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To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies., Competing Interests: Declaration of interests F.W. reports receiving research grants from Boehringer, Genentech, Roche, and Divide and Conquer Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diffuse gliomas, particularly glioblastomas, are incurable brain tumours 1 . They are characterized by networks of interconnected brain tumour cells that communicate via Ca 2+ transients 2-6 . However, the networks' architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca 2+ oscillations and are particularly connected to others. Their autonomous periodic Ca 2+ transients preceded Ca 2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca 2+ activity generates a vulnerability 7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Brain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions., Methods: To investigate the temporospatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice., Results: In vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced the growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation-permanent intravascular arrest, extravasation, and initial perivascular growth-are most vulnerable to dual PI3K/mTOR inhibition., Conclusion: These findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Passage of the United States Medical Licensing Exam (USMLE) is required to obtain a medical license in the United States. Currently the majority of US medical schools require passage of USMLE Step 1 for either promotion to the third year or graduation from medical school. Virginia Commonwealth University School of Medicine (VCUSOM) requires that students take the USMLE but does not require passing of USMLE Step 1 for promotion or graduation. This policy enabled the authors to analyze performance outcomes during clinical rotations and monitor the residency match for a group of students who failed USMLE Step 1 on the first attempt., Methods: Third year clerkship grades and residency match results were reviewed for 64 students of the graduating classes of 1999-2005 who failed Step 1 on the first attempt. An equal number of students who passed Step 1 were randomly selected from each class as a comparison group. Average clinical performance ratings, NBME subject exam scores and final third year clerkship grades for the two groups were compared. Residency match rates and specialty certification were also compared., Results: The USMLE Fail Group had more Pass and fewer Honors clerkship grades than the comparison group. Subject exam scores were significantly lower in the USMLE Fail Group in all clerkships. Clinical performance ratings were significantly lower in the Fail group in three out of six clerkships: Internal Medicine, Pediatrics, and Psychiatry. However, 82% of the USMLE Fail Group later passed USMLE Step 1 and 2. Fifty-nine of the 64 students in the USMLE Fail Group matched for a residency, whereas all of the students in the Pass Group matched for a residency., Conclusion: Students who fail USMLE Step 1 have lower final clerkship grades due in part to lower NBME subject exam scores. The majority of these students, however, successfully pass USMLE Step 1 prior to graduation, go on to graduate medical training, and become board certified in their specialty.

The Arabidopsis aberrant testa shape (ats) mutant produces a single integument instead of the two integuments seen in wild-type ovules. Cellular anatomy and patterns of marker gene expression indicate that the single integument results from congenital fusion of the two integuments of the wild type. Isolation of the ATS locus showed it to encode a member of the KANADI (KAN) family of putative transcription factors, previously referred to as KAN4. ATS was expressed at the border between the two integuments at the time of their initiation, with expression later confined to the abaxial layer of the inner integument. In an inner no outer (ino) mutant background, where an outer integument does not form, the ats mutation led to amorphous inner integument growth. The kan1kan2 double mutant exhibits a similar amorphous growth of the outer integument without affecting inner integument growth. We hypothesize that ATS and KAN1/KAN2 play similar roles in the specification of polarity in the inner and outer integuments, respectively, that parallel the known roles of KAN proteins in promoting abaxial identity during leaf development. INO and other members of the YABBY gene family have been hypothesized to have similar parallel roles in outer integument and leaf development. Together, these two hypotheses lead us to propose a model for normal integument growth that also explains the described mutant phenotypes.

Coordinated spacing and patterning of stomata allow efficient gas exchange between plants and the atmosphere. Here we report that three ERECTA (ER)-family leucine-rich repeat-receptor-like kinases (LRR-RLKs) together control stomatal patterning, with specific family members regulating the specification of stomatal stem cell fate and the differentiation of guard cells. Loss-of-function mutations in all three ER-family genes cause stomatal clustering. Genetic interactions with a known stomatal patterning mutant too many mouths (tmm) revealed stoichiometric epistasis and combination-specific neomorphism. Our findings suggest that the negative regulation of ER-family RLKs by TMM, which is an LRR receptor-like protein, is critical for proper stomatal differentiation.

Morphological transitions associated with ovule diversification provide unique opportunities for studies of developmental evolution. Here, we investigate the underlying mechanisms of one such transition, reduction in integument number, which has occurred several times among diverse angiosperms. In particular, reduction in integument number occurred early in the history of the asterids, a large clade comprising approximately one-third of all flowering plants. Unlike the vast majority of other eudicots, nearly all asterids have a single integument, with the only exceptions in the Ericales, a sister group to the other asterids. Impatiens, a genus of the Ericales, includes species with one integument, two integuments, or an apparently intermediate bifid integument. A comparison of the development of representative Impatiens species and analysis of the expression patterns of putative orthologs of the Arabidopsis thaliana ovule development gene INNER NO OUTER (INO) has enabled us to propose a mechanism responsible for morphological transitions between integument types in this group. We attribute transitions between each of the three integument morphologies to congenital fusion via a combination of variation in the location of subdermal growth beneath primordia and the merging of primordia. Evidence of multiple transitions in integument morphology among Impatiens species suggests that control of underlying developmental programs is relatively plastic and that changes in a small number of genes may have been responsible for the transitions. Our expression data also indicate that the role of INO in the outgrowth and abaxial-adaxial polarity of the outer integument has been conserved between two divergent angiosperms, the rosid Arabidopsis and the asterid Impatiens.

Purpose: To assess students' perceptions of the extent of diversity in their classes, the role of diversity in their first-year curriculum, and their predictions of the amount of diversity in their future patient populations., Method: In 1998, students at four southeastern U.S. medical schools that had distinct demographics and differing institutional missions completed a questionnaire on diversity at the end of the first year. In the instrument, diversity was defined according to nine population characteristics: age, sex, race, ethnic background, physical disability, religious affiliation, sexual orientation, socioeconomic status, and rural background (growing up in a community of less than 5,000). Responses were compared according to students' institution, sex, and race., Results: Questionnaires were returned by 349 of 474 students (74%). Students at the school with the most diverse first-year class placed the greatest value on the contributions of diversity to the learning environment. Women students placed more value on the inclusion of diversity issues in the curriculum than did men students, and they placed greater value on understanding diversity issues in their future medical practices than did men. Compared with Asian American, Hispanic, and white students, African American students were the least likely to think that the curriculum contained adequate information about diversity., Conclusions: The results indicate that perceptions of diversity were influenced by the students' own demographic characteristics and those of their medical school. The more diverse the class, the more comfortable the students were with diversity and the more they valued its contribution to their medical education.

Two cases of adult Hirschsprung's disease are reported along with a review of 47 cases reported in the literature. Chronic constipation is present in almost all cases. The barium enema examination may suggest the diagnosis if an area of smooth narrowing with proximal dilatation is seen (83%), but biopsy proof of absence of ganglion cells is necessary. Fourteen per cent of patients had a dilated colon without a narrowed segment. Anal manometry is helpful if it demonstrates absence of normal anorectal inhibitory reflex. Total colonic aganglionosis in the adult has been reported, but is exceptionally unusual. The diagnosis of adult Hirschsprung's disease should be suspected in patients with a history of chronic constipation and appropriate radiographic findings.

Intramural gastric diverticula are true diverticula, entirely contained within the wall of the stomach without deformity of the serosa. All of the 13 known reported cases are at the greater curvature of the distal antrum. This is true of our three cases as well. The unique location and characteristic change in shape with peristalsis distinguish them from pathological entities.

The interested radiologist can be a valuable consultant in the investigation of fatal gunshot wounds as well as in the identification of human remains.

A 39-yr-old woman was treated with Garren-Edwards gastric bubble, a new nonsurgical device for the treatment of obesity. The patient did well for 31/2 months before presenting with a partial small bowel obstruction caused by a spontaneously deflated bubble. After several days of observation and therapeutic maneuvers, a partially deflated bubble was removed surgically. Although the patient had had previous abdominal surgery, she had no adhesions that were considered contributory to the obstructive process at surgery; the deflated bubble did not deflate enough to traverse the distal ileum. This case represents the first case of bowel obstruction by this device in a patient with a "normal" intestinal tract. Patients considering placement of a Garren-Edwards gastric bubble must be fully informed of this potential complication even when there has been no prior abdominal surgery.

We have observed 16 cases of stomal stenosis occurring late after gastric surgery for morbid obesity. In one patient no stoma was apparent in the pouch on radiographic or endoscopic examination and reoperation was required for complete obstruction. We dilated stenoses in the remaining 15 patients. Stenosis in the three earliest patients in our series were dilated with Eder-Puestow dilators. All subsequent patients have received endoscopic dilation with pneumatic balloon catheters. Ten patients remain asymptomatic following dilation. Two patients have occasional vomiting, which is ameliorated by metoclopramide hydrochloride, despite a sufficiently patent stoma. Two patients with a torsion of the stoma received no benefit from dilation, and one patient with a sufficiently patent stoma has experienced frequent vomiting. Surgery has been repeated in the latter three patients. The technique of endoscopic pneumatic balloon catheter dilation is a safe and effective means of dilating stomal stenoses occurring late after gastric surgery for morbid obesity.

Undigested vegetable matter may reach the colon intact and be discovered on barium-enema examination. The authors demonstrate several examples of filling defects in the colon caused by vegetable matter. The characteristic shape and corresponding dietary history should allow for an appropriate diagnosis.

Sixty-nine patients with a Greenfield inferior vena cava (IVC) filter in place for 1-9 years were evaluated with supine abdominal radiographs. In 22 patients (32%) the filter span diameter had increased by 3-11 mm, and in six patients (9%) it had decreased by 3-18 mm. Twenty patients (29%) had caudad migration of 3-18 mm, and four (6%) had cephalad migration. In five patients (7%) the filter was at an angle of more than 16 degrees from the vertical. A decrease in filter span of 7 mm or more may result in IVC occlusion, whereas an increase of 6 mm or more may result in caval wall penetration. Caudad migration may be caused by a fibrous reaction around the struts which slowly draws the filter caudally. A change in filter angle may result from displacement of a strut into the right renal vein as well as from physiologic changes. The abdominal radiograph is a valuable method for follow-up study of patients with Greenfield filters if the filter position, span, migration, and angle are noted in the report.

Over an 8-year period, among 41 patients with obstructive jaundice caused by metastases to the liver or lymph nodes adjacent to the porta hepatis, palliative biliary decompression was established surgically in 11, by percutaneous transhepatic biliary drainage (PTBD) in 25, and by both methods in 2. Three patients had no drainage procedure performed. Early mortality after drainage occurred in 6 of 38 patients, and the median survivals (actuarial) for the remaining 32 patients were 4.5 months for the surgical group (range 2 to 21 months) and 4 months for the PTBD group (range 2 to 14 months). Although there were trends toward more frequent hospital readmissions and episodes of cholangitis in the PTBD group, the only statistically significant difference was in the number of catheter manipulations required. We concluded that when patients develop obstructive jaundice as a manifestation of metastatic cancer, useful palliation can be achieved by either surgical or percutaneous decompression.

Percutaneous transhepatic biliary drainage is performed for the relief of biliary obstruction, usually on a malignant basis. The basic pathology and indications for the procedure are discussed, and the technical materials and methods are detailed. The role of the radiologic technologist in performing this procedure is emphasized.

We report an unusual case of diffuse infiltration of the mesentery by amyloidosis. The CT, sonographic, and operative findings mimicked abdominal carcinomatosis.

A taste aversion test was used to evaluate possible toxic effects of magnetic resonance imaging (MRI). Thirty male Sprague-Dawley rats were randomly assigned to four groups: Group One (n = 10) received 30 minutes exposure inside the MRI scanner; Group Two (n = 10) received a sham exposure to the MRI scanner; Group Three (n = 5) was injected with 0.15 M lithium chloride; and Group Four (n = 5) was injected with vehicle. All groups were given 10 minutes access to a 0.1% saccharin solution immediately prior to their respective treatment. The rats treated with lithium chloride displayed a taste aversion to the saccharin solution upon subsequent testing over an eight day period. The two control groups (Two and Four) and the rats exposed to MRI did not display any aversion to the saccharin solution. These results are compared to other studies that have shown that magnetic fields can influence biological systems.

Twenty-two patients who had gastric partition surgery for morbid obesity and subsequently developed stomal dilatation were evaluated with both upper gastrointestinal barium examinations and upper endoscopy. Both examinations were positive in eight patients. Endoscopy alone was positive in 14, but retrospective view of the upper gastrointestinal series was positive in nine of the patients. The authors stress the importance of a dedicated radiologist in performing these difficult examinations and the need for specific measurements of the stomal diameter.

A case of forensic identification utilizing the vascular grooves within the skull is presented. The case is unique in that the antemortem radiographs were from childhood, rendering useless the more standard points of comparison. Calvarial vascular grooves represent unique points of comparison when the only available premortem radiographs were obtained during childhood, especially when one is attempting to identify children (living or dead).

Involvement of the larynx with metastatic disease is a rare occurrence. Batson's plexus was first proposed to explain metastatic disease to the head and neck from distant primaries, but more recent studies suggest that tumor cells in the thoracic duct may spread to the cervical region by way of retrograde flow through afferent cervical lymphatic vessels.

As part of a general medical curriculum renewal, a new one-week course in diagnostic radiology was given to students at the beginning of their third year. The course format consisted of didactic presentations to the entire class, a single afternoon session of small group discussions of unknowns, and three daily case-of-the-day unknowns with prizes for correct responses. One hundred fifty-eight students were tested on the first and last days of the course; testing consisted of two parallel 46-item multiple choice questions given in a crossed design. Questions covered radiographic anatomy and pathology as well as proper test ordering. Differences in achievement before and after the course as measured by the pre- and post-tests were highly significant. The class achieved a mean of 27 (59%) correct responses on the pre-test and a mean of 37 (80%) on the post-test (F(1156) = 15.79; P less than .001). The reliability coefficient of the pre- and post-tests was about .30. A course critique was returned by 88 students. There was anticipated variation in the evaluations of the different didactic lecturers. Instructors receiving the highest scores were cited for their enthusiasm, clarity, and the relevance of their presentation. Conversely, those receiving low marks were cited as being unenthusiastic and boring, merely presenting example after example of radiographic abnormalities with little explanation. The afternoon small group discussions were perceived as the best part of the course. Despite the fact that moderator experience ranged from second year resident to full professor, the seminars received uniformly positive comments.

Cholangiography is a well established method of evaluating the biliary tract, and the typical appearances of the more commonly encountered biliary tract disorders have been well described. There are many pitfalls, however, in the interpretation of cholangiograms that become apparent as large numbers of patients are examined. These pitfalls may be secondary to: congenital anatomic alteration, failure to appreciate normal biliary ductal anatomy, technical errors, and interpretative confusion. Awareness of these pitfalls is emphasized to avoid serious cholangiographic misdiagnosis.