Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Anatomic distribution of gadolinium contrast medium by high-resolution magnetic resonance imaging after peribulbar and retrobulbar injections.

OBJECTIVE: To examine the anatomic distribution of gadolinium contrast medium by high-resolution surface-coil magnetic resonance imaging after peribulbar and retrobulbar injection. METHODS: Comparative case series in which 4 healthy volunteers were randomized to peribulbar (n = 2) or retrobulbar (n = 2) injection of gadolinium and lidocaine hydrochloride, 2%, without epinephrine. Magnetic resonance imaging was performed before injection and at 5 minutes and 90 minutes after injection. RESULTS: The peribulbar injection technique resulted in contrast medium primarily in the extraconal space, with no gadolinium observed at the orbital apex; surprisingly, a small amount of contrast medium was observed in the pterygopalatine fossa immediately after peribulbar injection. The retrobulbar injection technique resulted in gadolinium signal diffusely enhancing the intraconal space, orbital apex, optic nerve sheath, and optic canal. The signal intensity was clearly observed in the cavernous sinus surrounding the cavernous portion of the internal carotid artery. A small amount of contrast medium was detected in the pterygopalatine fossa. CONCLUSIONS: The retrobulbar injection technique localizes to the intraconal space, with access to intracranial and central nervous system structures via the optic canal, superior orbital fissure, and cavernous sinus. In contrast, the peribulbar injection technique produces a mostly extraconal distribution; however, intraconal solution may communicate with the central nervous system via the inferior orbital fissure and pterygopalatine fossa. This novel finding suggests that peribulbar anesthesia has a readily accessible route for central nervous system toxic effects. Magnetic resonance imaging with gadolinium contrast medium administration provides an important methodological advantage over previously described techniques and is a safe, reproducible, and superior method of orbital imaging.

Hilbert series, Howe duality, and branching rules.

Let lambda be a partition, with l parts, and let F(lambda) be the irreducible finite dimensional representation of GL(m) associated to lambda when l < or = m. The Littlewood Restriction Rule describes how F(lambda) decomposes when restricted to the orthogonal group O(m) or to the symplectic group Sp(m2) under the condition that l < or = m2. In this paper, this result is extended to all partitions lambda. Our method combines resolutions of unitary highest weight modules by generalized Verma modules with reciprocity laws from the theory of dual pairs in classical invariant theory. Corollaries include determination of the Gelfand-Kirillov dimension of any unitary highest weight representation occurring in a dual pair setting, and the determination of their Hilbert series (as a graded module for p(-)). Let L be a unitary highest weight representation of sp(n, R), so*(2n), or u(p, q). When the highest weight of L plus rho satisfies a partial dominance condition called quasi-dominance, we associate to L a reductive Lie algebra g(L) and a graded finite dimensional representation B(L) of g(L). The representation B(L) will have a Hilbert series P(q) that is a polynomial in q with positive integer coefficients. Let delta(L) = delta be the Gelfand-Kirillov dimension of L and set c(L) equal to the ratio of the dimensions of the zeroth levels in the gradings of L and B(L). Then the Hilbert series of L may be expressed in the form H(L)(q)=c(L) P(q)(1-q)(delta). In the easiest example of the correspondence L --> B(L), the two components of the Weil representation of the symplectic group correspond to the two spin representations of an orthogonal group.