Recurrent FOXK1::GRHL and GPS2::GRHL fusions in trichogerminoma.

We report 21 cases of trichogerminoma harbouring previously undescribed FOXK1::GRHL1/2 or GPS2::GRHL1/2/3 in-frame fusion transcripts. Microscopic examination of a preliminary set of five cases revealed well-delimitated tumours located in the dermis with frequent extension to the subcutaneous tissue. Tumours presented a massive and nodular architecture and consisted of a proliferation of basaloid cells. A biphasic pattern sometime resulting in tumour cell nests ('cell balls') was present. Immunohistochemistry demonstrated the expression of cytokeratins (CKs) 15, 17, and PHLDA1. In addition, numerous CK20-positive Merkel cells were detected. RNA sequencing (RNA-seq) revealed a FOXK1::GRHL1 chimeric transcript in three cases and a FOXK1::GRHL2 fusion in two cases. In a second series for validation (n = 88), FOXK1::GRHL1/2 fusion transcripts were detected by RT-qPCR or FISH in an additional 12 trichogerminomas and not in any other follicular tumour entities or basal cell carcinoma cases (n = 66). Additional RNA-seq analysis in trichogerminoma cases without detected FOXK1::GRHL1/2 rearrangements revealed GPS2::GRHL1 fusion transcripts in two cases, GPS2::GRHL2 in one case, and GPS2::GRHL3 fusion transcript in one case. Therefore, our study strongly suggests that GRHL1/2/3 gene rearrangements might represent the oncogenic driver in trichogerminoma, a subset of follicular tumours characterized by immature features and numerous Merkel cells. © 2022 The Pathological Society of Great Britain and Ireland.

Centers for Medicare & Medicaid Services Transition From Payments for Volume to Value: Implications for North Carolina Physicians, Providers, and Patients.

The US Department of Health and Human Services and the Centers for Medicare & Medicaid Services have announced goals and timelines to transition from payments based on volume to payments based on value, quality, and efficient delivery of care. These value-based payments and alternative payment models will impact all health care professionals and provider organizations by encouraging better care, healthier people, and spending health care dollars wisely and efficiently.

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.

Methotrexate vs placebo in early tubal ectopic pregnancy: a multi- centre double-blind randomised trial.

BACKGROUND: In the 21st century, tubal ectopic pregnancies (EPs) are diagnosed earlier in their natural history due to transvaginal ultrasound technology. More women are haemodynamically stable and therefore can be offered non-invasive outpatient management with systemic Methotrexate (MTX). However there is no evidence that MTX is necessary in all these early EPs, as many may resolve spontaneously in the absence of any treatment. To date there are no published randomized trials comparing systemic MTX with a placebo. The aim of this study is to verify if MTX is more effective than the placebo in women with tubal EP and rising/plateauing serum human chorionic gonadotrophin (hCG) levels. METHODS/DESIGN: This is a multi-centre double-blind randomized controlled trial conducted in Australia. Haemodynamically stable women with a confirmed ultrasound diagnosis of tubal EP and a rising/plateauing serum hCG & < 1500 IU/L are eligible for the trial. Women with a declining serum hCG, hCG > 1500 IU/L at 48 hrs, viable tubal EP, severe abdominal pain, evidence of haemoperitoneum on ultrasound, diagnostic uncertainty, non-tubal ectopic pregnancy, or women with contraindications to MTX will be excluded. Systemic MTX in a single dose intramuscular regimen (50mg/m2) is compared to an identical placebo in an outpatient setting. All women will attend for a serum hCG measurement on day 4. Provided patients are haemodynamically stable, they will attend for another blood test on day 7. If a decline in serum hCG > 15% between days 4 - 7 is observed, weekly blood tests will be scheduled until undetectable hCG levels. If serum hCG levels increase or decrease < 15% between days 4 - 7, a second dose of MTX will be given and weekly blood tests will be scheduled until undetectable serum hCG. If any increase in serum hCG > 15% between days 4 - 7 or at any subsequent follow-up, women will be treated with MTX. Primary outcome measure is treatment success, defined as uneventful decline of serum hCG to an undetectable level ( < 5 IU/L) by the initial intervention. Secondary outcome measures are re-interventions (additional systemic MTX injections and/or surgery for haemodynamic instability/trophoblast persistence), treatment complications and length of follow-up. DISCUSSION: This trial will clarify the actual effectiveness of MTX in haemodynamically stable women with an early tubal EPs and rising or plateauing hCG.

Implications of the Emergency Medical Treatment and Labor Act (EMTALA) during public health emergencies and on alternate sites of care.

Hospitals throughout the country are using innovative strategies to accommodate the surge of patients brought on by the novel H1N1 virus. One strategy has been to help decompress the amount of patients seeking care within emergency departments by using alternate sites of care, such as tents, parking lots, and community centers as triage, staging, and screening areas. As at any other time an individual presents on hospital property, hospitals and providers must be mindful of the requirements of the Emergency Medical Treatment and Labor Act. In this article we review the act and its implications during public health emergencies, with a particular focus on its implications on alternative sites of care.

Diagnostic accuracy of community pathologists in the interpretation of colorectal polyps.

BACKGROUND AND AIMS: Management of patients with endoscopically removed colorectal polyps is generally dependent on pathological evaluation. The aim of this study was to assess the accuracy and clinical impact of pathologic interpretation of colorectal polyps by community pathologists. METHODS: Two expert gastrointestinal pathologists reviewed the slides of 300 colorectal polyps initially examined by 14 general pathologists. Polyps had been detected by a fecal occult blood test colorectal cancer screening program in Haut-Rhin, a French administrative district. RESULTS: Villous histology was overread in 24.8% of cases and high-grade dysplasia in 22.0%. The diagnosis of serrated adenoma was confirmed in 15.7% of cases. The diagnosis of T1 carcinoma was overestimated in seven cases (17.9%) and missed in four. In the screening program, the proportion of correct diagnoses of community pathologists was estimated at 45.3% of polyps, of misclassification without clinical impact at 27.5%, and of misclassification with a theoretical impact on management at 27.2%, leading to over-surveillance in 20.3% of polyps and to unnecessary surgical resection in three individuals. Overall, 37.5% of the pathology reports of malignant polyps were complete, presenting all criteria necessary for therapeutic decision-making. CONCLUSION: Community pathologists exhibited moderate accuracy for interpreting colorectal polyps, with an impact on patient management for around one out of five individuals. Our results confirm the intrinsic poor reliability of the pathologic interpretation of villous histology and high-grade dysplasia and suggest that these advanced pathologic features should be abandoned for clinical use. They illustrate the need for a clarification of the nomenclature of serrated polyps.