Unrelated Causes Research Articles

Surgical management and prognostic factors for Endolymphatic Sac Tumor: a single-institute experience with a systematic review

OBJECTIVETo evaluate the clinical features, surgical outcomes, and predictors of progression-free survival (PFS) in patients with Endolymphatic Sac Tumors (ELSTs). METHODSThis retrospective study analyzed 15 cases from Beijing Tiantan Hospital and 237 from literature (1988-2023), focusing on patients with pathologically confirmed intracranial or skull ELSTs who had comprehensive treatment and follow-up records. Univariate and multivariate Cox regression analyses were employed to identify factors influencing PFS. RESULTSCases from our institute comprised 10 males and 5 females with an average age of 39.1 years. Among these, 86.7% underwent gross total resection (GTR). During the follow-up period, two patients (13.3%) were lost to follow-up. After a mean follow-up of 74.9 months, one patient experienced recurrence and another died from unrelated causes. A review of literature identified 237 additional patients, including 134 females (56.5%), with an average age of 39.8 years; 22.8% of these patients had von Hippel-Lindau disease. The GTR rate was 69.2%. After a mean follow up of 53.2 months, 33 recurrences occurred, and the median PFS was 48 months. Additionally, eight patients died during the follow-up period, none of the deaths were attributed to ELSTs. Multivariate analysis identified GTR (HR 0.279, 95% CI 0.086-0.903, p = 0.033) as a significant protective factor against recurrence among the pooled cases. CONCLUSIONSGTR is crucial for improving PFS in ELST patients, emphasizing the need for advanced surgical techniques and long-term follow-up due to potential recurrences.

Clear Cell Adenocarcinoma of the Urinary Tract Primary to the Renal Pelvis: A Multi-institutional Clinicopathologic and Molecular Study of Five Patients.

Clear cell adenocarcinoma (CCA) of the urinary tract is a rare malignancy and tumors involving the renal pelvis are notably sparse in the literature, with only 5 other patients reported. We present 5 patients, 4 women, and 1 man, with CCA of the renal pelvis. The age at presentation ranged from 29 to 81 years. The tumor size ranged from 4.5 to 8.0 cm. Tumors exhibited shared morphologic and immunohistochemical features with CCA of the female genital tract and those originating in the bladder and urethra, including cells with large nuclei, prominent nucleoli, nuclear hobnailing, and scant clear cytoplasm. Common immunohistochemical findings included reactivity for PAX8, CK7, HNF1β, and Napsin-A. One of the tumors arose in the background of a mixed epithelial and stromal tumor. Another tumor occurred in a renal allograft and tumor cells were positive for the BK virus, demonstrated by SV40 immunohistochemistry. All tumors were negative for TFE3 and TFEB rearrangement and lacked TERT alterations. Follow-up was limited with no recurrence in 4 patients at a maximum of 20 months follow-up and 1 patient died of an unrelated cause at 25 months of follow-up. Next-generation sequencing analysis of all 5 CCAs revealed mutations within genes implicated in DNA damage repair and chromatin remodeling pathways, including ATM, BRCA1, BRCA2, ARID1A, DICER1, SMAD4, NOTCH1, and MYC amplification. These molecular findings underscore the dysregulation of fundamental cellular processes essential for genomic integrity maintenance.

Semaglutide in patients with kidney failure and obesity undergoing dialysis and wishing to be transplanted: A prospective, observational, open-label study.

Chronic kidney disease (CKD) and obesity are major global health challenges, eventually leading to kidney replacement therapy (KRT), but body mass index (BMI) thresholds hinder kidney transplantation. Glucagon-like peptide-1 receptor agonists induce weight loss, thereby offering attractive treatment options; however, their safety and efficacy have not been systematically investigated in patients undergoing dialysis. We conducted a prospective 12-week, open-label trial with 13 patients who had a BMI ≥ 30.00 kg/m2, were undergoing dialysis (12 haemodialysis and 1 peritoneal dialysis) and had not been listed for transplantation due to their weight. Semaglutide was administered once weekly subcutaneously, and the dose was increased from 0.25 mg to 0.5 mg and then to 1 mg. Study endpoints included change in body weight and BMI (primary - statistically evaluated by repeated measures analysis of variance [ANOVA]), side effects, adverse events, blood parameters and patient-reported outcomes (secondary). At baseline, the mean age ± standard deviation of patients was 64.0 ± 6.4 years, the mean weight was 113.9 ± 16.6 kg, and the mean BMI was 37.3 ± 3.9 kg/m2. At week 12, average weight reduction under semaglutide treatment was 4.6 ± 2.4 kg and ranged from 2.0 to 9.7 kg (p < 0.001 for weight and BMI reduction across the study period). One patient discontinued treatment due to nausea/vomiting, two patients died of unrelated causes and six patients reported side effects. Approximately 9 months after the treatment started, three patients were able to seriously reconsider being listed for transplantation. Semaglutide treatment resulted in significant reduction in weight and BMI in patients with obesity undergoing dialysis, while maintaining an acceptable side effect profile comparable to that of the non-dialysis population.

A-066 Does essential fatty acid deficiency alter ethanolamine plasmalogen concentrations in red blood cells? Implications for clinical testing

Abstract Background Plasmalogens are glycerophospholipids characterized by a fatty alcohol at the sn-1 position, a polyunsaturated fatty acid at the sn-2 position, most commonly docosahexaenoic acid (DHA) or arachidonic acid, and a polar head group at the sn-3 position, mainly phosphoethanolamine. Markedly reduced plasmalogens are seen in peroxisome biogenesis defects, including Zellweger spectrum disorders (ZSD), since the first two steps of plasmalogen synthesis occur in peroxisomes. Disruption of the peroxisomal β-oxidation pathway also causes DHA deficiency in ZSD patients. Since plasmalogens are composed of fatty acids, the deficiency of DHA or other essential fatty acids could further decrease the plasmalogen level in ZSD patients and lower the results of plasmalogen testing in patients without ZSD. To test this hypothesis, we evaluated the impact of essential fatty acid (EFA) deficiency on plasmalogens in patients with ZSD and individuals with EFA deficiency due to unrelated causes. Methods Red blood cell (RBC) samples were obtained from individuals without ZSD referred to ARUP laboratories for clinical EFA testing (n = 80; age range: birth - 89 years), and from patients with ZSD (n = 7; age range birth - 9 years). Three ZSD patients were older and with a less severe phenotype. A total of 18 intact ethanolamine plasmalogen species were extracted from packed RBCs and quantified using a XEVO TQ-XS Mass Spectrometer in conjunction with Ultra-High Performance Liquid Chromatography (Waters). Total plasmalogen values were also calculated; plasmalogen deficiency was defined as ≤60% of age-matched control median. Fatty acids (FAs) were quantified by gas chromatography negative chemical ionization-mass spectrometry (GC-NCI-MS). EFA deficiency was diagnosed by increased Triene/Tetraene ratio (Mead acid/Arachidonic acid). Data was analyzed using Prism v.8.3.0 software (La Jolla, CA). The study was approved by the Institutional Review Board of the University of Utah. Results Out of the 80 samples from individuals without ZSD referred for EFA testing, 18% had normal fatty acid profile, 57% were receiving dietary supplements and 25% had elevated Triene/Tetraene ratio suggesting EFA deficiency. EFA deficiency was accompanied by low DHA only in two individuals without ZSD, whereas it was present in most of the samples from ZSD patients evaluated (5/7). None of the individuals without ZSD were deficient in plasmalogens. Moreover, when compared to individuals without ZSD with a normal FA profile, there was no significant difference observed with EFA deficiency or FA supplementation. Although our ZSD cohort is small, no correlation between EFA deficiency and plasmalogen levels was also seen in ZSD: 2 patients with milder phenotype had EFA deficiency but normal plasmalogens, 2 patients had EFA deficiency and low plasmalogens, 2 patients with low plasmalogens had low DHA without EFA deficiency, and 1 patient had low plasmalogens but normal EFA. Conclusions Plasmalogen quantitation in RBCs by LC-MS/MS is not significantly affected by EFA deficiency. Although more data is warranted to elucidate the correlation between plasmalogen levels and ZSD phenotype, plasmalogens can be within normal reference intervals in ZSD regardless of EFA status.

Causes of Musculoskeletal Pain in Paget’s Disease of Bone

Paget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (p<0.019) and in older individuals (p<0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (p = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately.

Location and Extent of Paravascular Nerve Fiber Layer Clefts in Eyes with Epiretinal Membranes.

Purpose: The clinical use of en face optical coherence tomography (OCT) has revealed nerve fiber layer clefts in the retinal nerve fibers in eyes with macula-centered epiretinal membranes (ERMs). The purpose of this study is to describe the location and the extent of retinal nerve fiber layer (RNFL) clefts in eyes with symptomatic ERMs. Methods: We conducted a retrospective review of 17 individual eyes in 17 patients with symptomatic ERMs and a control group of 10 healthy eyes from 10 subjects who had been examined for unrelated causes. The examinations performed included best-corrected visual acuity, rebound tonometry, fundus photography, structural OCT and angiographic OCT (OCTA) made in the form of 12 × 12 mm angiographic volume scans. Results: Hyporeflective RNFL clefts, seen in 14 out of 17 eyes with ERMs, were sharply demarcated in the en face presentation of slabs extending from the internal limiting membrane through the RNFL or including only the latter. The clefts were capillary-free on OCTA scans and formed depressions of the retinal surface. Most of the clefts were adjacent to and followed the course of the retinal trunk vessels, but clefts were also seen along smaller macular vessels and beyond the retinal vascular arcades. Conclusions: Paravascular RNFL clefts can be observed beyond the vascular arcades and adjacent to small vessels on OCTA block scan data. This suggests that the direction and magnitude of tractional displacement of the inner retina in eyes with epimacular membranes can extend beyond the vascular arcades and add to an improved analysis of abnormal fundus findings.

Stratified Mucin-producing Lesions of the Anus

Primary anal cancers are rare and typically driven by high-risk human papillomavirus (HPV) infection. Though squamous cell carcinoma is most common, a spectrum of HPV-related nonsquamous anogenital neoplasms with similarities to cervical stratified mucin-producing carcinoma has been reported. In this study, we mined our institutional archives to characterize the clinicopathologic features of this emerging entity. Six cases were identified from the files at 2 institutions, including 4 cases of invasive stratified mucin-producing carcinoma and 2 stratified mucin-producing intraepithelial lesions (SMILE). Four patients were women, and the mean age was 70 years. Patients presented with rectal/anal mass or polyp, rectal bleeding or pain, weight loss, or at the time of screening colonoscopy. Tumors displayed histologic features as described in the gynecologic tract. Cases of invasive stratified mucinous carcinoma showed infiltrative tumor nests with variable intracytoplasmic mucin, peripheral palisading, prominent apoptosis, and neutrophilic infiltrate. One invasive stratified mucinous carcinoma associated with high grade glandular dysplasia, whereas 1 SMILE was next to conventional low-grade squamous intraepithelial lesion. All lesions stained with p16 showed block-like p16 expression. HPV in situ hybridization was performed in 5 cases, 4 of which were positive; one was interpreted as equivocal. Follow-up information, available in 4 patients, revealed 1 local recurrence followed by death due to unrelated causes in a patient with invasive stratified mucin-producing carcinoma. We report the first series of HPV-associated primary anal stratified mucin-producing neoplasms analogous to those seen in the gynecologic tract, further broadening the spectrum of HPV-related anal neoplasia.

Quality of Care and Quality of Life: Balancing Patient Safety and Physician Burnout.

Since the publication of the Institute of Medicine's landmark report on medical errors in 2000, a large number of safety programs have been implemented in American hospitals. Concurrently, there has been a dramatic increase in the rate of burnout among physicians. Although there are many unrelated causes of burnout (eg, loss of autonomy), and multiple safety programs that are applauded by physicians (eg, The Safe Motherhood Initiative), other programs created in the name of safety improvements may be contributing to physician distress. In this piece, we review several of those programs, describe their limitations and costs to physician well-being, and discuss the manner in which they might be modified to retain their benefits while mitigating the burdens they place on physicians.

Cemented Calcar-Guided Short-Stem Prostheses in Geriatric Patients: Short-Term Results from a Prospective Observational Study.

Both cementless and cemented stems have exhibited favorable long-term outcomes in total hip arthroplasty. Nonetheless, in elderly patients, cemented hips offer an advantage due to their reduced risk of periprosthetic fractures. This study aimed to assess the initial outcomes of 28 patients who underwent unilateral cemented total hip arthroplasty utilizing a calcar-guided A2 stem (ARTIQO GmbH, Lüdinghausen, Germany). Various types of antibiotic-loaded bone cement were employed. During follow-up, we recorded demographic data and comorbidities and employed standardized clinical assessment tools, including the Harris Hip Score. Radiographic assessments included preoperative, postoperative, and follow-up imaging to evaluate subsidence, osteolysis, and bone resorption. The results indicated that among the 28 patients, 5 withdrew consent and 2 patients passed away from unrelated causes. Additionally, one prosthesis was explanted due to the undersizing of the cement stopper, which resulted in an inadequate cement mantle. As a result, 20 patients underwent a 1-year follow-up, revealing noteworthy enhancements in clinical scores, with no instances of radiolucent lines or osteolysis. No infections were detected. In summary, our short-term experience with this particular cemented short-stem design yielded promising results, exhibiting excellent functional outcomes, no aseptic loosening attributable to the stem, and no infections. Further clinical studies and registry data are essential to corroborate these findings.

Candida auris cluster in a center with no previous infections associated with a single organ donor

Background: Candida auris is an opportunistic pathogen reported in the US since 2016. C. auris infections (CAI) are frequently healthcare-associated, but only one case of donor-derived CAI in a lung transplant recipient has been reported (PMID 28520901). We describe a cluster of two CAIs at a single center in South Carolina occurring in 2 different recipients from the same solid organ transplant donor. Methods: We describe two cases of invasive CAIs occurring in an academic medical center without prior CAI in Charleston, SC in October 2023. C. auris was identified using Bruker MALDI-TOF and confirmed by the state health department. Results: Patient 1: 40-49 year-old male underwent heart transplantation on day 19 from admission complicated by growth of C. auris on post-op day #15 from a drain. He was readmitted post-op days 22-63 with positive blood cultures for C. auris and underwent re-operation with debridement and hardware removal. C. auris pericarditis required multiple returns to the OR (Figure). He was discharged on micafungin/posaconazole with plans for long-term antifungal therapy. Patient 2: 50-59 year-old male underwent liver and kidney transplantation on day 25 from admission from the same donor as Patient 1 in a separate hospital complex. His course was complicated by possible infected biloma not amendable to drainage and C. auris/C. glabrata fungemia, which was further complicated by abdominal wall collection cultures growing C. auris on post-operative day 35 on washout. He was managed with dual micafungin/posaconazole however, he died of unrelated causes at 93 days after transplant (Figure). Investigation: The donor for both recipients was a 10-19 year-old male who suffered brain death after trauma and was hospitalized for 56 days prior to procurement in Atlanta, GA without known CAI. Airway cultures at the time of organ procurement were positive for rare Pseudomonas and light unidentified yeast of multiple morphologies; urine cultures also grew 40,000 cfu/ml un-identified yeast. Screening of 35 and 4 inpatients in units exposed to patients 1 &amp; 2, respectively, with axilla/groin PCR was negative (Figure). A third organ recipient for this donor (kidney) at our center was identified and had negative urine fungus cultures. Conclusions: Despite no definitive link to a known donor infection, this cluster of CAI occurring simultaneously in 2 patients in separate hospitals/units at a single center with no known prior cases represents likely donor-derived CAI. Our experience suggests that organ procurement organizations should consider improved screening techniques for C. auris in donor cultures.Disclosure: Scott Curry: Consultant- Ferring; Abbott Diagnostics- Speaker honorarium

Surgical management of squamous cell carcinoma of the canine male external genitalia: 15 cases (1994-2020)

Fifteen male dogs with squamous cell carcinoma of the external genitalia were admitted for further investigation and surgical management between 1994 and 2020. The dogs belonged to various breeds. Thirteen dogs were intact and two were castrated with a median age of 8 years and a median weight of 28 kg. Seven dogs were white-coated and eight nonwhite coated. Scrotal ablation and orchiectomy were performed in four dogs, partial penile amputation in two, partial penile amputation plus partial preputial ablation in one, penile amputation, and scrotal urethrostomy in seven, and local preputial excision in one dog. Postoperative complications included hemorrhage in 10 dogs, bruising at the urethrostomy site in seven, and urethrostomy dehiscence in one dog. Tumor recurrence was recorded in six dogs. Dogs with poorly differentiated tumors that had tumor recurrence had shorter survival and worse prognosis compared to those with well and moderately differentiated tumors. The mean survival time was 48.132 months. After a median follow-up of 23 months (range: 8 to 72 months), eight dogs were alive, five were euthanized and two dogs died from unrelated causes. Surgical excision seems to be a treatment option for dogs with squamous cell carcinoma of the external genitalia.

A Case Series and Literature Review of Alveolar Echinococcosis in Kashmir, India: An Emerging Endemic Zone for Echinococcus multilocularis.

A prospective study on 110 patients with echinococcosis at Dr. Khuroo's Medical Clinic, Srinagar, Kashmir, India, from March 2019 to April 2024 identified 12 cases (4 males, 8 females; mean age of 46.58 ± 11.97 years) of Alveolar echinococcosis (AE). Two patients were detected through ultrasound examinations carried out for unrelated causes; one presented with features of liver abscess, and nine had pain in the right upper quadrant for a mean period of 2.2 ± 1.79 years. All had the liver as the primary organ involved, with 15 tumor masses of a mean maximum diameter of 9.22 ± 3.21 cm and volume of 426 ± 374.61 cm3. Tumors placed centrally had invaded vessels and the biliary tract in eight patients, and those placed peripherally had invaded the liver capsule and adjacent organs in nine patients. Histologic examination of liver biopsies or resected organs revealed necrotic lesions, calcifications, and granulomatous inflammation with slender, thin-walled vesicles of bizarre configuration that stained strongly eosinophilic with periodic acid Schiff. Two patients had segmental liver resections; one was treated with liver aspiration, while the other nine with advanced disease received chemotherapy with albendazole along with praziquantel. Patients showed clinical improvement on a median follow-up of 12 months (range 1 to 60 months); however, MRI T2-weighted images and 18F-FDG-PET-CECT scans in two patients showed active disease on follow-up at one and five years, respectively. A systematic review detected 146 cases of AE in India from 1980 to April 2024. Twenty cases were from foreign countries, mostly from Central Asian republics, and 118 (93.65%) of the remaining 126 Indian patients were permanent residents of Kashmir Valley. The disease affected a population of 79,197 residing in 22 villages from 5 border districts of the valley. These villages were either high in or adjacent to the Himalayan mountain range. Disease prevalence in the affected population was 146.47/105 (males 131.53/105 and females 163.18/105) and the incidence was 12.41/105/year (males 11.16/105/year and females 13.81/105/year). Possible causes of the emergence of AE are discussed, and future directions for research to face this challenge arebeen identified.

Tangled: Unraveling a Rare Combination of Multiple Coronary Artery Fistulas and Severe Aortic Stenosis in a 70-Year-Old Man

INTRODUCTION: Coronary artery fistulas (CAFs) are rare congenital or acquired anomalies that connect one or more coronary arteries to a cardiac chamber or a great vessel without an intervening capillary bed. Most are asymptomatic and are usually incidental findings on echocardiography or angiography for an unrelated cause. Occasionally, complications occur, which include endocarditis, thrombosis, steal syndrome, and heart failure.Here, we present a rare case of multiple CAFs draining to the main pulmonary artery in a patient with severe aortic stenosis (AS) presenting a unique management dilemma. CASE PRESENTATION: Five weeks before admission, a 70-year-old man with good baseline functional capacity, independent on all activities of daily living, developed exertional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea. His symptoms persisted for a week prompting consult at another institution where he was managed as a case of acute heart failure and given diuretics, which resolved his symptoms. His two-dimensional (2D) echocardiogram showed eccentric left ventricular hypertrophy with adequate segmental and global wall motion and contractility, a left ventricular ejection fraction of 62% by the Simpson method, normal right ventricular diameter with adequate wall motion and contractility, dilated left atrial dimensions with a left atrial volume index of 50.98 mL/m2, moderate mitral regurgitation, normal right atrial diameter, thickened mitral valve leaflets without restriction of motion, thickened and calcified aortic valve, severe AS (aortic valve area of 0.37 cm2, mean gradient of 78.77 mm Hg, and peak gradient of 124.88 mm Hg), severe aortic regurgitation, mild tricuspid and pulmonic regurgitation, and normal pulmonary artery pressure (13 mm Hg by tricuspid regurgitant jet).

Surgical Therapy of Infective Prosthesis Endocarditis following TAVI: A Single Center's Experience.

Infective prosthesis endocarditis (IE) following transcatheter aortic valve implantation (TAVI) presents significant management challenges, marked by high mortality rates. This study reviews our center's experience with surgical interventions for IE in patients post-TAVI, focusing on outcomes, challenges, and procedural complexities, and providing an overview of the limited literature surrounding this subject. This study was executed as a comprehensive retrospective analysis, targeting the clinical outcomes of surgical treatment in patients presenting with PVE following TAVI procedures at our institution. From July 2017 to July 2022, we identified five patients who had previously undergone transfemoral transcatheter aortic valve implantation and were later diagnosed with PVE needing surgery, strictly adhering to the modified Duke criteria. All surgical procedures were reported successful with no intra- or postoperative mortality. Patients were predominantly male (80%), with an average age of 76 ± 8.6 years, presenting mostly with dyspnea (NYHA Class II). The mean follow-up was between 121 and 1973 days, with outcomes showing no occurrences of stroke, myocardial infarction, or major bleeding. One patient expired from unrelated causes 3.7 years post-surgery. The operative and postoperative protocols demonstrated effective disease management with enhanced survival and minimal complications. The surgical treatment of IE following TAVI, though challenging, can be successfully achieved with careful patient selection and a multidisciplinary approach. The favorable outcomes suggest that surgical intervention remains a viable option for managing this high-risk patient group. Our study also highlights the scarce literature available on this topic, suggesting an urgent need for more comprehensive research to enhance understanding and improve treatment strategies. Future studies with larger cohorts are needed to further validate these findings and refine surgical strategies for this growing patient population.

Durability of immune checkpoint inhibitor (ICI) response following treatment discontinuation in advanced merkel cell carcinoma (MCC).

9596 Background: Advanced MCC has a high response rate to ICI therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced MCC patients at our institution who discontinued ICI treatment after achieving favorable initial response. Methods: In an IRB-approved single institution retrospective review of advanced MCC patients, we analyzed all patients who received at least one dose of anti-PD(L)1 monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. Duration of response and outcomes of subsequent therapy were assessed. Results: Of 195 advanced MCC patients treated with ICI, we identified 45 who met study criteria. Of these, 21 (47%) had a complete response (CR) to initial ICI treatment, 23 (51%) a partial response (PR) and 1 (2%) SD. Twenty-five (56%) patients discontinued ICI electively and 20 (44%) discontinued due to toxicity. In total, 21 of the 45 patients (47%) experienced disease progression at a median of 11.2 months (range 2.1-22.7 months) from ICI cessation. The median follow-up after ICI discontinuation for patients who have not experienced progression is 22.8 months (5.8-82.0 months). There was a lower rate of progression in patients who achieved CR vs. non-CR (24% vs 67%, p=0.006) and a trend towards a lower rate in those who discontinued electively vs. due to toxicity (36% vs 60%, p=0.14). For patients in whom the molecular subtype was known, there was a higher risk for progression in patients with viral MCC (12 of 16, 75%) compared to UV-associated MCC (4 of 13, 31%, p=0.02). Fifteen of the 21 patients (71%) who experienced progression were rechallenged with ICI therapy, including both single agent (12 patients, 57%) and combination (3, 14%) therapy. The remaining patients received locally-directed therapy only (3, 14%), chemotherapy (1, 5%), declined further treatment (1, 5%), or transferred care and were lost to follow up (1, 5%). Eleven of 15 ICI-retreated patients (73%) achieved an objective response to rechallenge, including all 3 patients who received combination therapy with ipilimumab+nivolumab. Twelve of the 45 patients have expired; 6 due to progressive MCC and remaining 6 known or suspected from unrelated causes. Conclusions: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICI response, 47% in our series with a median time to event of 11.2 months, particularly in those that achieve less than a complete response. In the setting of disease progression post-ICI discontinuation, most patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.

Long-term prognosis and DNA damage status after oral mucosal epithelial cell sheet transplantation following esophageal endoscopic submucosal dissection for squamous cell carcinoma: A case series

Autologous oral mucosal epithelial cell sheet (AOMECS) transplantation has recently been applied in human patients to prevent postprocedural stenosis following endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma. However, the long-term safety of AOMECS transplantation remains unclear. We evaluated the long-term outcomes of 10 patients who participated in a clinical trial of AOMECS transplantation after esophageal ESD. Additionally, we assessed the local DNA damage response in the esophageal epithelium using p53 binding protein 1 (53BP1) immunofluorescence in post-AOMECS biopsy specimens. The median follow-up period was 118.5 months (range: 46–130 months). Two patients developed primary esophageal cancer near the AOMECS site and successfully underwent additional ESD. One patient developed lymph node metastasis and underwent chemotherapy. None of the patients died from the original disease, although one patient died from unrelated causes. The rate of abnormal 53BP1 nuclear foci, indicative of increased genome instability, increased with the progression of neoplasia in patients post AOMECS. Our case series suggests that AOMECS transplantation provides an acceptable long-term prognosis and 53BP1 foci may serve as a useful marker for assessing DNA instability in the post-AOMECS esophageal epithelium.

A phase Ib, open-label study of add-on therapy with CK0804 in participants with myelofibrosis and suboptimal response to ruxolitinib.

6580 Background: Suboptimal response to JAK2 inhibitor ruxolitinib in patients with myelofibrosis (MF) remains a major unmet medical need. Deregulated inflammatory pathways including CXCR4/CXCR12 axis might limit the therapeutic efficacy of ruxolitinib and contribute to disease progression. In preclinical studies, cord blood-derived, CXCR4 enriched T regulatory cells [CK0804; T-regs] showed ability to suppress inflammatory cytokines playing major role in MF (Huang et al., Cytotherapy, 2023). Methods: This phase Ib study evaluates the safety and activity of up to 6 doses of CK0804 (non-HLA matched, Cryopreserved) T-regs therapy, fixed dose of 100 million cells, added every 28 days to ruxolitinib. Patients with MF on ruxolitinib for ≥12 weeks and stable dose for ≥8 weeks, who have palpable splenomegaly, symptoms, or grade 2 cytopenia are eligible. Primary objective is safety, secondary objective is overall response per IWG-MRT criteria at 24 weeks. Present analysis includes cohort of initial run-in safety phase. Results: Nine patients of median age 68 years (range, 55-84) were enrolled, 44% were males. Median blood counts [range] showed while blood cells 10.6 [3.1-70.4] x10^9/L, hemoglobin 8.8 [7.8-11.5] g/dL, platelets 177 [148-311] x10^9/L. Three patients were transfusion dependent. Median spleen volume was 1449 cubic centimeters (176-5609), 7 patients (78%) had clinically worsening splenomegaly. Median symptoms score (MPN-SAF TSS) was 23 (20-40). Six (67%) had diploid karyotype, 5 (56%) had JAK2 mutation and 8 (89%) had additional no-driver mutations. Median duration of prior ruxolitinib was 35 months (range, 10-132), all patients were on ≥ 10 mg twice daily dose with no dose change throughout the study. Four patients received all six doses of CK0804, three patients have ongoing treatments. One patient experienced infusion reaction to second dose of CK0804 likely due to the excipient dimethylsulfoxide and withdrew consent. One patient died of unrelated cause prior to the infusion 6. There were no nonhematologic or hematologic adverse events. Two transfusion dependent patients who were evaluable for response had decreased monthly need for transfusions by the end of the sixth cycle: 4 to 2.8 units and 1.2 to 0.8 units, respectively. All patients noticed symptoms improvement; median best decline in MPN-SAF TSS was -38% (range, -20% to -71%); with ≥ 50% reduction in 3 patients. One patient achieved ≥ 35% spleen volume reduction at week 12. Longitudinal analysis of markers of inflammation is in progress and will be presented at the conference. Conclusions: This preliminary analysis of run-in phase of study evaluating CXCR4 enriched T regs cell therapy as addition to ruxolitinib shows initial safety with no myelosuppressive adverse events and promising clinical activity. Active enrollment of participants to the expansion cohort is ongoing. Clinical trial information: NCT05423691 .

The significance of BAP1 and MTAP/CDKN2A expression in well-differentiated papillary mesothelial tumour: a series of 21 cases and a review of the literature

The nomenclature and diagnostic criteria of well-differentiated papillary mesothelial tumour (WDPMT) have been changed in the 2021 World Health Organization (WHO) classification of thoracic tumours, and a new entity, mesothelioma in situ (MIS), introduced. Histologically these two entities may be similar. However, MIS is regarded as a precursor to invasive mesothelioma and requires demonstration of loss of BAP1 and/or MTAP/CDKN2A for diagnosis, whereas performance of these ancillary tests is desirable but not essential for a diagnosis of WDPMT, in which the significance of BAP1 and/or MTAP/CDKN2A loss is not well understood or well defined. Against this backdrop, we undertook an investigation of 21 cases of WDPMT, identified from our case files and diagnosed according to 2021 WHO criteria, to explore the relationship between histology and BAP1 and MTAP/CDKN2A expression with clinical features including asbestos exposure, focality of tumours and clinical outcome. There were 18 women and three men, with ages ranging from 23-77 years (median 62 years), in which six had a history of asbestos exposure, two had no exposure, and in 13 exposure history was unavailable. Of 20 peritoneal tumours and one pleural tumour, 13 were detected incidentally at the time of surgery for unrelated conditions and eight peritoneal tumours were multifocal at the time of diagnosis. BAP1 immunohistochemistry (IHC) was performed in all 21 tumours, with nine tumours showing BAP1 expression loss. MTAP/CDKN2A testing was performed in 14 tumours, comprising MTAP IHC in 12 and CDKN2A fluorescence in situ hybridisation (FISH) in two, with three tumours showing MTAP/CDKN2A expression loss. Two tumours with MTAP/CDKN2A loss also showed BAP1 expression loss. Four patients progressed to invasive mesothelioma, including one male with a pleural tumour and asbestos exposure, and three females with multifocal peritoneal tumours, two with asbestos exposure and one without exposure. BAP1 expression loss was seen in all tumours from the four patients who progressed to invasive mesothelioma, whilst two of these tumours showed retained MTAP IHC and two were not tested. There was one patient with a tumour with MTAP loss and retained BAP1 who died from unrelated causes 5 months after diagnosis. Eight patients received WDPMT-specific treatment in addition to the initial excision. Survival for all patients ranged from 4-218 months, with one patient dying of mesothelioma at 49 months. Based on our results in this series of 21 patients with WDPMT diagnosed according to 2021 WHO criteria, we propose that WDPMT with BAP1 expression loss may best be regarded as papillary MIS and that a history of asbestos exposure and the presence of multifocal tumours in patients diagnosed with WDPMT should prompt ancillary testing with BAP1 IHC. Further we propose that BAP1 IHC should be essential in the diagnosis of WDPMT, with the diagnosis restricted to those tumours which show retained BAP1 expression. However more studies in larger cohorts of patients are needed to explore the relationship between BAP1 expression and MTAP loss in WDPMT, which will help to define this entity and separate it more clearly from MIS and invasive mesothelioma.

STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause. Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.