of postoperative recurrence following treatment. However, due to the low quality of available research in the literature, it is difficult to draw a definitive conclusion on the validity of the presented treatment to manage patients affected by MRONJ associated with angiogenic therapy.

High Dose Rate Brachytherapy for Inoperable Endometrial Cancer: a Case Series and Systematic Review of the Literature.

Endometrial cancer is a common gynaecological cancer, is typically early stage and treated with surgery. For patients where surgery is difficult or dangerous, definitive radiation therapy is the next best option. This study included a single institution case series (step 1) and a systematic review of the literature (step 2). In step 1, all endometrial cancer cases that were treated with definitive image-guided brachytherapy at a single institution from 2008 to 2020 were retrospectively analysed. In step 2, a systematic review of Medline (PubMed) from 1975 to 2020 was carried out using the key words around endometrial cancer and brachytherapy, followed by a narrative synthesis. In total, in step 1, 31 cases were included in this study, stages I-IV, with 96.7% receiving external beam radiation. All patients received three fractions of 7.5 Gy or five fractions of 6 Gy high dose rate brachytherapy, with a median EQD2 of 75.55 (40-84.3). The 2-year Kaplan-Meier (KM) local control was 83.1% and the 2-year KM overall survival was 77.4%. There was no late toxicity ≥grade 3. In step 2, 19 articles were included in the final analysis, with between six and 280 patients. The local control ranged from 70 to 100%, with low toxicity. Definitive radiation therapy with image-guided brachytherapy seems to have good local control with low toxicity for patients who are poor surgical candidates.

Myths, facts and scope of spinal cord tolerance dose revision in Intensity modulated SIB treatment of locally advanced head and neck cancer: A dosimetrical and radiobiological demonstration.

PURPOSE: To explore the possibility of revising the spinal cord tolerance dose in Simultaneously Integrated Boost (SIB) intensity modulated treatment plan of locally advanced head and neck (H&N) cancer and assessment of achieved planning gain due to the revision. In SIB regimen, the Organ at Risk (OARs) tolerance dose is equally distributed throughout the treatment. Clinicians have usually considered the spinal cord tolerance to be the same as in conventional technique. However, in SIB fractionation regimen with intensity modulation treatment, the spinal cord may receive a physical dose of 45Gy, with much lesser dose per fraction than 2Gy per fraction. So when the dose of spinal cord is distributed throughout the treatment, the tolerance dose limit of physical dose can be considered higher than the usual conventional dose limits. In this study, an attempt has been made to explore the possibilities of dose escalation and treatment planning benefits while exploiting this "Window of Opportunity (WoO)" of increase in spinal cord and Planning Risk Volume (PRV) spinal cord tolerance dose. MATERIAL AND METHODS: A total of 12 patients CT data set along with approved structure set of H&N cancer used for treatment planning in. Three independent SIB VMAT plans named as SPC, SPR and SPDE were generated for the 12 patients. First plan (SPC) was generated by considering standard spinal cord tissue constraint of maximum dose of 45Gy and PRV spinal cord maximum dose 50Gy as per QUANTEC summary and second plan (SPR) was generated considering spinal cord tissue constraint of maximum dose 52.50Gy and PRV spinal cord maximum dose 56.35Gy while optimization and dose calculation. The objectives for rest of the Organ at Risk (OAR) were kept same in both the plans during optimization and dose calculation. The SPC plan was copied for creation of third plan (SPDE) in which dose was escalated by increasing dose per fraction for target volumes such that dose to spinal cord reached a maximum dose of 52.50Gy and PRV spinal cord maximum dose of 56.35Gy. In this plan there have been changes to only dose per fraction, however dose optimization and dose calculation have not been performed. Radiobiological parameters TCP and NTCP were also calculated by using indigenously developed software. RESULTS: Considering the increase of spinal cord tolerance dose as "window of opportunity", a sufficient escalation in physical dose, Biological Effective Dose (BED) and Tumor Control Probability (TCP) was observed for all target volumes with acceptable level of NTCP values. CONCLUSION: Sufficient dose escalation and increased in TCP for target volumes or effective planning benefits can be achieved by revising the spinal cord tolerance dose in intensity modulated SIB treatment of locally advanced H&N cancers.

Human basal cell carcinoma: the induction of anagen hair follicle differentiation.

BACKGROUND: Consistent with cancer stem cell driven pattern of growth, human basal cell carcinomas (BCCs) demonstrate differentiation along hair follicle (HF) lineages. AIM: To define the pattern of differentiation and therapeutic targets that promote BCC differentiation and therefore BCC cancer stem cell exhaustion. METHODS: An alkaline phosphatase substrate kit was used to determine dermal papilla cells within the BCC stroma. Autonomous HF cycle-dependent gene expression was identified by analysis of the human homologues of a murine gene set (total 2289 genes) that is differentially expressed in hair cycle phases. The findings were validated by quantitative real-time PCR and immunofluorescence, as well as in vitro transforming growth factor (TGF)-ß2 stimulation of BCC cancer stem cell colonies. RESULTS: As in the HF, keratin expression in the inner root sheath and matrix in BCC correlated with proliferative index and was tightly regulated, despite the absence of dermal papilla cells. Cross-species microarray analysis comparing human BCC and murine synchronous HF growth cycle datasets revealed 74% concordance with telogen differentiation compared with anagen (23%, P < 0.01) and catagen (49%; P < 0.01). Incomplete anagen differentiation within BCC was characterized by reduced expression of the anagen master regulator DLX3 (-5.5-fold), and increased expression of telogen-associated genes: AEBP1 (2.2-fold), DEFB8 (35.3-fold), MMP3 (106.0-fold) and MMP12 (12.9-fold). Restoration of dermal papilla signals by in vitro addition of TGF-ß2 enhanced anagen differentiation. CONCLUSION: Our findings show that BCC cells differentiate along HF lineages and may be susceptible to exogenous HF cycle modulators.

Hair follicle differentiation-specific keratin expression in human basal cell carcinoma.

BACKGROUND: Identification of human basal cell carcinoma (BCC) cancer stem cells and cellular hierarchy inherently implies the presence of differentiation. By conventional histological analysis, BCC demonstrates tumour nodules that appear relatively homogeneous. AIM: As BCCs arise from hair follicle (HF) keratinocytes, we sought to define the pattern of HF differentiation. METHODS: BCC, squamous cell carcinoma (SCC) and normal skin tissues were analysed using a microarray chip. The expression of individual keratins, regulatory pathways and proliferative states were analysed using reverse transcription-PCR and immunofluorescence microscopy. RESULTS: Microarray analysis of BCC, SCC and normal hair-bearing skin revealed that BCCs express a wide range of HF genes, including HF- specific keratins. BCC demonstrated outer (KRT5, KRT514, KRT516, KRT517 and KRT519) and inner (KRT25, KRT27, KRT28, KRT32, KRT35, KRT71, KRT75 and KRT85) root sheath differentiation, but not hair shaft differentiation. As in the HF, differentiation-specific keratins in BCC keratinocytes correlated with a reduced proliferative index and regulatory pathway activation despite the oncogenic drive towards tumour growth. Our findings show the close correlation between HF and BCC keratinocyte differentiation. CONCLUSION: This work has defined the differentiation pattern within BCCs, enabling development of targeted therapies that promote differentiation and result in BCC cancer stem cell exhaustion.

Public cost of privately inserted laparoscopic adjustable gastric bands.

Background: Laparoscopic adjustable gastric banding (LAGB) remains a commonly performed procedure for morbid obesity. Concerns regarding its long-term consequences include high rates of band removal from complications and failure to lose weight. Many private practices continue to perform LAGB but, owing to short follow-up periods, the burden of surgical complications falls upon National Health Service (NHS) bariatric units. This study aimed to review the NHS treatment of patients for complications related to privately performed LAGB. Methods: All surgical complications following bariatric surgery referred to the Welsh Institute of Metabolic and Obesity Surgery (WIMOS) between September 2010 and September 2014 were reviewed. Type of complication, procedures performed, and number of outpatient attendances and inpatient stays were recorded. Costs of treatment were estimated using standard tariffs. Results: A total of 78 patients presented with complications after privately performed bariatric surgery. Sixty had undergone LAGB; the remainder had had other bariatric procedures. Median age was 45 (range 22-78) years, and 65 (83 per cent) were women. Urgent band deflation was undertaken in 53 patients. Band removal surgery was required in 32 patients; one patient needed a subtotal gastrectomy. There was a total of 123 outpatient/ward attendances and 340 days of inpatient care, including 10 days of intensive care. The estimated total cost to the NHS of managing these patients was €337 400 (€84 350 per annum). Conclusion: The cost burden to the NHS of managing the complications of bariatric surgery performed in the private sector is considerable. Although it is imperative that such complications be managed in well equipped specialist units, private surgery providers should have better follow-up plans and/or contractual agreements with the NHS.

Resting state functional connectivity predictors of treatment response to electroconvulsive therapy in depression.

There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subtype depression and to predict treatment response. To date, identification of RSFC patterns associated with response to electroconvulsive therapy (ECT) remain limited, and focused on interactions between dorsal prefrontal and regions of the limbic or default-mode networks. Deficits in visual processing are reported in depression, however, RSFC with or within the visual network have not been explored in recent models of depression. Here, we support prior studies showing in a sample of 18 patients with depression that connectivity between dorsal prefrontal and regions of the limbic and default-mode networks serves as a significant predictor. In addition, however, we demonstrate that including visual connectivity measures greatly increases predictive power of the RSFC algorithm (>80% accuracy of remission). These exploratory results encourage further investigation into visual dysfunction in depression, and use of RSFC algorithms incorporating the visual network in prediction of response to both ECT and transcranial magnetic stimulation (TMS), offering a new framework for the development of RSFC-guided TMS interventions in depression.

Prolonged platelet storage associated with increased frequency of transfusion-related adverse events.

BACKGROUND: Platelets (PLTs) have been associated with the highest rate of transfusion-associated adverse events (AEs) among all blood products. Most of PLT-associated AEs are considered to have an inflammatory mechanism. However, it is still unclear whether prolonged storage of platelets is associated with an increased rate of transfusion-related AEs, especially in the era of universal prestorage leucoreduction. METHODS/MATERIALS: In this retrospective study, 52 649 PLT products consisting of about 80% apheresis PLTs and 20% whole blood-derived (WBD) PLTs were transfused to 9415 patients from July 2011 to March 2017. All the PLTs were leucoreduced prior to storage. All but 69 units of the apheresis PLTs were irradiated and none of WBD PLTs were irradiated. During this period, a total of 284 AEs that were reported to the transfusion service were analysed. RESULTS: Univariate and multivariate logistic analyses showed that apheresis/irradiated PLTs and PLT age were associated with a significantly increased frequency of inflammation type AEs (OR (95% CI): 2·24 (1·32, 4·15) and 1·30 (1·12, 1·52), respectively). There was a significant increase in the frequency of inflammation AEs associated with prolonged storage of apheresis/irradiated PLTs [OR (95% CI): 1·26 (1·03, 1·53)]. In contrast, there was no association between allergic symptoms and PLT age. Moreover, the frequency of transfusion AEs associated with apheresis/irradiated PLTs (57·2/10 000) was significantly higher than that of WBD/nonirradiated PLTs (26·0/10 000) (P < 0·01). CONCLUSION: Prolonged storage of apheresis/irradiated PLTs was associated with a higher frequency of inflammation AEs. Apheresis/irradiated PLTs caused more AEs than WBD/nonirradiated PLTs.

Utility of Tolvaptan in the Perioperative Management of Severe Hyponatremia During Liver Transplantation: A Case Report.

Severe hyponatremia can complicate the pretransplantation management of patients with decompensated cirrhosis while they await liver transplantation. Before the liver transplant, it is critical to correct severe hyponatremia to an appropriate level to reduce the risks of perioperative complications such as central pontine myelinolysis, cerebral edema, and seizures. Vasopressin receptor antagonists, and in particular tolvaptan, offer a therapeutic modality that can correct severe refractory hyponatremia in a timely and predictable manner before liver transplantation. In this case report, we describe a patient with decompensated cirrhosis and severe hyponatremia in whom administration of tolvaptan led to an optimal correction of preoperative severe hyponatremia and allowed for successful liver transplantation with no associated postoperative complications. In light of the increasing pretransplantation disease severity and higher risk of severe hyponatremia, the use of tolvaptan in the pretransplant period may gain increasing importance as a therapeutic intervention for maintaining peritransplant sodium homeostasis.

Platelet Rich Fibrin in Management of Complex Endoperio Cases.

Endo-perio lesions have been a dilemma to the dental practitioner. Both tissues share the same anatomical origin. Sometimes exact etiological passage of disease process cannot be traced; nevertheless traditional and newer treatment modalities must be employed to ensure best treatment possibilities. Patient reported with pain and pus exudates in upper left anterior region. Past dental history revealed no history of trauma. Initial examination revealed draining sinus with respect to 22. However, no Caries and pockets could be detected. Tooth was nonresponsive to vitality test. Patient symptoms did not relieve even two months after completion of RCT. Apical surgery was planned. Apicectomy was done and osseous defect was filled with PRF coagulum. Patient was followed up every three months and showed complete resolution of all symptoms. Radiographs showed complete resolution of osseous defect in nine months. PRF can be used to enhance bone augmentation in treatment of periapical defects as a potential treatment alternative for faster healing.

Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

Delayed onset of benign pleural effusion following concurrent chemoradiotherapy for inoperable non-small-cell lung cancer.

Chronic benign pleural effusion (BPE) is a rare complication of concurrent chemoradiotherapy (CRT) for inoperable stage IIIA non-small-cell lung cancer (NSCLC). This report presents three cases of BPE, the workup to differentiate this benign condition from recurrence of cancer and recommends a pleural biopsy as part of the diagnostic process. These inflammatory exudates often remain indolent, and may not require drainage or surgical intervention. In the absence of clinical, radiological and pathological evidence of recurrent disease, we recommend clinicians manage these patients expectantly, using regular clinical assessment and imaging.

Fulminant endocarditis and disseminated infection caused by carbapenem-resistant Acinetobacter baumannii in a renal-pancreas transplant recipient.

Acinetobacter baumannii is an important cause of healthcare-associated infections, and is particularly problematic among patients who undergo organ transplantation. We describe a case of fulminant sepsis caused by carbapenem-resistant A. baumannii harboring the blaOXA-23 carbapenemase gene and belonging to international clone II. This isolate led to the death of a patient 6 days after simultaneous kidney-pancreas transplantation. Autopsy findings revealed acute mitral valve endocarditis, myocarditis, splenic and renal emboli, peritonitis, and pneumonia. This case highlights the severe nature of certain A. baumannii infections and the vulnerability of transplanted patients to the increasingly intractable "high-risk" clones of multidrug-resistant organisms.

Transmission of methicillin-resistant Staphylococcus aureus via deceased donor liver transplantation confirmed by whole genome sequencing.

Donor-derived bacterial infection is a recognized complication of solid organ transplantation (SOT). The present report describes the clinical details and successful outcome in a liver transplant recipient despite transmission of methicillin-resistant Staphylococcus aureus (MRSA) from a deceased donor with MRSA endocarditis and bacteremia. We further describe whole genome sequencing (WGS) and complete de novo assembly of the donor and recipient MRSA isolate genomes, which confirms that both isolates are genetically 100% identical. We propose that similar application of WGS techniques to future investigations of donor bacterial transmission would strengthen the definition of proven bacterial transmission in SOT, particularly in the presence of highly clonal bacteria such as MRSA. WGS will further improve our understanding of the epidemiology of bacterial transmission in SOT and the risk of adverse patient outcomes when it occurs.