Cellular and transcriptional profiles of peripheral blood mononuclear cells pre-vaccination predict immune response to preventative MUC1 vaccine.

A single arm trial (NCT007773097) and a double-blind, placebo controlled randomized trial ( NCT02134925 ) were conducted in individuals with a history of advanced colonic adenoma to test the safety and immunogenicity of the MUC1 tumor antigen vaccine and its potential to prevent new adenomas. These were the first two trials of a non-viral cancer vaccine administered in the absence of cancer. The vaccine was safe and strongly immunogenic in 43% (NCT007773097) and 25% ( NCT02134925 ) of participants. The lack of response in a significant number of participants suggested, for the first time, that even in a premalignant setting, the immune system may have already been exposed to some level of suppression previously reported only in cancer. Single-cell RNA-sequencing (scRNA-seq) on banked pre-vaccination peripheral blood mononuclear cells (PBMCs) from 16 immune responders and 16 non-responders identified specific cell types, genes, and pathways of a productive vaccine response. Responders had a significantly higher percentage of CD4+ naive T cells pre-vaccination, but a significantly lower percentage of CD8+ T effector memory (TEM) cells and CD16+ monocytes. Differential gene expression (DGE) and transcription factor inference analysis showed a higher level of expression of T cell activation genes, such as Fos and Jun, in CD4+ naive T cells, and pathway analysis showed enriched signaling activity in responders. Furthermore, Bayesian network analysis suggested that these genes were mechanistically connected to response. Our analyses identified several immune mechanisms and candidate biomarkers to be further validated as predictors of immune responses to a preventative cancer vaccine that could facilitate selection of individuals likely to benefit from a vaccine or be used to improve vaccine responses.

Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous, Aggressive Cancer with Diverse Biomarkers and No Targeted Standard of Care: Review of the Literature and Ongoing Investigational Agents.

BACKGROUND: Malignant peripheral sheath tumor (MPNST) is a rare, aggressive form of soft-tissue sarcoma that presents a unique set of diagnostic and treatment challenges and is associated with major unmet treatment medical needs. OBJECTIVE: The chief aim of this review is to consider the epidemiology, histology, anatomic distribution, pathologic signaling pathways, diagnosis, and management of MPNST, with a focus on potential targeted therapies. A subordinate objective was to establish benchmarks for the antitumor activity of such treatments. RESULTS: MPNST has an incidence of 1:100,000 in the general population and 1:3500 among patients with the inherited condition of neurofibromatosis-1. Spindle-cell sarcomas of neural-crest origin, MPNSTs are frequently situated in the extremities and pelvis/trunk, often at the confluence of large nerve roots and bundles. Highly copy-number aberrant and enriched in chromosome 8, MPNSTs have a complex molecular pathogenesis that likely involves the interplay of multiple signaling pathways, including Ras/AKT/mTOR/MAPK, EGFR, p53, PTEN, and PRC2, as well as factors in the tumor microenvironment. A combination of magnetic resonance imaging (MRI) and positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) enables comprehensive assessment of both morphology and metabolism, while MRI- and ultrasound-guided core needle biopsy can confirm histopathology. Although surgery with wide excisional margins is now the chief curative approach to localized disease, MPNST-specific survival has not improved in decades. For advanced and metastatic MPNST, radiation and chemotherapy (chiefly with anthracyclines plus ifosfamide) have somewhat promising but still largely uncertain treatment roles, chiefly in local control, downstaging, and palliation. No single druggable target has emerged, no objective responses have been observed with a number of targeted therapies (cumulative disease control rate in our review = 22.9-34.8%), and combinatorial approaches directed toward multiple signal transduction mechanisms are hallmarks of ongoing clinical trials. CONCLUSIONS: Despite advances in our understanding of the genetics and molecular biology of MPNST, further research is warranted to: (1) unravel the complex pathogenesis of this condition; (2) improve diagnostic yield; (3) delineate the appropriate roles of chemotherapy and radiation; and (4) develop a targeted therapy (or combination of such treatments) that is well tolerated and prolongs survival.

Trends in Endometrial Cancer Incidence in the United States by Race/Ethnicity and Age of Onset from 2000 to 2019.

Endometrial cancer is one of few cancers that has continued to rise in incidence over the past decade with disproportionate increases in adults younger than 50 years old. We used data from the Surveillance, Epidemiology, and End Results Registry (2000-2019) to examine endometrial cancer incidence trends by race/ethnicity and age of onset among women in the United States. Case counts and proportions, age-adjusted incidence rates (per 100,000), and average annual percent changes were calculated by race/ethnicity, overall and stratified by age of onset (early vs late). We found a disproportionate increase in endometrial cancer incidence among women of color, for both early and late onset endometrial cancer. The highest increases in early onset endometrial cancer (<50 years old) were observed among American Indian/Alaska Native women (4.8), followed by Black (3.3), Hispanic/Latina (3.1), and Asian and Pacific Islander women (2.4), whereas white women (0.9) had the lowest increase. Late onset (>50 years old) endometrial cancer incidence followed a similar pattern, with the greatest increases for women of color. The increasing burden of endometrial cancer among women of color, particularly those younger than 50 years old, is a major public health problem necessitating further research and clinical efforts focused on health equity.

Robotising vitreoretinal surgeries.

The use of robotic surgery in ophthalmology has been shown to offer many potential advantages to current surgical techniques. Vitreoretinal surgery requires complex manoeuvres and high precision, and this is an area that exceeds manual human dexterity in certain surgical situations. With the advent of advanced therapeutics such as subretinal gene therapy, precise delivery and minimising trauma is imperative to optimize outcomes. There are multiple robotic systems in place for ophthalmology in pre-clinical and clinical use, and the Preceyes Robotic Surgical System (Preceyes BV) has also gained the CE mark and is commercially available for use. Recent in-vivo and in-human surgeries have been performed successfully with robotics systems. This includes membrane peeling, subretinal injections of therapeutics, and retinal vein cannulation. There is huge potential to integrate robotic surgery into mainstream clinical practice. In this review, we summarize the existing systems, and clinical implementation so far, and highlight the future clinical applications for robotic surgery in vitreo-retina.

Liver-specific Mettl14 deletion induces nuclear heterotypia and dysregulates RNA export machinery.

Modification of RNA with N6-methyladenosine (m6A) has gained attention in recent years as a general mechanism of gene regulation. In the liver, m6A, along with its associated machinery, has been studied as a potential biomarker of disease and cancer, with impacts on metabolism, cell cycle regulation, and pro-cancer state signaling. However these observational data have yet to be causally examined in vivo. For example, neither perturbation of the key m6A writers Mettl3 and Mettl14, nor the m6A readers Ythdf1 and Ythdf2 have been thoroughly mechanistically characterized in vivo as they have been in vitro. To understand the functions of these machineries, we developed mouse models and found that deleting Mettl14 led to progressive liver injury characterized by nuclear heterotypia, with changes in mRNA splicing, processing and export leading to increases in mRNA surveillance and recycling.

An Open-Label Phase II Study Assessing the Safety of Bilateral, Sequential Administration of Retinal Gene Therapy in Participants with Choroideremia: The GEMINI Study.

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus 2 (AAV2) vector encoding the cDNA of Rab escort protein 1 (REP1), augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). Up to 0.1 mL of timrepigene emparvovec, containing 1×1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intra-surgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec and 53 completed the study. Visual acuity was generally maintained in both eyes, independent of intra-surgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post-hoc analyses found these were not associated with clinically significant vision loss at Month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of anti-vector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced visual acuity after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

Squamoid eccrine ductal carcinoma: clinical, histological and immunohistochemical features.

Squamoid eccrine ductal carcinoma (SEDC) is a cutaneous adnexal malignancy that is histologically challenging to distinguish from squamous cell carcinoma. We report three cases of this rare entity and review the present literature regarding clinical, histological, and immunohistochemical features. Patients presented with a single nodule or plaque lesion on their back and temple. The shave biopsies for Patient A and C were interpreted as SEDC. Patient B's initial shave biopsy was interpreted as probable surface of squamous cell carcinoma, and subsequent excision revealed SEDC. Ductal differentiation was confirmed by positive expression of epithelial membrane antigen and carcinoembryonic antigen immunostains in all three patients. Review of the 67 previously reported cases emphasizes the importance of diagnosing SEDC accurately and promptly given its potential for distant metastasis and mortality. Perineural or lymphatic invasion is associated with higher rate of recurrence or metastasis. There should be high pathologic suspicion for SEDC in an elderly patient presenting with a palpable lesion, even if located outside of the head and neck area, particularly when there is suggestion of ductal differentiation in a sample of a squamous neoplasm.

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

Unmatched. What's Next? Is a Preliminary Year of Residency or Research Fellowship Better for Reapplicants to Plastic Surgery?

Background: Plastic and reconstructive surgery is one of the most competitive residency programs, and given the increased number of applicants for a relatively fixed number of positions, successfully matching is a challenge. Match rates have declined since 2018, with a match rate of ~55% in 2022. Two common options before reapplying are a preliminary year of residency (preliminary year) or a research fellowship. This study investigated which option is more beneficial for reapplicants seeking a successful match. Methods: This retrospective study included all applicants to an integrated plastic and reconstructive surgery residency from 2015 to 2023. Two cohorts based on reapplication strategy (research fellowship or preliminary year) were created. Demographic, applicant, and match data were collected. Pearson chi-squared, Fisher exact, and Wilcoxon rank sum testing were performed. Results: In total, 125 reapplicants were included. Seventy-one (56.8%) reapplicants pursued a preliminary year, and 29 (23.2%) completed a research fellowship. Research fellowship reapplicants had a greater mean number of first author publications (8.8 versus 3.2, P < 0.001), non-first author publications (11.3 versus 5.9, P = 0.021), poster presentations (9.7 versus 6.0, P = 0.028), and oral presentations (11.8 versus 6.4, P < 0.001). Research fellowship reapplicants were more likely to match into plastic and reconstructive surgery (PRS) than preliminary year reapplicants, with 72.4% (n = 21) of research fellowship reapplicants matching into PRS compared with 39.4% (n = 28) of preliminary year reapplicants (P = 0.003). Conclusions: Research fellowship reapplicants demonstrated greater research productivity and were almost twice as likely to match into PRS compared with preliminary reapplicants.

In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

Robot-Assisted Eye Surgery: A Systematic Review of Effectiveness, Safety, and Practicality in Clinical Settings.

Purpose: Surgical innovation in ophthalmology is impeded by the physiological limits of human motion, and robotic assistance may facilitate an expansion of the surgical repertoire. We conducted a systematic review to identify ophthalmic procedures in which robotic systems have been trialled, evaluate their performance, and explore future directions for research and development of robotic techniques. Methods: The Cochrane Library, Embase, MEDLINE, Scopus, and Web of Science were searched. Screening adhered to five criteria: (1) English language; (2) primary research article; (3) human patients; (4) ophthalmological surgery; and (5) robot-assisted surgery. Quality assessment was conducted with Joanna Briggs Institute Tools for Critical Appraisal. The study protocol was registered prospectively (PROSPERO ID CRD42023449793). Results: Twelve studies were included. In comparative studies, there was no difference in the occurrence of ocular harms in robot-assisted procedures and conventional surgery. However, robotic assistance did not demonstrate consistent benefits over manual surgery in terms of effectiveness or practicality, likely reflecting the learning curve associated with these systems. Single studies indicated the potential of robotic assistance to improve the consistency of subretinal drug infusion and efficiency of instrument manipulation in vitreoretinal surgery. Conclusions: Proof-of-concept studies have demonstrated the potential of robotic assistance to facilitate procedures otherwise infeasible or impractical, and may broaden access to surgery. However, robot-assisted surgery has not yet demonstrated any significant benefits over standard surgical practice. Improving the speed and reducing perioperative requirements of robot-assisted surgery are particular priorities for research and innovation to improve the practicality of these novel techniques. Translational Relevance: This systematic review summarizes the potential and limitations of robotic systems for assisting eye surgery and outlines what is required for these systems to benefit patients and surgeons.

Unconventional mechanism of action and resistance to rapalogs in renal cancer.

mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.

Transcriptomic Analysis of Metastatic Uveal Melanoma and Differences in Male and Female Patients.

BACKGROUND/AIM: Uveal melanoma is an ocular malignancy whose prognosis severely worsens following metastasis. In order to improve the understanding of molecular physiology of metastatic uveal melanoma, we identified genes and pathways implicated in metastatic vs non-metastatic uveal melanoma. PATIENTS AND METHODS: A previously published dataset from Gene Expression Omnibus (GEO) was used to identify differentially expressed genes between metastatic and non-metastatic samples as well as to conduct pathway and perturbagen analyses using Gene Set Enrichment Analysis (GSEA), EnrichR, and iLINCS. RESULTS: In male metastatic uveal melanoma samples, the gene LOC401052 is significantly down-regulated and FHDC1 is significantly up-regulated compared to non-metastatic male samples. In female samples, no significant differently expressed genes were found. Additionally, we identified many significant up-regulated immune response pathways in male metastatic uveal melanoma, including "T cell activation in immune response". In contrast, many top up-regulated female pathways involve iron metabolism, including "heme biosynthetic process". iLINCS perturbagen analysis identified that both male and female samples have similar discordant activity with growth factor receptors, but only female samples have discordant activity with progesterone receptor agonists. CONCLUSION: Our results from analyzing genes, pathways, and perturbagens demonstrate differences in metastatic processes between sexes.

A nucleosome switch primes Hepatitis B Virus infection.

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. Establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA drives X transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing molecule CBL137 inhibits X transcription and HBV infection in hepatocytes. Our results shed light on a long-standing paradox and represent a potential new therapeutic avenue for the treatment of chronic HBV infection.

A Mobile Post Anesthesia Care Unit Order Reminder System Improves Timely Order Entry.

Transition to the postanesthesia care unit (PACU) requires timely order placement by anesthesia providers. Computerized ordering enables automated order reminder systems, but their value is not fully understood. We performed a single-center, retrospective cohort study to estimate the association between automated PACU order reminders and primary outcomes (1) on-time order placement and (2) the degree of delay in placement. As a secondary post-hoc analysis, we studied the association between late order placement and PACU outcomes. We included patients with a qualifying postprocedure order from January 1, 2019, to May 31, 2023. We excluded cases transferred directly to the ICU, whose anesthesia provider was involved in the pilot testing of the reminder system, or those with missing covariate data. Order reminder system usage was defined by the primary attending anesthesiologist's receipt of a push notification reminder on the day of surgery. We estimated the association between reminder system usage and timely order placement using a logistic regression. For patients with late orders, we performed a survival analysis of order placement. The significance level was 0.05. Patient (e.g., age, race), procedural (e.g., anesthesia duration), and provider-based (e.g., ordering privileges) variables were used as covariates within the analyses. Reminders were associated with 51% increased odds of order placement prior to PACU admission (Odds Ratio: 1.51; 95% Confidence Interval: 1.43, 1.58; p ≤ 0.001), reducing the incidence of late PACU orders from 17.5% to 12.6% (p ≤ 0.001). In patients with late orders, the reminders were associated with 10% quicker placement (Hazard Ratio: 1.10; 95% CI 1.05, 1.15; p < 0.001). On-time order placement was associated with decreased PACU duration (p < 0.001), decreased odds of peak PACU pain score (p < 0.001), and decreased odds of multiple administration of antiemetics (p = 0.02). An order reminder system was associated with an increase in order placement prior to PACU arrival and a reduction in delay in order placement after arrival.

A Day in the Life of a Surgical Instrument: The Cycle of Sterilization.

Surgeons must be confident that the instruments they use do not pose risk of infection to patients due to bioburden or contamination. Despite this importance, surgeons are not necessarily aware of the steps required to ensure that an instrument has been properly sterilized, processed, and prepared for the next operation. At the end of an operation, instruments must be transported to the sterile processing unit. There, instruments are decontaminated before being sterilized by heat, chemical, or radiation-based methods. Following this, they are stored before being brought back into use. This review highlights the intricacies of the processing of surgical instruments at the conclusion of an operation so that they are ready for the next one.

Genetic alteration of SJ293TS cells and modification of serum-free media enhances lentiviral vector production.

Successful cell and gene therapy clinical trials have resulted in the US Food and Drug Administration and European Medicines Agency approving their use for treatment of patients with certain types of cancers and monogenetic diseases. These novel therapies, which rely heavily on lentiviral vectors to deliver therapeutic transgenes to patient cells, have driven additional investigations, increasing demand for both pre-clinical and current Good Manufacturing Practices-grade viral vectors. To better support novel studies by improving current production methods, we report the development of a genetically modified HEK293T-based cell line that is null for expression of both Protein Kinase R and Beta-2 microglobulin and grows in suspension using serum-free media, SJ293TS-DPB. Absence of Protein Kinase R increased anti-sense lentiviral vector titers by more than 7-fold, while absence of Beta-2 microglobulin, a key component of major histocompatibility complex class I molecules, has been reported to reduce the immunogenicity of lentiviral particles. Furthermore, we describe an improved methodology for culturing SJ293TS-DPB that facilitates expansion, reduces handling, and increases titers by 2-fold compared with previous methods. SJ293TS-DPB stably produced lentiviral vectors for over 4 months and generated lentiviral vectors that efficiently transduce healthy human donor T cells and CD34+ hematopoietic stem cells.

Safety of Antiandrogens for the Treatment of Female Androgenetic Alopecia with Respect to Gynecologic Malignancies.

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol.

Oxylipins in Breast Implant Associated Systemic Symptoms.

BACKGROUND: A subset of women with breast implants have reported a myriad of nonspecific systemic symptoms collectively termed systemic symptoms associated with breast implants (SSBI). SSBI symptoms are similar to manifestations associated with autoimmune and connective tissue disorders Breast tissue is rich in adipose cells, comprised of lipids. Insertion of an implant creates an oxidative environment leading to lipid oxidation. Oxylipins can influence immune responses and inflammatory processes. OBJECTIVES: This study explores the abundance of a spectrum of oxylipins in the peri-prosthetic tissue surrounding the breast implant. Since oxylipins are immunogenic, we sought to determine if they are associated with the SSBI subjects. We have also attempted to determine if the common manifestations exhibited by such subjects have any association with oxylipin abundance. METHODS: The study included 120 subjects divided in three cohorts. Forty-six subjects with breast implants exhibiting manifestation associated with SSBI, 29 in control cohort I subjects with breast implants not exhibiting manifestation associated with SSBI (non-SSBI) and 45 in control cohort II subjects without implants (normal tissue) were analyzed. Lipid extraction and oxylipin quantification was performed using LCMS. LC-MS/MS targeted analysis from the breast adipose tissue was performed. RESULTS: Of the fifteen oxylipins analyzed, four exhibited increased abundance in the SSBI cohort compared to the non-SSBI and normal cohorts. CONCLUSIONS: The study documents the association of the oxylipins with each manifestation reported by the subject. This study provides an objective assessment on the subjective questionnaire highlighting which symptoms could be more relevant than the others.