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Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

Abstract Background: VIPoma, also known as Watery Diarrhea-Hypokalemia- achlorhydria (WDHA) Syndrome is a rare manifestation of multiple endocrine neoplasia syndrome type 1 (MEN1). Vasoactive intestinal peptide, part of the secretin-glucagon family, may be overexcreted in tumors associated with MEN1 and results in diarrhea that persists while fasting, resulting in massive secretion of water and electrolytes. First-line treatment is surgical resection. Clinical Case: We present a 13-year-old male with a past medical history of chronic diarrhea for four years who was transferred from an outside hospital for severe diarrhea and associated electrolyte derangements, including hypokalemia of T, pArg527). A pylorus-preserving total pancreatectomy, duodenectomy, cholecystectomy, and splenectomy was performed and surgical pathology revealed a well-differentiated grade 1 neuroendocrine tumor in the head of the pancreas and a well-differentiated grade 2 neuroendocrine tumor in the tail of the pancreas. Since the surgery, the patient currently has no signs of other neuroendocrine tumors associated with MEN1 but continues to follow-up for regular screening for other tumors associated with MEN1. Clinical Lessons: 1. VIPoma, also known as Watery Diarrhea- Hypokalemia- Achlorhydria Syndrome, is characterized by secretory diarrhea that persists while fasting. 2. VIPoma should be considered in patients with a history of chronic diarrhea and a significant family history of neuroendocrine tumors.

IntroductionA step-up endoscopic or percutaneous approach improves outcomes in necrotizing pancreatitis (NP). However, these require multiple radiographic studies and fluoroscopic procedures, which use low-dose ionizing radiation. The cumulative radiation exposure for treatment of NP has not been well defined.MethodsWe conducted a retrospective study of consecutive patients with NP admitted to University of California San Francisco Medical Center from January 2011 to June 2019. We calculated effective doses for fluoroscopic procedures using the dose area product and used the National Cancer Institute tool for computed tomography studies. The primary outcome was the cumulative effective dose (CED). Multivariable logistic regression was used to evaluate risk factors of high exposure (CED > 500 mSv).ResultsOne hundred seventy-one patients with NP (mean follow-up 40 ± 18 months) underwent a median of 7 (interquartile range [IQR] 5-11) computed tomography scans and 7 (IQR 5-12) fluoroscopic procedures. The median CED was 274 mSv (IQR 177-245) and 30% (51) of patients received high exposure. Risk factors of high exposure include multiorgan failure (aOR 3.47, 95%-CI: 1.53-9.88, P = 0.003), infected necrosis (adjusted odds ratio [aOR] 3.89 95%-CI:1.53-9.88, P = 0.005), and step-up endoscopic approach (aOR 1.86, 95%-CI: 1.41-1.84, P = 0.001) when compared with step-up percutaneous approach.DiscussionPatients with NP were exposed to a substantial amount of ionizing radiation (257 mSv) as a part of their treatment, and 30% received more than 500 mSv, which corresponds with a 5% increase in lifetime cancer risk. Severity of NP and a step-up endoscopic approach were associated with CED > 500 mSv. Further studies are needed to help develop low-radiation treatment protocols for NP, particularly in patients receiving endoscopic therapy.

ObjectiveCurrent National Comprehensive Cancer Network guidelines for gastroenteropancreatic neuroendocrine tumors (GEPNETs) recommend complete (R0) surgical resection of the primary tumor and metastases, if feasible. However, large multicenter studies of recurrence patterns of GEPNETs after resection have not been performed.MethodsPatients 18 years or older who presented to 7 participating National Comprehensive Cancer Network institutions between 2004 and 2008 with a new diagnosis of a small bowel, pancreas, or colon/rectum neuroendocrine tumor (NET) and underwent R0 resection of the primary tumor, and synchronous metastases, if present, were included in this analysis. Descriptive statistics and Kaplan-Meier estimates were used to calculate recurrence rates and time-associated end points, respectively.ResultsOf 294 patients with GEPNETs, 50% were male, 88% were White, and 99% had Eastern Cooperative Oncology Group performance status 0 to 1. The median age was 55 years (range, 20-90). The median follow-up time from R0 resection was 62.1 months. Recurrence rates were 18% in small bowel NETs (n = 110), 26% in pancreatic NETs (n = 141), and 10% in colon/rectum NETs (n = 50). The frequency of surveillance imaging was highly variable.ConclusionsR0 resection was associated with variable risk of recurrence across subtypes. Further research to inform refinement of guidelines for the appropriate duration of surveillance after R0 resection is needed.

Abstract Background Autism spectrum disorder (ASD) is a common communication disorder, with an incidence rate of 3%. In most cases, clinicians can diagnose ASD in a single outpatient visit. However, in the case of ASD patients without intellectual disability, clinicians are sometimes unaware for a prolonged period that a patient has ASD. In such cases, delayed diagnosis can lead to serious complications. Case presentation An 18-year-old boy had repeated severe complications of peritoneal dialysis. At the age of 9, the patient presented with proteinuria, and 5 years later, he developed end-stage kidney disease. Percutaneous renal biopsy and the clinical symptoms revealed focal segmental glomerulosclerosis with Charcot-Marie-Tooth disease due to a gene mutation in INF2. Peritoneal dialysis was initiated at the age of 14, but led to many related complications, including peritonitis, hypertensive retinopathy and encephalopathy, and acute heart failure. Initially, we were unaware of his developmental characteristics and autism spectrum disorder without intellectual disability, but through lengthy observations by various healthcare professionals, his unique characteristics were noticed. Because the patient often displayed a discrepancy between behavior and speech, we cautiously studied his thoughts and behaviors, and developed a special approach to ensure safe peritoneal dialysis. Conclusions When many peritoneal dialysis-related complications occur in a patient with normal intelligence quotient, autism spectrum disorder should be considered as a possible cause.

BACKGROUND: Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. MATERIALS AND METHODS: We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/β = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. RESULTS: 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. CONCLUSIONS: These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.

Background: Hepatic cyst disease is often asymptomatic, but treatment is warranted if patients experience symptoms. We describe our management approach to these patients and review the technical nuances of the laparoscopic approach. Methods: Medical records were reviewed for operative management of hepatic cysts from 2012 to 2019 at a single, tertiary academic medical center. Results: Fifty-three patients (39 female) met the inclusion criteria with median age at presentation of 65 years. Fifty cases (94.3%) were performed laparoscopically. Fourteen patients carried diagnosis of polycystic liver disease. Dominant cyst diameter was median 129 mm and located within the right lobe (30), left lobe (17), caudate (2), or was bilobar (4). Pre-operative concern for biliary cystadenoma/cystadenocarcinoma existed for 7 patients. Operative techniques included fenestration (40), fenestration with decapitation (7), decapitation alone (3), and excision (2). Partial hepatectomy was performed in conjunction with fenestration/decapitation for 15 cases: right sided (7), left sided (7), and central (1). One formal left hepatectomy was performed in a polycystic liver disease patient. Final pathology yielded simple cyst (52) and one biliary cystadenoma. Post-operative complications included bile leak (2), perihepatic fluid collection (1), pleural effusion (1), and ascites (1). At median 7.1-month follow-up, complete resolution of symptoms occurred for 34/49 patients (69.4%) who had symptoms preoperatively. Reintervention for cyst recurrence occurred for 5 cases (9.4%). Conclusions: Outcomes for hepatic cyst disease are described with predominantly laparoscopic approach, approach with minimal morbidity, and excellent clinical results.

Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.

Abstract To investigate differences in biomechanical properties focusing on stiffness parameters between normal, treatment-naïve primary open-angle glaucoma (POAG), and treated POAG eyes. Retrospective case–control study, This study included 46 treatment-naïve POAG eyes, 46 POAG eyes treated with prostaglandin analogues, and 49 normal eyes used as controls; matched in terms of age and axial length. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured using an ocular response analyzer (ORA). Fifteen biomechanical parameters were measured with the Corneal Visualization Scheimpflug Technology (Corvis ST), including biomechanical glaucoma factor (BGF) and two stiffness parameters of ‘SP A1’ and ‘stress–strain index (SSI)’, which were compared among the three groups. Additionally, the area under the curve (AUC) values of the receiver-operating curve to discriminate control and treatment-naïve POAG eyes were calculated for BGF and CH. Treatment-naïve POAG eyes had higher ‘SSI’ than normal eyes even after controlling for IOP (p

Abstract Background Small intestinal neuroendocrine tumors (SI-NETs) are the most common neoplasms of the small bowel. The majority of tumors are located in the distal ileum with a high incidence of multiple synchronous primary tumors. Even though up to 50% of SI-NET patients are diagnosed with multifocal disease, the mechanisms underlying multiple synchronous lesions remain elusive. Methods We performed whole genome sequencing of 75 de-identified synchronous primary tumors, 15 metastases, and corresponding normal samples from 13 patients with multifocal ileal NETs to identify recurrent somatic genomic alterations, frequently affected signaling pathways, and shared mutation signatures among multifocal SI-NETs. Additionally, we carried out chromosome mapping of the most recurrent copy-number alterations identified to determine which parental allele had been affected in each tumor and assessed the clonal relationships of the tumors within each patient. Results Absence of shared somatic variation between the synchronous primary tumors within each patient was observed, indicating that these tumors develop independently. Although recurrent copy-number alterations were identified, additional chromosome mapping revealed that tumors from the same patient can gain or lose different parental alleles. In addition to the previously reported CDKN1B loss-of-function mutations, we observed potential loss-of-function gene alterations in TNRC6B, a candidate tumor suppressor gene in a small subset of ileal NETs. Furthermore, we show that multiple metastases in the same patient can originate from either one or several primary tumors. Conclusions Our study demonstrates major genomic diversity among multifocal ileal NETs, highlighting the need to identify and remove all primary tumors, which have the potential to metastasize, and the need for optimized targeted treatments.

Limbal epithelial stem cell deficiency (LSCD) is an abnormal corneal epithelial lesion with several causes. The patient was diagnosed using fluorescein staining. Bullous keratopathy, multiple surgeries, and drug-related damage can cause LSCD in glaucoma patients. We evaluated the medical treatment course for LSCD in patients with glaucoma. We retrospectively reviewed the electronic medical records of patients diagnosed with LSCD and investigated their background, course of treatment, and classification stages of LSCD before and after treatment. The global consensus classification system (stages IA–C, IIA–B, and III) proposed by Deng et al. (Cornea 2020) was used. Seven patients (two males) and eight eyes were studied. The median age of the patients was 82 years, and the mean duration of glaucoma treatment was 8 years. The patients had open-angle glaucoma (four eyes), exfoliation glaucoma (one eye), neovascular glaucoma (one eye), normal tension glaucoma (one eye), and uveitic glaucoma (one eye). Stage classifications at diagnosis were stage IA in four eyes and stages IC, IIA, IIB, and III in one eye each. All treatments were carried out with dry eye drops, steroid eye drops, and antibiotics. The mean duration of treatment was 1.4 years. The classifications at the time of the final visit were normal corneal epithelium (three eyes), stage IA (two eyes), IIA (one eye), and III (two eyes). Three eyes (37%) improved by more than one stage and one eye deteriorated by more than one stage. LSCD is long-lasting and difficult to treat in a short period; thus, it requires careful medical attention.

Lifestyle changes regarding diet composition and exercise training have been widely used as a non-pharmacological clinical strategy in the treatment of obesity, a complex and difficult-to-control disease. Taking the potential of exercise in the browning process and in increasing thermogenesis into account, the aim of this paper was to evaluate the effect of resistance, aerobic, and combination training on markers of browning of white adipose tissue from rats with obesity who were switched to a balanced diet with normal calorie intake. Different types of training groups promote a reduction in the adipose tissue and delta mass compared to the sedentary high-fat diet group (HS). Interestingly, irisin in adipose tissues was higher in the resistance exercise (RE) and aerobic exercise (AE) groups compared to control groups. Moreover, in adipose tissue, the fibroblast growth factor 21 (FGF21), coactivator 1 α (PGC1α), and peroxisome proliferator-activated receptor gamma (PPARγ) were higher in response to resistance training RE compared with the control groups, respectively. Additionally, uncoupling protein 1 (UCP1) showed higher levels in response to group AE compared to the HS group. In conclusion, the browning process in white adipose tissue responds differently toward different training exercise protocols, with resistance and aerobic training efficient in activating different biomarkers of the browning process, upregulating irisin, FGF21, PGC1α, PPARγ, and UCP1 in WAT, which together may suggest an improvement in the thermogenic process in the adipose tissue. Considering the experimental conditions of the present investigation, we suggest future research to pave new avenues to be applied in clinical practices to combat obesity.

PurposePrognostic schemes that rely on clinical variables to predict outcome after resection of colorectal metastases remain imperfect. We hypothesized that molecular markers can improve the accuracy of prognostic schemes.MethodsWe screened the transcriptome of matched colorectal liver metastases (CRCLM) and primary tumors from 42 patients with unresected CRCLM to identify differentially expressed genes. Among the differentially expressed genes identified, we looked for associations between expression and time to disease progression or overall survival. To validate such associations, mRNA levels of the candidate genes were assayed by qRT-PCR from CRCLM in 56 additional patients who underwent hepatectomy.ResultsSeven candidate genes were selected for validation based on their differential expression between metastases and primary tumors and a correlation between expression and surgical outcome: lumican; tissue inhibitor metalloproteinase 1; basic helix-loop-helix domain containing class B2; fibronectin; transmembrane 4 superfamily member 1; mitogen inducible gene 6 (MIG-6); and serpine 2. In the hepatectomy group, only MIG-6 expression was predictive of poor survival after hepatectomy. Quantitative PCR of MIG-6 mRNA was performed on 25 additional hepatectomy patients to determine if MIG-6 expression could substratify patients beyond the clinical risk score. Patients within defined clinical risk score categories were effectively substratified into distinct groups by relative MIG-6 expression.ConclusionsMIG-6 expression is inversely associated with survival after hepatectomy and may be used to improve traditional prognostic schemes that rely on clinicopathologic data such as the Clinical Risk Score.

IntroductionPrognosis after resection of hepatocellular carcinoma (HCC) is highly variable. Compared to clinicopathologic factors, the use of molecular markers to predict outcome has not been well studied. We investigated the prognostic importance of thymidylate synthase (TS) gene expression and polymorphisms in patients after resection of HCC.MethodsPatients who underwent complete resection of HCC for whom tissue was available were identified. TS gene expression level and polymorphisms were determined in HCC specimens. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazard models.ResultsThe study included 67 patients. In univariate analysis, variables that negatively influenced survival included TNM stage, microvascular invasion, and high TS expression. For the high TS expression group, median survival was 54 months and 5-year actuarial survival was 47%. For the low TS expression group, median survival was not reached and the 5-year actuarial survival was 91%. In multivariate analysis, only high TS expression remained an independent predictor of poor survival (HR = 10.77, 95% CI 1.36-84.91; P = 0.02). TS gene polymorphisms were not associated with TS expression or overall survival.ConclusionsHigh TS expression predicts poor outcome after resection of HCC. Molecular markers might be robust predictors of patient outcome after resection of HCC.

Sex-determining region Y-box 2 (SOX2)-positive cells are stem/progenitor cells in the adenohypophysis, comprising the anterior and intermediate lobes (AL and IL, respectively). The cells are located in the marginal cell layer (MCL) facing Rathke’s cleft (primary niche) and the parenchyma of the AL (secondary niche). We previously demonstrated in vitro that the tetraspanin superfamily CD9 and SOX2 double-positive (CD9/SOX2-positive) cells in the IL-side MCL migrate to the AL side and differentiate into hormone-producing and endothelial cells in the AL parenchyma. Here, we performed in vivo studies to evaluate the role of IL-side CD9/SOX2-positive cells in pregnancy, lactation, and treatment with diethylstilbestrol (DES; an estrogen analog) when an increased population of prolactin (PRL) cells was observed in the AL of the rat pituitary. The proportions of CD9/SOX2-, CD9/Ki67-, and PRL/TUNEL-positive cells decreased in the primary and secondary niches during pregnancy and DES treatment. In contrast, the number of CD9/PRL-positive cells increased in the AL-side MCL and AL parenchyma during pregnancy and during DES treatment. The proportion of PRL/Ki67-positive cells increased in the AL-side MCL and AL parenchyma in response to DES treatment. Next, we isolated CD9-positive cells from the IL-side MCL using an anti-CD9 antibody. During cell culture, the cells formed free-floating three-dimensional clusters (pituispheres). Furthermore, CD9-positive cells in the pituisphere differentiated into PRL cells, and their differentiation potential was promoted by DES. These findings suggest that CD9/SOX2-positive cells in the IL-side MCL may act as adult stem cells in the AL parenchyma that supply PRL cells under the influence of estrogen.

Abstract Background Although the survival rates of patients with relapsing polychondritis (RP) have increased remarkably, the high recurrence rate remains a significant concern for physicians and patients. This retrospective study aimed to investigate the risk factors for RP recurrence. Methods Patients with RP who presented to Kyoto University Hospital from January 2000 to March 2020 and fulfilled Damiani’s classification criteria were included. Patients were classified into recurrence and non-recurrence groups. Risk factors for RP recurrence were analysed using a Cox proportional hazards model, and Kaplan–Meier survival curves were drawn. Results Thirty-four patients were included. Twenty-five patients (74%) experienced 64 recurrences (mean: 2.56 recurrences per patient). The median duration before the first recurrence was 202 [55−382] days. The median prednisolone dose at the initial recurrence was 10 [5−12.75] mg/day. Tracheal involvement was significantly more frequent in the recurrence group at the initial presentation (44.0% vs. 0.0%, p=0.0172) than in the non-recurrence group, and pre-treatment C-reactive protein levels were significantly higher in the recurrence group than in the non-recurrence group (4.7 vs 1.15 mg/dL, p=0.0024). The Cox proportional hazards model analysis revealed that tracheal involvement (hazard ratio [HR] 4.266 [1.535−13.838], p=0.0048), pre-treatment C-reactive protein level (HR 1.166 [1.040−1.308], p=0.0085), and initial prednisolone monotherapy (HR 4.443 [1.515−16.267], p=0.0056) may be associated with recurrence. The median time before the initial recurrence was significantly longer in patients who received combination therapy with prednisolone and immunosuppressants or biologics (400 vs. 70 days, p=0.0015). Conclusions Tracheal involvement, pre-treatment C-reactive protein level, and initial prednisolone monotherapy were risk factors for recurrence in patients with RP. Initial combination therapy with prednisolone and immunosuppressants may delay recurrence.

Patients with pancreatic neuroendocrine tumors (PNET) commonly develop advanced disease and require systemic therapy. However, treatment options remain limited, in part, because experimental models that reliably emulate PNET disease are lacking. We therefore developed a patient-derived xenograft model of PNET (PDX-PNET), which we then used to evaluate two mTOR inhibitor drugs: FDA-approved everolimus and the investigational new drug sapanisertib. PDX-PNETs maintained a PNET morphology and PNET-specific gene expression signature with serial passage. PDX-PNETs also harbored mutations in genes previously associated with PNETs (such as MEN1 and PTEN), displayed activation of the mTOR pathway, and could be detected by Gallium-68 DOTATATE PET-CT. Treatment of PDX-PNETs with either everolimus or sapanisertib strongly inhibited growth. As seen in patients, some PDX-PNETs developed resistance to everolimus. However, sapanisertib, a more potent inhibitor of the mTOR pathway, caused tumor shrinkage in most everolimus-resistant tumors. Our PDX-PNET model is the first available, validated PDX model for PNET, and preclinical data from the use of this model suggest that sapanisertib may be an effective new treatment option for patients with PNET or everolimus-resistant PNET.

Abstract Background To evaluate the postoperative outcomes of initial trabeculectomy (Trab) and Ex-PRESS (EX) in terms of achieving an intraocular pressure (IOP) below 15 and 18 mmHg. Methods This study retrospectively analyzed 64 and 54 cases of Trab and EX, respectively, performed by the same surgeon with uniform management from April 2018 to March 2019. Surgical success was defined as 5

Abstract Objectives Weakening of lip‐closing strength (LCS) associated with an incompetent lip seal (ILS) may affect the oral balance between the lip and tongue pressures. The purpose of this study was to evaluate the effects of lip‐closing training in children with lower LCS and/or abnormal habits across different age groups and to compare its effects on increasing LCS in children with malocclusion and/or oral habits. Material and Methods Lip‐closing training was performed by 154 Japanese children aged 3–12 years using a specialized training device at home for 3 months. Children with oral habits and/or exhibiting less than standard LCS were included. LCS was measured using a digital strain force gauge at a dental clinic at the beginning (T0) and after each month (after 3 months: T3). Results Children had higher LCS responses after lip‐closing training. The first month of lip‐closing training was more effective than the subsequent months. With lip‐closing training, the LCS increased from an average of 6.2 N (T0) to 11.4 N (T3) in Group I, 7.9 N (T0) to 12.8 N (T3) in Group II, and 6.8 N to 11.4 N in Group III. Anterior cross bite, including reverse bite, open bite, and tongue thrusting, significantly reduced training effects. Conclusion Our findings showed that lower LCS in children with ILS resulted in greater responses to lip‐closing training in a short period, but oral dysfunction, such as abnormal habits, inhibited the positive effects of training. Our results suggest that less detrimental effects of malocclusion and abnormal oral habits lip‐closing training enhances LCS in younger children.

Pancreatoblastoma is perceived to be aggressive in adults; however, data are limited due to the rarity of the disease. We benchmarked clinico-pathologic characteristics, outcomes, and survival of adult patients with pancreatoblastoma to a comparable PDAC cohort using the National Cancer Database (NCDB). This study included 301,204 patients: 35 with pancreatoblastoma and 301,169 PDAC patients. Pancreatoblastoma patients were younger than PDAC patients (56 vs. 69 years, p < 0.001). More pancreatoblastoma patients were managed at academic institutions (63.0% vs. 40.7%, p = 0.047). The most frequent primary site was the head and the neck of the pancreas. There were no differences in tumor size (4.2 cm vs. 3.7 cm, p = 0.828), lymph node positivity (14.3% vs. 26.4%, p = 0.103), or metastasis at time of diagnosis (31.4% vs. 46.1%, p = 0.081). The majority of pancreatoblastoma patients underwent resection compared to a minority of PDAC patients (69.7% vs. 15.5%, p < 0.001). Time from diagnosis to surgery was longer for pancreatoblastoma patients (33 vs. 14 days, p = 0.030). Pancreaticoduodenectomy was the most common type of resection in the pancreatoblastoma and PDAC groups (47.8% vs. 67.7%, p = 0.124). Among resected patients, pancreatoblastoma patients were less likely to receive radiation (4.8% vs. 37.0%, p = 0.002), but the use of chemotherapy was similar to PDAC patients (60.9% vs. 70.7%). After matching, median overall survival was longer for pancreatoblastoma than PDAC (59.8 months vs. 15.2 months, p = 0.014). [ABSTRACT FROM AUTHOR]

Background/Objectives: This study aimed to examine the postoperative changes in the corneal biomechanical properties between solo cataract surgery and solo microhook ab interno trabeculotomy (LOT). Methods: This retrospective case–control study included 37 eyes belonging to 26 patients who underwent solo cataract surgery and 37 eyes belonging to 31 patients who underwent solo µLOT. These two groups were matched according to their preoperative intraocular pressure (IOP), axial length (AL), and age. Corneal Visualization Scheimpflug Technology (Corvis ST) was used to obtain four biomechanical parameters representing the corneal stiffness or corneal deformation at the highest concavity, including stiffness parameter A1 (SP-A1), stress–strain index (SSI), peak distance (PD), and deflection amplitude max (DefAmpMax). These parameters were compared preoperatively and 6 months postoperatively, and between the two surgical groups. Results: Preoperatively, the patients' IOP, age, and AL, as well as their results in four Corvis ST parameters, were similar between the two groups (p > 0.05). No significant difference was observed in SP-A1; however, PD and DefAmpMax were significantly larger, and SSI was significantly smaller postoperatively in the LOT group than in the cataract group. Conclusions: Corneal stiffness was reduced, and the cornea was more deformed with LOT than cataract surgery. [ABSTRACT FROM AUTHOR]

The functional maturation of the pituitary gland requires adequate cell differentiation and vascular network formation. Although spatiotemporal signaling and transcription factors are known to govern pituitary development, the involvement of primary cilia, nonmoving hair-like organelles, remains unclear. In this study, we uncovered the contribution of primary cilia to cell-type determination and vascular network formation during pituitary development. Homozygous knockout mice lacking a ciliary kinase, Dyrk2 −/−, exhibit abnormalities in ciliary structure and pituitary hypoplasia, accompanied by varying degrees of failure in differentiation among all types of hormone-producing cells in the anterior lobe. Aberrations in cell differentiation in Dyrk2 −/− mice arise from a decrease in the expression of crucial transcription factors, Lhx4 , Lhx3 , and Prop1 , resulting from the inactivity of Hedgehog (Hh) signaling during the early stages of development. Furthermore, the loss of Dyrk2 results in vascular system abnormalities during the middle to late stages of development. Mechanistically, transcriptome analyses revealed the downregulation of vitronectin-integrin αvβ3-VEGFR2 signaling, essential for orchestrating vascular development. Collectively, our findings demonstrate that primary cilia play a pivotal role as critical regulators of cell survival, cell determination, and angiogenesis during pituitary gland development through the activation of Hh signaling. These findings expand our understanding of the potential link between pituitary dysfunction in human disorders and ciliopathies. [ABSTRACT FROM AUTHOR]

Contamination with 2,4,6-trichloroanisole (TCA) often causes taste and odor (T&O) problems in drinking water due to its low odor threshold concentration. Microbial O-methylation of the precursor 2,4,6-trichlorophenol (TCP) would be the dominant mechanism for TCA formation. Simple and rapid measurement of TCP in the low concentration range is necessary to control the problems induced by TCA. In this study, the combination of microbial conversion and instrumental analysis was proposed as a method of TCP quantification. Fungi and bacteria were isolated from various water samples and examined for their ability to produce TCA from TCP. As a result, a strain exhibiting quantitative TCA production and a high growth rate was obtained and named Mycolicibacterium sp. CB14. The conversion rate of TCP to TCA by this strain was found to be high and stable (85.9 ± 5.3%), regardless of the applied TCP concentration, although within the range of 0.1–10 µg/L. The limits of detection and quantification for TCP by this proposed method were determined to be 5.2 ng/L and 17.3 ng/L, respectively. By improving the methods, Mycolicibacterium sp. CB14 could be used for the quantification of TCP at very low concentration levels, which is sufficient to manage the T&O problem caused by TCA.

In this article, we report two patients who experienced the first onset of branch retinal vein occlusion (BRVO) 3 days after the administration of the BNT162b2 (Pfizer–BioNTech) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Case 1: A 50-year-old woman without any history of retinal disease developed vision loss in her right eye 3 days after receiving the first dose of the SARS-CoV-2 mRNA vaccine. Case 2: A 56-year-old woman without any history of retinal disease developed vision loss in her right eye 3 days after receiving the first dose of the SARS-CoV-2 mRNA vaccine. Case 1: Temporal superior BRVO and secondary macular edema (ME) were observed in the patient's right eye. Her best-corrected visual acuity (BCVA) was 20/25. Case 2: Temporal inferior BRVO and secondary ME were observed in the patient's right eye. Her BCVA was 13/20. Case 1: Three doses of intravitreal ranibizumab (IVR) were administered. Case 2: Three doses of IVR were administered. Case 1: ME resolved and BCVA improved to 20/20. Case 2: ME resolved and BCVA improved to 20/20. Both the cases showed a possible association between the SARS-CoV-2 vaccination and the first onset of BRVO.

Tumors rich in stroma are associated with advanced stage and poor prognosis in colorectal adenocarcinoma (CRC). Abundance of stromal cells also has implications for genomic analysis of patient tumors as it may prevent detection of somatic mutations. As part of our efforts to interrogate stroma-cancer cell interactions and to identify actionable therapeutic targets in metastatic CRC, we aimed to determine the proportion of stroma embedded in hepatic CRC metastases by performing computational tumor purity analysis based on whole exome sequencing data (WES). Unlike previous studies focusing on histopathologically prescreened samples, we used an unbiased in-house collection of tumor specimens. WES from CRC liver metastasis samples were utilized to evaluate stromal content and to assess the performance of three in silico tumor purity tools, ABSOLUTE, Sequenza and PureCN. Matching tumor derived organoids were analyzed as a high purity control as they are enriched in cancer cells. Computational purity estimates were compared to those from a histopathological assessment conducted by a board-certified pathologist. According to all computational methods, metastatic specimens had a median tumor purity of 30% whereas the organoids were enriched for cancer cells with a median purity estimate of 94%. In line with this, variant allele frequencies (VAFs) of oncogenes and tumor suppressor genes were undetectable or low in most patient tumors, but higher in matching organoid cultures. Positive correlation was observed between VAFs and in silico tumor purity estimates. Sequenza and PureCN produced concordant results whereas ABSOLUTE yielded lower purity estimates for all samples. Our data shows that unbiased sample selection combined with molecular, computational, and histopathological tumor purity assessment is critical to determine the level of stroma embedded in metastatic colorectal adenocarcinoma.

PurposeTo determine whether multifocal electroretinograms (mfERGs) recorded with natural pupils and skin electrodes can be used to determine the stage of open angle glaucoma (OAG).MethodsTwo hundred eighteen eyes of 132 OAG patients and 62 eyes of 62 normal subjects whose best-corrected visual acuity (BCVA) was 0.1 logarithm of the minimum angle of resolution (logMAR) units (20/25) or less were studied. The mean deviations (MDs) obtained by Humphrey Visual Field Analyzer (HFA), optical coherence tomographic (OCT) images, and mfERGs were analyzed. The glaucoma was classified into 4 stages: preperimetric glaucoma (PPG), early stage, moderate stage, and advanced stage glaucoma. The parameters of the mfERGs examined were the amplitudes of the two positive peaks (P1, P2) of the second order kernels in the nasal and temporal fields within the central 15° diameter.ResultsThe mean age of all participants (patients and normals) was 63.8 ± 10.8 years. With the progression of glaucoma, the amplitudes of P1 in the nasal hemifield increased and the amplitudes of P2 decreased. The nasal to temporal ratio (N/T ratio) of the P1 amplitudes and the negative slope of the line between P1 and P2 (P1P2 Slope) in the nasal field were larger at each glaucoma stage except at the PPG stage. Both the N/T amplitude ratio and P1P2 Slope were weakly but significantly correlated with the MD (r = -0.3139, PConclusionsOur findings indicate that the amplitudes of P1 and P2 of the second order kernel of the mfERGs in the nasal field of the center region can be good markers for the stages of glaucoma.