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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.

Supplementary Figure from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Data from 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.

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 ...

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., Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

Key Points Question Can cell-free DNA analysis of cerebrospinal fluid provide additional diagnostic utility beyond cytologic assessment? Findings In this diagnostic study of 43 cerebrospinal fluid samples from 22 patients with leptomeningeal disease confirmed by cytologic assessment who did not have parenchymal tumors abutting their cerebrospinal fluid, tumor-derived cell-free DNA was detected in the cerebrospinal fluid of 40 (93%) samples, whereas 31 (72%) of the samples were positive for malignant neoplasm as determined by cytologic analysis, a significant difference. Meaning These findings suggest that cerebrospinal fluid cell-free DNA analysis may be more sensitive than cytologic analysis for diagnosing leptomeningeal disease., 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., This diagnostic study compares the sensitivity and accuracy for detecting leptomeningeal disease via genomic sequencing of cell-free DNA with that of cytologic assessment of cerebrospinal fluid obtained from patients with suspected or cytologically confirmed leptomeningeal disease.

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., Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.

Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.

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.

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.

© 2016 Elsevier Ltd This paper presents tractable information value functions for Dirichlet-process Gaussian-process (DPGP) mixture models obtained via collocation methods and Monte Carlo integration. Quantifying information value in tractable closed form is key to solving control and estimation problems for autonomous information-gathering systems. The properties of the proposed value functions are analyzed and then demonstrated by planning sensor measurements so as to minimize the uncertainty in DPGP target models that are learned incrementally over time. Simulation results show that sensor planning based on expected KL divergence outperforms algorithms based on mutual information, particle filters, and randomized methods.

(2008). Toward the Establishment of Evidence–Based Practices in Group Psychotherapy. International Journal of Group Psychotherapy: Vol. 58, No. 4, pp. 441-454.

"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.

To estimate the prevalence and to identify correlates of physical and sexual assaults or abuse among women with or at risk for HIV infection, a cross-sectional survey was conducted within a longitudinal cohort study. A total of 765 HIV-seropositive and 367 HIV-seronegative women with a history of injection drug use (51%) or high-risk sex (49%) completed the interview. Both physical abuse and sexual abuse as a child were common for both HIV-seropositive (41.3%, 41.0%) and uninfected women (43.3%, 45.8%), respectively. Both physical abuse and sexual abuse as adults were even more common in both HIV-seropositive (66.4%, 45.7%) and HIV-seronegative women (69.2%, 48.8%), respectively. In the 6 months prior to interview, the most important predictors for being the victim of violence was age

(1992). Experiences in Groups. International Journal of Group Psychotherapy: Vol. 42, No. 2, pp. 301-305.

Most writings about terminating psychotherapy begin with a comment about the relative dearth of previous publications on this subject. This paucity of discussion is evident particularly in comparison with the mountainous piles of communications on most other psychotherapeutic topics. There is some truth to the statement that termination has not been as well studied as have been the psychotherapeutic issues and variables that precede it during the course of treatment. The repeated mention of this imbalance also may express a more profound emotional truth that has nothing to do with numbers of articles or chapters but that touches on the conflictual feelings and ideas that are evoked in patients and therapists by this subject. Few topics in psychotherapy stir up so much doubt and debate, and equally few have such poorly defined empirical parameters and clinical benchmarks. How do we know when most or all of the work has been done? Is what is left important enough to justify more time and expense? Is the idea of ending the therapy a way for either or both parties in the dyad to avoid some important issue? Or, conversely, is the continuation of psychotherapy an avoidance of painful feelings of loss, separation, and anxiety? These and other such questions arise in the minds of patients and therapists alike when termination is (or sometimes isn't) addressed. Termination in Psychotherapy: A Psychodynamic Model of Processes and Outcomes goes a long way in filling in the gaps in the existing literature, particularly with regard to psychodynamically oriented psychotherapy, which is the approach that the authors emphasize. It works as an intellectual manual for the practicing psychotherapist, which will guide her or him down the slippery slope of the termination process. The book also will be effective in reducing the anxiety of those practitioners, as its comprehensive review of the literature and its clear, easily used model for understanding and working though termination can be adapted readily by most psychodynamic practitioners. The specific model of termination can be considered and adapted by therapists who work within theoretical orientations other than specifically psychodynamic. The authors have included a very useful chapter that focuses on the differences in the termination process in cognitive– behavioral therapy, interpersonal therapy, supportive therapy, and experiential therapy. The model that is developed in this volume also will serve as the framework for effective and important future research. The book is organized around a goal-oriented, conceptual framework for planning for and working through termination, which is effectively linked to central and necessary clinical techniques. It offers a set of practical guidelines for evaluating progress in therapy and in using movement toward consensual goals as triggers for consideration of the possibility of termination. These guidelines include clearly defined, termination-specific

Throughout the development of object relations theory and self psychology, the importance of attachments, availability, absences, limitations, and endings have been factors that have informed theory and practice. This article examines the multiple meanings and impacts of terminations in group psychotherapy at the intrapsychic, interpersonal, and group-as-a-whole levels, from the perspective of contemporary object relations theory and self psychology. Emphasis is placed on the initiation of a mourning process, with the dynamics of guilt, shame, and aggression toward objects who are separate or inaccessible, and the experience of a shortcoming or absence, associated with a loss of self-object oneness, soothing, and idealization from the narcissistic sector of the personality. Therapeutic opportunities afforded by terminations and the importance of resolving countertransference reactions are highlighted.

Mental health professionals are increasingly aware of the special difficulties encountered by therapists working with HIV-positive and AIDS patients. In this report, countertransference issues experienced by therapists leading a psychotherapy group for heterosexual, drug-using HIV-positive and AIDS patients in an inner city hospital are explored. Countertransference is discussed under the headings of helplessness, death anxiety, and anger.

Treating the chronically mentally ill involves not only working with patients suffering from schizophrenia and other prolonged or recurrent psychotic illnesses, it also means providing treatment for patients with severe personality disorders. Many of these patients are also active substance abusers. This article examines the therapeutic and management issues raised for outpatient clinicians who work with these patients. Consideration is devoted to the special problems in treating the dual diagnosis patient, issues of patient and therapist safety, limit setting, splitting dynamics, and countertransference reactions. A set of recommendations is offered for conducting outpatient group therapy, specifying what is needed from both the clinicians and the facility in which this type of treatment is provided.

(1981). The Patient-Staff Community Meeting: A Tea Party with the Mad Hatter. International Journal of Group Psychotherapy: Vol. 31, No. 2, pp. 205-222.