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Recent progress in multiplexed tissue imaging is deepening our understanding of tumor microenvironments related to treatment response and disease progression. However, analyzing whole-slide images with millions of cells remains computationally challenging, and few methods provide a principled approach for integrative analysis across images. Here, we introduce SpatialTopic , a spatial topic model designed to decode high-level spatial tissue architecture from multiplexed images. By integrating both cell type and spatial information, SpatialTopic identifies recurrent spatial patterns, or “topics,” that reflect biologically meaningful tissue structures. We benchmarked SpatialTopic across diverse single-cell spatial transcriptomic and proteomic imaging platforms spanning multiple tissue types. We show that SpatialTopic is highly scalable to large-scale images, along with high precision and interpretability. It consistently identifies biologically and clinically significant spatial topics, such as tertiary lymphoid structures, and tracks spatial changes over disease progression. Its computational efficiency and broad applicability will enhance the analysis of large-scale imaging datasets. Peng and colleagues present SpatialTopic, a scalable computational method that decodes spatial tissue structure from large-scale multiplexed images, thereby enabling rapid, integrative analysis of millions of cells across multiple tissue slides.

Background Acral melanoma (AM) is an unusual malignancy with poor survival. This study defines a cohort of patients, treated at a single institution, and the factors associated with survival and comparison with nonacral cutaneous melanoma (NACM). Methods All patients with AM presenting from 1995 to 2010 were identified from a prospectively maintained database. Analysis of clinicopathologic features of AM associated with disease-specific survival (DSS) was performed. A stratified, stage-matched survival analysis compared the outcome of 281 acral to 843 extremity NACM patients. Results A total of 281 AM patients (170 volar, 111 subungual) were identified. Pathologic stage ( p  < 0.001), ulceration ( p  < 0.001), Breslow thickness ( p  < 0.001), and a positive sentinel lymph node ( p  < 0.001) were found to be poor prognostic indicators associated with DSS. In stage-matched analysis, AM had a worse DSS compared with NACM (hazard ratio 1.8; 95 % CI 1.2–2.7; p  < 0.01). Conclusions This study represents the largest, single-institution series describing the characteristics and outcomes of AM. AM tumors exhibit aggressive histopathologic features associated with a poorer survival outcome. AM patients have an inferior survival than extremity NACM when matched for stage, perhaps reflecting inherent alterations in tumor biology. This warrants further investigation into the differences between acral and cutaneous melanoma.

IntroductionCheckpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear.MethodsPatients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions.ResultsOf the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001).ConclusionsPatients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1–seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1–seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1–specific CD4+ and CD8+ T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1–seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1–seropositive patients with associated CD8+ T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8+ T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53 dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Background Rosai–Dorfman–Destombes disease (RDD) is a rare histiocytic disorder with heterogeneous clinical manifestations and rare neurologic involvement. The existing clinical literature about neurologic RDD has yet to be critically examined. Methods We performed a four-database English-language systematic literature search for cases of RDD neurohistiocytosis, excluding secondary literature. Individual patient data for neurologic symptoms, disease sites, treatments, and responses were captured. Responses to first-line and second-line surgical interventions, post-surgical radiotherapy, and systemic therapies were analyzed. Results Among 4769 articles yielded by literature search, 154 articles were fully reviewed, containing data on 224 patients with neurologic RDD. 128 (83.1%) articles were single case reports. 149 (66.5%) patients were male, 74 (33.5%) female, with a median age of 37.6 years (range 2–79). Presenting neurologic symptoms included headache (45.1%), focal neurological deficits (32.6%), visual symptoms (32.1%), and seizures (24.6%). RDD involvement was multifocal in 32 (14.3%) cases. First-line treatment involved resection in 200 (89.6%) patients, with subsequent progression in 52 (26%), including 41 (78.8%) with unifocal disease. No difference was observed in progression-free survival comparing post-operative radiotherapy to no radiotherapy following partial resection. Chemotherapy given alone as first-line treatment led to complete or partial response in 3/7(43%) patients. Second-line treatments led to complete or partial response in 18/37(37.5%) patients. Mutational data were reported on 10 patients (4.46%). Conclusions This review highlights the limited published data about neurologic RDD, which presents with varied symptomatology and outcome. Further study is needed about its mutational landscape, and more effective therapies are needed for recurrent and refractory disease.

Background With numerous and fast approvals of different agents including immune checkpoint inhibitors, monoclonal antibodies, or chimeric antigen receptor (CAR) T-cell therapy, immunotherapy is now an established form of cancer treatment. These agents have demonstrated impressive clinical activity across many tumor types, but also revealed different toxicity profiles and mechanisms of action. The classic assumptions imposed by cytotoxic agents may no longer be applicable, requiring new strategies for dose selection and trial design. Description This main goal of this article is to summarize and highlight main challenges of early-phase study design of immunotherapies from a statistical perspective. We compared the underlying toxicity and efficacy assumptions of cytotoxic versus immune-oncology agents, proposed novel endpoints to be included in the dose-selection process, and reviewed design considerations to be considered for early-phase trials. When available, references to software and/or web-based applications were also provided to ease the implementation. Throughout the paper, concrete examples from completed (pembrolizumab, nivolumab) or ongoing trials were used to motivate the main ideas including recommendation of alternative designs. Conclusion Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining the optimal dose to be carried forward in later phases, incorporating additional endpoints in the dose selection process (PK, PD, immune-based biomarkers), developing personalized biomarker profiles, or testing drug combination therapies to improve efficacy and reduce toxicity.

Background The goal of posthospital care delivery is to improve patient access to providers and prevent unnecessary readmissions. This study assessed the feasibility, barriers, and facilitating factors of implementing remote patient monitoring (RPM) for oncology patients at the Hartford HealthCare Cancer Institute (HHC), Hartford CT, and a state-wide healthcare system. Methods A multi-model holistic approach to quantitative surveys, and qualitative interviews and focus groups were used to collect insights from hospital stakeholders about the culture, learning, leadership, and resources for implementing RPM. Stakeholders from HHC responded to the survey between September 1st through September 30th, 2022. The frequency and percentage distributions for survey item responses were calculated. Items with the highest percentage and frequency of neutral and disagreement responses informed the interview guide. A purposeful sample of hospital stakeholders and patients were recruited for interviews and focus groups, which were conducted from January 1st through January 30th, 2023. Current and future state organizational maps of clinical care models and processes were developed. Results Sixty-three stakeholders were sent the Readiness for Implementation Survey and 53 responded through an email link to a web-based database (84% response rate). Responses supported RPM to improve patient care (67%). Interviews and focus groups elicited stakeholder perceptions of implementing change, the change climate, available resources, and barriers and facilitators of RPM. Stakeholders ( n  = 78), inclusive of the 63 survey recipients, plus 15 stakeholders from the Cancer Patient and Family Advisory Council (PFAC) and hospital staff, agreed to participate in interviews and focus groups. Fifty-two individuals (67% response rate) agreed to participate. Eight individual interviews and 6 focus groups were conducted. The emerged themes included integrating change into hospital systems, relevance to patient care teams, and patient- and family-centered care. Subthemes were subsequently explored. Conclusion Stakeholders endorsed using RPM to improve communication among providers and patients’ access to care. Providers underscored key elements for program success that include a designated intervention team, strategies to assess symptom alerts, and an enterprise-wide availability of clinical data in future RPM development. Patient stakeholders emphasized integrating a patient-centered approach to RPM development.

Both the combination of nivolumab + ipilimumab and single‐agent anti‐PD‐1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti‐PD‐1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single‐center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil‐to‐lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti‐PD‐1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti‐PD‐1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti‐PD‐1 alone. The combination of nivolumab and ipilimumab is a highly effective treatment for patients with melanoma, and little is known about the patients who do the best after treatment. For the first time, we report basic clinical laboratory variables which are associated with overall survival following treatment.

Background We examined the association between academic center status and neurosurgical resection volume with surgical procedures performed and subsequent survival. Methods In a population‐based study using the Surveillance, Epidemiology, and End Results (SEER)‐Medicare‐linked databases, we identified patients > 65 years diagnosed with primary WHO grade III‐IV glioma from 2008 to 2017. Surgical procedures were identified through Medicare claims from 2007 to 2019. Associations between center type (academic vs. not) and center volume (top 10% of distribution of resections during the study period vs. the bottom 90%) were estimated with upfront surgery procedure (resection vs. biopsy vs. none) and survival by estimating hazard ratios (HRs) and 95% confidence intervals (CIs) from multivariable regression models accounting for within‐center provider cluster correlation. Results We identified 8592 patients, of whom 8128 could both be attributed to a provider and received neurosurgical intervention attributed to resection or biopsy. When considered together, center volume, not center academic status, drove surgical decisions for first procedure type such that patients treated by a top 10% volume center were 23% more likely to receive resection (95% CI: 14%–34%, p < 0.0001). When considered together, resection, not center volume, drove improvement in overall survival such that patients who received resection, regardless of center volume, were 22% less likely to die during the study period (95% CI: 17%–27%, p < 0.0001). Conclusions We provide the first population‐based evidence that older patients diagnosed with grade III–IV glioma who seek treatment from higher‐volume centers are more likely to receive aggressive neurosurgical care. Aggressive neurosurgical care, even if received from low‐volume centers, improves survival.