Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis.

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

Patients with psychiatric illness report worse patient-reported outcomes and receive lower rates of autologous breast reconstruction.

Psychiatric well-being impacts on general satisfaction and quality of life. This study explored how the presence of psychiatric diagnoses affects patient-reported outcomes in breast reconstruction and on selection of reconstructive modality. Patients who received breast reconstruction at a tertiary hospital between 2013 and 2018 and completed the BREAST-Q survey were included. BREAST-Q module scores were compared between patients who had a psychiatric diagnosis at presentation and the remaining cohort using t tests. General linear models (GLMs) were used to control for confounding factors. A chi-squared test was used to assess the effect on reconstructive modality, and binary logistic regression was used to control for confounding factors. Of the 471 patients included, 93 (19.7%) had at least one psychiatric diagnosis. Cohorts did not differ significantly by age, BMI, race, ASA classification, or insurance status. Patients with a psychiatric diagnosis experienced a decrease in BREAST-Q scores for the Psychosocial Wellbeing (B = 9.16, P = .001) and Sexual Wellbeing (B = 9.29, P = .025) modules. On binary logistic regression, patients with a psychiatric diagnosis were less likely to receive autologous reconstruction compared with implant reconstruction (OR = 0.489, P = .010). The presence of psychiatric diagnoses is an independent predictor of decreased BREAST-Q. Furthermore, there is a significant disparity in modality of reconstruction given to patients with psychiatric diagnoses. Further study is needed to evaluate interventions to improve satisfaction among at-risk populations and evaluate the reason for low autologous reconstruction in this population.

Heresy - Is there a role for ultrasound in management of the non-palpable testicle?

INTRODUCTION: AUA Guidelines do not support the routine use of ultrasound (US) in evaluation of boys with an undescended testicle (UDT) prior to urology referral. Multiple studies have demonstrated that real time US is inferior to a physical examination by a pediatric urologist in detecting an UDT. However, improved US technology, which now permits detection of the non-palpable testis located just proximal to the internal ring, may aid in guiding the surgical approach to the non-palpable testis. We evaluated US findings of boys deemed to have a non-palpable UDT and compared them to surgical findings. OBJECTIVE: To assess the role of pre-operative ultrasonography in guiding surgical management in boys deemed to have a non-palpable testis by a pediatric urologist. STUDY DESIGN: US of boys with a non-palpable UDT, as reported by a pediatric urologist on physical exam, during a 3-year period, were reviewed. All US were performed jointly by a technician and pediatric radiologist. Patient demographics, laterality, and intra-operative findings were assessed. RESULTS: Thirty-one boys with a non-palpable testicle on physical exam underwent scrotal/inguinal/pelvis US at a median age of 7.5 months (IQR 2.5-12.3 months). Two patients had bilateral non-palpable testicles, 21 had a non-palpable left sided testicle and 8 had a non-palpable right sided testicle. Of the 33 non-palpable testes, 5 (15.2%) were identified in the inguinal canal. Sixteen (48.5%) were visualized in the lower pelvis just proximal to the internal ring and graded as intra-abdominal. Four (12.1%) nubbins or very atrophic testes were identified in the inguinal region or scrotum and 5 (15.2%) testes were not identified on US. Three (9.1%) testes were observed to be mobile between the lower pelvis just proximal to the internal ring and the inguinal canal. Of the 8 patients with testes that were identified in the inguinal canal, or mobile between the lower pelvis and inguinal canal, 7 avoided a diagnostic laparoscopy and underwent an inguinal orchiopexy. Of the 16 testicles located in the lower pelvis proximal to the internal ring, only 2 underwent laparoscopy/laparoscopic orchiopexy. DISCUSSION: In cases of a non-palpable testicle following a physical examination by a urologist, an ultrasound can impact the operative plan, and allow for patients to avoid laparoscopy. In our cohort, 87.5% of non-palpable testes avoided laparoscopic surgery after ultrasound identification of a viable testis. CONCLUSIONS: US in the evaluation of cryptorchidism can guide surgical management in select cases in which a testis is non-palpable following careful examination by a urologist.

Smooth versus Textured Tissue Expanders: Comparison of Outcomes and Complications in 536 Implants.

Background Increasing concerns regarding the safety of textured surface implants have resulted in surgeons transitioning from textured tissue expanders (TEs) to smooth TEs. Given this change has only recently occurred, this study evaluated outcomes between smooth and textured TEs. Methods Women who underwent two-stage breast reconstruction using TEs from 2013 to 2022 were included. TE-specific variables, perioperative information, pain scores, and complications were collected. Chi-squared, t -test, and linear regression analyses were performed. Results A total of 320 patients received a total of 384 textured and 152 smooth TEs. Note that 216 patients received bilateral reconstruction. TEs were removed in 9 cases. No significant differences existed between groups regarding comorbidities. Smooth TEs had a higher proportion of prepectoral placement ( p < 0.001). Smooth TEs had less fills (3 ± 1 vs. 4 ± 2, p < 0.001), shorter expansion periods (60 ± 44 vs. 90 ± 77 days, p < 0.001), smaller expander fill volumes (390 ± 168 vs. 478 ± 177 mL, p < 0.001), and shorter time to exchange (80 ± 43 vs. 104 ± 39 days, p < 0.001). Complication rates between textured and smooth TEs were comparable. Smooth TE had a greater proportion of TE replacements ( p = 0.030). On regression analysis, pain scores were more closely associated with age ( p = 0.018) and TE texture ( p = 0.046). Additional procedures at time of TE exchange ( p < 0.001) and textured TE ( p = 0.017) led to longer operative times. Conclusion As many surgeons have transitioned away from textured implants, our study shows that smooth TEs have similar outcomes to the textured alternatives.

Esophageal adenocarcinoma with metastasis to the prostatic urethra and bladder.

Metastatic esophageal adenocarcinoma to the urinary bladder is extremely rare and aggressive. We discuss here the case of an 83-year-old male with history of esophageal adenocarcinoma treated with chemoradiation therapy and esophagectomy who presented with gross hematuria and lower urinary tract symptoms. Pathology of the bladder tumor after transurethral resection demonstrated invasive adenocarcinoma of both the bladder and the prostatic urethra consistent with metastatic esophageal adenocarcinoma.

Association Between a 22-feature Genomic Classifier and Biopsy Gleason Upgrade During Active Surveillance for Prostate Cancer.

BACKGROUND: Although the Decipher genomic classifier has been validated as a prognostic tool for several prostate cancer endpoints, little is known about its role in assessing the risk of biopsy reclassification for patients on active surveillance, a key event that often triggers treatment. OBJECTIVE: To evaluate the association between Decipher genomic classifier scores and biopsy Gleason upgrading among patients on active surveillance. DESIGN SETTING AND PARTICIPANTS: This was a retrospective cohort study among patients with low- and favorable intermediate-risk prostate cancer on active surveillance who underwent biopsy-based Decipher testing as part of their clinical care. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the association between the Decipher score and any increase in biopsy Gleason grade group (GG) using univariable and multivariable logistic regression. We compared the area under the receiver operating characteristic curve (AUC) for models comprising baseline clinical variables with or without the Decipher score. RESULTS AND LIMITATIONS: We identified 133 patients for inclusion with a median age of 67.7 yr and median prostate-specific of 5.6 ng/ml. At enrollment, 75.9% had GG1 and 24.1% had GG2 disease. Forty-three patients experienced biopsy upgrading. On multivariable logistic regression, the Decipher score was significantly associated with biopsy upgrading (odds ratio 1.37 per 0.10 unit increase, 95% confidence interval [CI] 1.05-1.79; p = 0.02). The Decipher score was associated with upgrading among patients with biopsy GG 1 disease, but not GG2 disease. The discriminative ability of a clinical model (AUC 0.63, 95% CI 0.51-0.74) was improved by integration of the Decipher score (AUC 0.69, 95% CI 0.58-0.80). CONCLUSIONS: The Decipher genomic classifier score was associated with short-term biopsy Gleason upgrading among patients on active surveillance. PATIENT SUMMARY: The results from this study indicate that among patients with prostate cancer undergoing active surveillance, those with higher Decipher scores were more likely to have higher-grade disease found over time. These findings indicate that the Decipher test might be useful for guiding the intensity of monitoring during active surveillance, such as more frequent biopsy for patients with higher scores.

Comparison of Autologous Breast Reconstruction Complications by Type of Neoadjuvant Chemotherapy Regimen.

BACKGROUND: Neoadjuvant chemotherapy before mastectomy helps reduce tumor burden and pathologic response in breast cancer. Limited evidence exists regarding how neoadjuvant chemotherapy impacts outcomes following microvascular breast reconstruction. This study examines the effects of neoadjuvant chemotherapy regimens and schedules on microvascular breast reconstruction complication rates and also assesses the effects of neoadjuvant chemotherapy on circulating immune cells related to wound healing. METHODS: Patients who underwent neoadjuvant chemotherapy and microvascular breast reconstruction at Yale New Haven Hospital between 2013 and 2018 were identified. Demographic variables, oncologic history, chemotherapy regimens, and complication profiles were collected. Chemotherapy regimens were stratified by inclusion of anthracycline and order of taxane administration. Chi-square, Fisher's exact, and t tests were used for univariate analysis. Multivariate binary logistic regression was used to control for covariates. RESULTS: One hundred patients met inclusion criteria. On multivariate analysis, the administration of taxane first in an anthracycline-containing chemotherapy sequence was associated with increased complications (OR, 3.521; p = 0.012), particularly fat necrosis (OR, 2.481; p = 0.040). In the logistic regression model evaluating the effect of the taxane-first regimen on complication rates, the area under the curve was estimated to be 0.760 (p < 0.0001), particularly fat necrosis 0.635 (p < 0.05). The dosage of chemotherapy, number of days between neoadjuvant chemotherapy completion and surgery, and number of circulating immune cells did not significantly differ among patients who experienced complications. CONCLUSIONS: Taxane-first, anthracycline-containing neoadjuvant chemotherapy regimens were associated with increased complications, particularly fat necrosis. The increased postreconstruction complication risk must be weighed against the benefits of taxane-first regimens in improving tumor outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells.

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack. SIGNIFICANCE: Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell-intrinsic type 1 interferon response.This article is highlighted in the In This Issue feature, p. 1861.

Worse overall health status negatively impacts satisfaction with breast reconstruction.

BACKGROUND: BREAST-Q is a validated measure of patient satisfaction and health-related quality of life following breast surgery. Limited evidence exists with regard to the influence of preoperative overall health status on BREAST-Q outcomes. The American Society of Anesthesiologists (ASA) physical status classification is representative of preoperative overall health and its impact on patient-reported outcomes can be assessed. METHODS: Patients who received breast reconstruction at Yale New Haven Hospital between 2013 and 2018 and completed the BREAST-Q were enrolled in the study. Associations between BREAST-Q scores within modules and between modules and ASA were analyzed. Pearson's correlation and Spearman's Rho were used to characterize correlations between patient factors and BREAST-Q scores. Significantly correlated factors were entered into a general linear model (GLM) to control for confounding variables and isolate the effect of ASA on BREAST-Q scores. RESULTS: A total of 1136 patients underwent breast reconstruction of whom 489 patients completed the BREAST-Q. Increasing ASA indicative of worsening overall health was associated with a decreased BREAST-Q score for all modules except Physical Well-being of the Abdomen (p<0.01 to p = 0.029). In a GLM controlling for relevant covariates, ASA remained a significant contributor for all modules except Physical Well-being of the Chest (p<0.01 to p = 0.021). BREAST-Q scores decreased by approximately twice as much from ASA 1 to 2 compared to ASA 2 to 3. CONCLUSION: ASA classification is an independent predictor of BREAST-Q patient-reported outcomes following breast reconstruction. Communicating the potential impact of overall health may help reduce the discrepancy in postoperative satisfaction across ASA classifications.

Hdac3 is an epigenetic inhibitor of the cytotoxicity program in CD8 T cells.

Cytotoxic T cells play a key role in adaptive immunity by killing infected or cancerous cells. While the transcriptional control of CD8 T cell differentiation and effector function following T cell activation has been extensively studied, little is known about epigenetic regulation of these processes. Here we show that the histone deacetylase HDAC3 inhibits CD8 T cell cytotoxicity early during activation and is required for persistence of activated CD8 T cells following resolution of an acute infection. Mechanistically, HDAC3 inhibits gene programs associated with cytotoxicity and effector differentiation of CD8 T cells including genes encoding essential cytotoxicity proteins and key transcription factors. These data identify HDAC3 as an epigenetic regulator of the CD8 T cell cytotoxicity program.