Eccrine Porocarcinoma of the Vulva With Sarcomatoid Transformation, a New Human Papillomavirus-associated Malignancy? Case Report and Review of the Literature.

Eccrine porocarcinoma is a rare cutaneous neoplasm, and rarer still in the anogenital region. In the vulva, the most common carcinoma by far is squamous cell carcinoma; however, eccrine porocarcinoma can arise at this site. As the distinction between porocarcinoma and squamous cell carcinoma has important prognostic implications at other cutaneous sites, it stands to reason that it may have these same implications in the vulva. We present a case of an eccrine porocarcinoma in the vulva of a 70-year-old woman that, in addition, showed sarcomatoid transformation. This tumor harbored human papillomavirus-18 DNA and mRNA, raising the question of the role of the oncogenic virus in sweat gland neoplasms of the vulva.

Characterization and first-in-human clinical dose-escalation safety evaluation of a next-gen human freeze-dried plasma.

BACKGROUND: Early plasma transfusion is life-saving for bleeding trauma patients. Freeze-dried plasma (FDP) provides unique formulation advantages for infusion in the prehospital setting. We describe characterization and clinical safety data of the first, next-generation FDP stored in plastic bags with rapid reconstitution. STUDY DESIGN AND METHODS: Coagulation and chemistry parameters on 155 pairs of fresh frozen plasma (FFP) and their derivative FDP units were compared. Next, a first-in-human, dose-escalation safety evaluation of FDP, involving 24 healthy volunteers who donated either whole blood or apheresis plasma to create autologous FDP, was performed in three dose cohorts (270, 540, and 810 ml) and adverse events (AEs) were monitored. Cohort 3 was randomized, double-blind with a cross-over arm that compared FDP versus FFP using descriptive analysis for AEs, coagulation, hematology, and chemistry parameters. RESULTS: FDP coagulation factors, clotting times, and product quality (pH, total protein, and osmolality) post-lyophilization were preserved. FDP infusions, of up to 810 ml per subject, were found to be safe and with no serious AEs (SAEs) related to FDP. The average time to reconstitute FDP was 67 s (range: 43-106). No differences in coagulation parameters or thrombin activation were detected in subjects infused with 810 ml of FDP compared with FFP. CONCLUSION: This first next-generation FDP product preserves the potency and safety of FFP in a novel rugged, compressible, plastic container, for rapid transfusion, allowing rapid access to plasma in resuscitation protocols for therapy in acute traumatic hemorrhage.

Older patients undergoing emergency laparotomy: observations from the National Emergency Laparotomy Audit (NELA) years 1-4.

BACKGROUND: older patients aged ≥65 years constitute the majority of the National Emergency Laparotomy Audit (NELA) population. To better understand this group and inform future service changes, this paper aims to describe patient characteristics, outcomes and process measures across age cohorts and temporally in the 4-year period (2014-2017) since NELA was established. METHODS: patient-level data were populated from the NELA data set years 1-4 and linked with Office of National Statistics mortality data. Descriptive data were compared between groups delineated by age, NELA year and geriatrician review. Primary outcomes were 30- and 90-day mortality, length of stay (LOS) and discharge to care-home accommodation. RESULTS: in total, 93,415 NELA patients were included in the analysis. The median age was 67 years. Patients aged ≥65 years had higher 30-day (15.3 versus 4.9%, P < 0.001) and 90-day mortality (20.4 versus 7.2%, P < 0.001) rates, longer LOS (median 15.2 versus 11.3 days, P < 0.001) and greater likelihood of discharge to care-home accommodation compared with younger patients (6.7 versus 1.9%, P < 0.001). Mortality rate reduction over time was greater in older compared with younger patients. The proportion of older NELA patients seen by a geriatrician post-operatively increased over years 1-4 (8.5 to 16.5%, P < 0.001). Post-operative geriatrician review was associated with reduced mortality (30-day odds ratio [OR] 0.38, confidence interval [CI] 0.35-0.42, P < 0.001; 90-day OR 0.6, CI 0.56-0.65, P < 0.001). CONCLUSIONS: older NELA patients have poorer post-operative outcomes. The greatest reduction in mortality rates over time were observed in the oldest cohorts. This may be due to several interventions including increased perioperative geriatrician input.

Modifiable life style factors and risk for incident endometriosis.

BACKGROUND: Caffeine, alcohol, smoking and physical activity are known to alter sex steroid synthesis, which may affect hormone-dependent gynaecologic disease risk, such as endometriosis; however, few studies have assessed life style factors prior to endometriosis diagnosis. METHODS: Four hundred and seventy three women, ages 18-44 years, underwent laparoscopy or laparotomy, regardless of clinical indication, at 14 clinic sites, 2007-2009. Women with prior surgically confirmed endometriosis were excluded. Life style factors were assessed prior to surgery. Adjusted risk ratios (RR) of endometriosis by caffeine, alcohol, smoking (serum cotinine), and physical activity were estimated, adjusting for age, marital status, education, race/ethnicity, age at menarche, gravidity, BMI, study site, and other life style factors. RESULTS: There were no associations between women with endometriosis and alcohol consumption (RR 0.9, 95% CI 0.7, 1.3), caffeine consumption (RR 1.1, 95% CI 0.8, 1.5), or smoking (serum cotinine <10 vs ≥10 ng/mL; RR 1.0, 95% CI 0.7, 1.6). Similar null findings were found between endometriosis and weekly occurrences of physical activity and total walking, moderate, and vigorous activity; a modest trend was found between total daily sitting time and increased endometriosis risk. CONCLUSIONS: This study, which is unique in its capture of life style exposures prior to incident endometriosis diagnosis, largely found no association between alcohol, caffeine, smoking, and physical activity and risk of endometriosis.

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination.

In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 µg per peptide dose, the 50 µg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50 µg dose (7 of 14) and 100 µg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.

Optimisation of Negative Fixed Charge Based Edge Termination for Vertical GaN Schottky Devices.

This study focuses on the impact of negative fixed charge, achieved through fluorine (F) implantation, on breakdown voltage (BV) enhancement in vertical GaN Schottky diodes. Several device and implant-related parameters are examined using Synopsys Sentaurus TCAD simulations in order to determine the optimum fixed negative charge concentration required to achieve the highest BV. The simulated structure consisted of a Schottky diode with a box consisting of negative fixed charges to achieve the edge termination of the Schottky device. An empirical equation is proposed to determine the optimum fixed charge concentration for the highest BV based on depth. The simulation also considered implantation profiles derived from SIMS data from an actual device implanted with multi-energy and multi-dose F. It is demonstrated that the BV has a similar dependence on the key parameters like in the box profile. In summary, this work provides valuable insights into optimizing edge termination techniques using negative fixed charge for improved BV in vertical GaN power devices.

Racial Disparities in Breast Imaging Wait Times Before and After the Implementation of a Same-Day Biopsy Program.

OBJECTIVE: To examine time from screening to diagnostic workup, biopsy, and surgery for non-Hispanic White (NHW) and Black women following implementation of a same-day biopsy program. METHODS: All NHW and Black women with BI-RADS category 0 screening mammogram at Duke University Hospital were identified between August 1, 2020, and August 1, 2021. Patient characteristics were recorded. Time between screening mammogram, diagnostic workup, breast biopsy, surgical consultation, and surgery were recorded. Comparisons were made between NHW and Black women using a multivariable regression model. Diagnostic imaging to biopsy time interval was compared to historical averages before same-day biopsy implementation. RESULTS: There were 2156 women: 69.9% NHW (1508/2156) and 30.1% Black (648/2156). Mean ± standard deviation time from screening to diagnostic imaging overall was 13.5 ±â€…32.5 days but longer for Black (18.0 ±â€…48.3 days) than for NHW women (11.5 ±â€…22.2 days) (P < 0.001). The mean time from diagnostic mammogram to biopsy was 5.9 ±â€…18.9 days, longer for Black (9.0 ±â€…27.9 days) than for NHW women (4.4 ±â€…11.8 days) (P = 0.017). The same-day biopsy program shortened the time from diagnostic imaging to biopsy overall (12.5 ±â€…12.4 days vs 5.9 ±â€…18.9 days; P < 0.001), with a significant reduction for NHW women (12.4 ±â€…11.7 days vs 4.4 ±â€…11.8 days) (P < 0.001) but not Black women (11.5 ±â€…9.9 days vs 9.0 ±â€…27.9 days) (P = 0.527). CONCLUSION: Disparities exist along the breast imaging pathway. A same-day biopsy program benefited NHW women more than Black women.

Development of Low-Resistance Ohmic Contacts with Bilayer NiO/Al-Doped ZnO Thin Films to p-type GaN.

The fabrication of low-resistance and thermally stable Ohmic contacts is essential for the realization of reliable GaN power devices. In the particular case of p-type GaN, a thin Ni/Au bilayer is commonly used for Ohmic contacts. However, Au metal contacts are quite expensive, are incompatible with the complementary metal oxide-semiconductor foundries, and also have poor thermal stability. Thus, seeking an alternative that is affordable and thermally stable is crucial. In the present study, we investigate Au-free Ohmic contact formation on p-type GaN using a bilayer Ni/Al-doped ZnO (AZO) thin film. Careful studies were focused on identifying the role of process parameters such as annealing parameters: temperature, time, and atmosphere in order to obtain an excellent Ohmic contact on p-GaN. Our results show that the contact resistance can be significantly reduced using a Ni/AZO bilayer with a suitable rapid thermal process. We demonstrate that the specific contact resistance for Ni/AZO on p-GaN can reach the lowest value of 1.85 × 10-4 Ω·cm2 for a sample with a 5 nm Ni layer annealed at 500 °C in air for 5 min. Our work demonstrates that the bilayer Ni/AZO contact could be suitable for efficient GaN power diodes or transistors.

Study of GaN coalescence by dark-field X-ray microscopy at the nanoscale.

This work illustrates the potential of dark-field X-ray microscopy (DFXM), a 3D imaging technique of nanostructures, in characterizing novel epitaxial structures of gallium nitride (GaN) on top of GaN/AlN/Si/SiO2 nano-pillars for optoelectronic applications. The nano-pillars are intended to allow independent GaN nanostructures to coalesce into a highly oriented film due to the SiO2 layer becoming soft at the GaN growth temperature. DFXM is demonstrated on different types of samples at the nanoscale and the results show that extremely well oriented lines of GaN (standard deviation of 0.04°) as well as highly oriented material for zones up to 10 × 10 µm2 in area are achieved with this growth approach. At a macroscale, high-intensity X-ray diffraction is used to show that the coalescence of GaN pyramids causes misorientation of the silicon in the nano-pillars, implying that the growth occurs as intended (i.e. that pillars rotate during coalescence). These two diffraction methods demonstrate the great promise of this growth approach for micro-displays and micro-LEDs, which require small islands of high-quality GaN material, and offer a new way to enrich the fundamental understanding of optoelectronically relevant materials at the highest spatial resolution.

The Event-Specific Benefits of Writing About a Difficult Life Experience.

Previous research demonstrates that writing about life's difficult moments benefits the writer cognitively and emotionally. However, it is unclear whether the benefits of writing are specific to the event written about or whether the benefits are global. This study was designed to address this issue. Participants were 120 undergraduate students who had experienced at least two difficult life events. Participants were randomly assigned into experimental and control groups. Experimental participants wrote about one of these difficult events and control participants wrote about an interesting life event of their choosing. Experimental participants reported their positive and negative emotions as well as their cognitive avoidance and intrusion concerning the event written about and another event not written about. Control participants reported their emotions and cognitions concerning two difficult life events. All participants also reported their general distress. These assessments were done immediately after writing and one week later. The results indicated that experimental participants were emotionally stronger, less upset, and less cognitively avoidant about the particular difficult life event they wrote about compared to an event they did not write about. Similar comparisons between ratings of a written-about and a not-written-about event were not significant for passion, fear, and cognitive intrusion. There was evidence for a possible indirect effect of writing on general distress through changes in event-specific cognitions and emotions. Discussion of these results focuses on how writing may specifically help change a writer's feelings and thoughts about a particular situation.

Factors and Outcomes Associated With Temporal Bone Resection for Primary Parotid Malignancy.

OBJECTIVE(S): Although parotid cancer invading into the temporal bone makes up only a small fraction of all parotid cancers, it is more common and relatively understudied compared with primary cancer of the external auditory canal. The objective of this study was to determine what factors are associated with receiving parotidectomy with temporal bone resection (TBR) and the immediate postoperative outcomes. METHODS: We reviewed the National Cancer Database (2004-2015) for patients with primary parotid malignancy who received parotidectomy with or without TBR. Patient demographic, clinical, and perioperative variables were collected and then compared. Multivariate logistic regression was performed to determine factors associated with receiving TBR. RESULTS: We identified 134 patients who received parotidectomy with TBR and 16,595 who received parotidectomy only. Reported in terms of odds ratios (95% confidence interval), our multivariate model showed having surgery at an academic facility (1.91 [1.34-2.71], P < .001), clinical stage III or IV (7.48 [1.65-33.96] and 31.37 [7.61-129.32], P = .009 and P < .001, respectively), histologic grade II to IV (4.36 [1.51-12.57], 4.31 [1.53-12.15], and 6.74 [2.26-20.13], P = .006, .006, and .001, respectively), and adenoid cystic histology (3.23 [2.02-5.17], P < .001) were significantly and independently associated with receiving TBR. There was no significant difference in 30-day readmission, or 30-day or 90-day mortality, but the rate of positive surgical margins was significantly higher in those who underwent TBR. CONCLUSION: Demographic variables are not significant factors for receiving TBR. Tumor characteristics, such as clinical stage and histologic type, and receiving surgical treatment at an academic facility were more strongly associated with receiving TBR. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2461-E2468, 2021.

Appearance and management of COVID-19 laryngo-tracheitis: two case reports.

We present two cases of coronavirus disease 2019 (COVID-19)-related laryngotracheitis in good-prognosis, ventilated patients who had failed extubation. As the pandemic continues to unfold across the globe and better management of those with respiratory failure develops, this may be an increasingly common scenario. Close ENT-intensivist liaison, meticulous team preparation, early consideration of rigid endoscopy and prospective data collection and case sharing are recommended.

Application of microRNA profiling to understand sevoflurane-induced adverse effects on developing monkey brain.

We have described that prolonged sevoflurane exposure at a clinically-relevant concentration of 2.5 % caused neuronal cell death in the developing monkey brain. Postnatal day 5 or 6 rhesus monkeys (n = 3) were exposed to 2.5 % sevoflurane for 8 h. Monkeys kept at environmental conditions in the procedure room served as controls (n = 3). Brain tissues were harvested four hours after sevoflurane exposure for histological analysis, and RNA or protein extraction. MicroRNA (miRNA) profiling on the frontal cortex of monkey brains was performed using next-generation sequencing. 417 miRNAs were identified in the frontal cortex, where most neuronal cell death was observed. 7 miRNAs were differentially expressed in frontal cortex after sevoflurane exposure. Five of these were expressed at significantly lower levels than controls and the other two miRNAs were expressed significantly higher. These differentially expressed miRNAs (DEMs) were then loaded to the Ingenuity Pathway Analysis database for pathway analysis, in which targeting information was available for 5 DEMs. The 5 DEMs target 2,919 mRNAs which are involved in pathways that contribute to various cellular functions. Of note, 78 genes that are related to axon guidance signaling were targeted, suggesting that development of the neural circuit may be affected after sevoflurane exposure. Such changes may have long-term effects on brain development and function. These findings are supplementary to our previous observations and provide more evidence for better understanding the adverse effects of sevoflurane on the developing brain after an 8 -h exposure.

Benign and Premalignant Lesions of the Endometrium.

In this review, we highlight the benign and premalignant lesions of the endometrium that the pathologist may encounter in daily practice. We begin by detailing our current understanding of excess estrogen in the progression of endometrial neoplasia. We outline the currently accepted terminology to be used when evaluating proliferative endometrial lesions, while highlighting their key features. Attention is then turned to the molecular underpinnings of neoplastic progression and how this can be exploited with immunohistochemical stains when appropriate. Finally, we discuss types of metaplasia and their associations, including so-called papillary proliferations of the endometrium.

Accentuated p53 staining in usual type vulvar dysplasia-A potential diagnostic pitfall.

Evaluation of vulvar intraepithelial neoplasia (VIN) may be difficult due to overlapping histologic features seen in both usual (UVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). DVIN represents a diagnostic challenge; poor inter-observer agreement is well documented. P53 has been described as a potentially helpful adjunct in some cases; however, intricacies in its interpretation remain. This study evaluated 41 consecutive cases which consisted of 23 keratinizing dysplasias that were morphologically suggestive of DVIN and 18 UVINs. All cases were stained with p16 and p53. Our results revealed that 22 of 41 (54%) VINs showed novel accentuated wild type (WT) staining with non-linear basal staining for p53, including 12 (52%) cases histologically suggestive of DVIN and 10 (56%) described as UVIN. P16 was positive in 100% of the accentuated wild type cases, consistent with a diagnosis of UVIN. Positive p53 and negative p16 staining was seen in 4 (17%) cases histologically suggestive of DVIN. Of these, 75% progressed to carcinoma, whereas only 1 of 35 (3%) patients with UVIN progressed to carcinoma. In conclusion, DVIN is difficult to diagnose due to potential histologic overlap with UVIN, especially the warty, or keratinizing, subtype. Accentuated WT p53 in absence of concurrent p16 staining may lead to misdiagnosis of DVIN, especially in small biopsy samples. P16/p53 staining should be performed in tandem with strict adherence to patterns considered positive, as patients with UVIN have significantly less risk of progression.

Uterine rhabdomyosarcoma in adults.

Rhabdomyosarcoma (RMS) is an aggressive mesenchymal tumor most commonly diagnosed in the pediatric population, and when occurring in adults, tends to develop in the deep soft tissue of the limbs. Primary uterine RMS comprises an even more restricted subset, with little known or reported when compared to most other gynecologic sarcomas. Our goal with this study was to retrospectively evaluate cases from two academic institutions and describe the main histopathologic findings of this rare gynecologic malignancy. A total of 8 cases were identified, consisting of 4 pleomorphic rhabdomyosarcomas (PRMS), 2 alveolar rhabdomyosarcomas (ARMS), and 2 embryonal rhabdomyosarcomas (ERMS). They occurred in patients ranging from 22 to 70 years old, and the most common presenting symptom was vaginal bleeding. Most patients presented with advanced stage at diagnosis, including metastatic disease to lymph nodes and to distant sites. The masses were mostly (6/8) centered in the myometrium, while two cases arose in the cervix (2/8). Histologic characteristics of the tumors were dependent on the RMS subtype, although all cases demonstrated a similar immunohistochemical profile regardless of their subclassification. RMS of the uterus has a very poor prognosis, and data regarding treatment of this rare malignancy is limited, and usually extrapolated from non-uterine sites.

Coherent tunneling in an AlGaN/AlN/GaN heterojunction captured through an analogy with a MOS contact.

Due to their wide band gaps, III-N materials can exhibit behaviors ranging from the semiconductor class to the dielectric class. Through an analogy between a Metal/AlGaN/AlN/GaN diode and a MOS contact, we make use of this dual nature and show a direct path to capture the energy band diagram of the nitride system. We then apply transparency calculations to describe the forward conduction regime of a III-N heterojunction diode and demonstrate it realizes a tunnel diode, in contrast to its regular Schottky Barrier Diode designation. Thermionic emission is ruled out and instead, a coherent electron tunneling scenario allows to account for transport at room temperature and higher.