[How frequently are depressive disorders recognized in primary care patients? : A cross-sectional epidemiological study in Germany]. / Wie häufig werden Patienten mit depressiven Störungen in der hausärztlichen Praxis erkannt? : Eine epidemiologische Querschnittsstudie.

BACKGROUND: Primary care physicians (PCPs) play a crucial role for guideline-oriented intervention in patients with depression. OBJECTIVES: Based on a diagnostic screening questionnaire, this study investigates the sensitivity of PCPs to recognize patients with depression as well as the factors facilitating recognition and concordant diagnostic decisions. METHOD: In a cross-sectional epidemiological study in six regions of Germany, 3563 unselected patients filled in questionnaires on mental and physical complaints and were diagnostically evaluated by their PCP (N = 253). The patient reports on an established Depression-Screening-Questionnaire (DSQ), which allows the approximate derivation of an ICD-10 depression diagnosis, were compared with the physician diagnosis (N = 3211). In a subsample of discordant cases a comprehensive standardized clinical-diagnostic interview (DIA-X/CIDI) was applied. RESULTS: On the study day, the prevalence of ICD-10 depression was 14.3% according to the DSQ and 10.7% according to the physician diagnosis. Half of the patients identified by DSQ were diagnosed with depression by their physician and two thirds were recognized as mental disorder cases. More severe depression symptomatology and the persistent presence of main depression symptoms were related to better recognition and concordant diagnostic decisions. Diagnostic validation interviews confirmed the DSQ diagnosis in the majority of the false-negative cases. Indications for at least a previous history of depression were found in up to 70% of false-positive cases. CONCLUSION: Given the high prevalence of depression in primary care patients, there is continued need to improve the recognition and diagnosis of these patients to assure guideline-oriented treatment.

Relevance of cohort design for studying the frequency of the ERG rearrangement in prostate cancer.

AIMS: ERG rearrangements, mostly resulting in TMPRSS2-ERG fusions, are frequent alterations in prostate cancer (PCa), with a frequency ranging from 15% to 78%. As the reason for this variability is unknown, our aim was to investigate the ERG rearrangement frequency with a cohort design. METHODS AND RESULTS: We assessed three well-defined cohorts for ERG rearrangements, using fluorescence in situ hybridization (FISH). The first cohort comprised 119 prostatectomy specimens. The second and third cohorts included incidentally diagnosed PCa [71 cystoprostatectomy specimens, and 105 transurethral resection of the prostate (TURP) specimens]. Seventy of 119 (59%) cases of the prostatectomy cohort harboured ERG rearrangements. Regarding zonal origin, 2/11 (18%) transition zone (TZ) foci and 75/145 (52%) peripheral zone (PZ) foci harboured ERG rearrangements. Within the cystoprostatectomies, 24/71 (34%) cases harboured ERG rearrangements. Regarding zonal origin, 2/9 (22%) TZ foci and 26/86 (30%) PZ foci harboured ERG rearrangements. PCa incidentally identified by TURP harboured ERG rearrangements in 31/105 (29%) cases. CONCLUSIONS: ERG rearrangements occur in TZ PCa, although at a lower frequency than in PZ PCa. We confirmed that approximately half of all prostatectomies harbour ERG rearrangements. However, the frequency in incidentally diagnosed PCa cohorts was significantly lower, even if multifocality was considered. Consequently, zonal origin and cohort design are key for studying the clinical implications of ERG rearrangements.

SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer.

The transcription factor SOX2 (3q26.3-q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2 to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2 in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situ hybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2 amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2 amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2 amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis.

Frequency and clinicopathologic correlates of KRAS amplification in non-small cell lung carcinoma.

BACKGROUND: Characterization of the non-small cell lung cancer (NSCLC) genome has suggested that KRAS amplification is one of the commonest molecular abnormalities in NSCLC. However, the prevalence and clinicopathologic significance of KRAS amplification, and its relationship with KRAS activating mutations have not been well-defined. The purpose of this study was to establish the prevalence of KRAS amplification in two separate, large NSCLC cohorts, to define the clinicopathologic features of KRAS-amplified NSCLC in a single uniformly treated cohort, and to investigate the interplay between KRAS amplification and KRAS mutation. METHODS: Fluorescence in situ hybridization was utilized to detect KRAS amplification on tissue microarrays constructed from a Swiss cohort of 538 NSCLCs and a series of 402 patients with NSCLC treated in a single institution in New York. DNA sequencing to detect KRAS codon 12 activating mutations was performed on a subset of tumors. Amplification and mutation status were compared with patient baseline characteristics, tumor characteristics, and overall- and disease-free survival. RESULTS: The prevalence of KRAS amplification was 13.7% in the Swiss cohort and 15.1% in the New York cohort. Among adenocarcinomas, KRAS amplification was associated with larger (mean size 2.8±1.8 cm vs. 2.1±1.3 cm, p=0.003), less well-differentiated tumors (18% vs. 42%, p=0.004) that were more likely to be invasive (95% vs. 77%, p=0.004) and to exhibit angiolymphatic invasion (24% vs. 12%, p=0.04). These differences were statistically significant within the subset of adenocarcinomas harboring activating KRAS mutations, suggesting a synergistic relationship between amplification and mutation. No significant association between KRAS amplification and nodal metastasis or survival was seen. CONCLUSIONS: KRAS amplification is a common molecular alteration in NSCLC, characterizing ∼15% of tumors. This alteration is associated with indicators of local aggressiveness, and may act synergistically with KRAS mutations to promote tumor progression.

SOX2 amplification is a common event in squamous cell carcinomas of different organ sites.

Acquired chromosomal aberrations, including gene copy number alterations, are involved in the development and progression of human malignancies. SOX2, a transcription factor-coding gene located at 3q26.33, is known to be recurrently and specifically amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. In these organs, the SOX2 protein plays an important role in tumorigenesis and tumor survival. The aim of this study was to determine whether SOX2 amplification is also found in squamous cell carcinomas in other organs commonly affected by this tumor entity. In addition, we examined a large spectrum of lung cancer entities with neuroendocrine differentiation (ie, small cell cancers, large cell cancers, typical and atypical carcinoids) for SOX2 and TTF1 copy number gains to reveal potential molecular ties to squamous cell carcinomas or adenocarcinomas of the lung. Applying fluorescence in situ hybridization, we assessed squamous cell carcinomas of the cervix uteri (n = 47), the skin (n = 57), and the penis (n = 53) for SOX2 copy number alterations and detected amplifications in 28%, 28%, and 32% of tumors, respectively. Furthermore, we performed immunohistochemical SOX2 staining and found that SOX2 amplification is significantly associated with overexpression of the corresponding protein in squamous cell carcinomas (P < .001). Of the lung cancer entities with neuroendocrine differentiation, only small cell cancers and large cell cancers exhibited SOX2 or TTF1 amplifications at significant frequencies, indicating that at least a subset of these might be dedifferentiated forms of squamous cell carcinomas or adenocarcinomas of the lung. We conclude that SOX2 amplification and consequent SOX2 protein overexpression may represent important mechanisms of tumor initiation and progression in a considerable subset of squamous cell carcinomas.

ERG rearrangement in small cell prostatic and lung cancer.

AIMS: Small cell prostatic cancer is a rare but aggressive disease. Currently, its histogenetic origin is unclear and its distinction from metastatic small cell lung cancer is challenging. The aim of our study was to determine whether the ERG rearrangement commonly observed in acinar prostatic cancer can distinguish small cell prostatic cancer from small cell lung cancer samples. METHODS AND RESULTS: We assessed 15 small cell prostatic cancers and 22 small cell lung cancers for ERG rearrangement using fluorescence in situ hybridization. Commonly used and novel immunohistochemical markers (i.e. androgen receptor, calcium activated nucleotidase 1, Golgi phosphoprotein 2, prostate-specific antigen, prostate-specific membrane antigen, CD56, epithelial membrane antigen, thyroid transcription factor 1, chromogranin A, synaptophysin and Ki67) were further studied. ERG rearrangement occurred in 86% of small cell prostatic cancers but in none of the small cell lung cancers and was the best marker to differentiate between both tumours (P < 0.0001). CONCLUSIONS: The ERG rearrangement is commonly observed in small cell prostatic cancer, supporting the hypothesis that ERG rearrangement occurs in aggressive prostatic cancers. Furthermore, the ERG rearrangement is the most significant marker to differentiate between small cell prostatic cancer and small cell lung cancer. Moreover, our data suggest that small cell prostatic cancer is not a tumour entity on its own, but a dedifferentiated variant of common acinar prostatic cancer.

ERG rearrangement is specific to prostate cancer and does not occur in any other common tumor.

Identification of specific somatic gene alterations is crucial for the insight into the development, progression, and clinical behavior of individual cancer types. The recently discovered recurrent ERG rearrangement in prostate cancer might represent a prostate cancer-specific alteration that has not been systematically assessed in tumors other than prostate cancer. Aim of this study was to assess, whether the ERG rearrangement and the distinct deletion site between TMPRSS2 and ERG, both predominantly resulting in a TMPRSS2-ERG fusion, occur in tumors other than prostate cancer. We assessed 54 different tumor types (2942 samples in total) for their ERG rearrangement status by fluorescence in situ hybridization (FISH). To calibrate, we analyzed 285 prostate cancer samples for the ERG rearrangement frequency. Additionally, we interrogated a high-resolution single nucleotide polymorphism (SNP) data set across 3131 cancer specimens (26 tumor types) for copy number alterations. None of the 54 different tumor types assessed by FISH harbored an ERG rearrangement, whereas the prostate cancer samples revealed an ERG rearrangement in 49.5% of cases. Furthermore, within the 26 tumor types assessed for copy number alterations by SNP, the distinct deletion site between TMPRSS2 and ERG (21q22.2-3) was detectable exclusively in prostate cancer. Although Ewing's sarcoma and AML have known rearrangements rarely involving ERG, we hypothesize that the ERG rearrangement as well as the distinct deletion site on 21q22.2-3 between TMPRSS2 and ERG are prostate-cancer-specific genomic alterations. These observations provide further insight into the oncogenesis of prostate cancer and might be critical for the development of ERG rearrangement assessment as a clinical tool.

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations, is necessary for normal esophageal squamous development, promotes differentiation and proliferation of basal tracheal cells and cooperates in induction of pluripotent stem cells. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.