Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

An Integrative Systems-Oriented Interpersonal/Relational Group Approach to Understanding and Treating Mass Trauma, Dissociation and Enactments During the COVID-19 Pandemic.

The coronavirus pandemic (COVID-19) is a new ongoing, long-term mass trauma event occurring simultaneously with overwhelming sociopolitical stressors. We propose an integrative, psychodynamic, systems-oriented, interpersonal/relational trauma group model to address the multiple losses, heightened anxieties, and complicated grief that have resulted from the pandemic, as well as various forms of interpersonal abuse associated with racist and oppressive systems. These manifest as dissociation and unconscious enactments in small and large psychotherapy groups. We examine the role and responsibilities of the group leader in working therapeutically with these phenomena. Case examples for large and small psychotherapy groups are provided.

Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid.

Importance: Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective: To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants: This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results: In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance: This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Introduction to the Special Issue on Migration Problems in the US and Their Implications for Group Work.

In this introduction I provide an overview of this Special Issue on migration problems at the southwestern border of the United States. These problems are framed against the rising world-wide tide of anti-immigrant rhetoric and the ascendance of right-wing nationalist leaders. I maintain that, from a group dynamic perspective, we in the US are witnessing the emergence of an authoritarian fight group leader (Bion, 1961) who has capitalized on the systematic arousal and manipulation of our most primitive fears, and who encourages the use of developmentally regressive projective mechanisms that permit us to disown, externalize and deposit into the "other" all that is bad or destructive. A series of critical interrelated questions is posed for group therapists to consider in order to respond effectively to the challenges we face. I explain the context in which this volume took shape and offer a set of guidelines for how to address these problems. In addition, I review more recent developments regarding how our government is responding to this situation, and explore the linkages between the "immigration crisis", racism, White nationalism and violence. I then describe the articles that comprise this Special Issue, acknowledging that these contributions depart from the more typically neutral and "objective" pieces published in a professional journal, and represent an amalgam of both professional and more personal statements that emanate from deeply held ethical principles and humanitarian concerns. I conclude by inviting our readers to share their reactions to this volume and to the concept that is advanced of the group therapist as a potential social change advocate.

Reaching Our 75th Anniversary: A History of AGPA 1992-2017-Part 3.

This is the third in a series of three articles that chronicle and examine the 25-year history of the American Group Psychotherapy Association from 1992 to 2017. This time period has been divided into three naturally occurring eras: the pre-9/11 era, the 9/11 era, and the post-9/11 era. To permit meaningful comparisons across time, an effort has been made to contextualize events and to examine each era using the same set of seven facets/dimensions: (1) mission(s); (2) structure and administration; (3) jewels in the crown; (4) membership; (5) financial health; (6) organizational tensions and family dynamics; (7) relationships with the outside world.This account while based on objective data, like all such histories, is inherently subjective. Choices about which specific events to chronicle, as well as their meaning and significance, are filtered through the authors' perceptual and conceptual lenses.This third section focuses on the post-9/11 era.

Reaching Our 75th Anniversary: A History of AGPA 1992-2017-Part 1.

This is the first in a series of three articles that chronicle and examine the 25-year history of the American Group Psychotherapy Association from 1992 to 2017. This time period has been divided into three naturally occurring eras: the pre-9/11 era, the 9/11 era, and the post-9/11 era. To permit meaningful comparisons across time, an effort has been made to contextualize events and to examine each era using the same set of seven facets/dimensions: (1) mission(s); (2) structure and administration; (3) jewels in the crown; (4) membership; (5) financial health; (6) organizational tensions and family dynamics; and (7) relationships with the outside world. This account, while based on objective data, like all such histories, is inherently subjective. Choices about which specific events to chronicle, as well as their meaning and significance, are filtered through the authors' perceptual and conceptual lenses. This first section focuses on the pre-9/11 era.

Reaching Our 75th Anniversary: A History of AGPA 1992-2017-Part 2.

This is the second in a series of three articles that chronicle and examine the 25-year history of the American Group Psychotherapy Association from 1992 to 2017. This time period has been divided into three naturally occurring eras: the pre-9/11 era, the 9/11 era, and the post-9/11 era. To permit meaningful comparisons across time, an effort has been made to contextualize events and to examine each era using the same set of seven facets/dimensions: (1) mission(s); (2) structure and administration; (3) jewels in the crown; (4) membership; (5) financial health; (6) organizational tensions and family dynamics; and (7) relationships with the outside world.This account, while based on objective data, like all such histories, is inherently subjective. Choices about which specific events to chronicle, as well as their meaning and significance, are filtered through the authors' perceptual and conceptual lenses.This second section focuses on the 9/11 era.

Toward understanding and treating violence in America: some contributions from group dynamic and group therapy perspectives: introduction to part II.

The co-editors of the journal's two special issues on "Violence in America" from group psychotherapy and mental health standpoints review the articles in Part I and introduce the articles in Part II. The latter includes articles on anger management in groups, group psychotherapy for domestic violence, domestic "homegrown" terrorism, and two general commentaries. The co-editors provide broad reference points for the focus on clinical concerns, levels of treatment, variations in types of perpetrators, screening for groups, and the group-as-a-whole, relational, and social contexts of violence. Whether in small therapy groups, social interventions, or society's management of violence, empathy, boundaries, holding, and containment must be provided in such a way that they prevent violent acts while healing the hurts and shame that underlie violence in all its forms. Therapists' familiarity with these issues in their work can contribute fruitfully to treatment efforts and addressing a pressing social problem.

Toward understanding and treating violence in America: some contributions from group dynamic and group therapy perspectives: introduction to part I.

The co-editors introduce a two-part Special Section of the Journal devoted to understanding and treating violence in America. They examine the relevance of clinical experience for contributions that can be made by group therapists and group dynamic thinkers to the growing national dialogue about this problem. The pervasive nature, causes, and different forms of violence in the United States are compared with those found in other countries. Underlying sociocultural values and myths, historical and current cultural contexts are considered breeding grounds for potential violence. How therapists can promote healthy change in their groups and in the broader society is explored. The articles contained in part one are reviewed against this backdrop.

At the core: how we steer our course.

"The force that through the green fuse drives the flower drives my green age..."--Dylan Thomas (1952). The beautiful evocative words of Dylan Thomas speak to the driving life force that pulses through all creation. So what, then, drives our organization, the American Group Psychotherapy Association (AGPA)? What underlying stream can we tap into to provide the energy, power, and vitality we need to go on being in a meaningful and productive fashion? And, what internal compass can we rely on to steer us in the right direction, to guide us in how we function as an organization? My purpose here is to consider how we formulate our objectives, determine our priorities, make decisions, and insure, as best we can, that we are pursuing that which is meaningful and essential, not veering drastically off course. To do this, I would like to focus briefly on the current organizational structure of AGPA, then examine the use of a strategic planning process, review our accomplishments, and lastly explore hopes and dreams for our future as the premier group psychotherapy organization in the United States.