Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Label-free electrochemical immunosensor as a reliable point-of-care device for the detection of Interleukin-6 in serum samples from patients with psoriasis.

Interleukin-6 (IL-6) plays a crucial role in autoimmunity and chronic inflammation. This study aims to develop a low-cost, simple-to-manufacture, and user-friendly label-free electrochemical point-of-care device for the rapid detection of IL-6 in patients with psoriasis. Precisely, a sandwich-based format immunosensor was developed using two primary antibodies (mAb-IL6 clone-5 and clone-7) and screen-printed electrodes modified with an inexpensive recycling electrochemical enhancing material, called biochar. mAb-IL6 clone-5 was used as a covalently immobilized capture bioreceptor on modified electrodes, and mAb-IL6 clone-7 was used to recognize the immunocomplex (Anti-IL6 clone-5 and IL-6) and form the sandwich. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to conduct electrochemical characterization of the layer-by-layer assembly of the immunosensor, while square wave voltammetry (SWV) was used to perform the sensing. The developed immunosensor demonstrated robust analytical performance in buffer solution, with a wide linear range (LR) by varying from 2 to 250 pg/mL, a good limit of detection (LOD) of 0.78 pg/mL and reproducibility (RSD<7%). In addition, a spectrophotometric ELISA kit was employed to validate the results obtained with the label-free device by analyzing twenty-five serum samples from control and patients affected by psoriasis. A strong correlation in terms of pg/mL concentration of IL-6 was found comparing the two methods, with the advantage for our label-free biosensor of an ease use and a quicker detection time. Based on IL-6 levels, the proposed immunosensor is a dependable, non-invasive screening device capable of predicting disease onset, progression, and treatment efficacy.

Cdk4 Regulates Glioblastoma Cell Invasion and Stemness and Is Target of a Notch Inhibitor Plus Resveratrol Combined Treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer characterized by poor patient outcomes. To date, it is believed that the major cause of its recurrence and chemoresistance is represented by the enrichment of GBM stem cells (GSCs) sustained by the abnormal activation of a number of signaling pathways. In this study, we found that in GBM cells, treatment with low toxicity doses of the γ-secretase inhibitor RO4929097 (GSI), blocking the Notch pathway activity, in combination with resveratrol (RSV) was able to reverse the basal mesenchymal phenotype to an epithelial-like phenotype, affecting invasion and stemness interplay. The mechanism was dependent on cyclin D1 and cyclin-dependent kinase (CDK4), leading to a reduction of paxillin (Pxn) phosphorylation. Consequently, we discovered the reduced interaction of Pxn with vinculin (Vcl), which, during cell migration, transmits the intracellular forces to the extracellular matrix. The exogenous expression of a constitutively active Cdk4 mutant prevented the RSV + GSI inhibitory effects in GBM cell motility/invasion and augmented the expression of stemness-specific markers, as well as the neurosphere sizes/forming abilities in untreated cells. In conclusion, we propose that Cdk4 is an important regulator of GBM stem-like phenotypes and invasive capacity, highlighting how the combined treatment of Notch inhibitors and RSV could be prospectively implemented in the novel therapeutic strategies to target Cdk4 for these aggressive brain tumors.

Gender Diversity in Urology Residency Program Leadership Is Associated With Gender Diversity in Residency Cohort.

OBJECTIVE: To evaluate the association of program director (PD) gender on the proportion of female residents in urology residency programs. METHODS: Demographics for program faculty and current residents matched in the 2017-2022 cycles at United States' accredited urology residency programs were collected from institutional websites. Data verification was completed using the American Urological Association's (AUA) list of accredited programs and the programs' official social media channels. Proportion of female residents across cohorts was compared using two-tailed Student's t-tests. RESULTS: One hundred forty-three accredited programs were studied, and 6 were excluded for lack of data. Thirty (22%) of the 137 programs studied have female PDs. Of 1799 residents, 571 (32%) are women. There has been an upward trend in the proportion of females matched from 26% in 2018 to 30% in 2019, 33% in 2020, 32% in 2021, to 38% in 2022. When compared to programs with male PDs, those with female PDs had a significantly higher proportion of female residents (36.2% vs 28.8%, p = .02). CONCLUSION: Nearly one-quarter of urology residency PDs are female, and approximately one-third of current urology residents are women, a proportion that has been increasing. Programs with female PDs are more likely to match female residents, whether those programs with female leadership rank female applicants more favorably or female applicants rank those programs higher. Given the ongoing gender disparities in urology, these findings indicate notable benefit in supporting female urologists in academic leadership positions.

Lithium poisoning and renal replacement therapy: pathophysiology and current clinical recommendations.

Lithium intoxication is still an undefined and underestimated disease, especially those cases requiring extracorporeal treatment. Lithium is a monovalent cation with small molecular mass of 7 Da that has been regularly and successfully used since 1950 in the treatment of mania and bipolar disorders. However, its careless assumption can lead to a wide spectrum of cardiovascular, central nervous system and kidney diseases in case of acute, acute on chronic and chronic intoxications. In fact, lithium serum range is strict between 0.6 and 1.3 mmol/L, with a mild lithium toxicity observed at the steady-state of 1.5-2.5 mEq/L, moderate toxicity when lithium reaches 2.5-3.5 mEq/L, and severe intoxication with observed serum levels > 3.5 mEq/L. Its favorable biochemical profile allows the complete filtration and partial reabsorption in the kidney due to the similarity to sodium and also the complete removal by renal replacement therapy, that should be considered in specific poisoning conditions. In this narrative and updated review we discussed a clinical case of lithium intoxication, the different pattern of diseases attributable to excessive lithium load and the current indications for extracorporeal treatment.

The Relationship between Histological Composition and Metabolic Profile in Breast Tumors and Peritumoral Tissue Determined with 1H HR-MAS NMR Spectroscopy.

Breast tumors constitute the complex entities composed of cancer cells and stromal components. The compositional heterogeneity should be taken into account in bulk tissue metabolomics studies. The aim of this work was to find the relation between the histological content and 1H HR-MAS (high-resolution magic angle spinning nuclear magnetic resonance) metabolic profiles of the tissue samples excised from the breast tumors and the peritumoral areas in 39 patients diagnosed with invasive breast carcinoma. The total number of the histologically verified specimens was 140. The classification accuracy of the OPLS-DA (Orthogonal Partial Least Squares Discriminant Analysis) model differentiating the cancerous from non-involved samples was 87% (sensitivity of 72.2%, specificity of 92.3%). The metabolic contents of the epithelial and stromal compartments were determined from a linear regression analysis of the levels of the evaluated compounds against the cancer cell fraction in 39 samples composed mainly of cancer cells and intratumoral fibrosis. The correlation coefficients between the levels of several metabolites and a tumor purity were found to be dependent on the tumor grade (I vs II/III). The comparison of the levels of the metabolites in the intratumoral fibrosis (obtained from the extrapolation of the regression lines to 0% cancer content) to those levels in the fibrous connective tissue beyond the tumors revealed a profound metabolic reprogramming in the former tissue. The joint analysis of the metabolic profiles of the stromal and epithelial compartments in the breast tumors contributes to the increased understanding of breast cancer biology.

Resveratrol, Epigallocatechin Gallate and Curcumin for Cancer Therapy: Challenges from Their Pro-Apoptotic Properties.

Plant-derived bioactive compounds are gaining wide attention for their multiple health-promoting activities and in particular for their anti-cancer properties. Several studies have highlighted how they can prevent cancer initiation and progression, improve the effectiveness of chemotherapy, and, in some cases, limit some of the side effects of chemotherapy agents. In this paper, we provide an update of the literature on the anti-cancer effects of three extensively studied plant-derived compounds, namely resveratrol, epigallocatechin gallate, and curcumin, with a special focus on the anti-cancer molecular mechanisms inducing apoptosis in the major types of cancers globally.

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy.

Various literature data show how a diet rich in vegetables could reduce the incidence of several cancers due to the contribution of the natural polyphenols contained in them. Polyphenols are attributed multiple pharmacological actions such as anti-inflammatory, anti-oxidant, antibiotic, antiseptic, anti-allergic, cardioprotective and even anti-tumor properties. The multiple mechanisms involved in their anti-tumor action include signaling pathways modulation associated with cell proliferation, differentiation, migration, angiogenesis, metastasis and cell death. Since the dysregulation of death processes is involved in cancer etiopathology, the natural compounds able to kill cancer cells could be used as new anticancer agents. Apoptosis, a programmed form of cell death, is the most potent defense against cancer and the main mechanism used by both chemotherapy agents and polyphenols. The aim of this review is to provide an update of literature data on the apoptotic molecular mechanisms induced by some representative polyphenol family members in cancer cells. This aspect is particularly important because it may be useful in the design of new therapeutic strategies against cancer involving the polyphenols as adjuvants.

Correlates of nephrolithiasis in US black women: data from the black women's health study.

Nephrolithiasis is a common urologic condition and a significant source of patient morbidity and healthcare expenditure. There are few epidemiologic studies of kidney stones focusing exclusively on Black women. We retrospectively assessed the prevalence and correlates of self-reported kidney stones within the Black Women's Health Study (BWHS). Descriptive statistics and multivariable logistic regression models were used to explore factors associated with nephrolithiasis. As of the 2005 follow-up questionnaire, a cumulative total of 1063 women among 43,178 reported ever being diagnosed with kidney stones for a prevalence of 2.64%. Women with a history of nephrolithiasis were older, slightly heavier, and were more likely to have a comorbid condition (e.g., type-2 diabetes, gallstones), drink alcohol, and consume a Western-style diet. A history of gallstone disease was associated with an odds ratio (OR) of 3.59 (95% confidence interval (CI) 3.09-4.17). The OR for consuming ≥ 7 alcoholic beverages/week, compared to none was 0.61 (0.39-0.94), while the OR for high adherence to the Western diet, compared to low adherence was 1.53 (1.23-1.90). Our findings are consistent with previous studies of primarily white populations relating lifestyle-associated risk factors with nephrolithiasis. Despite their lower prevalence of kidney stones, it is important to focus on vulnerable populations such as Black women given their disproportionate burden of metabolic conditions (e.g., obesity, diabetes) related to kidney stone disease.

The rights of migrants to the identification of their dead: an attempt at an identification strategy from Italy.

Europe is turning a blind eye on a humanitarian disaster unfolding at its doorsteps, with thousands of migrants dying unidentified in Mediterranean waters. Since 2014, Italy has been struggling in an almost indifferent international scenario to identify its dead migrants. Despite the lack of sufficient resources, of the difficulties in collecting post mortem data from the disseminated bodies, and of the problems of contacting and collecting ante mortem information from relatives, it has been proven, with a series of pilot studies, that not only can these bodies be identified but that relatives are also looking for their loved ones and need death certificates. This article focuses on the administrative limbo and lack of regulations obliging single states to engage in appropriate procedures to maximise identification.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

Characteristics of Giant Nodular Melanomas in Special Locations: a Case Series and Review of the Literature.

INTRODUCTION: Nodular melanoma (NM) is a rare subtype of melanoma, responsible for more than 40% of melanoma deaths, characterized by rapid growth and high metastatic potential. Only a few case studies concerning the dermoscopic presentations of giant nodular melanoma have been reported so far. OBJECTIVES: The aim of the study was to assess dermoscopic features of giant nodular melanomas in special locations, along with their clinical and histopathologic aspects. METHODS: Among 120 patients with histopathologically confirmed melanoma treated by the Skin Cancer and Melanoma Team between September 2020 and February 2021, we identified six patients with giant nodular melanoma in special locations. We retrospectively assessed the archived dermoscopic images to determine the dermoscopic features of these tumors. RESULTS: The group consisted of six cases of giant melanoma in special locations, including the scalp (4/6) and the heel (2/6). The giant tumors were large in size (at least 5 cm in diameter). The most common dermoscopic structures in polarized light included asymmetric distribution of dermoscopic structures, the presence of structureless, multicolored zones (showing three or more colors), and the presence of white perpendicular lines or small, pink globules. CONCLUSIONS: It seems that there are no significant differences in dermoscopy between small and giant melanomas; however, further studies should be conducted on a larger scale.

Hemorrhagic cystitis: a review of the literature and treatment options.

INTRODUCTION: Hemorrhagic cystitis (HC) is a morbid condition for patients and can be challenging for urologists to manage. There are many potential contributing etiologies and the severity of bleeding can be variable. It is important to consider each clinical scenario when formulating management strategies in order to provide the highest quality of care to patients. We provide a review of the literature including diagnosis and treatment options. MATERIALS AND METHODS: We performed a literature search on PubMed using the following keywords: hemorrhagic cystitis, cystitis, gross hematuria, intractable hematuria. We considered all available published articles with no specific inclusion or exclusion criteria for the purposes of this review. RESULTS: We reviewed a total of 41 articles and identified a broad differential diagnosis for intractable hemorrhagic cystitis including infection, chemical exposure, malignancy, nephropathy, trauma, radiation therapy, and idiopathic etiology. Depending on the severity of bleeding, many treatments have been described. These range from conservative strategies (bladder fulguration and continuous irrigation) to more extreme and morbid therapies (intravesical instillations, embolization, and urinary diversion). CONCLUSION: Hemorrhagic cystitis is a relatively common and can be a difficult condition to manage for urologists. It is important to understand the etiology and available treatments options in order to best treat our patients. We provide a comprehensive and thorough review of the literature and propose a stepwise treatment approach.

A scoping review of penile implant biofilms-what do we know and what remains unknown?

Background: Penile prosthesis (PP) is a gold standard for treatment of erectile dysfunction given its reliability and efficacy. Infection remains the most feared complication of prosthetic surgery, which usually results in device removal, and places a significant economic burden on the healthcare system. While biofilms have shown to support the persistence of microorganisms, the degree by which this matrix is truly pathogenic remains unknown given its high prevalence even in asymptomatic patients. We aim to review and summarize the current literature pertaining to biofilm formation in the setting of PP surgeries in clinically infected and non-infected cases. Methods: Searches were performed in the MEDLINE online database through PubMed using a combination of keywords "penile prosthetic" OR "penile prosthesis" OR "penile implant" AND "biofilm" OR "revision" OR "removal" OR "infection" OR "explant". Eleven articles met inclusion criteria. There were only three studies that explicitly listed the number of biofilms identified in their cohort, but we also included eight articles that mentioned swabbing and culturing of any bacterial biofilm during revision procedures for both clinically infected and non-infected implants. Results: Infected PP yielded a 11-100% rate of biofilm presence, while non-infected PP yielded a 3-70% rate of biofilm presence. Time to reoperation from initial PP placement were also largely variable, ranging from 2 weeks to over 2 years. Coagulase-negative staphylococcus (i.e., Staphylococcus epidermidis) were the most commonly reported organisms among non-infected implants, however, newer studies have identified a change towards more virulent organisms. Conclusions: Since the advent of PP surgery, diabetes control, revision washout protocols and antibiotic-impregnated devices have led to an overall decrease in biofilm formation and infectious complications. There is an overall paradigm shift in microbial profiles with more virulent organisms, such as Escherichia coli, Pseudomonas aeruginosa, Enterococcus species, and even fungal species beginning to replace the more common coagulase-negative staphylococcal species, especially in clinically infected implants. Additional studies are necessary to define the significance of bacterial presence in biofilms using impactful technologies such as next-generation sequencing. Currently, preliminary and experimental biofilm-control strategies are also underway to further address this clinical issue.

Urethral Cancer After Urethroplasty: A Case Report and Review of the Literature.

OBJECTIVE: To review and report data on transformation to urethral carcinoma after urethroplasty for urethral stricture disease. Primary urethral carcinoma is a rare entity, and guidelines lack high quality data from which to cite. Urethroplasty is a highly effective treatment for urethral stricture disease, though in rare cases complications may include development of urethral carcinoma. METHODS: A systematic PubMed search was performed to identify all articles describing patients with urethral carcinoma after urethroplasty. Data were collected on the following parameters: patient age and sex, indication for urethroplasty, presentation of cancer, imaging, pathology, presence of metastasis, intervention, and outcome. RESULTS: The final cohort included fourteen patients, 13 from previously published cases and one from our institution. The median patient age at presentation was 60, most had endoscopic management prior to urethroplasty, and the majority presented with decreased urinary stream. All patients developed squamous cell carcinoma of the urethra. Patients underwent radical resection, lymph node dissection, chemotherapy, or radiotherapy, often in combination. A majority of patients had died at the time of case report. CONCLUSION: Development of urethral squamous cell carcinoma, particularly after urethroplasty, is a rarely encountered process. Patients and urologists must have a high index of suspicion and investigate symptoms such as fistula or lower urinary tract symptoms, even if these occur many months or even years after buccal mucosa graft . By compiling previously reported cases and adding an additional case to the literature, we hope that familiarity with this entity will lead to earlier recognition and diagnosis of disease.