Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche.

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

scHumanNet: a single-cell network analysis platform for the study of cell-type specificity of disease genes.

A major challenge in single-cell biology is identifying cell-type-specific gene functions, which may substantially improve precision medicine. Differential expression analysis of genes is a popular, yet insufficient approach, and complementary methods that associate function with cell type are required. Here, we describe scHumanNet (https://github.com/netbiolab/scHumanNet), a single-cell network analysis platform for resolving cellular heterogeneity across gene functions in humans. Based on cell-type-specific gene networks (CGNs) constructed under the guidance of the HumanNet reference interactome, scHumanNet displayed higher functional relevance to the cellular context than CGNs built by other methods on single-cell transcriptome data. Cellular deconvolution of gene signatures based on network compactness across cell types revealed breast cancer prognostic markers associated with T cells. scHumanNet could also prioritize genes associated with particular cell types using CGN centrality and identified the differential hubness of CGNs between disease and healthy conditions. We demonstrated the usefulness of scHumanNet by uncovering T-cell-specific functional effects of GITR, a prognostic gene for breast cancer, and functional defects in autism spectrum disorder genes specific for inhibitory neurons. These results suggest that scHumanNet will advance our understanding of cell-type specificity across human disease genes.

Safety and feasibility of single-port surgery for posterior retroperitoneal adrenalectomy using the da Vinci SP robotic system: a retrospective cohort study.

BACKGROUND: This study demonstrates our experience of single-port robotic posterior retroperitoneal adrenalectomy (RPRA) using the da Vinci SP robot system and evaluates its technical feasibility and surgical outcomes. METHODS: We conducted a retrospective analysis of 250 RPRAs, including 117 conventional 3-port RPRAs, 103 reduced 2-port RPRAs, and 30 single-port RPRAs. Each RPRA type was compared by analyzing 30 patients in the early phase of surgery. RESULTS: All patients who underwent single-port RPRA showed excellent surgical outcomes. Age, sex, BMI, and tumor location site did not significantly differ between the three groups. In the early phase, the size of the adrenal tumor was similar between three groups, and it tended to increase as the number of ports increased (p < 0.001). The mean operation time was shorter for patients who underwent single-port RPRA than those who underwent RPRA types (p < 0.001). The numeric rating scale score did not significantly differ between the groups on most days. No major complications were observed, and no patients were converted to open surgery or required additional port insertion. CONCLUSION: Single-port RPA using the da Vinci SP robotic system showed the effectiveness of the surgical procedure and improved cosmetic outcomes for patients, while also enabling surgeons to perform operations with greater ease and convenience. Therefore, single-port RPRA could be a good alternative option for the treatment of adrenal tumors in selected situations.

Associations of patient-generated subjective global assessment (PG-SGA) and NUTRISCORE with survival in gastric cancer patients: timing matters, a retrospective cohort study.

BACKGROUND: The timing of nutritional assessment may be important to treat cancer patients and predict their prognosis. This study examined whether Patient-Generated Subjective Global Assessment (PG-SGA) and NUTRISCORE scores were associated with survival among gastric cancer patients who underwent surgery and chemotherapy and whether the timing of the assessment after surgery mattered. METHODS: A total of 952 gastric cancer patients (622 men and 330 women) were included in this retrospective cohort study. The PG-SGA and NUTRISCORE scores were calculated at 1 month (n = 952), 2 months (n = 657), and 3 months (n = 294) after surgery. Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The PG-SGA scores assessed at 1 month after gastrectomy were not associated with survival. However, high PG-SGA scores at 2 months after gastrectomy (median = 65 days) were associated with an increased risk of mortality; the HR (95% CI) was 2.26 (1.22-4.21) for 9-11 vs. ≤ 5 of PG-SGA scores. When we included patients who received all three consecutive consultations, HR (95% CI) was 2.56 (1.02-6.42) for ≥ 9 (malnutrition) vs. ≤ 8 of PG-SGA scores assessed at 3 months after surgery (median days = 98 days). Likewise, high NUTRISCORE scores assessed at the 3-month follow-up were associated with higher mortality; the HR (95% CI) was 3.84 (1.18-12.55) for ≥ 7 vs. ≤ 4 of NUTRISCORE scores. CONCLUSION: Malnutrition assessed with the PG-SGA and NUTRISCORE at 2 to 3 months after gastrectomy was associated with poor survival among gastric cancer patients. Our findings suggest that the timing of the nutritional evaluation may be important in identifying and treating malnutrition related to gastric cancer prognosis.

The association between the type of anesthesia and hemodynamic instability during pheochromocytoma surgery: a retrospective cohort study.

BACKGROUND: Pheochromocytoma often carries a risk for perioperative hemodynamic instability (HDI). The aim of this study is to evaluate the risk factors of intraoperative HDI during minimally invasive posterior retroperitoneal adrenalectomy (PRA) for pheochromocytoma. MATERIALS AND METHODS: This retrospective study analyzed the prospectively collected data of 172 patients who underwent laparoscopic PRA or robotic PRA for pheochromocytoma between January 2014 and December 2020 at a single tertiary center. The patients were divided into two groups according to the intraoperative hypertensive event of systolic blood pressure (> 160 mmHg). The clinical manifestations and perioperative hemodynamic conditions were analysed. RESULTS: In the multivariate logistic regression analysis, the tumor size (> 3.4 cm) [OR 3.14, 95% confidence intervals (CI) (1.48-6.64), p = 0.003], type of preoperative alpha-blocker (selective type) [OR 3.9, 95% CI (1.52-10.02), p = 0.005], preoperative use of beta-blockers [OR 3.94, 95% CI (1.07-14.49), p = 0.039] and type of anesthesia [total intravenous anesthesia (TIVA) vs. balanced anesthesia (BA)] [OR 2.57, 95% CI (1.23-5.38), p = 0.012] were determined as independent risk factors of intraoperative hypertensive events during minimally invasive adrenalectomy. CONCLUSIONS: The type of anesthesia was independently associated with intraoperative HDI along with larger tumor size, type of preoperative alpha-blocker and the use of preoperative beta-blockers. TIVA increased the risk of intraoperative hypertensive events compared with BA. Thus, the consideration of the type of anesthesia prior to adrenal surgery for pheochromocytoma along with the use of preoperative non-selective alpha-blockers may be beneficial in minimizing the risk of intraoperative HDI.

TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions.

Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF-target interactions is a key step toward understanding the regulatory circuitry underlying complex traits such as human diseases. We previously published a reference TF-target interaction database for humans-TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)-which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF-target interactions in mice, including 6552 TF-target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF-target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.

Dynamic risk stratification system in post-lobectomy low-risk and intermediate-risk papillary thyroid carcinoma patients.

OBJECTIVE: The dynamic risk stratification (DRS) and its current definition of each response-to-therapy category in post-lobectomy papillary thyroid carcinoma (PTC) patients have not been well studied. This study aimed to validate the DRS system and to investigate useful thyroglobulin (Tg) or anti-Tg antibody (Ab)-related parameters in defining each response-to-therapy category. DESIGN: Retrospective observational study. PATIENTS: This historical cohort study included 619 patients with PTC treated by thyroid lobectomy. MEASUREMENTS: All enrolled participants were stratified according to the American Thyroid Association (ATA) initial risk stratification system and DRS system, respectively. The association between these stratifications and structural recurrence was evaluated. RESULTS: The median follow-up period was 103 months. Structural recurrence occurred in 1.6% of the patients with excellent response, 3.8% of those with indeterminate response, 2.9% of those with biochemical incomplete response, and all patients with structural incomplete response. Five (1.5%) of the low-risk patients and 14 (5.0%) of the intermediate-risk patients had structural recurrence. The disease-free survival curves showed significant differences according to the DRS (P < .001) and ATA initial risk stratification (P = .012), respectively. The proportion of variance explained the DRS system and ATA risk stratification system for structural recurrence was 32.4% and 29.4%, respectively. A thyroid-stimulating hormone (TSH) level >2.75 µU/mL at 1 year after the initial operation (P < .001) was the only valuable risk factor for structural recurrence identified in this study. CONCLUSION: The long-term postoperative management of PTC patients treated with thyroid lobectomy could be guided based on the DRS.

Dynamic risk stratification in papillary thyroid carcinoma measuring 1 to 4 cm.

BACKGROUND AND OBJECTIVES: This study aimed to validate the dynamic risk stratification (DRS) system, evaluate its correlation with structural recurrence, and assess the clinicopathological risk factors associated with a nonexcellent response to initial therapy in patients with papillary thyroid cancer (PTC) measuring 1 to 4 cm. METHODS: A total of 762 patients with classic PTC measuring 1 to 4 cm were classified into four categories based on their response to initial therapy 2 years postoperatively. RESULTS: Structural recurrent disease occurred in 4.7%, 17.1%, 48.4%, and 83.9% of patients with excellent, indeterminate, biochemically incomplete, and structurally incomplete responses, respectively, at the time of the last follow-up. The response to initial therapy in the DRS was one of the independent risk factors for structural recurrence. The disease-free survival curves of patients with different responses showed significant differences (P < 0.001). Extensive extrathyroidal extension, lymph node (LN) metastasis, number of metastatic LNs greater than 2.0, metastatic LN ratio greater than 0.22, and extranodal extension were independent risk factors for nonexcellent response to initial therapy. CONCLUSIONS: DRS can be a useful tool in predicting structural recurrence and guiding postoperative management and follow-up strategies in patients with PTC measuring 1 to 4 cm.

Effect of nutritional status on survival outcome of diffuse large B-cell lymphoma patients treated with rituximab-CHOP.

The impact of pretreatment nutritional status on the treatment outcome of non-Hodgkin lymphoma has never been explored. Among the 953 patients who were registered in a prospective cohort at Samsung Medical Center., we analyzed 262 patients who had been treated with Ruximab-cyclophosphamide, doxorubicin, vincristine, and prednisone for newly diagnosed diffuse large B-cell lymphoma (DLBCL) and for whom data were available regarding pretreatment nutritional status. Nutritional status at diagnosis was assessed by triceps skin fold (TSF), mid-arm muscle circumference (MAMC), body mass index (BMI), serum albumin, prealbumin, and transferrin. For patients aged 60 yr and older, poor performance and higher tumor burden were associated with malnourishment represented by albumin <3.5 g/dL, prealbumin < 17 g/dL, and transferrin <170 mg/L. Lower BMI (<20), serum albumin, prealbumin, and transferrin were identified as risk factors for febrile neutropenia in univariate analysis, but not in multivariate analysis. In the univariate analysis for OS, all nutritional parameters except MAMC showed a significant association with survival. However, BMI was the only parameter that was independently prognostic for OS in the multivariate analysis (P = 0.031; hazards ratio = 3.32). Nutritional insufficiency encountered in DLBCL patients might influence the occurrence of treatment-related toxicity and poor survival outcome of patients.

Joint analysis of mutational and transcriptional landscapes in human cancer reveals key perturbations during cancer evolution.

BACKGROUND: Tumors are able to acquire new capabilities, including traits such as drug resistance and metastasis that are associated with unfavorable clinical outcomes. Single-cell technologies have made it possible to study both mutational and transcriptomic profiles, but as most studies have been conducted on model systems, little is known about cancer evolution in human patients. Hence, a better understanding of cancer evolution could have important implications for treatment strategies. RESULTS: Here, we analyze cancer evolution and clonal selection by jointly considering mutational and transcriptomic profiles of single cells acquired from tumor biopsies from 49 lung cancer samples and 51 samples with chronic myeloid leukemia. Comparing the two profiles, we find that each clone is associated with a preferred transcriptional state. For metastasis and drug resistance, we find that the number of mutations affecting related genes increases as the clone evolves, while changes in gene expression profiles are limited. Surprisingly, we find that mutations affecting ligand-receptor interactions with the tumor microenvironment frequently emerge as clones acquire drug resistance. CONCLUSIONS: Our results show that lung cancer and chronic myeloid leukemia maintain a high clonal and transcriptional diversity, and we find little evidence in favor of clonal sweeps. This suggests that for these cancers selection based solely on growth rate is unlikely to be the dominating driving force during cancer evolution.

Diagnostic consistency between computed tomography and adrenal vein sampling of primary aldosteronism: leading to successful curative outcome after adrenalectomy; a retrospective study.

BACKGROUND: Adrenal computed tomography (CT) is a useful tool for locating adrenal lesion in primary aldosteronism (PA) patients. However, adrenal vein sampling (AVS) is considered as a gold standard for subtype diagnosis of PA. The aim of this study was to investigate the consistency of CT and AVS for the diagnosis of PA subtypes and evaluate the concordance of surgical outcomes. MATERIALS AND METHODS: This retrospective study included 264 PA patients having both CT and AVS. Diagnostic consistency between CT and AVS was accessed, and clinical and biochemical outcomes were evaluated at 6 months after adrenalectomy. RESULTS: Of all, 207 (78%) had a CT unilateral lesion, 31 (12%) CT bilateral lesion, and 26 (10%) CT bilateral normal findings. Among the CT unilateral lesion group, 138 (67%) had ipsilateral AVS lateralization. For CT bilateral lesion and bilateral normal, AVS unilateral lateralization was found in 17 (55%) and 2 (8%), respectively. The consistency between CT lesion and AVS lateralization including CT unilateral with AVS ipsilateral, and CT bilateral lesion with AVS bilateral patients was 63.8% (152/238). Of 77 patients with available data out of 138 patients who underwent adrenalectomy with consistency between CT and AVS, the clinical success rate was 96%, for 17 inconsistency patients out of 22 patients who underwent adrenalectomy, the clinical success rate was 94% after adrenalectomy following the lateralization result of AVS. CONCLUSION: CT is a useful tool to diagnose the adrenal lesion in PA patients. However, AVS is more sufficient to detect the unilateral PA subtype, which could provide curable treatment to surgical candidates of PA such that AVS can identify patients with contralateral PA in CT unilateral lesion and unilateral PA in CT bilateral lesion. The surgical outcome was successful when an adrenalectomy was performed according to the AVS lateralization result.

Predictive factors for persistent hypercalcemia following parathyroidectomy in patients with persistent hyperparathyroidism after kidney transplantation: a retrospective cohort study.

BACKGROUND: Surgery for irreversible hyperparathyroidism is the preferred management for kidney transplant patients. The authors analyzed the factors associated with persistent hypercalcemia after parathyroidectomy in kidney transplant patients and evaluated the appropriate extent of surgery. MATERIALS AND METHODS: The authors retrospectively analyzed 100 patients who underwent parathyroidectomy because of persistent hyperparathyroidism after kidney transplantation at a tertiary medical center between June 2011 and February 2022. Patients were divided into two groups: 22 with persistent hypercalcemia after parathyroidectomy and 78 who achieved normocalcemia after parathyroidectomy. Persistent hypercalcemia was defined as having sustained hypercalcemia (≥10.3 mg/dl) 6 months after kidney transplantation. The authors compared the biochemical and clinicopathological features between the two groups. Multivariate logistic regression analysis was used to identify potential risk factors associated with persistent hypercalcemia following parathyroidectomy. RESULTS: The proportion of patients with serum intact parathyroid hormone (PTH) level is greater than 65 pg/ml was significantly high in the hypercalcemia group (40.9 vs. 7.7%). The proportion of patients who underwent less than subtotal parathyroidectomy was significantly high in the persistent hypercalcemia group (17.9 vs. 54.5%). Patients with a large remaining size of the preserved parathyroid gland (≥0.8 cm) had a high incidence of persistent hypercalcemia (29.7 vs. 52.6%). In the multivariate logistic regression analysis, the drop rate of intact PTH is less than 88% on postoperative day 1 (odds ratio 10.3, 95% CI: 2.7-39.1, P =0.001) and the removal of less than or equal to 2 parathyroid glands (odds ratio 6.8, 95% CI: 1.8-26.7, P =0.001) were identified as risk factors for persistent hypercalcemia. CONCLUSION: The drop rate of intact PTH is less than 88% on postoperative day 1 and appropriate extent of surgery for controlling the autonomic function were independently associated with persistent hypercalcemia. Confirmation of parathyroid lesions through frozen section biopsy or intraoperative PTH monitoring can be helpful in preventing the inadvertent removal of a parathyroid gland and achieving normocalcemia after parathyroidectomy.

Silent pheochromocytoma in adrenal incidentaloma: unveiling clinical and radiological characteristics.

Purpose: Silent pheochromocytoma refers to tumors without signs and symptoms of catecholamine excess. This study aimed to clarify the clinical, radiological characteristics, and perioperative features of silent pheochromocytomas diagnosed after adrenalectomy for adrenal incidentaloma. Methods: Medical records of patients who underwent adrenalectomy for adrenal incidentaloma and were subsequently diagnosed with silent pheochromocytoma between January 2000 and December 2020 were retrospectively reviewed for demographic, diagnostic, surgical, and pathological findings. Results: Of the 130 patients who underwent adrenalectomy for incidentaloma, 8 (6.1%) were diagnosed with silent pheochromocytoma. Almost all patients had no hypertensive symptoms and their baseline hormonal levels remained within normal ranges. All patients exhibited tumor size >4 cm, precontrast Hounsfield unit >10, and absolute washout <60%. Intraoperative hypertensive events were noted in 2 patients (25.0%) in whom antiadrenergic medications were not administered. All patients in the intraoperative hypertensive event group exhibited atypical features on CT, whereas 83.3% of patients in the non-intraoperative hypertensive event group showed atypical features on CT imaging. Conclusion: Silent pheochromocytomas share radiological traits with malignant adrenal tumors. Suspicious features on CT scans warrant surgical consideration for appropriate treatment. Administering alpha-blockers can enhance hemodynamic stability during adrenalectomy in suspected silent pheochromocytoma cases.

Effect of thyroid-stimulating hormone suppression on quality of life in thyroid lobectomy patients: interim analysis of a multicenter, randomized controlled trial in low- to intermediate-risk thyroid cancer patients (MASTER study).

Purpose: Current clinical practices favor less or no thyroid-stimulating hormone (TSH) suppression for low- to intermediate-risk thyroid cancer patients who receive thyroid lobectomy. The association of TSH suppression on health-related quality of life (HR-QoL) in patients after thyroid lobectomy is not well studied. This study aimed to evaluate the effect of TSH suppression on patient HR-QoL after thyroid lobectomy. Methods: This study included patients enrolled in an ongoing, multicenter, randomized controlled study investigating the effects of TSH suppression. Patients were randomized to either the low-TSH group (TSH target range, 0.3-1.99 µIU/mL) or the high-TSH group (TSH target range, 2.0-7.99 µIU/mL). The HR-QoL, hyperthyroidism symptom, and depression symptom questionnaires performed preoperatively and 2 weeks and 3 months postoperatively were evaluated. Results: Total of 669 patients (low-TSH group, 340; high-TSH group, 329) were included. Although total HR-QoL score changes were not different between the 2 groups, the high-TSH group had a significantly higher score in the physical domain at postoperative 3 months (P = 0.046). The 2 groups did not have significant differences in hyperthyroidism and depression scores. Conclusion: In the short-term postoperative period, the physical HR-QoL scores in thyroid lobectomy patients were better when they did not receive TSH suppression. This study suggests the importance of considering HR-QoL when setting TSH suppression targets in thyroid lobectomy patients.

Exploring the Benefits of a Reduced-Port Approach in Robotic Posterior Retroperitoneoscopic Adrenalectomy: A Comparative Study of the Two-Port and Three-Port Techniques.

Background: Robotic adrenalectomy has become a surgical treatment option for benign and selected malignant adrenal diseases. We aimed to evaluate the eligibility of two-port robotic posterior retroperitoneoscopic adrenalectomy (PRA) as an alternative to the conventional three-port technique by comparing their surgical outcomes. Materials and Methods: This retrospective cohort study compared the clinicopathological factors and surgical outcomes among 197 patients who underwent two-port or three-port robotic adrenalectomy between 2016 and 2020 in a single tertiary center. For further evaluation, propensity score matching was performed to reduce the selection bias in population characteristics. Results: Patients were categorized by the number of ports (two-port group, 87; and three-port group, 110). The two-port group compared with the three-port group was significantly older (P = .006) and had a smaller mean tumor size (P = .003) and shorter mean operation time (P = .001). Upon comparing clinicopathologic characteristics according to adrenal disorders, for pheochromocytoma, the three-port group had a larger tumor size and a longer operation time. For Cushing's syndrome, the operation time was short and numeric rating scale pain score was significantly low in the two-port group. After propensity score matching, the two-port group had a short operation time and a significantly low postoperative pain score (P < .05). Predictive factors associated with prolonged operation time included male gender, an increased number of ports, and large tumor size. Conclusions: The two-port technique resulted in a shorter operation time and lower pain score compared with the three-port technique. The two-port technique may be a safe alternative to the conventional three-port technique for robotic PRA.

Single-cell analysis reveals cellular and molecular factors counteracting HPV-positive oropharyngeal cancer immunotherapy outcomes.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear. METHODS: To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets. RESULTS: We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4+ follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8+ resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161+ Trm and changes in tumor size. CONCLUSIONS: We found that CD161+ Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers. TRIAL REGISTRATION NUMBER: NCT03737968.

Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.

One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

MCDAL: Maximum Classifier Discrepancy for Active Learning.

Recent state-of-the-art active learning methods have mostly leveraged generative adversarial networks (GANs) for sample acquisition; however, GAN is usually known to suffer from instability and sensitivity to hyperparameters. In contrast to these methods, in this article, we propose a novel active learning framework that we call Maximum Classifier Discrepancy for Active Learning (MCDAL) that takes the prediction discrepancies between multiple classifiers. In particular, we utilize two auxiliary classification layers that learn tighter decision boundaries by maximizing the discrepancies among them. Intuitively, the discrepancies in the auxiliary classification layers' predictions indicate the uncertainty in the prediction. In this regard, we propose a novel method to leverage the classifier discrepancies for the acquisition function for active learning. We also provide an interpretation of our idea in relation to existing GAN-based active learning methods and domain adaptation frameworks. Moreover, we empirically demonstrate the utility of our approach where the performance of our approach exceeds the state-of-the-art methods on several image classification and semantic segmentation datasets in active learning setups.

Contralateral Low-to-Intermediate Suspicion Nodule Is Not a Contraindication for Lobectomy in Patients with Papillary Thyroid Carcinoma.

Background: The optimal extent of surgery for unilateral papillary thyroid carcinoma (PTC) with contralateral nodules remains unclear. This study evaluated the long-term outcomes in a large cohort of patients with unilateral PTC and contralateral low-to-intermediate suspicious nodules who underwent lobectomy. Methods: This retrospective cohort study included patients with unilateral PTC who underwent lobectomy between January 2016 and December 2017 at Asan Medical Center in Korea. Patients were divided into two groups, those with and without contralateral nodules at the time of lobectomy: the Present group and the Absent group. All contralateral nodules observed at the time of surgery and during follow-up were evaluated. Results: The study cohort consisted of 1761 patients (1879 nodules), including 700 (39.8%) with and 1061 (60.2%) without contralateral nodules. The median size of the contralateral nodules was 0.5 cm. After a median follow-up of 59 months, the median growth of the contralateral nodules in the Present group was 0.1 cm (range, -3.4 to 4.7 cm). Of the contralateral nodules present at the time of lobectomy, 54.7% remained unchanged, decreased in size, or disappeared; whereas 14.8% increased ≥0.3 cm. Of the 700 patients with contralateral nodules, 20 (2.9%) were diagnosed with contralateral PTC. The 5-year contralateral PTC disease-free survival rates in patients with and without contralateral nodules were 98.2% and 99.3% (p = 0.003), respectively, whereas the 5-year recurrence-free survival rates did not differ significantly in these two groups. Of the 39 patients who underwent completion thyroidectomy, 2 (5.1%) experienced permanent hypocalcemia. Conclusions: Lobectomy may be a safe and feasible initial treatment option for patients with unilateral low-risk PTC and contralateral low-to-intermediate suspicious nodules.

Short-term outcome of adrenal radiofrequency ablation of adrenal cysts: a single-center experience.

Percutaneous thermal ablation is a minimally invasive treatment for liver, kidney, lung, bone, and thyroid tumors. This treatment also has been used to treat adrenal tumors in patients, but there is no evidence for the efficacy of thermal ablation of adrenal cysts. The present study was performed to analyze the experience of a single center with percutaneous radiofrequency ablation (RFA) of adrenal cysts and to evaluate its efficacy. The present study enrolled all patients who underwent percutaneous RFA for unilateral adrenal cysts from 2019 to 2021. All patients underwent USG-guided percutaneous aspiration of cystic fluid, followed by RFA. A total nine patients with adrenal cysts were included in this study. All of them underwent technically successful percutaneous RFA, with no immediate complication. Follow-up CT 3 months after RFA showed that six of the nine adrenal cysts showed good responses, with reductions in cyst volume ranging from 86.4 to 97.9%. One patient had poor response in the cyst size (volume reduction rate 11.2%). She underwent secondary RFA with resulting that the cyst volume reduced by 91.1%. After a median follow-up period of 17.2 months, eight patients showed no evidence of regrowth. The patient, who showed evidence of regrowth, declined any other treatment and has been under regular surveillance. None of the nine patients developed adrenal insufficiency during the follow-up period. In conclusion, percutaneous RFA is a safe and effective minimally invasive treatment for adrenal cysts, suggesting that percutaneous RFA may be a good alternative option in selected patients.