Histiocytoid Sweet syndrome harboring an isocitrate dehydrogenase 1 mutation: A case report and retrospective analysis of 29 cases of histiocytoid Sweet syndrome.

Histiocytoid Sweet syndrome (HSS) is a rare histopathologic variant of Sweet syndrome that demonstrates dermal and/or subcutaneous infiltrate with a prominent component of myeloid cells resembling histiocytes. It has been known to occur in association with hematologic neoplasms, including myelodysplastic syndrome (MDS) and acute myelogenous leukemia, but whether it confers an increased risk of such neoplasms is controversial. Here, we describe a case of a HSS that led to the diagnosis of MDS with an isocitrate dehydrogenase 1 (IDH-1) mutation and a corresponding study looking for additional cases of IDH-1 mutations in biopsies of histiocytoid and conventional Sweet syndrome.

Peritumoral hyperplasia of the liver: a response to portal vein invasion by hypervascular neoplasms.

AIMS: Several cases of focal nodular hyperplasia (FNH) or similar hyperplastic lesions have been reported adjacent to hepatic neoplasms, including hepatocellular carcinoma, epithelioid haemangioendothelioma and hepatoblastoma. We refer to this hyperplastic response as peritumoral hyperplasia (PTH). Here, we report eight cases of PTH adjacent to primary hepatocellular carcinomas (two) and metastatic neuroendocrine tumours (three), gastrointestinal stromal tumour (one) and colon carcinomas (two). METHODS AND RESULTS: Sections were stained with H&E and trichrome, and for glutamine synthetase, CD34 and cytokeratin 7. PTH was composed of a peritumoral rim of hyperplastic hepatocytes up to 7.0 mm wide, delimited by adjacent hepatocellular atrophy. PTH had altered plate architecture, strong glutamine synthetase expression and variable sinusoidal endothelial cell CD34 expression. The central tumour deposit typically invaded portal veins and was markedly hypervascular with CD34-positive capillaries. CONCLUSIONS: We suggest that PTH is a hyperplastic response to increased blood flow in the peritumoral parenchyma. The increased flow occurs when portal vein invasion by a hypervascular tumour causes arterio-portal shunting. While PTH shares some morphological features with FNH, it lacks the defining nodular architecture, central scar and bile ductules. PTH may be related pathophysiologically to FNH, but should be classified as a separate entity because of its distinct morphology and peritumoral location.

Glutamine synthetase expression in activated hepatocyte progenitor cells and loss of hepatocellular expression in congestion and cirrhosis.

BACKGROUND & AIMS: In normal human liver, glutamine synthetase (GS) is expressed in a rim of hepatocytes surrounding hepatic veins. GS expression is decreased in cirrhosis and increased in chronic hepatitis, focal nodular hyperplasia, peritumoural hyperplasia and some hepatocellular neoplasms. For the non-neoplastic conditions, there is limited information available on histological pattern of altered GS expression and the mechanisms of these changes. METHODS: We examined GS expression in 58 large specimens and 45 needle biopsies with a variety of non-neoplastic human liver conditions and in 12 normal control livers. Expression was correlated with clinical and histological disease states. RESULTS: We identified four patterns of GS expression: (i) Loss of normal perivenular expression was seen in states of chronic congestion, severe cirrhosis and zone 3 necrosis. (ii) Diffuse expression was seen in states with active hepatocellular injury and correlated with Ki-67 expression. (iii) Interface expression was seen in feathery degeneration of chronic cholestasis. (iv) GS expression in activated hepatocyte progenitor cells (HPCs) associated with small ducts and ductules was seen in fulminant hepatic failure and in early and late chronic liver disease and rarely in normal livers. CONCLUSIONS: Glutamine synthetase expression is increased in regenerating hepatocytes and in early HPCs prior to morphological evidence of hepatocellular differentiation. This may be the earliest marker of HPCs yet demonstrated. Loss of expression may be a reflection of disrupted endothelium-hepatocyte contact in hepatic vein walls caused by congestive injury as found in congestive heart failure and advanced cirrhosis.

Home away from home: international students' experiences during the COVID-19 pandemic and the role of US higher education.

Introduction: This study focuses on the impact of the COVID-19 pandemic on international students' overall experiences. Method: We interviewed 22 international students from 11 countries and 17 universities in the US who participated in a large longitudinal study that aims to understand the physical and emotional wellbeing of young adults during the COVID-19 pandemic. Guided by Bronfenbrenner's ecological model, the findings suggested that students were impacted by the COVID-19 pandemic at interpersonal, institutional, political, and personal levels. Results: The results showed that the pandemic exacerbated existing stressors such as the lack of social support from family, various visa regulations, competitive and limited job opportunities, discrimination and xenophobia, particularly toward students from Asia, and financial burdens. Additionally, the findings highlighted students' perceived loss of the "American dream" and the uneven return on investment due to the pandemic. Discussion: This study reveals the importance of US higher education institutions in supporting international students during the pandemic, particularly in terms of their sense of belonging. Recommendations for institutions drawn from the findings are proposed to better support international students during times of COVID-19 and beyond.

Scleromyxedema and the dermato-neuro syndrome: case report and review of the literature.

Scleromyxedema is a generalized form of lichen myxedematosus which is characterized by a papular and sclerodermoid skin eruption resulting from dermal fibroblast proliferation and mucin deposition. The majority of patients with scleromyxedema have a monoclonal gammopathy, and other systemic manifestations are common. Herein we describe a case of the 'dermato-neuro syndrome', a rare and sometimes fatal neurologic manifestation of scleromyxedema which consists of fever, convulsions and coma, often preceded by a flu-like prodrome. In addition, we provide a comprehensive summary of previously published cases of the dermato-neuro syndrome and discuss the current etiopathogenic theories and treatment options for this rare disease.

Morphological patterns of metastases from combined Merkel cell carcinomas: study of an eastern Canadian cohort of cases.

Combined Merkel cell carcinomas are hybrid tumors composed of neuroendocrine and other phenotypic (usually squamous) elements. They form a minority of Merkel cell carcinomas (MCCs) as a whole, are usually Merkel cell polyomavirus-negative, and have rarely been segregated for specific study. Sporadic reports have indicated that metastases from these tumors can show a combined phenotype. We retrospectively studied 38 cases (24 men [63%], 14 women [37%], mean age 78 years [range, 46-99 years]) of combined MCC. Metastases occurred in 20 patients (53%) (at presentation and/or in follow-up [mean 38 months (range, 0.6-185 months)]). Those from 17 individuals (45%) were examined microscopically. These were mainly nodal in distribution. In 12 patients (71%), the secondary deposits were of pure neuroendocrine type, whereas in 5 (29%), combined deposits were identified. Squamous elements were the most common divergent component, in the primary and secondary tumors. The combined metastases varied from obvious squamous nests in a neuroendocrine background to scattered bizarre tumor giant cells expressing CK5/6 on immunohistochemistry. In one case, individual nodes within a single basin displayed purely squamous or purely neuroendocrine deposits. The mean overall survival in the cohort was 48 months (range, 30-67 months) and the mortality was 82%. Our work sheds light on the frequency and patterns of metastases in combined MCCs. In concert with the poor outcome data documented by others, it also raises a question as to the potential prognostic significance of a combined phenotype per se, independent of a virus-negative status and other variables. This issue deserves further study.

Relationship between p63 and p53 expression in Merkel cell carcinoma and corresponding abnormalities in TP63 and TP53: a study and a proposal.

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine carcinoma. Oncogenesis occurs via Merkel cell polyomavirus-mediated (MCPyV+) and/or ultraviolet radiation-associated (MCPyV-) pathways. Advanced clinical stage and an MCPyV- status are important adverse prognostic indicators. There is mounting evidence that p63 expression is a negative prognostic indicator in MCC and that it correlates with MCPyV- status. p63 is a member of the p53 family of proteins among which complex interactions occur. It has two main isoforms (proapoptotic TAp63 and oncogenic ΔNp63). Paradoxically, TAp63 predominates in MCC. To explore this quandary, we examined relationships between p63 and p53 expression and corresponding abnormalities in the TP63 and TP53 genes in MCC. A cohort of 26 MCCs (12 MCPyV+ and 14 MCPyV-) was studied. Comparative immunohistochemical expression of p63 and p53 was evaluated semiquantitatively (H scores) and qualitatively (aberrant patterns). The results were compared with genetic abnormalities in TP63 and TP53 via next-generation sequencing. p63 was positive in 73% of cases. p53 showed "wild-type" expression in 69%, with "aberrant" staining in 31%. TP63 mutations (predominantly low-level copy gains; 23% of cases) and mainly pathogenic mutations in TP53 (50% of cases) featured in the MCPyV- subset of cases. p63 expression correlated quantitatively with p53 expression and qualitatively with aberrant patterns of the latter. Increased expression of p63 and p53 and aberrant p53 staining correlated best with TP53 mutation. We propose that p63 expression (ie, proapoptotic TAp63) in MCC is most likely functionally driven as a compensatory response to defective p53 tumor suppressor activity.

p63 expression in Merkel cell carcinoma: comparative immunohistochemistry invokes TAp63 as the dominant isoform involved.

The literature suggests that p63 expression in Merkel cell carcinoma (MCC) is associated with a poor prognosis. p63 immunohistochemistry marks the 2 main isoforms of this transcriptional protein: TAp63 (tumor suppressor-like properties) and ∆Np63 (oncogenic properties). Little information about the isoform of relevance in MCC exists. p40 immunohistochemistry specifically marks ∆Np63, and using comparative, semiquantitative expression of p63 and p40, we sought to clarify the issue. Our cohort of 53 cases (28 men and 25 women, median age 79 years, interquartile range 71-88) was stratified by morphology and viral status. Immunohistochemistry (p63, p40, and cytokeratin 5/6) was performed, H-scores for nuclear expression of p63 and p40 were derived (2 observers; positivity ≥ 10), and interobserver agreement was evaluated. Clinical, pathological, and outcome data were documented. The results were analyzed statistically. Mortality amounted to 57% (median follow-up 686 days, interquartile range 292-1599). Positivity for Merkel cell polyomavirus was observed in 29 (55%) of cases. Expression of p63 and p40 was present in 36 (69%) and 4 (8%) of cases, respectively. Increased age (P = .0241), negative Merkel cell polyomavirus status (P = .0185), and p63 positivity (P = .0012) were significantly associated with mortality. The latter 2 variables were highly correlated (P = .004). The interclass correlation between the 2 sets of H-scores was 0.95. Our findings support an association between p63 expression and reduced overall survival in MCC and show consistency in scoring this prognostic parameter. TAp63 is the dominant isoform of the protein involved. The paradoxical tumor suppressor-like activity of this isoform in p63-positive MCCs with reduced overall survival requires further study.

Does Health Coaching Grow Capacity in Cancer Survivors? A Systematic Review.

Interventions that grow patient capacity to do the work of health care and life are needed to support the health of cancer survivors. Health coaching may grow capacity. This systematic review of health coaching interventions explored coaching's ability to grow capacity of cancer survivors. The authors included randomized trials or quasi-experimental studies comparing coaching to alternative interventions, and adhered to PRISMA reporting guidelines. Data were analyzed using the Theory of Patient Capacity (BREWS: Capacity is affected by factors that influence ability to reframe Biography ["B"], mobilize or recruit Resources ["R"], interact with the Environment of care ["E"], accomplish Work ["W"]), and function Socially ["S"]). The authors reviewed 2210 references and selected 12 studies (6 randomized trials and 6 pre-post). These studies included 1038 cancer survivors, mean age 57.2 years, with various type of cancers: breast, colorectal, prostate, and lung. Health coaching was associated with improved quality of life, mood, and physical activity but not self-efficacy. Classified by potential to support growth in patient capacity, 67% of included studies reported statistically significant outcomes that support "B" (quality of life, acceptance, spirituality), 75% "R" (decreased fatigue, pain), 67% "W" (increased physical activity), and 33% "S" (social deprivation index). None addressed changing the patient's environment of care. In cancer survivors, health coaching improved quality of life and supported patient capacity by several mechanisms, suggesting an important role for "Capacity Coaching." Future interventions that improve self-efficacy and patients' environments of care are needed. Capacity Coaching may improve health and quality of life of cancer survivors.

Myelodysplastic Syndrome and Sweet's Syndrome Are Associated with a Mutation in Isocitrate Dehydrogenase 1.

BACKGROUND: Sweet's syndrome (SS) is a febrile neutrophilic dermatosis that has been clinically linked to hematological malignancies, particularly myelodysplastic syndrome (MDS), in a number of case series. Many epigenetic changes underlying MDS have been identified, such as a mutation in the isocitrate dehydrogenase 1 (IDH1) gene, which causes DNA hypermethylation and alteration of a number of genes that lead to leukemogenesis. However, the pathogenesis of malignancy-associated SS is unknown. CASE REPORT: We present two patients who were diagnosed with SS and concomitant IDH1-mutated MDS. Immunohistochemical staining of their skin lesions showed neutrophils diffusely positive for the IDH1 mutation. CONCLUSION: These cases demonstrate that IDH1 mutation may be implicated in the pathogenesis of malignancy-associated SS. Future investigation to elucidate this pathway is warranted. Establishing this molecular link can provide an earlier identification of patients with SS who are also at increased risk for developing MDS.

A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma.

The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases.

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors.

Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies.

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography.

OBJECTIVE: Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. METHOD: Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. RESULTS: The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. CONCLUSIONS: Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.

Neurocognitive performance does not correlate with suicidality in schizophrenic and schizoaffective patients at risk for suicide.

BACKGROUND: Almost 50% of schizophrenic persons attempt suicide at some time in their lives and 9-13% of patients ultimately commit suicide. While numerous studies have elucidated the relationship between psychiatric symptomatology and neurocognition in patients with schizophrenia, this is the first report, to our knowledge, to investigate the relationship between suicidal behavior and neurocognition in schizophrenia and schizoaffective disorder. METHODS: A subgroup of 188 patients participating in the InterSePT trial was assessed at baseline with an extensive neurocognitive battery and measures of suicidality and psychiatric symptomatology. RESULTS: Measures of suicidality did not significantly correlate with neurocognitive performance. Confirmatory analyses between patients currently judged to be at high and low risk for suicide also revealed no neurocognitive differences. Consistent with previous studies, poor neurocognitive performance tended to be modestly correlated with the Positive and Negative Syndrome Rating Scale (PANSS) negative symptom scale. The relationship between suicidality and neurocognitive performance was similar for schizoaffective and schizophrenic patients. CONCLUSIONS: The findings suggest that suicidality in patients with schizophrenia and schizoaffective disorder is not correlated with cognition and may, in fact, be a separate domain worthy of investigation and intervention.

Brain metabolic effects of Neotrofin in patients with Alzheimer's disease.

Neotrofin, a reported inducer of CNS neurotrophic factor synthesis and release, with memory-enhancing activity and demonstrated restoration of age-induced memory deficits in animals, was tested in patients with mild to moderate Alzheimer's disease. Nineteen subjects were treated with 1 week of low-dose (150 mg per day) and 1 week of high-dose (500 or 1000 mg per day) Neotrofin. Cognitive composite scores demonstrated improvement in memory (F=9.6, P=0.0004), executive functioning (P=0.004), and attention (P=0.004). PET scanning was obtained before, after low, and after high dosing. The brain areas most affected were the cerebellum, and sensory and prefrontal cortices, where increases in GMR (Glucose Metabolic Rate) were observed. Increases and decreases were observed in the posterior superior temporal (BA 22), parahippocampal, inferior temporal (BA 37, 20), and fusiform gyri as well as the superior parietal lobule and postcentral gyrus. There were strong hemispheric differences, producing opposite metabolic effects in homologous brain regions. Subcortically, the posterior thalamic region, meso-pontine tegmentum, and tectum had increases in GMR on the left side. At the low dose, GMR was generally increased, but to a lesser degree. The brain areas subserving memory, attention and executive functions were significantly altered in GMR by Neotrofin; however, the directions of these changes were complex. There were significant correlations between improvement in memory and executive function in brain areas involved in circuits subserving these functions. Thus, Neotrofin appears to induce metabolic changes in brain regions involved in circuits underlying memory, attention, and executive functioning.

Memory for emotional stimuli in patients with Alzheimer's disease.

Although a hallmark of Alzheimer's disease (AD) is memory impairment, there is speculation that recall may be enhanced when an emotional component is associated with an event. The current study aims to assess whether patients with AD would recall emotionally laden material better than neutral stimuli. DSM-IV-diagnosed AD patients with mild to moderate dementia, as well as groups of young and elderly healthy controls, participated in this study. All subjects were administered three word lists for three trials each. The words were positive, negative, or neutral in valence and matched for concreteness, emotionality, and pleasantness. As expected, the controls performed significantly better than the AD patients. Importantly, the pattern of recall for the emotions was different, such that both control groups recalled all emotions equally, whereas the AD patients recalled significantly more negative words than positive or neutral. These findings of improved immediate memory for emotional material in AD lends support to the notion that mnemonic functions are differentially affected in the disease.

Support for p63 expression as an adverse prognostic marker in Merkel cell carcinoma: report on a Canadian cohort.

Recent evidence has invoked immunohistochemical expression of p63 in Merkel cell carcinoma as an adverse prognostic factor. Conflicting data led us to evaluate this. An Eastern Canadian cohort diagnosed between 1990 and 2012 was studied. Demographic and clinical data were obtained from pathology records and Provincial Cancer Registries. Pathological features were evaluated by the investigators. Merkel cell polyomavirus status was known in a subset of cases. Clinicopathological features were correlated with overall survival. The cohort consisted of 83 patients (mean age, 75.8 ± 11.7 years) with a male/female ratio of 1.24:1. In a mean follow-up period of 175 weeks (±177), 51 patients died (61.4%). Of several parameters examined, 6 showed significant adverse associations with survival on univariate analysis: age (hazard ratio [HR], 1.05 [1.02-1.08]), clinical stage (III/IV versus I/II; HR, 2.24 [1.18-4.27]), tumor size (HR, 1.16 [1.05-1.28]), combined versus pure morphology (HR, 1.82 [1.04-3.18]), minimal tumor-infiltrating lymphocytes (HR, 2.23 [1.04-4.78]), and expression of p63 (positive in 49.4%; HR, 1.93 [1.09-3.43]). In the stage I/II subgroup, p63 expression was associated with a trend toward poor survival. On multivariate analysis, p63 expression was not significantly associated with reduced survival. Our data support existing evidence that p63 expression in Merkel cell carcinoma carries adverse implications for survival. That it was not an independent prognostic factor may be due to study size and/or its potential as a confounding variable with clinical stage. Of clinical importance is its association with a trend toward a poor outcome in early stage disease.