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Breast abscess as initial manifestation of extensive DCIS: a rare presentation and literature review

Ranjbar, Suedeh; Marks, Douglas K; Natoli, Noel B; Sarmiento, Ruth; Flieder, Andrea; Rossmer, Irene E
PMID: 32914488
ISSN: 1524-4741
CID: 4590242

Distinguishing melanophages from tumor in melanoma patients treated with talimogene laherparepvec

Audrey-Bayan, Claire; Trager, Megan H; Gartrell-Corrado, Robyn D; Rizk, Emanuelle M; Pradhan, Jaya; Silverman, Andrew M; Lopez, Adriana; Marks, Douglas K; Niedt, George; Geskin, Larisa J; Saenger, Yvonne M
Response to talimogene laherparepvec (T-Vec) is difficult to assess as pigmented macrophages that have ingested melanoma cells ('melanophages') persist after injection, mimicking melanoma. We used quantitative immunofluorescence (qIF) to (1) distinguish melanophages from melanoma in biopsies from two patients treated with T-Vec and (2) evaluate the tumor microenvironment pretreatment and posttreatment. Tissues were stained with 4',6-diamidino-2-phenylindole, cluster of differentiation (CD) 3, CD8, CD68, human leukocyte antigen-DR isotype (HLA-DR), and SRY-Box Transcription Factor 10 (SOX10), and multispectral images were analyzed. Post-T-Vec samples showed melanophages with cytoplasmic costaining of CD68, SOX10, and HLA-DR, without nuclear SOX10 expression. qIF revealed a dense immune infiltrate of CD3, CD8, and CD68 cells in post-T-Vec samples. Melanophages from tumors post-T-Vec stain the nuclear melanoma marker SOX10 in their cytoplasms as compared to melanoma cells that stain nuclear SOX10. This novel finding highlights the phagocytosis of melanoma cell components by macrophages after treatment with T-Vec. qIF may assist pathologists in determining whether lesions treated with immunotherapy contain residual viable melanoma.
PMID: 32379409
ISSN: 1473-5636
CID: 4428862

Linking transcriptomic and imaging data defines features of a favorable tumor immune microenvironment and identifies a combination biomarker for primary melanoma

Gartrell-Corrado, Robyn D; Chen, Andrew X; Rizk, Emanuelle M; Marks, Douglas K; Bogardus, Margaret H; Hart, Thomas D; Silverman, Andrew M; Bayan, Claire-Audrey Y; Finkel, Grace G; Barker, Luke W; Komatsubara, Kimberly M; Carvajal, Richard D; Horst, Basil A; Chang, Rui; Monod, Anthea; Rabadan, Raul; Saenger, Yvonne M
Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an interferon-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTLs) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary to metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR- macrophages. The HLA-DR- subset co-expressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy.
PMID: 31948941
ISSN: 1538-7445
CID: 4264572

Distinguishing melanophages from tumor in melanoma patients treated with talimogene laherparepvec (T-VEC) [Meeting Abstract]

Trager, M H; Audrey-Bayan, C; Gartrell-Corrado, R; Rizk, E; Pradhan, J; Silverman, A M; Hart, T D; Lopez, A T; Marks, D K; Niedt, G; Geskin, L; Saenger, Y M
Talimogene laherparepvec (T-VEC) is the first FDA-approved oncolytic virus for the treatment of advanced melanoma. T-VEC is injected into melanoma lesions, but response may be difficult to assess because pigmented macrophages that have ingested melanoma cells (termed "melanophages") persist after immunotherapy at injected sites mimicking melanoma. Thus, novel methods are critically needed to clearly identify the nature of the cells found in tissue specimens from patients treated with T-VEC. We evaluated skin biopsy specimens which were obtained pre-and post-T-VEC therapy of the melanoma patients (stages III-IV) at Columbia University. We used quantitative immunofluorescence (qIF) to: 1) Distinguish melanophages from melanoma in biopsies from patients treated with T-VEC; 2) Evaluate tumor immune micro-environment pre-and post-T-VEC. Tissue specimens were stained with the antibody panel: DAPI, CD3, CD8, CD68, HLA-DR, and Sox10. Multispectral images were acquired and analyzed using machine learning. Using multiplex staining, post T-VEC samples showed only a few residual melanoma cells within the skin biopsies confirmed by nuclear Sox10+ expression, and many melanophages with cytoplasmic co-staining of CD68, Sox10, and HLA-DR, with no nuclear expression of Sox10. This is a novel finding and highlights the phagocytosis of melanoma cells by macrophages following immunotherapy. QIF also revealed a dense immune infiltrate of CD3+ CD8+ and CD68+ cells in post T-VEC samples. QIF methods may assist pathologists in determining whether lesions from patients treated with immunotherapy contain residual viable melanoma. It also maybe helpful to assess immune response to the therapy
EMBASE:631885312
ISSN: 1755-148x
CID: 4472782

The Effect of Glucose Levels Prior to Hematopoietic Cell Transplantation on Post-Transplant Complications and Health Resource Utilization

Steinberg, Amir; Van Cleave, Janet H; Parikh, Anish B; Moshier, Erin; Ru, Meng; Lawson, Molly; Marks, Douglas; Montelibano, Antoinette; Philpott, Amanda; Garner, Kourtney; Hammer, Marilyn J
Background: Abnormal blood glucose (BG) levels during hematopoietic cell transplantation (HCT) are associated with increased infections, delayed engraftment, and prolonged hospitalization, though little is known about these associations. Materials and Methods: We retrospectively evaluated mean BG levels in the week prior to HCT and subsequent outcomes for 852 HCTs at our hospital from 1/2009 - 12/2013 pertaining to 745 patients. Outcomes included infections (pneumonia, C. difficile, positive cultures, administration of antimicrobials, or neutropenic fever), time-to-engraftment (TTE), and quality indicators (30- and 90-day readmission rates [RR] and median length-of-stay [LOS]). Results: 404 patients met the criteria for involvement in this study. The population was 55% male and was racially and ethnically mixed (White 38%, African American 23%, Hispanic 6%, Asian 7%, Other 21%). Mean age was 57+14 years. Significantly more patients in Group 2 were diagnosed with pneumonia (19%) compared with the Group 1 (7%) and Group 3 (10%) [p=.0054]. Patients in Group 2 also had significantly longer median LOS: Group 1-23 days, Group 2-26 days, Group 3-22 days [p = .0157]. No significant differences were noted in terms of the other infectious complications or in time-to-engraftment or readmissions. Conclusion: Pre-HCT BG trends may be a prognostic biomarker for adverse outcomes, and thus can help improve quality of care for HCT patients.
PMCID:6801324
PMID: 31649802
ISSN: 2008-3009
CID: 4161842

Validation of Melanoma Immune Profile (MIP), a Prognostic Immune Gene Prediction Score for Stage II-III Melanoma

Gartrell, Robyn D; Marks, Douglas K; Rizk, Emanuelle M; Bogardus, Margaret; Gérard, Camille L; Barker, Luke W; Fu, Yichun; Esancy, Camden L; Li, Gen; Ji, Jiayi; Rui, Shumin; Ernstoff, Marc S; Taback, Bret; Pabla, Sarabjot; Chang, Rui; Lee, Sandra J; Krolewski, John J; Morrison, Carl; Horst, Basil A; Saenger, Yvonne M
PURPOSE/OBJECTIVE:Biomarkers are needed to stratify patients with stage II-III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population. EXPERIMENTAL DESIGN/METHODS:A retrospective cohort of 78 patients with stage II-III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan-Meier curves, and standard univariable and multivariable Cox proportional hazards models. RESULTS:= 0.015; HR = 3.2). CONCLUSIONS:MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II-III melanoma for enrollment in clinical trials.
PMID: 30647081
ISSN: 1078-0432
CID: 3931412

Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

Kalinsky, K; Sparano, J A; Zhong, X; Andreopoulou, E; Taback, B; Wiechmann, L; Feldman, S M; Ananthakrishnan, P; Ahmad, A; Cremers, S; Sireci, A N; Cross, J R; Marks, D K; Mundi, P; Connolly, E; Crew, K D; Maurer, M A; Hibshoosh, H; Lee, S; Hershman, D L
INTRODUCTION/BACKGROUND:The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS/METHODS:in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS:Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION/CONCLUSIONS:While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
PMID: 29736694
ISSN: 1699-3055
CID: 3218092

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition

Blake, Zoë; Marks, Douglas K; Gartrell, Robyn D; Hart, Thomas; Horton, Patti; Cheng, Simon K; Taback, Bret; Horst, Basil A; Saenger, Yvonne M
BACKGROUND:Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. CASE PRESENTATION/METHODS:We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. CONCLUSION/CONCLUSIONS:Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.
PMCID:5887256
PMID: 29622046
ISSN: 2051-1426
CID: 3218082

Quantitative Analysis of Immune Infiltrates in Primary Melanoma

Gartrell, Robyn D; Marks, Douglas K; Hart, Thomas D; Li, Gen; Davari, Danielle R; Wu, Alan; Blake, Zoë; Lu, Yan; Askin, Kayleigh N; Monod, Anthea; Esancy, Camden L; Stack, Edward C; Jia, Dan Tong; Armenta, Paul M; Fu, Yichun; Izaki, Daisuke; Taback, Bret; Rabadan, Raul; Kaufman, Howard L; Drake, Charles G; Horst, Basil A; Saenger, Yvonne M
Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR-) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR- macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67- tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481-93. ©2018 AACR.
PMCID:5882545
PMID: 29467127
ISSN: 2326-6074
CID: 3218062

Diagnosis and management of neuropathies associated with plasma cell dyscrasias

Rosenbaum, Evan; Marks, Douglas; Raza, Shahzad
Neuropathies associated with plasma cell dyscrasias are a major cause of morbidity for patients managed by medical oncologists. Because of similarities in clinical presentation and on nerve conduction studies, identifying the underlying disease leading to a paraproteinemic neuropathy can often be difficult. In addition, the degree of neurologic deficit does not strictly correlate with the extent of abnormalities on common clinical laboratory testing. Fortunately, with increasing understanding into the biologic mechanisms of underlying hematologic diseases, additional biomarkers have recently been developed, thus improving our diagnostic capacity. Neuropathies associated with plasma cells dyscrasias are seen with Monoclonal gammopathy of undetermined significance (MGUS) particularly IgM subtype, followed by IgG and IgA MGUS, multiple myeloma, Waldenström's macroglobulinemia, amyloid, Castleman's disease, and POEMS syndrome. The mechanisms of neuronal injury associated with plasma cell dyscrasia vary based on underlying diagnosis and include malignant infiltration, immune-mediated antibody deposition, or local compression of nerve roots. The polyneuropathies are frequently demyelinating, although axonal and mixed neuropathies can also be seen. As demonstrated by the cases included in this review, patients frequently present with symmetric sensory disturbance, followed by progressive motor weakness. Unfortunately, because of the complexity of diagnostic testing, patients are frequently examined late, often after receiving several ineffective therapies. The aim of this case-based review is to provide clinicians with insight on how to properly recognize these atypical neuropathies and send the appropriate diagnostic work, increasing the likelihood of accurately classify the patient's underlying hematologic disorder.
PMID: 28397326
ISSN: 1099-1069
CID: 3218052