CD8+ T cell activation in cancer comprises an initial activation phase in lymph nodes followed by effector differentiation within the tumor.

Improvements in tumor immunotherapies depend on better understanding of the anti-tumor T cell response. By studying human tumor-draining lymph nodes (TDLNs), we found that activated CD8+ T cells in TDLNs shared functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. The phenotype and TCR overlap suggested that these TDLN cells were precursors to tumor-resident stem-like CD8+ T cells. Murine tumor models revealed that tumor-specific CD8+ T cells were activated in TDLNs but lacked an effector phenotype. These stem-like cells migrated into the tumor, where additional co-stimulation from antigen-presenting cells drove effector differentiation. This model of CD8+ T cell activation in response to cancer is different from that of canonical CD8+ T cell activation to acute viruses, and it proposes two stages of tumor-specific CD8+ T cell activation: initial activation in TDLNs and subsequent effector program acquisition within the tumor after additional co-stimulation.

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

Impact of COVID-19 pandemic on physician-scientist trainees to faculty one year into the pandemic.

PURPOSE: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on stress levels, research productivity, and optimism for physician-scientists at all levels of training. METHODS: A multi-institutional cross-sectional survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. RESULTS: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). CONCLUSIONS: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Regarding a human costoscapular joint by Prof. Dr. H. von Luschka (1870): A translation.

Knowledge of variant anatomy was important during the time of Dr. Hubert von Luschka (1820-1875) and continues to be of relevance in current practice to prevent medical and surgical errors and to improve patient outcomes. Dr. H. von Luschka described an anatomical variant observed in the left scapula of a 40-year-old male: a connection between the medial superior angle of the scapula, piercing through the serratus posterior muscle to connect via a synovial capsule to the articular surface of the thoracic wall. The clinical relevance of this so-called "Luschka's tubercle" of the shoulder continues to be discussed. This translation is intended to broaden access to this hallmark manuscript to a wide audience of English readers. The introduction places the manuscript in the context of historical and current discussions. Three authors, all proficient in the German and English languages and educated in the anatomy of the shoulder, conducted the translation. The skeletal process that is part of the described joint structure appears similar to what is now called Luschka's tubercle. The full structure, including its connecting parts, are not currently included in anatomical nomenclature. In conclusion, Luschka's text and named tubercle continue to contribute to the discussion of scapulothoracic joint disorders.

Translation of Runge's 1873 publication "On the etiology and treatment of writer's cramp": The first description of "tennis elbow".

This publication by Dr Ferdinand Runge is ubiquitously credited as first to describe the symptoms, pathology, and treatment of patients with lateral epicondylosis (tennis elbow). However, the main focus of his work was to provide insight into causes of writer's cramp and treatments for the condition, elegantly illustrated in four case reports. This work, recently cited as unavailable, is written in German. Given the high frequency of citations in the English literature, it was considered useful to translate it into English to widen access to a broader readership. The purpose of this project was briefly to introduce the life and clinical expertise of Dr. Ferdinand Runge and the content of his work, followed by a translation of the entire manuscript into English. The paper was translated by the three authors using a process of sequential consensus. All are proficient in German and English, with clinical expertise in both topics. A brief reflection is provided to place Dr Runge's observations, clinical reasoning, and contemporaneously available treatments in the context of current thinking about lateral epicondylalgia. Dr. Runge shares his expertise, carefully reporting pertinent examination findings for each case, sharing hypotheses about the etiology of writer's cramp, and using the effectiveness of his applied treatment as confirmation. He concludes that careful evaluation of the patient's activities that hindered writing prior to the onset of the writer's cramp is key to managing this ailment. The topics addressed in this classic work are still thought-provoking.

Lateral epicondylosis: A literature review to link pathology and tendon function to tissue-level treatment and ergonomic interventions.

BACKGROUND: Common treatments for lateral epicondylosis (LE) focus on tissue healing. Ergonomic advice is suggested broadly, but recommendations based on biomechanical motion parameters associated with functional activities are rarely made. This review analyzes the role of body functions and activities in LE and integrates the findings to suggest motion parameters applicable to education and interventions relevant to activities and life roles for patients. PURPOSE: This study examines LE pathology, tendon and muscle biomechanics, and population exposure outlining potentially hazardous activities and integrates those to provide motion parameters for ergonomic interventions to treat or prevent LE. A disease model is discussed to align treatment approaches to the stage of LE tendinopathy. STUDY DESIGN: Integrative review METHODS: We conducted in-depth searches using PubMed, Medline, and government websites. All levels of evidence were included, and the framework for behavioral research from the National Institutes of Health was used to synthesize ergonomic research. RESULTS: The review broadened the diagnosis of LE from a tendon ailment to one affecting the enthesis of the capitellum. It reinforced the continuum of severity to encompass degeneration as well as regeneration. Systematic reviews confirmed the availability of evidence for tissue-based treatments, but evidence of well-defined harm reducing occupational interventions was scattered amongst evidence levels. Integration of biomechanical studies and population information gave insight into types of potentially hazardous activities and provided a theoretical basis for limiting hazardous exposures to wrist extensor tendons by reducing force, compression, and shearing during functional activities. CONCLUSIONS: These findings may broaden the first treatment approach from a passive, watchful waiting into an active exploration and reduction of at-risk activities and motions. Including the findings into education modules may provide patients with the knowledge to lastingly reduce potentially hazardous motions during their daily activities, and researchers to define parameters of ergonomic interventions.

Psychosocial influences in the development of cumulative trauma disorders.

STUDY DESIGN: This study is a single-phase, qualitative study using grounded theory methodology. INTRODUCTION: Cumulative trauma disorders (CTDs) are musculoskeletal disorders that impact health and productivity. CTD risk factors are present in the workplace, home, and community. Occupational and physical therapists specializing in hand and upper extremity rehabilitation (hand therapists) are widely involved with this population. Hand therapists often employ a medical model in the assessment and treatment of these conditions; however, the medical model has not proven to be consistently effective in relieving symptoms or producing a durable return to daily living activities. PURPOSE OF THE STUDY: The purpose of this study was to explore the lived experiences of individuals diagnosed with CTD, and investigate the psychosocial phenomena influencing CTD development as an impediment to occupational performance. METHODS: The principal investigator recruited 11 participants who met specific inclusion criteria, then used semi-structured interviews aimed at exploring the lived experiences of the participants while investigating the psychosocial phenomenon influencing CTD development. Interviews were transcribed and analyzed using a process of constant comparison, up until saturation occurred. Trustworthiness techniques were used in the data analysis phase and included peer reviews and member checking. FINDINGS: The findings suggest that many psychosocial factors contribute to the development and impact of CTDs, at both onset of symptoms and throughout the duration of the condition. A significant number of contextual factors influence participants' function, behavior, relationships, and the course of medical care. Themes derived from the participants' expressions, included the following: 1) an initial strategy of "work through the pain," can be detrimental to symptom resolution and leads to progressive failure to meet role expectations, 2) a pervasive notion of CTDs as "an invisible disability," leaving participants feeling isolated and frustrated when significant others fail to offer support or reject them, 3) participants often delayed reporting symptom development to employers, family members, and medical personnel, risking permanent injury and disability, 4) a "stigma" is attached to CTDs that encourages isolation; however, the social support of even one significant other in a person's life can facilitate adaptation. DISCUSSION AND CONCLUSION: All participants experienced hardship because of their conditions; however, two of the eleven participants capably navigated the process, using past experience and support from family and employer to successfully adapt. These findings offer support that CTDs are adaptive disorders. The study's conclusion suggests a new model to describe CTD dysfunction and presents new ways of thinking for clinicians who treat the CTD population.

Rater Variation in Ultrasound Detection of Dorsal Cortex Screw Protrusion in Fixed-Angle Volar Plating of the Distal Radius.

This study evaluates rater accuracy and variation for the purpose of using intraoperative ultrasound (US) imaging to detect dorsal screw protrusion during fixed-angle volar plating of distal radius fractures. Stabilizing volar plates and screws with varying lengths of dorsal protrusion were applied to 10 cadaver wrist pairs. After a brief training session, seven surgeons without prior ultrasound experience assessed screw protrusion on two separate occasions using a diagnostic ultrasound machine. Screw protrusions were visually confirmed after data collection was completed. Statistical analyses included percent agreement and Cohen's kappa for accuracy and intra- and inter-rater reliability, sensitivity, specificity, and positive and negative predictive values. Only two out of seven raters met acceptable levels of accuracy and consistency. Our findings inform us that accuracy and consistency of ultrasound-guided detection of dorsal screw protrusion are negatively impacted by rater variation. Further investigations are needed to improve rater effectiveness. (Journal of Surgical Orthopaedic Advances 28(4):260-267, 2019).

A geographical workforce analysis of hand therapy services in relation to US population characteristics.

INTRODUCTION: A paucity of work force planning literature exists for hand therapy services. PURPOSE: This descriptive study aimed to map the geographical distribution of US Certified Hand Therapists (CHTs) and describe characteristics of US populations living in respective CHT workplace Zip Code Tabulation Areas (ZCTAs). METHODS: A de-identified Zip Code list of all active CHTs through April 2016 from the Hand Therapy Certification Commission, included 5572 CHTs with US ZCTAs. The CHT ZCTAs were matched with population parameters "rurality", "poverty" and "race and ethnicity" from the 2010 US Census and 2014 American Community Survey. RESULTS: The 5,572 CHTs practice ZCTAs mostly overlapped with high density US population areas, covering just 9% of the total number of 33,120 US ZCTAs. The population in CHT ZCTAs was 1) urban in nature, 2) with lower poverty rates than ZCTAs without CHTs, and 3) mostly reflecting US race and ethnicity population distribution. Only 3.7% of CHTs worked in large concentrations of 11 to 26 CHTs per ZCTA near or in urban centers. Most CHTs, 67%, worked in one to three CHTs per ZCTA concentrations, contributing to a larger geographic spread of CHT locations than expected. DISCUSSION AND CONCLUSION: This study provides a foundational snap shot of the distribution, the potential availability, of the 2016 CHT workforce in the context of US population characteristics. It may serve as baseline for supply and demand studies and interventions to grow the CHT profession and optimize the distribution of CHTs to better meet population needs.

Validity and reliability of the Functional Dexterity Test in children.

STUDY DESIGN: Clinical measurement study. INTRODUCTION: The Functional Dexterity Test (FDT) has not been validated in children. PURPOSE OF THE STUDY: To determine reliability and validity of the FDT in a pediatric population. METHODS: Intraclass Correlation Coefficients (ICCs) were used to calculate interrater and test-retest reliability in typically developing children. Pearson correlation coefficients were used to compare FDT speed with the Jebsen-Taylor Hand Function Test (JHFT) and with 2 activities of daily living tasks to establish validity in children with congenital hand differences. RESULTS: The FDT demonstrated excellent interrater (ICC, 0.99) and test-retest (ICC, 0.90) reliability. Pearson correlation coefficients exceeded 0.67 for JHFT subsets of fine dexterity and were all less than 0.66 for JHFT subsets of gross grasp. Correlations with the activities of daily living tasks were good to excellent. FDT speeds in TD children exceeded those of children with congenital hand differences (P < .001), demonstrating discriminant validity. DISCUSSION: Children with congenital hand differences are often treated early in life, making it important to reliably assess hand function of these young children to distinguish developmental change from changes due to interventions. The FDT can reliably measure functional progress over time, help clinicians monitor the efficacy of treatment, and provide families realistic feedback on their child's progress. CONCLUSION: The FDT is a valid and reliable instrument for the measurement of fine motor dexterity in children.

Role of the Gut Microbiota of Children in Diarrhea Due to the Protozoan Parasite Entamoeba histolytica.

BACKGROUND: An estimated 1 million children die each year before their fifth birthday from diarrhea. Previous population-based surveys of pediatric diarrheal diseases have identified the protozoan parasite Entamoeba histolytica, the etiological agent of amebiasis, as one of the causes of moderate-to-severe diarrhea in sub-Saharan Africa and South Asia. METHODS: We prospectively studied the natural history of E. histolytica colonization and diarrhea among infants in an urban slum of Dhaka, Bangladesh. RESULTS: Approximately 80% of children were infected with E. histolytica by the age of 2 years. Fecal anti-galactose/N-acetylgalactosamine lectin immunoglobulin A was associated with protection from reinfection, while a high parasite burden and expansion of the Prevotella copri level was associated with diarrhea. CONCLUSIONS: E. histolytica infection was prevalent in this population, with most infections asymptomatic and diarrhea associated with both the amount of parasite and the composition of the microbiota.

Circulating Tumor DNA in Genitourinary Cancers: Detection, Prognostics, and Therapeutic Implications.

CtDNA is emerging as a non-invasive clinical detection method for several cancers, including genitourinary (GU) cancers such as prostate cancer, bladder cancer, and renal cell carcinoma (RCC). CtDNA assays have shown promise in early detection of GU cancers, providing prognostic information, assessing real-time treatment response, and detecting residual disease and relapse. The ease of obtaining a "liquid biopsy" from blood or urine in GU cancers enhances its potential to be used as a biomarker. Interrogating these "liquid biopsies" for ctDNA can then be used to detect common cancer mutations, novel genomic alterations, or epigenetic modifications. CtDNA has undergone investigation in numerous clinical trials, which could address clinical needs in GU cancers, for instance, earlier detection in RCC, therapeutic response prediction in castration-resistant prostate cancer, and monitoring for recurrence in bladder cancers. The utilization of liquid biopsy for ctDNA analysis provides a promising method of advancing precision medicine within the field of GU cancers.

Established and emerging biomarkers of immunotherapy in renal cell carcinoma.

Immunotherapies, such as immune checkpoint inhibitors, have heralded impressive progress for patient care in renal cell carcinoma (RCC). Despite this success, some patients' disease fails to respond, and other patients experience significant side effects. Thus, development of biomarkers is needed to ensure that patients can be selected to maximize benefit from immunotherapies. Improving clinicians' ability to predict which patients will respond to immunotherapy and which are most at risk of adverse events - namely through clinical biomarkers - is indispensable for patient safety and therapeutic efficacy. Accordingly, an evolving suite of therapeutic biomarkers continues to be investigated. This review discusses biomarkers for immunotherapy in RCC, highlighting current practices and emerging innovations, aiming to contribute to improved outcomes for patients with RCC.

Renal cell carcinoma (RCC) is a type of kidney cancer. Treatments that target the body's immune system, called immunotherapies, are generally effective in RCC, but not all patients' cancer will respond (shrink or disappear) after receiving this treatment. Because of this, signals, called biomarkers, are needed to signal which patients' cancer will respond and which patients may experience unwanted side effects after treatment. This article highlights biomarkers that have been or are being studied for understanding immunotherapy in RCC.

Understanding and overcoming resistance to immunotherapy in genitourinary cancers.

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.

Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.

The Evolving Landscape of Biomarkers for Immune Checkpoint Blockade in Genitourinary Cancers.

In the past decade, immune checkpoint inhibitors (ICI) have been approved for treatment of genitourinary malignancies and have revolutionized the treatment landscape of these tumors. However, despite the remarkable success of these therapies in some GU malignancies, many patients' tumors do not respond to these therapies, and others may experience significant side effects, such as immune-related adverse events (iRAEs). Accordingly, biomarkers and improved prognostic tools are critically needed to help predict which patients will respond to ICI, predict and mitigate risk of developing immune-related adverse events, and inform personalized choice of therapy for each patient. Ongoing clinical and preclinical studies continue to provide an increasingly robust understanding of the mechanisms of the response to immunotherapy, which continue to inform biomarker development and validation. Herein, we provide a comprehensive review of biomarkers of the response to immunotherapy in GU tumors and their role in selection of therapy and disease monitoring.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

BACKGROUND: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: The treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression. RESULTS: In this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5-30). The median age at the time of ICI initiation was 63 years (IQR 56-70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043). CONCLUSIONS: Patients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.

Localized high-risk prostate cancer harbors an androgen receptor low subpopulation susceptible to HER2 inhibition.

Patients diagnosed with localized high-risk prostate cancer have higher rates of recurrence, and the introduction of neoadjuvant intensive hormonal therapies seeks to treat occult micrometastatic disease by their addition to definitive treatment. Sufficient profiling of baseline disease has remained a challenge in enabling the in-depth assessment of phenotypes associated with exceptional vs. poor pathologic responses after treatment. In this study, we report comprehensive and integrative gene expression profiling of 37 locally advanced prostate tumors prior to six months of androgen deprivation therapy (ADT) plus the androgen receptor (AR) inhibitor enzalutamide prior to radical prostatectomy. A robust transcriptional program associated with HER2 activity was positively associated with poor outcome and opposed AR activity, even after adjusting for common genomic alterations in prostate cancer including PTEN loss and expression of the TMPRSS2:ERG fusion. Patients experiencing exceptional pathologic responses demonstrated lower levels of HER2 and phospho-HER2 by immunohistochemistry of biopsy tissues. The inverse correlation of AR and HER2 activity was found to be a universal feature of all aggressive prostate tumors, validated by transcriptional profiling an external cohort of 121 patients and immunostaining of tumors from 84 additional patients. Importantly, the AR activity-low, HER2 activity-high cells that resist ADT are a pre-existing subset of cells that can be targeted by HER2 inhibition alone or in combination with enzalutamide. In summary, we show that prostate tumors adopt an AR activity-low prior to antiandrogen exposure that can be exploited by treatment with HER2 inhibitors.

Case Report: Exceptional response to nivolumab plus cabozantinib in a patient with extrarenal clear cell renal cell carcinoma.

Extrarenal clear cell renal cell carcinoma (eccRCC) is a rare type of RCC that arises in areas other than the kidney. Given its rarity, consensus guidelines for optimal treatment of eccRCC have not been established, and the literature is lacking any reports of patient response to systemic therapy and any reports of administration of immunotherapy to patients with ecRCC. Here, we present the case of a patient in their 60s with eccRCC arising in the spleen. The patient underwent splenic resection and then received systemic therapy, due to disease recurrence, with a combination of immunotherapy (IO) and tyrosine kinase inhibitor targeted therapy (VEGF-TKI). The patient had an excellent and durable response to this therapeutic regimen with minimal adverse effects, completing 2 years of therapy of nivolumab and cabozantinib. At the time of this report, the disease remains stable. This case demonstrates that combination therapy with IO+VEGF-TKI represents a reasonable and well-tolerated treatment option with activity in eccRCC and reveals interesting correlative data, including nests of stem-like CD8+T-cell infiltration in tumor tissue, which provide important biological context to this patient's exceptional therapeutic response.

Cutaneous T-cell lymphoma with CNS involvement: a case series and review of the literature.

Cutaneous T-cell lymphoma (CTCL) is a rare hematologic malignancy that traditionally presents with cutaneous lesions, though metastases are not uncommon in progressive disease. We describe four cases of CTCL with central nervous system (CNS) involvement, detailing the history, pathological characteristics, treatment response, and progression. Median time from initial diagnosis to CNS metastasis was ∼5.4 years (range 3.4-15.5 years) and survival after metastasis was ∼160 days (range 19 days-4.4 years). No patients achieved long-term (>5 years) survival, though some displayed varying degrees of remission following CNS-directed therapy. We conclude that clinicians must be attentive to the development of CNS metastases in patients with CTCL. The growing body of literature on such cases will inform evolving therapeutic guidelines on this rare CTCL complication.

Cutaneous T-cell lymphoma (CTCL) is a rare cancer of the blood, which typically manifests with skin lesions, such as itchy, scaly rashes that may thicken to form tumors on the skin. Though uncommon, metastases do occur in CTCL. A particularly rare location for these metastases is the central nervous system. This case series recounts the story of four unique patients and the presentation, diagnosis, and treatment of their CTCL, which unfortunately progressed to involve the central nervous system. Outcomes with central nervous system involvement in CTCL are poor, but may occur sometime later than a patient's initial diagnosis. Our patients had a median time from initial diagnosis to central nervous system metastases of ∼5.4 years and a survival of ∼160 days after central nervous system metastases. Some types of therapy, such as radiation, surgery, or chemotherapy, may be beneficial in extending survival or providing symptomatic relief for patients. It can be difficult to recognize symptoms of central nervous system metastases, so this case series emphasizes that vigilance for potential metastases and use of interdisciplinary teams is important in caring for these patients. This case series demonstrates the importance of continued research in this area, with the hope of improving outcomes for patients with central nervous system metastases of CTCL.

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS.

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.