Stress reactions following acute situations involving moral challenges among health care professionals.

Many health care professionals have to make morally difficult decisions during acute, stressful situations. The aim was to explore the applicability of an existing qualitatively developed model of individual reactions among professional first responders following such situations using a quantitative approach. According to the model, the interaction of antecedent individual and contextual characteristics affect the immediate emotional reactions to acute, stressful events involving a moral dilemma. Continuous coping efforts and the quality of social support will also affect the long-term positive and negative reactions to the event. The participants (n = 204, about 50% response rate) represented three Swedish health care professions stationed at a university hospital and a regional hospital: Physicians (n = 50), nurses (n = 94) and "others" (n =60, mainly social welfare officers and assistant nurses). Except for the personality dimension emotional stability which was measured using an established instrument, all measurement scales were operationalizations of codes and categories from the qualitative study (ten scales altogether). Four multiple regression analyses were performed with long-term positive and negative reactions in everyday acute and morally extremely taxing situations respectively as dependent variables. The outcome showed that long-term positive reactions covaried with much use of the coping strategies Emotional distancing and Constructive emotional confrontation and a perception of a well-functioning Formal social support. Regarding long-term negative reactions, higher age and little use of Emotional distancing accounted for much of the variance. Immediate emotional reactions also contributed significantly. CONCLUSION: the results largely supported the model concepts and their assumed relationships.

Intraductal Carcinoma of the Prostate on Diagnostic Needle Biopsy Predicts Prostate Cancer Mortality: A Population-Based Study.

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is a distinct histopathologic feature associated with high-grade, advanced prostate cancer. Although studies have shown that IDC-P is a predictor of progression following surgical or radiation treatment for prostate cancer, there are sparse data regarding IDC-P on diagnostic needle biopsy as a prognosticator of prostate cancer mortality. MATERIALS AND METHODS: This was a population-based study of all prostate cancer patients diagnosed using needle biopsy and without evidence of systemic disease between 1991 and 1999 within a defined geographic region of Norway. Patients were identified by cross-referencing the Norwegian Cancer Registry. Of 318 eligible patients, 283 had biopsy specimens available for central pathology review. Clinical data were obtained from medical charts. We examined whether IDC-P on diagnostic needle biopsy was associated with adverse clinicopathological features and prostate cancer mortality. RESULTS: Patients with IDC-P on diagnostic needle biopsy had a more advanced stage and a higher Gleason score compared to patients without IDC-P. IDC-P was also associated with an intensively reactive stroma. The 10-year prostate cancer-specific survival was 69% for patients with IDC-P on diagnostic needle biopsy and 89% for patients without IDC-P (Log rank P-value < 0.005). The presence of IDC-P on diagnostic needle biopsy remained an independent predictor of prostate cancer mortality after adjustments for clinical prognostic factors and treatment. After adjustment for the newly implemented Grade Group system of prostate cancer, IDC-P showed a strong tendency toward statistical significance. However, IDC-P did not remain a statistically significant predictor in the multivariable analysis. CONCLUSION: IDC-P on diagnostic needle biopsy is an indicator of prostate cancer with a high risk of mortality. Accordingly, a diagnosis of IDC-P on needle biopsy should be reported and considered a feature of high-risk prostate cancer. Moreover, the association between IDC-P and reactive stroma provides evidence in support of the idea that stromal factors facilitate carcinoma invasion to the prostatic acini and ducts. Prostate 77:859-865, 2017. © 2017 Wiley Periodicals, Inc.

Combining lymphovascular invasion with reactive stromal grade predicts prostate cancer mortality.

BACKGROUND: Previous studies suggest that lymphovascular invasion (LVI) has a weak and variable effect on prognosis. It is uncertain whether LVI, determined by diagnostic prostate biopsy, predicts prostate cancer death. Data from experimental studies have indicated that carcinoma-associated fibroblasts in the reactive stroma could promote LVI and progression to metastasis. Thus, combining LVI with reactive stromal grade may identify prostate cancer patients at high risk of an unfavorable outcome. The purpose of the present study was to examine if LVI, determined by diagnostic biopsy, alone and in combination with reactive stromal grade could predict prostate cancer death. METHODS: This population-based study included 283 patients with prostate cancer diagnosed by needle biopsy in Aust-Agder County (Norway) from 1991 to 1999. Clinical data were obtained by medical charts review. Two uropathologists evaluated LVI and reactive stromal grade. The endpoint was prostate cancer death. RESULTS: Patients with LVI had marginally higher risk of prostate cancer death compared to patients without LVI (hazard ratio: 1.8, P-value = 0.04). LVI had a stronger effect on prostate cancer death risk when a high reactive stromal grade was present (hazard ratio: 16.0, P-value <0.001). Therefore, patients with concomitant LVI and high reactive stromal grade were at particularly high risk for prostate cancer death. CONCLUSIONS: Evaluating LVI together with reactive stromal grade on diagnostic biopsies could be used to identify patients at high risk of death from prostate cancer. Prostate 76:1088-1094, 2016. © 2016 Wiley Periodicals, Inc.

The relationship between perineural invasion, tumor grade, reactive stroma and prostate cancer-specific mortality: A clinicopathologic study on a population-based cohort.

BACKGROUND: In vitro and in vivo studies have shown that nerves, tumor epithelium, and stroma interact and promote prostate cancer (PC) progression. Perineural invasion (PNI) is established amidst these interactions and may therefore indicate an aggressive PC phenotype. The purpose of the present study was to determine the relationship between PNI, tumor grade, reactive stroma, and PC-specific mortality. METHODS: A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period of 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. Diagnostic prostate needle biopsies were reviewed with respect to presence of PNI, percentage of biopsy cores with PNI, Gleason score (GS), and reactive stromal grade (RSG). The endpoint was PC-specific mortality. RESULTS: The presence of PNI was significantly associated with high tumor grade and abundant reactive stroma. The 10-year PC-specific survival for patients with and without PNI was 72% and 91%, respectively (P = 0.001, log rank). PNI predicted PC-specific mortality independently of clinical factors, though the effect of PNI was attenuated when adjusting for GS and RSG. However, a percentage of biopsy cores with PNI >50% was found to predict PC-specific mortality independently of other clinicopathologic parameters. CONCLUSIONS: The present population-based study shows that PNI on diagnostic prostate needle biopsy is associated with increased risk of PC-specific mortality. Our findings demonstrate that the prognostic effect of PNI is dependent on an association with high grade carcinoma and reactive stroma. However; the impact of PNI on clinical outcome becomes stronger and independent of other clinicopathologic factors upon increased percentage of PNI positive biopsy cores. Thus, our study highlights the importance of PNI and microenvironmental interactions for the long-term outcome of PC.

The prognostic value of reactive stroma on prostate needle biopsy: a population-based study.

BACKGROUND: Reactive tumor stroma has been shown to play an active role in prostatic carcinogenesis. A grading system for reactive stroma in prostate cancer (PC) has recently been established and found to predict biochemical recurrence and prostate cancer-specific mortality (PCSM) in prostatectomized patients. To the best of our knowledge, there has been no study investigating the prognostic value of reactive stromal grading (RSG) with regard to PCSM when evaluated in diagnostic prostate needle biopsies. METHODS: A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. The endpoint was PCSM. RSG was evaluated on haematoxylin and eosin stained sections according to previously described criteria; grade 0, 0-5% reactive stroma; grade 1, 6-15%; grade 2, 16-50%; grade 3, 51-100%. RESULTS: RSG could be evaluated in 278 patients. The median follow- up time was 110 months (interquartile range: 51-171). The 10-year PC - specific survival rate for RSGs of 0, 1, 2, and 3 was 96%, 81%, 69%, and 63%, respectively (P < 0.005). RSG remained independently associated with PCSM in a multivariate Cox regression analysis adjusting for prostate-specific antigen level, clinical stage, Gleason score, and mode of treatment. The concordance index of the multivariate model was 0.814 CONCLUSIONS: Our study demonstrates that RSG in diagnostic prostate needle biopsies predicts PCSM independently of other evaluable prognostic factors. Hence, RSG could be used in addition to traditional prognostic factors for prognostication and treatment stratification of PC patients.

Prostate-specific antigen doubling time subsequent to radical prostatectomy is a predictor of outcome following salvage external beam radiation therapy: a single-centre experience.

OBJECTIVE: The aim of this study was to review the impact of salvage external beam radiotherapy (EBRT) of postprostatectomy patients with long-term follow-up on biochemical-free recurrence (BFR) and metastatic-free survival, and to describe pathological and clinical predictors of outcome. MATERIALS AND METHODS: In the period 1987-2010, 76 postprostatectomy patients with biochemical and clinical recurrence received salvage EBRT. Patients were treated with conformal EBRT and 68 (90%) received a dose of 70 Gy; eight patients (10%) received a dose of 60-64 Gy. No patients received adjuvant or neoadjuvant androgen deprivation therapy in conjunction with salvage EBRT. RESULTS: The median follow-up time after salvage EBRT was 82 months (range 5-192 months). Seventeen patients (22%) developed biochemical recurrence subsequent to postprostatectomy salvage EBRT during the observation time, and the overall 50 and 75 month actuarial BFR rates after salvage EBRT were 84% and 79%, respectively. Seven patients (9%) developed metastatic disease and two patients died of prostate cancer. Independent predictors of biochemical recurrence were seminal vesicle invasion (SVI) in the prostatectomy specimen (p < 0.05) and prostate-specific antigen doubling time (PSADT) of 6 months or less (p = 0.041) before salvage EBRT. CONCLUSIONS: Salvage EBRT provides effective long-term BFR and metastatic-free survival in a selected group of patients with detectable, rising prostate-specific antigen values following radical prostatectomy. SVI and PSADT are prognostic variables for a non-durable response to salvage EBRT and thus predictors of high-risk prostate cancer in patients in whom neoadjuvant and adjuvant androgen deprivation therapy should be considered.

The length of a positive surgical margin is of prognostic significance in patients with clinically localized prostate cancer treated with radical prostatectomy.

OBJECTIVE: To establish predictors of clinical failure in patients operated with radical prostatectomy (RP) for clinically localized prostate cancer (PC) by analyzing the pathological characteristics of positive surgical margins (PSM). PATIENTS AND METHODS: The RP specimens of 303 consecutive patients operated with RP between 1985 and 2009 were reviewed. PSM were analyzed with regard to the PSM length, location and multifocality and the Gleason score (GS) at the PSM. RESULTS: Of the 163 patients with PSM, 79 (48%) progressed to clinical failure compared to 30 (22%) in the negative-margin-status group. In univariate analysis, a GS at the PSM ≥4 + 3 = 7 (p = 0. 013) and a PSM length >3.0 mm (p < 0.005) were significantly associated with higher clinical failure rates compared to a GS at the PSM ≤3 + 4 = 7 and ≤3.0 mm in extent, respectively. A linear extent of the PSM ≤3.0 mm appeared to have the same clinical outcome as in the group with a negative margin status. In multivariate analysis, a PSM length >3.0 mm remained an independent predictor of clinical failure. CONCLUSIONS: PSM length is an independent predictor of clinical failure following RP.

SHBG is an important factor in stemness induction of cells by DHT in vitro and associated with poor clinical features of prostate carcinomas.

Androgen plays a vital role in prostate cancer development. However, it is not clear whether androgens influence stem-like properties of prostate cancer, a feature important for prostate cancer progression. In this study, we show that upon DHT treatment in vitro, prostate cancer cell lines LNCaP and PC-3 were revealed with higher clonogenic potential and higher expression levels of stemness related factors CD44, CD90, Oct3/4 and Nanog. Moreover, sex hormone binding globulin (SHBG) was also simultaneously upregulated in these cells. When the SHBG gene was blocked by SHBG siRNA knock-down, the induction of Oct3/4, Nanog, CD44 and CD90 by DHT was also correspondingly blocked in these cells. Immunohistochemical evaluation of clinical samples disclosed weakly positive, and areas negative for SHBG expression in the benign prostate tissues, while most of the prostate carcinomas were strongly positive for SHBG. In addition, higher levels of SHBG expression were significantly associated with higher Gleason score, more seminal vesicle invasions and lymph node metastases. Collectively, our results show a role of SHBG in upregulating stemness of prostate cancer cells upon DHT exposure in vitro, and SHBG expression in prostate cancer samples is significantly associated with poor clinicopathological features, indicating a role of SHBG in prostate cancer progression.

Dendritic and lymphocytic cell infiltration in prostate carcinoma.

We examined the distribution of CD1a⁺ cells and CD8⁺ and CD4⁺ T lymphocytes in prostate cancer (PCa) and correlated these with clinicopathological parameters. We also investigated whether the distribution of these cells was related to the expression of the cell membrane protein B7-H3, a putative negative regulator of the immune response expressed on PCa cells. A cohort of 151 PCa patients treated with radical prostatectomy (RP) was followed prospectively from 1985 until 2006 with a median follow-up of 9 years. Whole-mount sections of PCa specimens were immunostained to identify immune cells. A low number of CD1a⁺ cells was significantly associated with a high Gleason score and high pathological stage of pT3. The number of CD1a⁺ cells correlated significantly with the number of intratumoral and stromal CD8⁺ and stromal CD4⁺ lymphocytes. Kaplan-Meier analysis showed a tendency toward impaired biochemical progression-free survival in patients with few CD1a⁺ cells within their RP specimens. The expression of B7-H3 correlated inversely with the number of CD1a⁺ cells and intratumoral CD4⁺ lymphocytes; there was a trend for a similar inverse relationship between B7-H3 expression and the number of CD8⁺ lymphocytes.

Is the clinical malignant phenotype of prostate cancer a result of a highly proliferative immune-evasive B7-H3-expressing cell population?

OBJECTIVES: To assess the expression of the cell surface protein B7-H3 in prostate cancer, and its association to clinically relevant parameters after radical prostatectomy and to the proliferation marker Ki-67. METHODS: Radical prostatectomy specimens from a cohort of 130 patients with a median clinical follow up of 8 years were used for the analysis. The expression of B7-H3 and the proliferation marker Ki-67, as well as other standard clinicopathological parameters, were evaluated. RESULTS: A high expression of B7-H3 was associated with pathological stage T3a and T3b, high Gleason score, extraprostatic extension, seminal vesicle invasion and high proliferative activity. Univariable analysis showed that a high expression level of B7-H3 was also correlated with biochemical failure and clinical relapse, and with the expression of Ki-67. A high expression level of Ki-67 was associated with clinical progression and a tendency towards higher rates of prostate-specific antigen relapse in multivariate analyses. CONCLUSIONS: Our findings show that a high expression level of B7-H3 in prostate cancer correlates with the expression of the proliferation marker Ki-67, biochemical failure and clinical relapse. Thus, expression of the cell surface molecule B7-H3 adds to the malignant phenotype of prostate cancer cells expressing high levels of Ki-67. The impact of B7-H3 function on prostate cancer and its potential role in immunotherapy should be explored further.

Impact of a tertiary Gleason pattern 4 or 5 on clinical failure and mortality after radical prostatectomy for clinically localised prostate cancer.

UNLABELLED: Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? It is known that a tertiary Gleason grade pattern 4 or 5 found in RP specimens has a negative impact on recurrence rate regarding biochemical relapse after radical prostatectomy. This is the first publication addressing clinical outcome in patients with a tertiary Gleason grade pattern 4 or 5 showing a negative influence on clinical failure rates. OBJECTIVE: To investigate the impact of a tertiary Gleason grade (TGG) pattern 4 or 5 on clinical failure, as the presence of a TGG pattern 4 or 5 in radical prostatectomy (RP) specimens has been associated with biochemical failure. PATIENTS AND METHODS: In all, 151 consecutive patients undergoing RP between 1985 and 2006 were reviewed, and 148 patients met study inclusion criteria. The RP specimens were pathologically re-examined and the presence of a TGG pattern 4 or 5 was recorded. The endpoint was clinical failure defined as local recurrence and/or development of metastasis at a mean follow-up of 108 months. Univariate analyses were performed using the Kaplan-Meier method. Multivariate analyses were performed using Cox proportional hazards regression. RESULTS: Clinical failure was more likely among men with presence of a TGG pattern 4 or 5 than in men without a TGG pattern 4 or 5 (P= 0.006). In the subgroup of patients with Gleason score 7 the presence of a TGG 5 was significantly associated with clinical failure rate (P= 0.002). In patients with Gleason score <7 or >7, a TGG pattern 4 or 5 was not associated with increased failure rates. Multivariate Cox regression analyses in patients with Gleason score 7 showed that a TGG pattern 5 was a statistically significant predictor of clinical failure when adjusting for pathological stage, surgical margin status, extraprostatic extension and seminal vesicle invasion (hazard ratio 4.03, 95% confidence interval 1.72-9.46; P= 0.001). Further subgroup analyses showed that a TGG pattern 5 was associated with statistically higher clinical progression rates in patients with Gleason score 3 + 4 (P= 0.03). In patients with Gleason score 4 + 3, a TGG pattern 5 was associated with a trend towards a higher clinical progression rate, although this was not statistically significant (P= 0.189). CONCLUSION: A TGG pattern 4 or 5 is associated with decreased clinical recurrence-free survival in Gleason score 7.

Does a tertiary Gleason pattern 4 or 5 influence the risk of biochemical relapse after radical prostatectomy for clinically localized prostate cancer?

OBJECTIVE: The presence of a tertiary Gleason grade (TGG) pattern 4 or 5 in radical prostatectomy (RP) specimens has been reported with adverse pathology and a higher biochemical relapse rate after RP. This study investigated the impact of a TGG pattern 4 or 5 on biochemical and pathological outcome in men operated with RP. MATERIAL AND METHODS: The study reviewed 151 consecutive cases treated at the hospital between 1985 and 2006; 148 were included in the study. All prostatectomy specimens were re-examined by a genitourinary pathologist and among others parameters the presence of TGG pattern 4 or 5 was recorded. The hospital files were examined retrospectively for clinical follow-up data. Prostate-specific antigen (PSA) relapse was defined as two subsequent rising measurements above 0.20 ng/ml. The influence of a TGG pattern 4 or 5 on prognosis was assessed in a Cox proportional hazards regression model controlling for pathological stage, surgical margin (SM) status, seminal vesicle invasion (SVI) and extraprostatic extension (EPE). RESULTS: Fifty-six patients (38%) experienced PSA relapse during follow-up. Twenty-one patients (58%) with a TGG pattern 4 or 5 had a biochemical relapse compared with 35 patients (31%) without TGG pattern 4 or 5. In the Cox regression model, TGG pattern 4 or 5 was an independent predictor of biochemical failure (p = 0.020). CONCLUSIONS: In patients undergoing RP the presence of a TGG pattern 4 or 5 is an independent predictor for biochemical relapse. Consequently, the RP specimens should routinely be investigated for TGG pattern 4 or 5.