Clinicopathological and immunohistochemical characteristics of surgically treated primary carcinoma of the nasal vestibule - an evaluation of 30 cases.

OBJECTIVES/HYPOTHESIS: Squamous cell carcinoma of the nasal vestibule (SCCNV) is a rare tumour entity. Treatment modality, particularly indication of neck dissection, is still a controversial subject of debate. We sought to evaluate the occurrence of lymph node metastases, the prognosis and the immunohistochemical characteristics of SCCNV. STUDY DESIGN: Retrospective cohort study. METHODS: This study included 30 consecutive patients with SCCNV treated with primary tumour resection and neck dissection in cases of suspicious lymph nodes between 2003 and 2013. According to therapeutical standard adjuvant radiotherapy or chemotherapy were applied in some cases. Clinicopathological data and immunohistochemical expression of CK5/6, EGFR, Ki-67, MMP-2, MMP-9, p53 and VEGFR were analysed. RESULTS: The median follow-up period was 47.1 months. Five-year disease-free (5-year DFS) and 5-year overall survival (5-year OS) were 91.7% and 92.3%. Five-year OS in low-grade tumours (G1, G2) was 100.0%, in high-grade tumours (G3) 75.0% (P = 0.028), respectively. We did not detect any lymph node metastases in the neck dissections. Overexpression of p53 showed a trend for better 5-year OS (p53-positive 100% versus p53-negative 77.8%, n.s.). We found a positive correlation between p53 and EGFR (P = 0.0001). There was no significant relationship between the expression rates of the markers and tumour stage and grading. CONCLUSIONS: We propose no prophylactic neck dissection in small-sized SCCNV. Subtile endoscopic follow-up and periodic ultrasound examination of the cervical lymph nodes after surgical treatment are recommended. Further evaluation of the p53- and EGFR-pathways might pave the way to identify possible molecular targets in an attempt to tailor tumour management.

Patterns of autophagy in urothelial cell carcinomas--the significance of "stone-like" structures (SLS) in transurethral resection biopsies.

OBJECTIVES: To investigate the microtubule-associated protein LC3A, presumed to reflect autophagic activity, in urothelial cell carcinomas (UCC) for its relevance with muscle invasion in transurethral resection (TUR) biopsies. The LC3A antibody is specific for identifying the autophagy-related protein Atg8 and, hence, autophagy-a self-degradation mechanism by which cells recycle their own cytoplasmic constituents, providing with additional energy the rapidly proliferating cells. METHODS: The study comprised 210 TUR specimens of UCC of the urinary bladder: 70 low-grade non-muscle-invasive (NMI, group A), 70 high-grade NMI (group B), and 70 high-grade muscle invasive tumors (group C). These, together with 40 controls, were stained for Atg8/LC3 using an automated immunohistochemical technique. RESULTS: The LC3A was detected as diffuse cytoplasmic staining, and as dense, spheroidal, "stone-like" structures (SLS) of variable size (1.2-12.0 µm in diameter), typically enclosed within cytoplasmic vacuoles. The LC3A reactivity, whether expressed in the form of SLS or as diffuse cytoplasmic staining, was higher in high-grade UCC than in low-grade disease and, more importantly, it was associated with muscle invasion. The median number of SLS per optical field, per section was 17.0, 19.0, and 37.0 for groups A, B, and C, respectively (A, B vs. C P < 178> 0.0001; A vs. B P = 0.27). The median SLS diameter was 4.9, 5.3, and 9.3 µm for groups A, B, and C respectively (A, B, vs. C P < 0.0001; A vs. B P = 0.03). CONCLUSION: It appears that the LC3A protein is closely connected with muscle invasion, but whether this finding is of clinical value in TUR specimens lacking muscularis propria remains to be proven.

Utilization trends and positive biopsy rates for prostate biopsies in the United States: 2005 to 2011.

This article assesses the positive biopsy rate and core sampling pattern in patients undergoing needle biopsy of the prostate in the United States at a national reference laboratory (NRL) and anatomic pathology laboratories integrated into urology group practices, and analyzes the relationship between positive biopsy rates and the number of specimen vials per biopsy. For the years 2005 to 2011 we collected pathology data from an NRL, including number of urologists and urology practices referring samples, total specimen vials submitted for prostate biopsies, and final pathologic diagnosis for each case. The diagnoses were categorized as benign, malignant, prostatic intraepithelial neoplasia, or atypical small acinar proliferation. Over the same period, similar data were gathered from urology practices with in-house laboratories performing global pathology services (urology practice laboratories; UPLs) as identified by a survey of members of the Large Urology Group Practice Association. For each year studied, positive biopsy rate and number of specimen vials per biopsy were calculated in aggregate and separately for each site of service. From 2005 to 2011, 437,937 biopsies were submitted in > 4.23 million vials (9.4 specimen vials/biopsy); overall positive biopsy rate was 40.3%-this was identical at both the NRL and UPL (P = .97). Nationally, the number of specimen vials per biopsy increased sharply from a mean of 8.8 during 2005 to 2008 to a mean of 10.3 from 2009 to 2011 (difference, 1.5 specimen vials/biopsy; P = .03). For the most recent 3-year period (2009-2011), the difference of 0.6 specimen vials per biopsy between the NRL (10.0) and UPL (10.6) was not significant (P = 0.08). Positive biopsy rate correlated strongly (P < .01) with number of specimen vials per biopsy. The positive prostate biopsy rate is 40.3% and is identical across sites of service. Although there was a national trend toward increased specimen vials per biopsy from 2005 to 2011, from 2009 to 2011 there was no significant difference in specimen vials per biopsy across sites of service. Increased cancer detection rate correlated significantly with increased number of specimens examined. Segregation of prostate biopsy cores into 10 to 12 unique specimen vials has been widely adopted by urologists across sites of service.

Periprostatic lymph node metastasis in prostate cancer and its clinical significance.

AIMS: To evaluate the potential of periprostatic lymph node (LN) as a staging indicator, particularly with the use of methods for enhanced detection of micrometastasis. METHODS AND RESULTS: We retrieved cases with periprostatic LN from radical prostatectomy specimens accrued between 1997 and 2007 at our institution. Twenty-one (0.8%) of 2663 radical prostatectomy specimens had periprostatic LNs (total number of LNs = 22). LN size ranged from 0.8 to 4.7 mm. Most of the periprostatic LNs were located close to the posterior base. Seven (32%) of 22 LNs were involved by metastatic prostate cancer (PCa), including five detected on routine haematoxylin and ceosin slides and an additional two detected only by immunohistochemistry. Cases with periprostatic LNs had a significantly higher metastatic rate (29%; six of 21) compared to those with pelvic LNs sampled at radical prostectatomy in our institution (1.9%). When compared to cases with negative periprostatic LNs (n = 15), the tumour characteristics of cases with metastatic periprostatic LNs (n = 6) included higher tumour volume, Gleason score, stage and a greater propensity for prostate-specific antigen (PSA) recurrence. CONCLUSIONS: Despite their infrequent identification, periprostatic LNs if detected in the radical prostatectomy specimen should be evaluated with greater scrutiny (step sections and/or immunohistochemical studies) to evaluate their prognostic potential.

Beclin-1 and LC3A expression in cutaneous malignant melanomas: a biphasic survival pattern for beclin-1.

Autophagy is an intracellular pathway for the degradation of long-lived proteins and damaged organelles. It is, in essence, a recycling process allowing cells to survive oxygen and nutrient depletion. The expression of two autophagy-related proteins, beclin 1 and light chain 3A (LC3A) was investigated in 79 nodular cutaneous melanomas. The results were correlated with histopathological factors, vascular density, and hypoxia-related proteins [hypoxia-inducible factors (HIF1α and HIF2α) and lactate dehydrogenase 5]. The reactivity of both autophagy-related proteins was uniformly cytoplasmically diffused. High beclin 1 and LC3A reactivity was related to tumor hypoxia, as this was inferred from the intense expression of HIF1α and lactate dehydrogenase 5, whereas low beclin 1 and LC3A expression was linked with an increased vascular density. In addition, beclin 1 was related to disease-specific survival which, however, exposed a biphasic pattern. A strong beclin 1 expression extending over a tumor area of more than 50% (high) was associated with an increased rate of early deaths, whereas a similarly strong, but less-extensive cytoplasmic reactivity (<10% tumor area; low) defined a sharp fall in the survival 5 years after surgery. Furthermore, the low beclin 1 expression was associated with high Breslow's depth, high Clark's level, and ulceration. Low LC3A expression was also related to ulceration, but not to other histopathological features nor prognosis. In multivariate analysis, beclin 1 was an independent prognostic variable. It is concluded that extensive autophagic activity is generated by tumor hypoxia and anaerobic glycolysis, whereas angiogenesis maintains low autophagic activity. Atg6/beclin 1 was proved to be capable of deciphering the prognosis in cutaneous malignant melanoma, but the matter requires further investigation.

The Esteem System: a totally implantable hearing device.

The Esteem totally implantable active middle ear implant is a new technology to augment hearing in patients suffering from moderate-to-severe and severe sensorineural hearing loss. In contrast to conventional (acoustic) hearing aids, the system uses two piezoelectric transducers (PZTs). PZTs are used as the sensor and driver to replace the function of the middle ear. Sound is received via a PZT sensor that picks up eardrum vibrations, following the piezoelectric principle, and transforms them into an electric signal. This signal is filtered, modified, amplified and transferred to a PZT driver, which mechanically drives the stapes and thereby the inner ear. The sound processor also contains a power source, which is an implantable lithium iodide battery. All components of the hearing restoration system are totally implantable to offer good sound fidelity and reduce hearing aid stigma caused by the visibility of conventional and semi-implantable hearing systems. Our experience shows that this system can provide considerable benefit to patients with sensorineural hearing loss.

Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts.

Mutations in sclerostin function or expression cause sclerosing bone dysplasias, involving decreased antagonism of Wnt/Lrp5 signaling. Conversely, deletion of the VHL tumor suppressor in osteoblasts, which stabilize HIF-alpha isoforms and thereby enables HIF-alpha/beta-driven gene transcription, increases bone mineral content and cross-sectional area compared to wild-type controls. We examined the influence of cellular hypoxia (1% oxygen) upon sclerostin expression and canonical Wnt signaling. Osteoblasts and osteocytes cultured under hypoxia revealed decreased sclerostin transcript and protein, and increased expression and nuclear localization of activated beta-catenin. Similarly, both hypoxia and the hypoxia mimetic DFO increased beta-catenin gene reporter activity. Hypoxia and its mimetics increased expression of the BMP antagonists gremlin and noggin and decreased Smad-1/5/8 phosphorylation. As a partial explanation for the mechanism of regulation of sclerostin by oxygen, MEF2 reporter assays revealed decreased activity. Modulation of VEGF signaling under normoxia or hypoxia revealed no influence upon Sost transcription. These data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF.

Modulation of sclerostin expression by mechanical loading and bone morphogenetic proteins in osteogenic cells.

The anabolic effect of dynamic mechanical loading on skeletal architecture has been repeatedly demonstrated, but the cellular and molecular events occurring between load and ultimate bone formation remain obscure. The discovery of sclerostin, an antagonist of Wnt/Lrp5 signaling, and the sclerosing bone dysplasias that result from its mutation suggest its pivotal role in modulating bone formation. We examined expression of Sost mRNA across a variety of clonal cell lines spanning the osteogenic phenotype from immature osteoblast to mature osteocyte. No sclerostin expression was detected in immature MC3T3-E1 osteoblasts and, surprisingly, mature MLO-Y4 osteocytes, whereas immature MLO-A5 osteocytic cells expressed very low levels of Sost. Highest expression was observed in mature UMR 106.01 osteoblasts. We examined the influence of bone morphogenetic proteins on Sost expression. Treatment with BMP-2, -4 or -6 was without effect on Sost in mature MLO-Y4 osteocytes but elicited a robust increase in Sost expression in immature MLO-A5 osteocytes. Oscillatory fluid flow applied to mature UMR 106.01 osteoblasts transiently decreased expression of sclerostin at both the mRNA and protein level. Overall, our results indicate that BMP treatment and in vitro mechanical loading demonstrate opposite effects upon sclerostin expression.

Economic viability of stapes surgery in Germany.

OBJECTIVE: The purpose of this study was to determine the economic viability of stapes surgery in Germany. We compared the cost of the operation to the retail value and average cost of a lifelong supply of hearing aids. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: One hundred and sixty-four consecutive cases of primary stapedotomy performed on patients with otosclerosis at our institution served as the representative group for the calculation. The post-operative air-bone gap average at the frequencies 500, 1000, 2000 and 4000 Hz was less than 10 dB for 62 per cent of the patients, and less than 20 dB for 92 per cent of the patients. There was a post-operative sensorineural hearing loss in 1.2 per cent of the patients. RESULTS: Analysis showed that, even for an elderly patient aged 65 years with a life expectancy of 15 years, the cost of a lifelong supply of hearing aids was greater than that of a stapedotomy procedure. Based on our group of patients, the stapedotomy procedure proved to be euro 800,000 K cheaper than treatment with an averagely priced hearing aid. The economic benefit was still present when taking into account possible revision surgery in 5-10 per cent of cases, and also when, in addition to the surgery, a post-operative hearing aid was required, in for example 20 per cent of cases. CONCLUSION: Stapes surgery is economically beneficial for the individual patient as well as for the general patient cohort, irrespective of age. The stapedotomy procedure also prevents the known disadvantages of conventional hearing aids, thus improving the patient's quality of life.