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.

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.

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.

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.

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.

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.

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.

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.

Comparison of peripherally inserted central venous catheters (PICC) versus subcutaneously implanted port-chamber catheters by complication and cost for patients receiving chemotherapy for non-haematological malignancies.

PURPOSE: Indwelling central venous catheters (CVCs) have been increasingly used to enable delivery of intravenous chemotherapy. We aimed to compare the safety and cost of two commonly used CVCs, peripherally inserted central venous catheter (PICCs) and ports, in the delivery of chemotherapy in patients with non-haematological malignancies. METHODS: Seventy patients were randomly assigned to receive either a PICC or a port. The primary endpoint was occurrence of major complications, which required removal of the CVC and secondary endpoints included occurrence of any complications. RESULTS: Port devices were associated with fewer complications compared with PICC lines (hazard ratio of 0.25, CI, 0.09-0.86, P = 0.038). Major complication rate was lower in the port arm compared to the PICC arm (0.047 versus 0.193 major complications/100 catheter days, P = 0.034) with 6 versus 20 % of patients experiencing major complications, respectively. Thrombosis, the most common complication, was significantly higher in the PICC arm compared to the port arm (25 versus 0 %, P = 0.013). Quality of life and cost estimates did not differ significantly between the two arms. CONCLUSIONS: Port devices are associated with a lower risk of complications, with no difference in cost, compared to PICC lines in patients with non-haematological malignancies receiving intravenous chemotherapy.

Keratocystic odontogenic tumor: treatment modalities: study of 3 cases.

Management of the keratocystic odontogenic tumor has been one of the most controversial entities of the maxillofacial surgery. It can become quite large because of its ability for significant expansion, extension into adjacent tissues and rapid growth and also has high reccurence rate as it shows a thin, friable wall, which is often difficult to enucleate from the bone in toto, and have small satellite cysts within the fibrous wall. There are various treatment modalities suggested from conservative to radical approach, but studies have shown even with conservative approach good results are achieved. In this paper we are presenting various treatment modalities and 3 cases have been discussed.

Donor-derived Trypanosoma cruzi infection in solid organ recipients in the United States, 2001-2011.

Although Trypanosoma cruzi, the parasite that causes Chagas disease, can be transmitted via organ transplantation, liver and kidney transplantation from infected donors may be feasible. We describe the outcomes of 32 transplant recipients who received organs from 14 T. cruzi seropositive donors in the United States from 2001 to 2011. Transmission was confirmed in 9 recipients from 6 donors, including 3 of 4 (75%) heart transplant recipients, 2 of 10 (20%) liver recipients and 2 of 15 (13%) kidney recipients. Recommended monitoring posttransplant consisted of regular testing by PCR, hemoculture, and serology. Thirteen recipients had no or incomplete monitoring; transmission was confirmed in five of these recipients. Four of the five recipients had symptomatic disease and all four died although death was directly related to Chagas disease in only one. Nineteen recipients had partial or complete monitoring for T. cruzi infection with weekly testing by PCR, hemoculture and serology; transmission was confirmed in 4 of 19 recipients with no cases of symptomatic disease. Our results suggest that liver and kidney transplantation from T. cruzi seropositive donors may be feasible when the recommended monitoring schedule for T. cruzi infection is followed and prompt therapy with benznidazole can be administered.

Klebsiella necrotizing soft tissue infections in liver transplant recipients: a case series.

Necrotizing soft tissue infections (NSTI) are rare but carry high mortality rates. NSTI with Klebsiella species have been previously described as associated with Klebsiella liver abscesses and endophthalmitis. Here, we describe 6 cases of NSTI in liver transplant recipients associated with Klebsiella pneumoniae, 4 of which were K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (CRKP). Increased awareness of this emerging pathogen and its association with necrotizing skin and soft tissue infection is critical, as early recognition and debridement may improve survival. Antimicrobial treatment of CRKP infections remains an ongoing challenge and implementation of enhanced infection control measures is essential.

Primary hepatic aspergillosis following induction chemotherapy for acute leukemia.

Invasive aspergillosis (IA) contributes significantly to the burden of infectious complications in heavily immunosuppressed patients with acute leukemia. The infection is typically acquired via inhalation into the respiratory tract, and the lungs are most commonly involved. However, disseminated disease may occur and reports of isolated extrapulmonary infection suggest the gastrointestinal tract is likely an additional portal of entry for this organism. We describe a case of primary hepatic aspergillosis in a patient with acute myelogenous leukemia. The patient did not respond to medical therapy with antifungals and ultimately required surgical exploration and drainage. IA should be considered in an immunosuppressed patient with hepatic abscesses and may require a combined surgical and medical approach to therapy.

Heart transplantation in a patient with heteroresistant vancomycin-intermediate Staphylococcus aureus ventricular assist device mediastinitis and bacteremia.

Vancomycin-intermediate Staphylococcus aureus (VISA) infections are an emerging problem and antibiotic options are limited. We report the first case, to our knowledge, of heteroresistant VISA mediastinitis and bacteremia in a patient with a ventricular assist device who underwent orthotopic heart transplantation with clinical cure.

A multicenter evaluation of pandemic influenza A/H1N1 in hematopoietic stem cell transplant recipients.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients have increased morbidity from respiratory viral infections. Pandemic influenza A - A(H1N1)/pdm09 - in 2009-2010 was associated with increased severity of illness in patients with underlying co-morbidities including HSCT, but the factors that contribute to severe disease in HSCT patients are not well characterized. METHODS: We conducted a multicenter review of microbiologically proven influenza A(H1N1)pdm09 in the HSCT population between April 2009 and April 2010 to determine factors that are associated with severe disease. RESULTS: We identified 37 adult patients (26 allogeneic and 11 autologous HSCT recipients). Median time from transplant to diagnosis was 411 days (range 4 days-14.9 years). Three cases were hospital acquired. Twenty-eight of 37 (75.7%) had confirmed A(H1N1)pdm09. Presumed viral lower respiratory tract infection was present in 12/37 (32.4%) patients. Antiviral therapy was given to 33/37 (89%) patients, primarily oseltamivir (n = 24) and oseltamivir before or after another antiviral (n = 8). Excluding those with nosocomial A(H1N1)pdm09, 18/34 (52.9%) were hospitalized and 6 (33%) required admission to an intensive care unit. Mortality within 30 and 60 days of symptom onset was 7/37 (18.9%) and 11/37 (29.7%), respectively. Factors associated with mortality included nosocomial acquisition (P = 0.023), receipt of mycophenolate mofetil (P = 0.001), or antilymphocyte antibody (P = 0.005) within the past 6 months, reduced-intensity conditioning (P = 0.027), and bacteremia (P = 0.021). CONCLUSIONS: A(H1N1)pdm09 infection was particularly severe in HSCT recipients, specifically among those receiving augmented immunosuppression for graft-versus-host disease. The high mortality of the nosocomial cases highlights the need for strict infection-control measures in hospitals during influenza outbreaks.