Sarah L. Jensen

Certain neurochemical and connectional characteristics common to extended amygdala and the nucleus accumbens shell suggest that the two represent a single functional-anatomical continuum. If this is so, it follows that the outputs of the two structures should be substantially similar. To address this, projections from the caudomedial shell and central nucleus of the amygdala, a key extended amygdala structure, were demonstrated in Sprague-Dawley rats with different anterograde axonal tracers processed separately to exhibit distinguishable brown and blue-black precipitates. The caudomedial shell projection is strong in the ventral pallidum and along the medial forebrain bundle through the lateral preopticohypothalamic continuum into the ventral tegmental area, distal to which it thins abruptly. The central nucleus projects strongly to the bed nucleus of the stria terminalis and the sublenticular extended amygdala, but substantially to the lateral hypothalamus only at levels behind the rostral part of the entopeduncular nucleus. Innervation of the ventral tegmental area by the central amygdala is minimal, but the lateral one-third of the substantia nigra, pars compacta and an adjacent lateral part of the retrorubral field receive substantial central amygdala input. Central amygdaloid projections are robust in caudal brainstem sites, such as the reticular formation, parabrachial nucleus, nucleus of the solitary tract and dorsal vagal complex, all of which receive little input from the accumbens. The substantial differences in the output systems of the caudomedial shell of accumbens and central amygdala suggest that the two represent distinct functional-anatomical systems.

// Elizabeth Shurell 1, * , Arun S. Singh 2, 7, * , Joseph G. Crompton 1 , Sarah Jensen 2 , Yunfeng Li 3 , Sarah Dry 3, 7 , Scott Nelson 3, 7 , Bartosz Chmielowski 2, 7 , Nicholas Bernthal 4, 7 , Noah Federman 2, 7 , Paul Tumeh 5, 7 , Fritz C. Eilber 1, 6, 7 1 Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095, USA 2 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 3 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 4 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA 5 Department of Dermatology, University of California, Los Angeles, CA 90095, USA 6 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 7 UCLA JCCC Sarcoma Program, University of California, Los Angeles, CA 90095, USA * indicates co-first authors Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: immune microenvironment, MPNST, PD-L1, CD8, sarcoma Received: June 29, 2016      Accepted: August 16, 2016      Published: August 31, 2016 ABSTRACT Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. Results: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. Methods: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. Conclusions: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.

Acrodermatitis enteropathica (AE) is a rare disorder associated with poor absorption of zinc. A variety of clinical and histological findings have been reported in the literature, described mainly in isolated case reports. Because of the varied nature of these cases, the histological features of AE are described often as non-specific. We describe lesions of AE in two patients who presented with vesiculobullous and erosive skin lesions, both showing intra-epidermal, inflammatory vesiculation with surrounding eosinophilic epidermis and necrotic keratinocytes. The lack of clinical suspicion of AE led to their misdiagnosis. We present these two patients to further characterize the bullous variant of AE, and we review the previously reported clinical and histopathological findings.

BACKGROUND: The histogenesis and differentiation of eccrine tumors, including cylindroma, poroma, spiradenoma and syringoma, remains controversial. This controversy may be because of sporadic and incomplete studies of these neoplasms. METHODS: Ten examples each of normal eccrine structures and of four benign eccrine tumors are analyzed with antibodies to cytokeratin (CK) 7, CD34, CK6, CK10, smooth muscle actin (SMA) and CD10. These markers represent two different immunohistochemical stains for each part of the eccrine structure; CK7 and CD34 stain the secretory coil, CK6 and CK10 stain the straight duct and SMA and CD10 stain the myoepithelial cells. This redundancy in staining is performed on four benign eccrine tumors to better interpret the existing literature. RESULTS: We find that CK7 is a sensitive marker for the secretory coil; both cylindromas and spiradenomas express CK7. We also find that CK6 is a marker for the inner ductal cells, while CK10 is a marker for the middle ductal cells; syringomas express both these markers. SMA appears to be a more specific marker for myoepithelial cells surrounding normal eccrine coils, and none of the studied tumors express SMA or CD10. CONCLUSIONS: Our studies suggest that syringomas are tumors of the eccrine duct, while cylindromas and spiradenomas are tumors of the secretory coil.