Routine Elastin Staining in Surgically Resected Colorectal Cancer: Impact on Venous Invasion Detection and its Association With Oncologic Outcomes.

Venous invasion (VI) is a powerful yet underreported prognostic factor in colorectal cancer (CRC). Its detection can be improved with an elastin stain. We evaluated the impact of routine elastin staining on VI detection in resected CRC and its relationship with oncologic outcomes. Pathology reports from the year before (n=145) and the year following (n=128) the implementation of routine elastin staining at our institution were reviewed for established prognostic factors, including VI. A second review, using elastin stains, documented the presence/absence, location, number, and size of VI foci. The relationship between VI and oncologic outcomes was evaluated for original and review assessments. VI detection rates increased from 21% to 45% following implementation of routine elastin staining (odds ratio [OR]=3.1; 95% confidence interval [CI]: 1.8-5.3; P<0.0001). The second review revealed a lower VI miss rate postimplementation than preimplementation (22% vs. 48%, respectively; P=0.007); this difference was even greater for extramural VI-positive cases (9% vs. 38%, respectively; P=0.0003). Missed VI cases postimplementation had fewer VI foci per missed case (P=0.02) and a trend towards less extramural VI than those missed preimplementation. VI assessed with an elastin stain was significantly associated with recurrence-free survival (P=0.003), and cancer-specific survival (P=0.01) in contrast to VI assessed on hematoxylin and eosin alone (P=0.053 and 0.1, respectively). The association between VI and hematogenous metastasis was far stronger for elastin-detected VI (OR=11.5; 95% CI: 3.4-37.1; P<0.0001) than for hematoxylin and eosin-detected VI (OR=3.7; 95% CI: 1.4-9.9; P=0.01). Routine elastin staining enhances VI detection and its ability to stratify risk in CRC and should be considered for evaluation of CRC resection specimens.

The association between placebo arm inclusion and adverse event rates in antidepressant randomized controlled trials: An examination of the Nocebo Effect.

BACKGROUND: Antidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo. METHODS: RCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo. RESULTS: Among the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p<0.001 and B=17.8, p<0.001, respectively). AE rates in patients receiving placebo were not different between study designs. LIMITATIONS: The present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials. CONCLUSIONS: The inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.

Predictors of suicide at time of diagnosis in schizophrenia spectrum disorder: A 20-year total population study in Ontario, Canada.

BACKGROUND: Suicide is a major cause of mortality for individuals with schizophrenia spectrum disorders (SSD). Understanding the risk factors for suicide at time of diagnosis can aid clinicians in identifying people at risk. METHODS: Records from linked administrative health databases in Ontario, Canada were used to identify individuals aged 16 through 45 years who received a first lifetime diagnosis of SSD (schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified (NOS)) using a validated algorithm between 01/01/1993 and 12/31/2010. The main outcome was death by suicide following cohort entry until 12/31/2012. OUTCOMES: 75,989 individuals with a first SSD diagnosis (60.1% male, 39.9% female) were followed for an average of 9.56 years. During this period, 1.71% of the total sample (72.1% male, 27.9% female) died by suicide, after an average of 4.32 years. Predictors of suicide death included male sex (HR 2.00, 95% CI 1.76-2.27), age at diagnosis between 26 and 35 (HR 1.27, 95% CI 1.10-1.45) or 36-45 (HR 1.34, 95% CI 1.16-1.54), relative to 16-25, and suicide attempt (HR 2.23, 95% CI 1.86-2.66), drug use disorder (HR 1.21, 95% CI 1.04-1.41), mood disorder diagnosis (HR 1.32, 95% CI 1.17-1.50), or mental health hospitalization (HR 1.30 95% CI 1.13-1.49) in the 2 years prior to SSD diagnosis. INTERPRETATION: Death by suicide occurs in 1 out of every 58 individuals and occurred early following first diagnosis of SSD. Psychiatric hospitalizations, mood disorder diagnoses, suicide attempts prior to SSD diagnosis, as well as a later age at first diagnosis, are all predictors of suicide and should be integrated into clinical assessment of suicide risk in this population.

Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review.

BACKGROUND: Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects. METHODS: This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A "nocebo index" was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group). RESULTS: Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13-1.99) but had a nocebo index of 0.67. LIMITATIONS: This study relied on multiple RCTs with subtle design differences. CONCLUSIONS: This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.

Service utilization and suicide among people with schizophrenia spectrum disorders.

OBJECTIVE: To compare individuals with and without schizophrenia spectrum disorders (SSD) (schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified) who die by suicide. METHOD: This is a retrospective case control study which compared all individuals who died by suicide in Ontario, Canada with (cases) and without (controls) SSD between January 1, 2008 and December 31, 2012. Cases (individuals with SSD) were compared to controls on demographics, clinical characteristics, and health service utilization proximal to suicide. A secondary analysis compared the characteristics of those with SSD and those with severe mental illness (defined as those without SSD who have had a psychiatric hospitalization within the five-years before suicide (excluding the 30 days prior to death)). RESULTS: Among 5650 suicides, 663 (11.7%) were by individuals with SSD. Compared to other suicides, SSD suicides were significantly more likely to be between the ages of 25-34. SSD suicide victims were significantly more likely to reside in the lowest income neighbourhoods and to reside in urban areas. SSD victims were also significantly more likely to have comorbid mood and personality disorders and all types of health service utilization, including outpatient mental health service contact in the 30 days prior to death, even when compared only with those who had a history of mental health hospitalization. CONCLUSIONS: Individuals with schizophrenia spectrum disorder account for over 1 in 10 suicide deaths, tend to be younger, poorer, urban, more clinically complex, and have higher rates of mental health service contact prior to death. The demographic and service utilization differences persist even when the SSD group is compared with a population with severe mental illness that is not SSD. Suicide prevention strategies for people with schizophrenia spectrum disorder should emphasize the importance of clinical suicide risk assessment during clinical encounters, particularly early in the course of illness.

The impact of knowledge transfer on the detection of venous invasion in colorectal cancer.

Venous invasion (VI) is an independent predictor of hematogenous metastasis and mortality in colorectal cancer (CRC) yet remains widely underreported. Its detection may require recognition of subtle morphologic clues, which at times are only unmasked with an elastin stain. This study evaluates the impact of a knowledge transfer initiative (KTI) on VI detection in a "real-world" pathology practice setting. Following participation in an interobserver variability study of VI detection (Kirsch et al, 2013), 12 participants received educational materials highlighting key issues in VI detection. Eighteen months later, participants were invited to submit pathology reports from all CRC resections signed out 18 months prior to and 18 months following the KTI (n = 266 and n = 244, respectively). Nine pathologists participated. Reports were reviewed for VI and other established prognostic factors. Numbers of elastin stains and tumor-containing blocks were also recorded. Comparative analyses were adjusted for baseline differences in tumor, lymph node, and metastasis stage; tumor location; use of neoadjuvant therapy; and number of tumor-containing blocks. VI detection increased significantly post-KTI versus pre-KTI (39.3% versus 18.4%, adjusted odds ratio [OR] 2.86 [1.91-4.28], P < .001). Increased VI detection post-KTI was observed in both stage II (31.8% versus 12.5%, adjusted OR 3.27 [1.45-7.42], P = .004) and stage III CRC (62.4% versus 28.2%, adjusted OR 4.23 [2.37-7.55], P < .001). All pathologists demonstrated increased VI detection post-KTI. Use of elastin stains was significantly higher post-KTI versus pre-KTI (61.5% versus 5.3% of cases respectively, P < .001). This study demonstrates the effectiveness of knowledge transfer in increasing VI detection in routine pathology practice.

Frequency and factors influencing publication of abstracts presented at three major nephrology meetings.

BACKGROUND AND OBJECTIVES: There have been no contemporary studies assessing abstract publication rates and the factors associated with full publication within the field of nephrology. As such, it is unclear whether a publication bias exists for abstracts presented at nephrology meetings, which may hinder the dissemination of potentially important results. Our objective was to review a selection of abstracts presented at 3 major nephrology meetings to determine the proportion that reach full publication and factors associated with full publication. METHODS: 300 randomly selected abstracts presented as posters at three annual nephrology meetings in 2006 [American Society of Nephrology (ASN), European Renal Association (ERA), and National Kidney Foundation (NKF)] were reviewed. Accepted methods of literature search were performed to determine subsequent journal publication. Univariate and multivariate analyses were performed to determine the association between abstract characteristics and subsequent full publication. RESULTS: 127 (42%) abstracts were published in peer-reviewed journals at 4.5 years. On multivariable analysis, basic science research (OR 2.84, 95% CI 1.44-5.61 as compared to clinical research) and the scientific meeting [OR 2.87, 95% CI 1.60-5.15 (ASN); OR 1.92, 95% CI 1.07-3.45(ERA) as compared to NKF] were significantly associated with full publication. CONCLUSIONS: Almost two-fifths of abstracts presented at three major nephrology meetings are subsequently published in peer-reviewed journals. Basic science content and the meeting at which the abstract was presented are associated with publication. Further research is needed to ascertain the impact of other important factors on abstract publication rates to address publication bias in the renal literature.