We examined the efficacy of an early autism intervention for use in early childhood intervention (ECI) and mutual gaze as a contributor to social development. Seventy-eight families were randomly ...assigned to one of three 12-week interventions: Pathways (with a mutual gaze component), communication, or services-as-usual (SAU). The Pathways/SAU comparison concerned the efficacy of Pathways for ECI, and the Pathways/communication comparison, mutual gaze. The Pathways group made significantly more change on social measures, communicative synchrony, and adaptive functioning compared with the SAU group and on social measures compared with the communication group. There were no group differences for communicative acts. The results support Pathways as a potential ECI program and mutual gaze as an active ingredient for social and communication development.
Intratumoral CD8+ lymphocytes (IT-CD8s) have shown promise as a prognostic indicator for Merkel cell carcinoma (MCC). We tested whether IT-CD8s predict survival among a population-based MCC cohort.
...One hundred thirty-seven MCC cases that had not previously been analyzed for IT-CD8s were studied.
Three-year MCC-specific survival rates were 56%, 72%, and 100% for patients with absent (n = 46), low (n = 85), and moderate or strong (n = 6) IT-CD8s, respectively. Increased IT-CD8s were associated with improved MCC-specific survival in a multivariate competing risk-regression analysis including stage, age, and sex (hazard ratio HR = 0.5; 95% confidence interval CI = 0.3-0.9). Although a similar trend was observed for overall survival, statistical significance was not reached (HR = 0.8; 95% CI = 0.6-1.0), likely because of the high rate of non-MCC deaths among older patients.
This study of prospectively captured MCC cases supports the concept that cellular immunity is important in MCC outcome and that CD8+ lymphocyte infiltration adds prognostic information to conventional staging.
Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve ...prognostic accuracy and provide insight into MCC biology.
Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed.
Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival.
Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
Nipple-sparing mastectomy (NSM) offers improved, patient-centered outcomes with demonstrated oncologic safety ( Ann Surg Oncol 2020;27:344-351). Indications for NSM continue to expand to patients ...outside of the traditional eligibility criteria, including those with prior breast-conserving therapy (BCT) with radiotherapy. Currently, limited data exist evaluating both short- and long-term outcomes in patients proceeding to NSM after prior BCT.
All patients undergoing bilateral NSM in a single institution from 2002 through 2017 with history of prior BCT were included in the final cohort, without exclusions. A retrospective chart review was performed to identify patient demographics, operative details, and complications. Outcomes assessed included early complications (<30 days from NSM), late complications (>30 days), rates of prosthetic failure, unplanned reoperations, and reconstructive failures, as well as oncologic safety. Student t , χ 2 , and Fisher exact tests were used to analyze outcomes of paired (BCT vs non-BCT) breasts within each patient.
A total of 17 patients undergoing 34 NSMs were included. Each had a history of BCT and either ipsilateral breast recurrence (64.7%), risk-reducing NSM (23.5%), or a new contralateral primary cancer (11.8%). The cohort had a mean age of 51.1 years. With regard to acute complications (ischemia, infection, nipple-areolar complex or flap ischemia or necrosis, and wound dehiscence), there was no significant difference noted between breasts with prior BCT versus no prior BCT overall (41.2% vs 35.3%, respectively; P = 0.724). Complications occurring after 30 days postoperatively (capsular contracture, contour abnormality, animation deformity, bottoming out, rotation, and rippling) in prior BCT breasts versus no prior BCT had no significant differences overall (58.8% vs 41.2% respectively; P = 0.303). The mean follow-up was 5.5 years, during which no patients had a reported locoregional or distant recurrence in either breast.
No significant differences in early or late complications were identified between breasts in patients undergoing bilateral NSM with a history of unilateral BCT and XRT. In the 5.5 years of follow-up, there were no recurrences, lending support to NSM for management of recurrent disease in addition to National Comprehensive Cancer Network-recommended total mastectomy. We propose that NSM should not be contraindicated in patients exposed to radiation with BCT.
Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-associated skin cancer. Robust cellular immune responses are associated with excellent outcomes in patients with MCC, but these responses ...are typically absent. We determined the prevalence and reversibility of major histocompatibility complex class I (MHC-I) downregulation in MCC, a potentially reversible immune-evasion mechanism. Cell-surface MHC-I expression was assessed on five MCC cell lines using flow cytometry as well as immunohistochemistry on tissue microarrays representing 114 patients. Three additional patients were included who had received intralesional IFN treatment and had evaluable specimens before and after treatment. mRNA expression analysis of antigen presentation pathway genes from 35 MCC tumors was used to examine the mechanisms of downregulation. Of note, 84% of MCCs (total n = 114) showed reduced MHC-I expression as compared with surrounding tissues, and 51% had poor or undetectable MHC-I expression. Expression of MHC-I was lower in polyomavirus-positive MCCs than in polyomavirus-negative MCCs (P < 0.01). The MHC-I downregulation mechanism was multifactorial and did not depend solely on HLA gene expression. Treatment of MCC cell lines with ionizing radiation, etoposide, or IFN resulted in MHC-I upregulation, with IFNs strongly upregulating MHC-I expression in vitro, and in 3 of 3 patients treated with intralesional IFNs. MCC tumors may be amenable to immunotherapy, but downregulation of MHC-I is frequently present in these tumors, particularly those that are positive for polyomavirus. This downregulation is reversible with any of several clinically available treatments that may thus promote the effectiveness of immune-stimulating therapies for MCC.
To determine the clinical utility of p63 expression, which has been identified in several cohorts as a predictor of poorer prognosis in Merkel cell carcinoma (MCC).
Immunohistochemistry was used to ...determine p63 expression on MCC tumors from 128 patients.
Of the patients, 33% had detectable p63 expression. p63 Positivity was associated with an increased risk of death from MCC (hazard ratio, 2.05; P = .02) in a multivariate Cox regression model considering stage at presentation, age at diagnosis, and sex. Although p63 expression correlated with diminished survival in this largest cohort reported thus far, the effect was weaker than that observed in prior studies. Indeed, within a given stage, p63 status did not predict survival in a clinically or statistically significant manner.
It remains unclear whether this test should be integrated into routine MCC patient management.
Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin ...carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc–/–. Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies.
Breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare lymphoma that has been associated with textured breast implants. Most cases present as a delayed (>1 year) seroma, which ...can be aspirated for diagnosis. Fewer patients present with masses or skin signs. Surgical resection is the cornerstone of treatment for this form of lymphoma. For advanced disease, treatment is multidisciplinary and incorporates adjuvant chemotherapy, radiation therapy, and potentially, the immunotherapeutic agent brentuximab vedotin, an anti-CD30 antibody-drug conjugate. However, relapse rates are high among patients with peripheral ALCL. We present the case of a 39-year-old woman who developed BIA-ALCL 13 years after augmentation with silicone, textured implants and had a complete pathologic response to neoadjuvant cyclophosphamide, doxorubicin (hydroxydaunomycin), vincristine (Oncovin), etoposide, prednisolone (CHOEP) at time of bilateral removal of implants and capsules. CHOEP is a long-standing regimen for treatment of peripheral ALCL and is a suggested regimen for treatment of BIA-ALCL. This case report is the first to demonstrate the use of neoadjuvant chemotherapy in the treatment of BIA-ALCL and suggests a role for its use in advanced disease.
Merkel cell carcinoma is a polyomavirus-associated cancer that is strongly linked with T lymphocyte immune suppression in epidemiologic studies. CD8+ T cell infiltration into MCC tumors ...(intratumoral) has recently been shown to be strongly predictive of improved survival. In contrast, the presence of CD8+ T cells at the border of the tumor (peritumoral) had no independent prognostic value. Spontaneous regression has been reported for MCC approximately one thousand times more often than would be expected given the frequency of this cancer. Many of these events began shortly after biopsy, and in some cases lymphocytic infiltration was described.
To determine whether CD8+ lymphocyte infiltration in MCC tumors is commonly altered by biopsy.33 MCC patients who had microscopic confirmation of MCC on both an initial biopsy and a re-excision specimen were included in this study. Intratumoral and peritumoral CD8 lymphocyte infiltration was quantitated using immunohistochemistry and compared using the paired t-test in biopsy versus re-excision samples. There was a trend toward increased CD8 infiltration after biopsy in a peritumoral ('stalled') pattern (p = 0.08), however, biopsy was not associated with a significant increase in CD8 T cells in the clinically more important intratumoral location (p = 0.58).
The initial diagnostic biopsy for MCC does not commonly alter intratumoral CD8+ T cell infiltration, suggesting it does not directly induce immunologic recognition of this cancer. Because CD8 infiltration is typically stable after biopsy, this parameter may be useful to assess the efficacy of future immune therapies for this virus-associated, immunogenic, often-lethal cancer.
Killifish are euryhaline teleosts that adapt to rapid changes in the salinity of the seawater. It is generally accepted that acclimation to seawater is mediated by cortisol activation of the ...glucocorticoid receptor (GR), which stimulates CFTR mRNA expression and CFTR-mediated Cl- secretion by the gill. Because there is no direct evidence in killifish that the GR stimulates CFTR gene expression, quantitative PCR studies were conducted to test the hypothesis that cortisol activation of GR upregulates CFTR mRNA expression and that this response is required for acclimation to seawater. Inhibition of the GR by RU-486 prevented killifish from acclimating to increased salinity and blocked the increase in CFTR mRNA. In contrast, inhibition of the mineralocorticoid receptor by spironolactone had no effect on acclimation to seawater. Thus acclimation to increased salinity in killifish requires signaling via the GR and includes an increase in CFTR gene expression. Because arsenic, a toxic metalloid that naturally occurs in the aquatic environment, has been shown to disrupt GR transcriptional regulation in avian and mammalian systems, studies were also conducted to determine whether arsenic disrupts cortisol-mediated activation of CFTR gene expression in this in vivo fish model and thereby blocks the ability of killifish to acclimate to increased salinity. Arsenic prevented acclimation to seawater and decreased CFTR protein abundance. However, arsenic did not disrupt the GR-induced increase in CFTR mRNA. Thus arsenic blocks acclimation to seawater in killifish by a mechanism that does not disrupt GR-mediated induction of CFTR gene expression.
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