Spotlight on NKG2C and the human NK‐cell response to CMV infection

Immune responses to cytomegalovirus (CMV) infection in the mouse and human involve the expansion of specific subsets of natural killer (NK) cells with specific phenotypic characteristics and a heightened ability to produce interferon (IFN)‐gamma. In humans, these NK‐cell responses are largely driven by the activating receptor NKG2C, which recognize human leukocyte antigen (HLA)‐E in complex with leader sequence peptides. In this issue of the European Journal of Immunology, Noyola et al. [Eur. J. Immunol. 2012, 42: 3256‐3266] examine NK‐cell responses in a unique cohort of young children with asymptomatic and symptomatic congenital CMV infection. They also address NK‐cell responses to CMV in relation to NKG2C gene copy number. Children with a symptomatic congenital infection exhibited a marked expansion of NKG2C⁺ NK cells. However, despite having slightly lower frequencies of NKG2C⁺ NK cells, children with a heterozygous deletion of the NKG2C gene seemed to control the virus as efficiently as those with two copies of the NKG2C gene. The present studies shed new light on the role of NKG2C copy number variation on the human NK‐cell response to CMV infection.     

Amplification of ERBB2 (HER2) in embryonal rhabdomyosarcoma: A potential treatment target in rare cases?

The ERBB2 gene encodes a receptor tyrosine kinase also known as HER2. The gene is amplified and overexpressed in one-fifth of breast carcinomas; patients with such tumors benefit from targeted treatment with trastuzumab or other drugs blocking the receptor. In addition, ERBB2 has been shown to be amplified and/or overexpressed in a variety of other malignancies. Notably, both alveolar and embryonal rhabdomyosarcoma (RMS), especially in children, often show increased expression of ERBB2. Although high-level amplification of the gene has not been described in RMS, its frequent expression at the cell surface of RMS cells has been exploited for chimeric antigen receptor T-cell (CAR T)-based treatment strategies. We here describe two cases of pediatric, fusion-negative embryonal RMS with high-level amplification of the ERBB2 gene. One patient is currently treated with conventional chemotherapy for a recently detected standard risk RMS, whereas the other patient died from metastatic disease. Both tumors displayed focal amplicons (210 and 274 Kb, respectively) in chromosome band 17q12, with proximal and distal borders corresponding to those typically seen in breast cancer. In both tumors, the ERBB2 amplicon correlated with high expression at the RNA and protein levels. Thus, breast cancer-like ERBB2 amplification is a very rare, but recurrent feature of pediatric RMS, and should be exploited as an alternative treatment target.     

Is delayed radical prostatectomy in men with low‐risk screen‐detected prostate cancer associated with a higher risk of unfavorable outcomes?

BACKGROUND:

Strategies of active surveillance (AS) of low‐risk screen‐detected prostate cancer have emerged, because the balance between survival outcomes and quality of life issues when radically treating these malignancies is disputable. Delay before radical treatment caused by active surveillance may be associated with an impaired chance of curability.

METHODS:

Men diagnosed with low‐risk (T1c/T2; prostate‐specific antigen [PSA] = <10.0; PSA density, <0.2 ng/mL; Gleason score, 3 + 3=6; 1‐2 positive biopsies) prostate cancer in the Swedish section of the European Randomized Study of Screening for Prostate Cancer who received radical prostatectomy (RP) were studied. One group received immediate RP, whereas another group received delayed RP after an initial period of expectant management. These groups were compared regarding histopathological and biochemical outcomes, correcting for baseline differences.

RESULTS:

Mean follow‐up after diagnosis was 5.7 years (standard deviation [SD], 3.2). The immediate RP group (n = 158) received RP a mean of 0.5 (SD, 0.2) years after diagnosis; the delayed RP group (n = 69) received RP after 2.6 (SD, 2.0) years (P < .001). After adjustment for small baseline dissimilarities, no differences in RP frequencies of Gleason score >6 (odds ratio [OR], 1.54; P = .221), capsular penetration (OR, 2.45; P = .091), positive margins (OR, 1.34; P = .445), RP tumor volume (difference, 0.099; P = .155), or biochemical progression rates (P = .185, P = .689) were found between groups, although all data were in favor of immediate RP.

CONCLUSIONS:

With limited patient numbers available for analysis, differences in intermediate outcomes between immediate RP and delayed RP were nonsignificant. The delayed RP group may be subject to a selection bias. Prospective evaluation of active surveillance protocols is essential. Cancer 2010. © 2010 American Cancer Society.     

Distribution and origin of the peripheral innervation of rat cervical esophagus

Several neurotransmitters, neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), galanin, enkephalin, calcitonin-gene related peptide (GGRP), substance P, as well as nitric oxide synthase (NOS), and the noradrenergic marker tyrosine-hydroxylase (TH) were localized by immunocytochemistry in the cervical esophagus of rat. Nerve fibers containing the neuropeptides, NOS, and TH were distributed in the myenteric plexus, around muscle bundles and small blood vessels. Injection of the retrograde tracer True Blue (TB) into the cervical esophagus resulted in the appearance of labeled nerve cell bodies in the superior cervical, the stellate, the nodose, the sphenopalatine, the dorsal root ganglia at levels C₂–C₇, and in local ganglia close to the thyroid. Most of the TB-labeled nerve cell bodies in the superior cervical ganglia contained NPY. In the stellate ganglion, a few labeled nerve cell bodies contained VIP whereas an additional few cell bodies stored NPY. In local ganglia, the majority of labeled cell bodies contained VIP. In the nodose ganglion and cervical dorsal root ganglia, the majority of the labeled nerve cell bodies stored CGRP. The results indicate that the cervical esophagus has a dense innervation with multiple neurotransmitters emanating from several ganglia. As judged by the pattern of nerve fiber distribution, they may regulate esophageal peristalsis and blood flow, some of them possibly in a cooperative manner.     

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR)

Background

Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance.

Methods

Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009–2018) were retrospectively analyzed.

Results

Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively.

Conclusion

Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.