The impact of intraductal carcinoma of the prostate on the site and timing of recurrence and cancer-specific survival.

BACKGROUND: To investigate the effect of intraductal carcinoma of the prostate (IDC-P) in radical prostatectomy (RP) specimens in the context of the site of recurrence, time to recurrence, and cancer-specific survival in two academic cohorts of locally, regionally, or distantly recurrent prostate cancer. METHODS: Our cohort included men enrolled into two academic tissue repositories from 1993 to 2011, who were treated with first-line RP who later experienced local recurrence, regional recurrence, or distant metastasis (together termed clinical recurrence, CR). RP material was reviewed to identify IDC-P and to update grading to current standards. The primary endpoint was the initial location of CR. Secondary endpoints included time to CR and cancer-specific survival. Pearson's chi-square, Welch's t-test, Mann-Whitney U test and Fisher's exact test were performed for univariate analyses. Multinomial logistic regression was used for multivariate analyses. Cancer-specific survival was analyzed with the generalized Wilcoxon test and Cox regression. RESULTS: Eighty-five patients with CR were included in the analysis. IDC-P was present in 78.5% of patients from Center 1 and 70.0% from Center 2 (P = 0.547). IDC-P was independently associated with distant metastasis at initial CR (multivariate odds ratio = 6.27, P = 0.015). IDC-P status did not affect time to recurrence; median survival without recurrence was at 53 months for IDC-P(+) and at 50 months for IDC-P(-) (P = 0.441). Distant metastases at the initial CR event had a 36% reduction of cancer-specific survival compared to local recurrences (P = 0.007). Additionally, prostatic-bed radiotherapy (adjuvant or salvage for biochemical recurrence before distant metastasis) was associated with a 25% reduction in cancer-specific mortality compared to no radiotherapy (P = 0.023). Similar reduction in cancer-specific mortality was observed in the subgroup of patients with distant metastasis and IDC-P when treated with radiotherapy (29%, P = 0.050). CONCLUSIONS: In our cohort, presence of IDC-P was an independent factor for distant metastasis at initial CR, but did not have a significant impact on time to CR. Furthermore, metastatic patients showed statistically reduced cancer-specific mortality when treated with radiotherapy. This reduction in cancer-specific mortality was also identified in patients with IDC-P. Future large scale validation studies should take into account the presence of IDC-P and confirm its impact on disease progression.

Phospho-histone-H3 immunostaining for pulmonary carcinoids: impact on clinical appraisal, interobserver correlation, and diagnostic processing efficiency.

Lung carcinoid tumors are classified as either typical or atypical based on the presence of necrosis and the maximum mitotic count per 2 mm2 area. Determining the mitotic count, which is manually conducted on slides stained with hematoxylin and eosin (HE), is time-consuming and subject to high interobserver variability. The objective of this study was to test the sensitivity and specificity of a surrogate mitosis marker, phospho-histone-H3 (PHH3) immunostaining, in the processing of pulmonary carcinoids as compared with the standard HE evaluation. Carcinoid tissue blocks that were available from lung resection specimens were analyzed using HE and PHH3 stains. Two thoracic pathologists and two residents determined the mitotic count on HE and PHH3 stains in accordance with the 2015 WHO guidelines and recorded the time required to complete this task. For both methods, the interobserver agreement among raters for the mitotic count/2 mm2 was assessed by conducting intraclass correlation analyses. We found that for both pathologists and residents, the time required to determine the mitotic count using the PHH3 method was reduced compared with the traditional HE method. Furthermore, residents detected more mitoses/2 mm2 using the PHH3 stain compared with the HE method. More importantly, the PHH3 method yielded better interobserver agreement than the HE method in terms of mitoses/mm2 detection. Overall, our data confirmed that histologic assessments of carcinoid tumors using PHH3 staining provides practical benefits in terms of scoring times, mitosis detection, and reproducibility of mitotic counts. In addition, we found that the benefit was even greater for less experienced pathologists.

The Effect of Lesion Size on the Organization of the Ipsilesional and Contralesional Motor Cortex.

Recovery of hand function following lesions in the primary motor cortex (M1) is associated with a reorganization of premotor areas in the ipsilesional hemisphere, and this reorganization depends on the size of the lesion. It is not clear how lesion size affects motor representations in the contralesional hemisphere and how the effects in the 2 hemispheres compare. Our goal was to study how lesion size affects motor representations in the ipsilesional and contralesional hemispheres. In rats, we induced lesions of different sizes in the caudal forelimb area (CFA), the equivalent of M1. The effective lesion volume in each animal was quantified histologically. Behavioral recovery was evaluated with the Montoya Staircase task for 28 days after the lesion. Then, the organization of the CFA and the rostral forelimb area (RFA)--the putative premotor area in rats--in the 2 cerebral hemispheres was studied with intracortical microstimulation mapping techniques. The distal forelimb representation in the RFA of both the ipsilesional and contralesional hemispheres was positively correlated with the size of the lesion. In contrast, lesion size had no effect on the contralesional CFA, and there was no relationship between movement representations in the 2 hemispheres. Finally, only the contralesional RFA was negatively correlated with chronic motor deficits of the paretic forelimb. Our data show that lesion size has comparable effects on motor representations in premotor areas of both hemispheres and suggest that the contralesional premotor cortex may play a greater role in the recovery of the paretic forelimb following large lesions.

Inhibition of the contralesional hemisphere after stroke: reviewing a few of the building blocks with a focus on animal models.

The last decade of neuroscience research has revealed that the adult brain can undergo substantial reorganization following injury. Plasticity after stroke has traditionally been perceived as adaptive and supporting recovery, but recent studies have suggested that some plasticity may also be detrimental. In particular, increased activity in the unaffected (contralesional) hemisphere has been proposed to contribute to motor deficits of the paretic hand in some patients. Longitudinal imaging studies in humans have reported a progressive behavioral improvement associated with a decrease of contralesional activity and have correlated the intensity of contralesional hemisphere activity with the degree of motor impairment. Consequently, inhibitory neuromodulatory protocols have been applied to the contralesional hemisphere of stroke patients. Such protocols can facilitate the activation of the ipsilesional motor cortex and improve the function of the paretic limb. Although the use of noninvasive techniques after brain injury shows promise, much work needs to be done to understand better how these approaches affect postlesion plasticity and motor recovery. Ultimately, this knowledge will allow for the design of more effective treatments and will potentially lead to protocols adapted to the specific condition of each patient. In this chapter, we review the literature on the basic pathways that can support the effects of contralesional inhibition, interhemispheric interactions, and some of the changes that can occur in the sensorimotor network after stroke. Finally, we show work in rats that demonstrates how parameters of contralesional inactivation can affect postlesion recovery.

Acute inactivation of the contralesional hemisphere for longer durations improves recovery after cortical injury.

A rapidly growing number of studies using inhibition of the contralesional hemisphere after stroke are reporting improvement in motor performance of the paretic hand. These studies have used different treatment onset time, duration and non-invasive methods of inhibition. Whereas these results are encouraging, several questions regarding the mechanisms of inhibition and the most effective treatment parameters are currently unanswered. In the present study, we used a rat model of cortical lesion to study the effects of GABA-mediated inactivation on motor recovery. In particular, we were interested in understanding better the effect of inactivation duration when it is initiated within hours following a cortical lesion. Cortical lesions were induced with endothelin-1 microinjections. The contralesional hemisphere was inactivated with continuous infusion of the GABA-A agonist Muscimol for 3, 7 or 14days in three different groups of animals. In a fourth group, Muscimol was infused at slower rate for 14days to provide additional insights on the relation between the effects of inactivation on the non-paretic forelimb behavior and the recovery of the paretic forelimb. In spontaneously recovered animals, the lesion caused a sustained bias to use the non-paretic forelimb and long-lasting grasping deficits with the paretic forelimb. Contralesional inactivation produced a general decrease of behavioral activity, affected the spontaneous use of the forelimbs and caused a specific reduction of the non-paretic forelimb function. The intensity and the duration of these behavioral effects varied in the different experimental groups. For the paretic forelimb, increasing inactivation duration accelerated the recovery of grasping function. Both groups with 14days of inactivation had similar recovery profiles and performed better than animals that spontaneously recovered. Whereas the plateau performance of the paretic forelimb correlated with the duration of contralesional inactivation, it was not correlated with the spontaneous use of the forelimbs or with grasping performance of the non-paretic hand. Our results support that contralesional inactivation initiated within hours after a cortical lesion can improve recovery of the paretic forelimb. In our model, increasing the duration of the inactivation improved motor outcomes but the spontaneous use and motor performance of the non-paretic forelimb had no impact on recovery of the paretic forelimb.