Publications by authors named "Genevieve Boland"

82 Publications

Evolution of delayed resistance to immunotherapy in a melanoma responder.

Nat Med 2021 May 3. Epub 2021 May 3.

Department of Pathology, Harvard Medical School, Brigham and Woman's Hospital, Boston, MA, USA.

Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01331-8DOI Listing
May 2021

Temporal trends in inpatient oncology census before and during the COVID-19 pandemic and rates of nosocomial COVID-19 among patients with cancer at a large academic center.

Oncologist 2021 May 1. Epub 2021 May 1.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: The Coronavirus Disease-2019 (COVID-19) pandemic has significantly impacted healthcare systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied and the frequency of nosocomial spread to cancer patients is not well-understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in cancer patients admitted at a large academic center.

Materials And Methods: Medical records of cancer patients diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID (Jan 2019-Feb 2020), COVID (March-May 2020), and post-COVID surge (June-August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed.

Results: Overall, the daily inpatient census was steady in 2019 (median=103; range:92-118) and until February 2020 (median=112; range:102-114). However, there was a major decline from March to May 2020 (median=68; range:57-104), with 45.4% lower admissions during April 2020. As the COVID surge eased, the daily inpatient census over time returned to the pre-COVID baseline (median=103; range:99-111). One patient (1/231, 0.004%) had SARS-CoV-2 positive test 13 days after hospitalization and it is unclear if it was nosocomial or community spread.

Conclusion: In this study, inpatient oncology admissions decreased substantially during the COVID surge, but over time returned to the pre-COVID baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary.

Implications For Practice: The COVID-19 pandemic has had a major impact on the healthcare system, and cancer patients are a vulnerable population. As a result of the urgent need for inpatient capacity, non-COVID care has been deferred or delayed. In our study, we observe a drastic decline in the daily inpatient oncology census from March to May 2020 compared to the same time frame in the previous year. We investigate reasons for this decline. The concern is that some patients and providers may be deferring admission because of fear of the individual acquiring COVID in the hospital. However, we analyzed the nosocomial rate of COVID infection in admitted cancer patients to our center confirming that none of the patients in this study acquired the infection while hospitalized. These findings suggest that aggressive infection control measures can help mitigate the nosocomial infection risk among cancer patients and that the inpatient setting is a safe environment, providing reassurance to those seeking medical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13807DOI Listing
May 2021

Minimal Residual Disease Detection using a Plasma-Only Circulating Tumor DNA Assay in Colorectal Cancer Patients.

Clin Cancer Res 2021 Apr 29. Epub 2021 Apr 29.

Division of Hematology/Oncology, Massachusetts General Hospital.

Purpose: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.

Experimental Design: 252 prospective serial plasma specimens from 103 colorectal cancer (CRC) patients undergoing curative intent surgery were analyzed and correlated with recurrence.

Results: Of 103 patients, 84 (stage I (9.5%), II (23.8%), III (47.6%), IV (19%)) had evaluable plasma drawn post-completion of definitive therapy, defined as surgery only (n=39) or completion of adjuvant therapy (n=45). In "landmark" plasma drawn one-month (median 31.5 days) post-definitive therapy and >1 year follow up, 15 patients had detectable ctDNA, and all 15 recurred (positive predictive value (PPV) 100%, hazard ratio 11.28 (p<0.0001)). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4-months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen (CEA) levels did not predict recurrence (hazard ratio 1.84 (p=0.18); PPV=53.9%).

Conclusions: Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable to tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0410DOI Listing
April 2021

Impact of Cancer History on Outcomes Among Hospitalized Patients with COVID-19.

Oncologist 2021 Apr 15. Epub 2021 Apr 15.

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Early reports suggested increased mortality from COVID-19 in patients with cancer but lacked rigorous comparisons to patients without cancer. We investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death in hospitalized patients with COVID-19.

Patients And Methods: We identified patients with a history of cancer admitted to two large hospitals between March 13, 2020, and May 10, 2020, with laboratory-confirmed COVID-19 and matched them 1:2 to patients without a history of cancer.

Results: Men made up 56.2% of the population, with a median age of 69 years (range, 30-96). The median time since cancer diagnosis was 35.6 months (range, 0.39-435); 80% had a solid tumor, and 20% had a hematologic malignancy. Among patients with cancer, 27.8% died or entered hospice versus 25.6% among patients without cancer. In multivariable analyses, the odds of death/hospice were similar (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.65-1.82). The odds of intubation (OR, 0.46; 95% CI, 0.28-0.78), shock (OR, 0.54; 95% CI, 0.32-0.91), and intensive care unit admission (OR, 0.51; 95% CI, 0.32-0.81) were lower for patients with a history of cancer versus controls. Patients with active cancer or who had received cancer-directed therapy in the past 6 months had similar odds of death/hospice compared with cancer survivors (univariable OR, 1.31; 95% CI, 0.66-2.60; multivariable OR, 1.47; 95% CI, 0.69-3.16).

Conclusions: Patients with a history of cancer hospitalized for COVID-19 had similar mortality to matched hospitalized patients with COVID-19 without cancer, and a lower risk of complications. In this population, patients with active cancer or recent cancer treatment had a similar risk for adverse outcomes compared with survivors of cancer.

Implications For Practice: This study investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death or hospice admission in hospitalized patients with COVID-19. Active cancer, systemic cancer therapy, and a cancer history are not independent risk factors for death from COVID-19 among hospitalized patients, and hospitalized patients without cancer are more likely to have severe COVID-19. These findings provide reassurance to survivors of cancer and patients with cancer as to their relative risk of severe COVID-19, may encourage oncologists to provide standard anticancer therapy in patients at risk of COVID-19, and guide triage in future waves of infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13794DOI Listing
April 2021

Rapid corticosteroid taper versus standard of care for immune checkpoint inhibitor induced nephritis: a single-center retrospective cohort study.

J Immunother Cancer 2021 Apr;9(4)

Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Background: Current guidelines for treatment of immune checkpoint inhibitor (ICI)-induced nephritis are not evidence based and may lead to excess corticosteroid exposure. We aimed to compare a rapid corticosteroid taper to standard of care.

Methods: Retrospective cohort study in patients with ICI-induced nephritis comparing a rapid taper beginning with 60 mg/day prednisone and tapered to 10 mg within 3 weeks to a historical control group that began 60 mg/day tapered to 10 mg within 6 weeks (standard of care). Renal recovery was defined as creatinine returning to within 1.5-fold baseline. The log-rank test compared the differences in time to renal recovery between the groups. We report rates of renal recovery at 30, 60 and 90 days, and timing and outcomes of ICI rechallenge.

Results: Thirteen patients received rapid corticosteroid taper and 14 patients received standard of care. Baseline characteristics were similar between groups. The median time to ≤10 mg/day prednisone was 20 days (IQR 15-25) in the rapid-taper group compared with 38 days (IQR 30-58) in the standard-of-care group. There was no significant difference in the time to renal recovery between the groups, though numerically higher numbers of patients recovered by 30 days, 11 (85%) in the rapid-taper arm versus 6 (46%) in the standard of care arm. Exposure to other nephritis-causing medications (proton pump inhibitor or trimethoprim-sulfamethoxazole) during the corticosteroid taper was more common in the standard of care group, 9 (64%) versus rapid-taper group, 2 (15%), and was associated with longer time to renal recovery, 20 days (IQR 14-101) versus 13 days (IQR 7-34) in those that discontinued nephritis-causing medications. Fifteen (56%) of patients were rechallenged with ICIs, and only two (13%) developed recurrent nephritis.

Conclusions: Patients with ICI-induced nephritis have excellent kidney outcomes when treated with corticosteroids that are tapered over 3 weeks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-002292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051410PMC
April 2021

Low expression of the PPARγ-regulated gene thioredoxin-interacting protein accompanies human melanoma progression and promotes experimental lung metastases.

Sci Rep 2021 Apr 12;11(1):7847. Epub 2021 Apr 12.

Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015, Lausanne, Switzerland.

The thioredoxin system plays key roles in regulating cancer cell malignancy. Here we identify the Thioredoxin-interacting protein (TXNIP) as a gene, which expression is regulated by PPARγ in melanoma cells. We show that high TXNIP expression levels associate with benign melanocytic lesions, with tumor regression in patients on MAP kinase targeted therapy, with decreased proliferation in patients' melanoma biopsies, and with cell cycle arrest in human melanoma cell lines. In contrast, reduced TXNIP expression associates with advanced melanoma and with disease progression in patients. TXNIP depletion in human melanoma cells altered the expression of integrin beta-3 and the localization of the integrin alpha-v/beta-3 dimer at their surface. Moreover, TXNIP depletion affected human melanoma cell motility and improved their capacity to colonize mouse lungs in an in vivo assay. This study establishes TXNIP as a PPARγ-regulated gene in melanoma cells, thereby suggesting a link between these two proteins both involved in the regulation of cancer and of energy metabolism. It also reveals that the decrease in TXNIP expression, which is observed in advanced patient tumors, likely favors lung metastatic seeding of malignant cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-86329-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042115PMC
April 2021

NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021.

J Natl Compr Canc Netw 2021 Apr 1;19(4):364-376. Epub 2021 Apr 1.

30Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2021.0018DOI Listing
April 2021

Radiological dynamics and SITC-defined resistance types of advanced melanoma during anti-PD-1 monotherapy: an independent single-blind observational study on an international cohort.

J Immunother Cancer 2021 Feb;9(2)

Department of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

Background: Although the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world data regarding differences in these resistance subtypes with respect to radiological dynamics and clinical manifestations.

Methods: We performed single-blind re-evaluations of radiological images by independent radiologists on a retrospectively assembled cohort of patients with advanced melanoma (n=254, median follow-up 31 months) receiving anti-PD-1 monotherapy at Massachusetts General Hospital and Peking University Cancer Hospital. Radiological characteristics and timing at multiple crucial time points were analyzed and correlated with each other and with survival. Primary and secondary resistance was defined as per the SITC Immunotherapy Resistance Taskforce definitions.

Results: The most significant target lesion measurement change took place within the first 3 months after anti-PD-1 initiation. Patients with stable disease with versus without tumor shrinkage at the initial evaluation exhibited distinct disease trajectory, as the rate of further upgrade to a partial or complete remission (CR/PR) was 44% and 0%, respectively. Eleven per cent of PR patients ultimately achieved a CR. In multivariate analyses, deeper response depth was independently associated with a more limited progression pattern, fewer involved organs, lower tumor burden, slower growth rate at disease progression (PD) (all p≤0.001), and longer post-progression survival (PPS) (bivariate analysis, p=0.005). Compared with primary resistance, secondary resistance was associated with less widespread PD pattern, lower tumor burden and slower tumor growth (all p≤0.001). Patients with secondary resistance were less likely to receive further systemic therapy (28% vs 57%, p<0.001) yet had significantly better PPS (HR 0.503, 95% CI 0.288 to 0.879, p=0.02).

Conclusions: Radiological dynamics were variable, yet significantly correlated with survival outcomes. SITC-defined primary and secondary resistance are distinct clinical manifestations in patients with melanoma, suggesting the possibility of resistance-type-based therapeutic decision-making and clinical trial design, once further validated by future prospective studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-002092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908917PMC
February 2021

Epitope spreading toward wild-type melanocyte-lineage antigens rescues suboptimal immune checkpoint blockade responses.

Sci Transl Med 2021 Feb;13(581)

Experimental Cancer Genetics, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.

Although immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8 T cell populations specific for melanocyte antigens was observed only in patients who responded to anti-PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti-PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti-PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abd8636DOI Listing
February 2021

Adjuvant Radiation Therapy for Clinical Stage III Melanoma in the Modern Therapeutic Era.

Ann Surg Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

Background: Adjuvant radiation therapy (RT) can decrease lymph node basin (LNB) recurrences in patients with clinically evident melanoma lymph node (LN) metastases following lymphadenectomy, but its role in the era of modern systemic therapies (ST), immune checkpoint or BRAF/MEK inhibitors, is unclear.

Patients And Methods: Patients at four institutions who underwent lymphadenectomy (1/1/2010-12/31/2019) for clinically evident melanoma LN metastases and received neoadjuvant and/or adjuvant ST with RT, or ST alone, but met indications for RT, were identified. Comparisons were made between ST alone and ST/RT groups. The primary outcome was 3-year cumulative incidence (CI) of LNB recurrence. Secondary outcomes included 3-year incidences of in-transit/distant recurrence and survival estimates.

Results: Of 98 patients, 76 received ST alone and 22 received ST/RT. Median follow-up time for patients alive at last follow-up was 44.6 months. The ST/RT group had fewer inguinal node metastases (ST 36.8% versus ST/RT 9.1%; P = 0.04), and more extranodal extension (ST 50% versus ST/RT 77.3%; P = 0.02) and positive lymphadenectomy margins (ST 2.6% versus ST/RT 13.6%; P = 0.04). The 3-year CI of LNB recurrences was lower for the ST/RT group compared with the ST group (13.9% versus 25.2%), but this reduction was not statistically significant (P = 0.36). Groups did not differ significantly in in-transit/distant recurrences (P = 0.24), disease-free survival (P = 0.14), or melanoma-specific survival (P = 0.20).

Conclusions: In the era of modern ST, RT may still have value in reducing LNB recurrences in melanoma with clinical LN metastases. Further research should focus on whether select patient populations derive benefit from combination therapy, and optimizing indications for RT following neoadjuvant ST.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09384-8DOI Listing
November 2020

The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis.

Cancer Discov 2021 Mar 17;11(3):678-695. Epub 2020 Nov 17.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.

Circulating tumor cells (CTC) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastasis. We show that single CTCs from patients with melanoma coordinately upregulate lipogenesis and iron homeostasis pathways. These are correlated with both intrinsic and acquired resistance to BRAF inhibitors across clonal cultures of -mutant CTCs. The lipogenesis regulator SREBP2 directly induces transcription of the iron carrier Transferrin (), reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby conferring resistance to inducers of ferroptosis. Knockdown of endogenous impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic antioxidants ferrostatin-1 and vitamin E. In a prospective melanoma cohort, presence of CTCs with high lipogenic and iron metabolic RNA signatures is correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBP2-driven iron homeostatic pathways contribute to cancer progression, drug resistance, and metastasis. SIGNIFICANCE: Through single-cell analysis of primary and cultured melanoma CTCs, we have uncovered intrinsic cancer cell heterogeneity within lipogenic and iron homeostatic pathways that modulates resistance to BRAF inhibitors and to ferroptosis inducers. Activation of these pathways within CTCs is correlated with adverse clinical outcome, pointing to therapeutic opportunities..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-19-1500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933049PMC
March 2021

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Otolaryngology, Stanford University School of Medicine, Stanford, California, USA.

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

Plasma-derived extracellular vesicle analysis and deconvolution enable prediction and tracking of melanoma checkpoint blockade outcome.

Sci Adv 2020 Nov 13;6(46). Epub 2020 Nov 13.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Immune checkpoint inhibitors (ICIs) show promise, but most patients do not respond. We identify and validate biomarkers from extracellular vesicles (EVs), allowing non-invasive monitoring of tumor- intrinsic and host immune status, as well as a prediction of ICI response. We undertook transcriptomic profiling of plasma-derived EVs and tumors from 50 patients with metastatic melanoma receiving ICI, and validated with an independent EV-only cohort of 30 patients. Plasma-derived EV and tumor transcriptomes correlate. EV profiles reveal drivers of ICI resistance and melanoma progression, exhibit differentially expressed genes/pathways, and correlate with clinical response to ICI. We created a Bayesian probabilistic deconvolution model to estimate contributions from tumor and non-tumor sources, enabling interpretation of differentially expressed genes/pathways. EV RNA-seq mutations also segregated ICI response. EVs serve as a non-invasive biomarker to jointly probe tumor-intrinsic and immune changes to ICI, function as predictive markers of ICI responsiveness, and monitor tumor persistence and immune activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abb3461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673759PMC
November 2020

Fitness Landscape of Clonal Hematopoiesis Under Selective Pressure of Immune Checkpoint Blockade.

JCO Precis Oncol 2020 9;4. Epub 2020 Sep 9.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: Conventional cytotoxic therapies increase the risk of clonal hematopoiesis and select for -mutant clones, which carry a high risk for transformation to therapy-related myelodysplastic neoplasms. In contrast, the effect of immune checkpoint blockade (ICB) on clonal hematopoiesis is unknown.

Methods: Paired peripheral-blood samples taken before and after treatment with ICB were obtained for 91 patients with either cutaneous melanoma or basal cell carcinoma. Error-corrected sequencing of a targeted panel of genes recurrently mutated in clonal hematopoiesis was performed on peripheral-blood genomic DNA.

Results: The average interval between acquisition of the paired samples was 180 days. Forty-one percent of the patients had clonal hematopoiesis at a variant allele frequency (VAF) > 0.01 in the pretreatment sample. There was near-complete agreement in the distribution and burden of clonal hematopoiesis mutations in the paired blood samples, with 87 of 88 mutations identified across the cohort present in paired samples, regardless of the duration between sample collection. The VAF in the paired samples also showed a high correlation, with an = 0.95 ( < .0001). In contrast to cytotoxic therapy, exposure to ICB did not lead to selection of - or -mutant clones. However, consistent with the known effects of DNA-damaging therapy, we identified one patient who had eight unique mutations in the posttreatment blood sample after receiving two courses of radiation therapy.

Conclusion: There was no expansion of hematopoietic clones or selection for clones at high risk for malignant transformation in patients who received ICB, observations that warrant further validation in larger cohorts. These findings highlight an important difference between ICB and conventional cytotoxic therapies and their respective impacts on premalignant genetic lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.20.00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529531PMC
September 2020

The Human and Mouse Enteric Nervous System at Single-Cell Resolution.

Cell 2020 09 3;182(6):1606-1622.e23. Epub 2020 Sep 3.

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address:

The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.08.003DOI Listing
September 2020

Targeting Extracellular Matrix Remodeling Restores BRAF Inhibitor Sensitivity in BRAFi-resistant Melanoma.

Clin Cancer Res 2020 Nov 20;26(22):6039-6050. Epub 2020 Aug 20.

Department of Dermatology, University of Miami Miller School of Medicine, Miami, Florida.

Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy.

Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line-derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi.

Results: MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinβ1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFβ dependent, as inhibition of TGFβ receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition.

Conclusions: BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669662PMC
November 2020

Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling.

Nat Biotechnol 2021 04 12;39(4):451-461. Epub 2020 Aug 12.

Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Natural mitochondrial DNA (mtDNA) mutations enable the inference of clonal relationships among cells. mtDNA can be profiled along with measures of cell state, but has not yet been combined with the massively parallel approaches needed to tackle the complexity of human tissue. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), a method that combines high-confidence mtDNA mutation calling in thousands of single cells with their concomitant high-quality accessible chromatin profile. This enables the inference of mtDNA heteroplasmy, clonal relationships, cell state and accessible chromatin variation in individual cells. We reveal single-cell variation in heteroplasmy of a pathologic mtDNA variant, which we associate with intra-individual chromatin variability and clonal evolution. We clonally trace thousands of cells from cancers, linking epigenomic variability to subclonal evolution, and infer cellular dynamics of differentiating hematopoietic cells in vitro and in vivo. Taken together, our approach enables the study of cellular population dynamics and clonal properties in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-020-0645-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878580PMC
April 2021

Reversal of pre-existing NGFR-driven tumor and immune therapy resistance.

Nat Commun 2020 08 7;11(1):3946. Epub 2020 Aug 7.

Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFR population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFR cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFR tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFR multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17739-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414147PMC
August 2020

Surgical delay and mortality for primary cutaneous melanoma.

J Am Acad Dermatol 2021 Apr 22;84(4):1089-1091. Epub 2020 Jul 22.

Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.07.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375294PMC
April 2021

Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.

Cell 2020 08 29;182(3):655-671.e22. Epub 2020 Jun 29.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415717PMC
August 2020

Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors.

Front Oncol 2020 14;10:757. Epub 2020 May 14.

Department of Surgery, Massachusetts General Hospital, Boston, MA, United States.

Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify "hot" areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.00757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247820PMC
May 2020

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

Nat Med 2020 07 1;26(7):1114-1124. Epub 2020 Jun 1.

New York Genome Center, New York, NY, USA.

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-0915-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108131PMC
July 2020

Mixed Response to Immunotherapy in Patients with Metastatic Melanoma.

Ann Surg Oncol 2020 Sep 29;27(9):3488-3497. Epub 2020 May 29.

Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Immunotherapy has improved overall survival in metastatic melanoma. Response to therapy can be difficult to evaluate as the traditionally used RECIST 1.1 criteria do not capture heterogeneous responses. Here we describe the clinical characterization of melanoma patients with a clinically defined mixed response to immunotherapy.

Methods: This was a single institution, retrospective analysis of stage IV melanoma patients who received first-line anti-CTLA-4, anti-PD1, or combination anti-CTLA-4/anti-PD1. Therapy response was assessed via clinical definitions, which consisted of cross-sectional imaging combined with clinical exam. Course of disease, clinicopathological characteristics, and management in patients with a mixed clinical response were analyzed.

Results: In 292 patients (anti-CTLA4 = 63; anti-PD1 = 148, anti-CTLA4/anti-PD1 = 81), 103 were responders (35%), 64 mixed responders (22%), and 125 patients had progressive disease (43%). Of patients with a mixed response, 56% eventually had response to therapy (mixed response followed by response, MR-R), while 31% progressed on therapy (MR-NR). MR-NR patients had higher median LDH (p < 0.01), 3 or more organ sites with metastases (p < 0.01), and more frequently had M1d disease (p < 0.01). Mixed responders who underwent surgery (n = 20) had a significantly longer mean OS compared to patients who did not undergo surgery (6.9 years, 95% CI 6.2-7.6 vs. 6.0 years, 95% CI 4.6-7.3, p = 0.02).

Discussion: Mixed response to immunotherapy in metastatic melanoma was not uncommon in our cohort (22%). Clinical characteristics associated with progression of disease after initial mixed response included higher LDH, brain metastases, and ≥ 3 organ sites with metastases. Surgical treatment for highly selected patients with a mixed response was associated with improved outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08657-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410859PMC
September 2020

ASO Author Reflections: Adjuvant Treatment of Melanoma in the Modern Era.

Ann Surg Oncol 2020 Dec 28;27(13):5137-5138. Epub 2020 May 28.

Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08671-8DOI Listing
December 2020

ASO Author Reflections: Mixed Response in Metastatic Melanoma Patients Treated with Immunotherapy.

Ann Surg Oncol 2020 Sep 26;27(9):3498-3499. Epub 2020 May 26.

Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08663-8DOI Listing
September 2020

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.

Ann Surg Oncol 2020 Dec 23;27(13):5128-5136. Epub 2020 May 23.

Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Background: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era.

Methods: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs.

Results: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months; p = 0.04] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months; p = 0.01) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%; p = 0.03).

Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08631-2DOI Listing
December 2020

CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma.

Genomics Proteomics Bioinformatics 2020 02 13;18(1):26-40. Epub 2020 May 13.

Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address:

BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gpb.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393575PMC
February 2020

Targeting the cyclin-dependent kinase 5 in metastatic melanoma.

Proc Natl Acad Sci U S A 2020 04 19;117(14):8001-8012. Epub 2020 Mar 19.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215;

The cyclin-dependent kinase 5 (CDK5), originally described as a neuronal-specific kinase, is also frequently activated in human cancers. Using conditional CDK5 knockout mice and a mouse model of highly metastatic melanoma, we found that CDK5 is dispensable for the growth of primary tumors. However, we observed that ablation of CDK5 completely abrogated the metastasis, revealing that CDK5 is essential for the metastatic spread. In mouse and human melanoma cells CDK5 promotes cell invasiveness by directly phosphorylating an intermediate filament protein, vimentin, thereby inhibiting assembly of vimentin filaments. Chemical inhibition of CDK5 blocks the metastatic spread of patient-derived melanomas in patient-derived xenograft (PDX) mouse models. Hence, inhibition of CDK5 might represent a very potent therapeutic strategy to impede the metastatic dissemination of malignant cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1912617117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149478PMC
April 2020

Use of immunotherapy and surgery for stage IV melanoma.

Cancer 2020 06 10;126(11):2614-2624. Epub 2020 Mar 10.

Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Immunotherapy for stage IV melanoma has dramatically changed the overall prognosis and treatment strategies. The aim of this study was to evaluate whether changes in systemic immunotherapy options have significantly altered surgical resection rates for patients with stage IV melanoma.

Methods: The National Cancer Database (2004-2015) was used to perform a difference-in-difference analysis to evaluate whether the rate of surgical resection of metastatic disease for stage IV melanoma differed with the use of immunotherapy in the checkpoint inhibitor era in comparison with the use of immunotherapy in the pre-checkpoint inhibitor era. An adjusted difference-in-difference analysis stratified by facility type was performed. An adjusted Poisson regression analysis evaluated predictors of surgical resection in patients with stage IV melanoma who received immunotherapy.

Results: There were 14,433 patients with stage IV melanoma (median age, 66 years [interquartile range, 56-76 years]; female, 31.7%), and of all patients in the checkpoint inhibitor era (n = 7,524), 25% (n = 1,879) received immunotherapy. Patients with stage IV disease who received immunotherapy in the checkpoint inhibitor era were more likely to be younger, be healthier, have private insurance, come from upper income quartiles, and be treated at academic programs. A difference-in-difference analysis revealed similar rates of surgical resection of metastatic disease with the use of immunotherapy in the checkpoint inhibitor era and the pre-checkpoint inhibitor era, regardless of facility type.

Conclusions: The distribution of immunotherapy was unequal among patients with stage IV melanoma. Across all facilities, the rates of surgical resection of metastatic disease for stage IV melanoma did not differ with the use of immunotherapy between the checkpoint inhibitor era and the pre-checkpoint inhibitor era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32817DOI Listing
June 2020

NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.

J Natl Compr Canc Netw 2020 02;18(2):120-131

The University of Texas MD Anderson Cancer Center.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2020.0007DOI Listing
February 2020