Publications by authors named "Luis A Diaz"

268 Publications

Clonal hematopoiesis is associated with risk of severe Covid-19.

Nat Commun 2021 10 13;12(1):5975. Epub 2021 Oct 13.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
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http://dx.doi.org/10.1038/s41467-021-26138-6DOI Listing
October 2021

Association of Antineoplastic Therapy With Decreased SARS-CoV-2 Infection Rates in Patients With Cancer.

JAMA Oncol 2021 Aug 19. Epub 2021 Aug 19.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity.

Objectives: To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates.

Design, Setting, And Participants: We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020.

Main Outcome And Measure: The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test.

Results: In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87).

Conclusions And Relevance: In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti-SARS-CoV-2 properties of identified antineoplastic compounds is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2021.3585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377603PMC
August 2021

A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers.

J Natl Cancer Inst 2021 Aug 18. Epub 2021 Aug 18.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC).

Methods: Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided.

Results: In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01).

Conclusions: EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.
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http://dx.doi.org/10.1093/jnci/djab124DOI Listing
August 2021

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

Cell 2021 Jul 24;184(15):4032-4047.e31. Epub 2021 Jun 24.

Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.

Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.
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http://dx.doi.org/10.1016/j.cell.2021.05.038DOI Listing
July 2021

Therapeutic Implications of Germline Testing in Patients With Advanced Cancers.

J Clin Oncol 2021 Aug 16;39(24):2698-2709. Epub 2021 Jun 16.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.

Methods: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype-directed therapy were determined.

Results: Among 11,947 patients across > 50 malignancies, 17% (n = 2,037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). variants accounted for 42% of therapeutically actionable findings, followed by (13%), (12%), mismatch repair genes (11%), and (5%). When limited to the 9,079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype-directed therapy. Germline genotype-directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of , 75% of mismatch repair, 43% of , 35% of , 24% of , and 19% of carriers. Of patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting.

Conclusion: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype-directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.
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http://dx.doi.org/10.1200/JCO.20.03661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376329PMC
August 2021

Anti-PD-1 elicits regression of undifferentiated pleomorphic sarcomas with UV-mutation signatures.

J Immunother Cancer 2021 06;9(6)

Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA

Undifferentiated pleomorphic sarcoma (UPS), an aggressive soft-tissue sarcoma of adults, has been characterized by low tumor mutational burden (TMB) and high copy number alterations. Clinical trials of programmed death-1 (PD-1) blockade in UPS have reported widely varying efficacy. We describe two patients with recurrent scalp UPS that experienced clinical benefit from PD-1 blockade. These tumors had high TMB with a UV-induced mutational pattern. Analysis of additional head and neck UPS cases identified five out of seven tumors with high TMB and an ultraviolet (UV) mutational signature. Head and neck UPS tumors also had increased programmed death-ligand 1 (PD-L1) expression and CD8+ T cell infiltration as compared with UPS tumors arising from other sites. In summary, we found that UPS tumors of the head and neck, but not elsewhere, have a PD-L1+, T-cell-inflamed tumor microenvironment and high TMB, suggesting that these tumors represent a distinct genetic subgroup of UPS for which immune checkpoint inhibitor therapy might be effective.
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http://dx.doi.org/10.1136/jitc-2021-002345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190056PMC
June 2021

Horizons in Veterinary Precision Oncology: Fundamentals of Cancer Genomics and Applications of Liquid Biopsy for the Detection, Characterization, and Management of Cancer in Dogs.

Front Vet Sci 2021 23;8:664718. Epub 2021 Mar 23.

PetDx, La Jolla, CA, United States.

Cancer is the leading cause of death in dogs, in part because many cases are identified at an advanced stage when clinical signs have developed, and prognosis is poor. Increased understanding of cancer as a disease of the genome has led to the introduction of liquid biopsy testing, allowing for detection of genomic alterations in cell-free DNA fragments in blood to facilitate earlier detection, characterization, and management of cancer through non-invasive means. Recent discoveries in the areas of genomics and oncology have provided a deeper understanding of the molecular origins and evolution of cancer, and of the "one health" similarities between humans and dogs that underlie the field of comparative oncology. These discoveries, combined with technological advances in DNA profiling, are shifting the paradigm for cancer diagnosis toward earlier detection with the goal of improving outcomes. Liquid biopsy testing has already revolutionized the way cancer is managed in human medicine - and it is poised to make a similar impact in veterinary medicine. Multiple clinical use cases for liquid biopsy are emerging, including screening, aid in diagnosis, targeted treatment selection, treatment response monitoring, minimal residual disease detection, and recurrence monitoring. This review article highlights key scientific advances in genomics and their relevance for veterinary oncology, with the goal of providing a foundational introduction to this important topic for veterinarians. As these technologies migrate from human medicine into veterinary medicine, improved awareness and understanding will facilitate their rapid adoption, for the benefit of veterinary patients.
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http://dx.doi.org/10.3389/fvets.2021.664718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021921PMC
March 2021

Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial.

Lancet Oncol 2021 05 1;22(5):665-677. Epub 2021 Apr 1.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

Background: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here.

Methods: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed.

Findings: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001).

Interpretation: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
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http://dx.doi.org/10.1016/S1470-2045(21)00064-4DOI Listing
May 2021

Microsatellite-Instability-High Advanced Colorectal Cancer. Reply.

N Engl J Med 2021 03;384(10):972-973

Hôpital Saint Antoine, Paris, France.

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http://dx.doi.org/10.1056/NEJMc2036233DOI Listing
March 2021

CD4 T Cell-Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair-Deficient Tumors.

Cancer Discov 2021 Jul 2;11(7):1844-1859. Epub 2021 Mar 2.

Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.

Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, loss does not appear to affect response to ICPis in mismatch repair-deficient (MMRd) colorectal tumors where biallelic inactivation of is frequently observed. We inactivated in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd null tumors did not require CD8 T cells but relied on the presence of CD4 T cells. Human tumors expressing low levels of B2M display increased intratumoral CD4 T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4 T cells in tumor rejection. SIGNIFICANCE: alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4 T-cell activation..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0987DOI Listing
July 2021

A Decade of .

Cancer Discov 2021 04 22;11(4):795-797. Epub 2021 Feb 22.

Weill Cornell Medicine, New York, New York.

As turns 10, we reflect on the journal's success and look ahead to the future.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0082DOI Listing
April 2021

Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis.

Nat Commun 2021 01 12;12(1):338. Epub 2021 Jan 12.

Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.
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http://dx.doi.org/10.1038/s41467-020-20565-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804935PMC
January 2021

Randomized Trial of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406).

J Clin Oncol 2021 02 23;39(4):285-294. Epub 2020 Dec 23.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab.

Methods: One hundred six patients with -mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily).

Results: Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, = .001). The response rate was 17% versus 4% ( = .05), with a disease control rate of 65% versus 21% ( < .001). A decline in circulating tumor DNA variant allele frequency was seen in 87% versus 0% of patients ( < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype.

Conclusion: Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in -mutated CRC.
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http://dx.doi.org/10.1200/JCO.20.01994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462593PMC
February 2021

DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity.

Cancer Cell 2021 01 17;39(1):96-108.e6. Epub 2020 Dec 17.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2020.11.006DOI Listing
January 2021

Clonal hematopoiesis is associated with risk of severe Covid-19.

medRxiv 2020 Nov 27. Epub 2020 Nov 27.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of (HR=2.0, 95% CI: 1.2-3.3, p=6×10 ) and infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.
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http://dx.doi.org/10.1101/2020.11.25.20233163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709186PMC
November 2020

Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

N Engl J Med 2020 12;383(23):2207-2218

From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) - all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) - both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (C.P.); Hospital Universitario 12 de Octubre, Imas12, Madrid (R.G.-C.), Hospital Regional Universitario, Malaga (M.B.), Hospital Universitario Marques de Valdecilla, Santander (F.R.), and Vall d'Hebron Institute of Oncology, Barcelona (E.E.) - all in Spain; Western Health, St. Albans, VIC, Australia (P.G.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J.B.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.T.L.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); MSD China, Beijing (P.Y.); Merck, Kenilworth, NJ (M.Z.H.F., P.M.); and Memorial Sloan Kettering Cancer Center, New York (L.A.D.).

Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.

Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.

Results: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.

Conclusions: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
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http://dx.doi.org/10.1056/NEJMoa2017699DOI Listing
December 2020

Are Financial Payments From the Pharmaceutical Industry Associated With Physician Prescribing? : A Systematic Review.

Ann Intern Med 2021 03 24;174(3):353-361. Epub 2020 Nov 24.

Memorial Sloan Kettering Cancer Center, New York, New York (A.P.M., N.U.T., R.L.G., S.C., S.M.T., L.A.D., D.K.).

Background: Financial payments from the drug industry to U.S. physicians are common. Payments may influence physicians' clinical decision making and drug prescribing.

Purpose: To evaluate whether receipt of payments from the drug industry is associated with physician prescribing practices.

Data Sources: MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science, and EconLit were searched without language restrictions. The search had no limiting start date and concluded on 16 September 2020.

Study Selection: Studies that estimated the association between receipt of industry payments (exposure) and prescribing (outcome).

Data Extraction: Pairs of reviewers extracted the primary analysis or analyses from each study and evaluated risk of bias (ROB).

Data Synthesis: Thirty-six studies comprising 101 analyses were included. Most studies ( = 30) identified a positive association between payments and prescribing in all analyses; the remainder ( = 6) had a mix of positive and null findings. No study had only null findings. Of 101 individual analyses, 89 identified a positive association. Payments were associated with increased prescribing of the paying company's drug, increased prescribing costs, and increased prescribing of branded drugs. Nine studies assessed and found evidence of a temporal association; 25 assessed and found evidence of a dose-response relationship.

Limitation: The design was observational, 21 of 36 studies had serious ROB, and publication bias was possible.

Conclusion: The association between industry payments and physician prescribing was consistent across all studies that have evaluated this association. Findings regarding a temporal association and dose-response suggest a causal relationship.

Primary Funding Source: National Cancer Institute.
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http://dx.doi.org/10.7326/M20-5665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315858PMC
March 2021

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Nat Genet 2020 11 26;52(11):1219-1226. Epub 2020 Oct 26.

Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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http://dx.doi.org/10.1038/s41588-020-00710-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891089PMC
November 2020

Machine learning-based prediction of microsatellite instability and high tumor mutation burden from contrast-enhanced computed tomography in endometrial cancers.

Sci Rep 2020 10 20;10(1):17769. Epub 2020 Oct 20.

Body Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

To evaluate whether radiomic features from contrast-enhanced computed tomography (CE-CT) can identify DNA mismatch repair deficient (MMR-D) and/or tumor mutational burden-high (TMB-H) endometrial cancers (ECs). Patients who underwent targeted massively parallel sequencing of primary ECs between 2014 and 2018 and preoperative CE-CT were included (n = 150). Molecular subtypes of EC were assigned using DNA polymerase epsilon (POLE) hotspot mutations and immunohistochemistry-based p53 and MMR protein expression. TMB was derived from sequencing, with > 15.5 mutations-per-megabase as a cut-point to define TMB-H tumors. After radiomic feature extraction and selection, radiomic features and clinical variables were processed with the recursive feature elimination random forest classifier. Classification models constructed using the training dataset (n = 105) were then validated on the holdout test dataset (n = 45). Integrated radiomic-clinical classification distinguished MMR-D from copy number (CN)-low-like and CN-high-like ECs with an area under the receiver operating characteristic curve (AUROC) of 0.78 (95% CI 0.58-0.91). The model further differentiated TMB-H from TMB-low (TMB-L) tumors with an AUROC of 0.87 (95% CI 0.73-0.95). Peritumoral-rim radiomic features were most relevant to both classifications (p ≤ 0.044). Radiomic analysis achieved moderate accuracy in identifying MMR-D and TMB-H ECs directly from CE-CT. Radiomics may provide an adjunct tool to molecular profiling, especially given its potential advantage in the setting of intratumor heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-72475-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575573PMC
October 2020

Non-Cell-Autonomous Activity of the Hemidesmosomal Protein BP180/Collagen XVII in Granulopoiesis in Humanized NC16A Mice.

J Immunol 2020 11 30;205(10):2786-2794. Epub 2020 Sep 30.

Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

BP180 (also termed type XVII collagen) is a hemidesmosomal protein and plays a critical role in cell-cell matrix adhesion in the skin; however, its other biological functions are largely unclear. In this study, we generated a BP180 functional-deficient mouse strain by deleting its extracellular domain of humanized NC16A (termed mice). We found that BP180 is expressed by bone marrow mesenchymal stem cells (BM-MSC), and its functional deficiency leads to myeloid hyperplasia. Altered granulopoiesis in mice is through bone marrow stromal cells evidenced by bone marrow transplantation. Furthermore, the level of G-CSF in bone marrow and circulation were significantly increased in mice as compared with wild-type mice. The increased G-CSF was accompanied by an increased activation of the NF-κB signaling pathway in bone marrow and BM-MSC of mice. Blockade of G-CSF restored normal granulopoiesis in mice. Inhibition of NF-κB signaling pathway significantly reduces the release of G-CSF from BM-MSC in vitro and the level of serum G-CSF in mice. To our knowledge, these findings provide the first direct evidence that BP180 plays an important role in granulopoiesis through regulating NF-κB signaling pathway in BM-MSC.
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http://dx.doi.org/10.4049/jimmunol.2000784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658030PMC
November 2020

Viral shedding dynamics reveals sputum as a reliable and cost-saving specimen for SARS-CoV-2 diagnosis within the first 10 days since symptom onset: A prospective cohort study.

medRxiv 2020 Sep 1. Epub 2020 Sep 1.

Background: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome virus (SARS-CoV-2) is challenging global public health, due to an increasing demand for testing and the shortage of diagnostic supplies. Nasopharyngeal swab (NPS) is considered the optimal sample for SARS-CoV2 diagnosis and sputum (SPT) has been proposed as an economic alternative. However, the temporal concordance of diagnosis in NPS and SPT has not been addressed.

Methods: Through a longitudinal study we compared the shedding dynamics of SARS-CoV-2 RNA evaluated by RT-qPCR in serially collected SPT and NPS obtained from 82 ambulatory and hospitalized patients during acute infection and convalescence. The concordance during the follow-up and cost analysis between both collected specimens was evaluated.

Findings: We analyzed 379 samples, 177 NPS and 202 SPT. The highest proportion of positive samples was detected within the first 15 days after the symptoms onset. The median time of positivity was higher for NPS (median= 25 days) than SPT (median= 21 days). There was no significant difference in the median RT-qPCR CT values between both sample types. The temporal categorization of matched-paired samples indicated substantial correlation (r=0.6023) and substantial agreement (87.23%) during the first ten days since symptoms onset (kappa = 0.697). A cost analysis demonstrated a significant saving when the SPT specimen was used.

Interpretation: Sputum is a feasible and cost-saving alternative to NPS, providing an equivalent value for the detection and follow-up of SARS-CoV-2 RNA.
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http://dx.doi.org/10.1101/2020.08.30.20183889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480028PMC
September 2020

Chemotherapy and COVID-19 Outcomes in Patients With Cancer.

J Clin Oncol 2020 10 14;38(30):3538-3546. Epub 2020 Aug 14.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Coronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully characterized.

Patients And Methods: We reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event.

Results: Cytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19.

Conclusion: Recent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri-COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.
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http://dx.doi.org/10.1200/JCO.20.01307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571792PMC
October 2020

Culex interfor and Culex saltanensis (Diptera: Culicidae) are susceptible and competent to transmit St. Louis encephalitis virus (Flavivirus: Flaviviridae) in central Argentina.

Trans R Soc Trop Med Hyg 2020 10;114(10):725-729

Laboratorio de Arbovirus y Arenavirus, Instituto de Virología "Dr J. M. Vanella", CONICET, Facultad de Medicina, Universidad Nacional de Córdoba, Córdoba, Argentina.

Background: St. Louis encephalitis virus (SLEV) is endemic and autochthonous on the American continent. Culex pipiens quinquefasciatus is a vector of SLEV; however, Culex interfor and Culex saltanensis have also been found to be naturally infected with SLEV. The aim of this study was to determine the vector competence of C. interfor and C. saltanensis for SLEV from Argentina compared with C. p. quinquefasciatus.

Methods: Female of the Culex species were orally infected by feeding on viraemic chicks that had been inoculated with SLEV. Abdomens, legs and saliva blood-fed mosquitoes were analysed by viral plaque assay.

Results: Mosquitoes were susceptible to orally acquired infection, dissemination and transmission of SLEV in the saliva.

Conclusions: Our results demonstrate that C. saltanensis and C. interfor are susceptible to SLEV and competent for its transmission.
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http://dx.doi.org/10.1093/trstmh/traa058DOI Listing
October 2020

Academic excellence in Latin America: Social accountability of medical schools.

Med Teach 2020 08 5;42(8):929-936. Epub 2020 Jun 5.

Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Social accountability of medical schools has emerged as a standard of excellence in medical education during the last decade. However, the lack of valid and reliable instruments to estimate social accountability has limited the possibility of measuring the impact that medical schools have in society. Our aim was to develop an instrument and validate its use for assessing social accountability in Latin American countries. We used a three-phase mixed methods research design to develop, validate and estimate social accountability in a diverse convenient sample of 49 medical schools from 16 Latin American countries. We used a qualitative framework approach and a Delphi consensus method to design an instrument with high content validity. Finally, we assessed the psychometric properties of the instrument. The Social Accountability Instrument for Latin America (SAIL contained 21 items in four domains: mission and quality improvement, public policy, community engagement, and professional integrity. Its reliability index, estimated using Cronbach's alpha, was very high (0.96). Most of the medical schools that had ranked over the 80th percentile on traditional national academic estimates did not reach the 80th percentile using SAIL. There are validity arguments (content and reliability) to support the measurement of social accountability using the SAIL instrument. Its application showed that it provides a complementary dimension to that traditionally obtained when estimating quality in medical schools.
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http://dx.doi.org/10.1080/0142159X.2020.1770712DOI Listing
August 2020

C-reactive protein, interleukin-6 and pre-eclampsia: large-scale evidence from the GenPE case-control study.

Scand J Clin Lab Invest 2020 Sep 13;80(5):381-387. Epub 2020 May 13.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.

Multiple small studies have suggested that women with pre-eclampsia present elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6). However, little is known regarding the source of this CRP and IL-6 increase. Therefore, the aim of this study was to evaluate the relationship between CRP and IL-6 levels with pre-eclampsia considering different confounding factors. Using data from a large Colombian case-control study (3,590 cases of pre-eclampsia and 4,564 normotensive controls), CRP and IL-6 levels were measured in 914 cases and 1297 controls. The association between maternal serum levels of CRP and IL-6 with pre-eclampsia risk was evaluated using adjusted logistic regression models. Pre-eclampsia was defined as presence of blood pressure ≥140/90 mmHg and proteinuria ≥300mg/24 h (or ≥1 + dipstick). There was no evidence of association between high levels of CRP and IL-6 with pre-eclampsia after adjusting for the following factors: maternal and gestational age, ethnicity, place and year of recruitment, multiple-pregnancy, socio-economic position, smoking, and presence of infections during pregnancy. The adjusted OR for 1SD increase in log-CRP and log-IL-6 was 0.96 (95%CI 0.85, 1.08) and 1.09 (95%CI 0.97, 1.22), respectively. Although previous reports have suggested an association between high CRP and IL-6 levels with pre-eclampsia, sample size may lack the sufficient power to draw robust conclusions, and this association is likely to be explained by unaccounted biases. Our results, the largest case-control study reported up to date, demonstrate that there is not a causal association between elevated levels of CRP and IL-6 and the presence of pre-eclampsia.
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http://dx.doi.org/10.1080/00365513.2020.1747110DOI Listing
September 2020

A Lutzomyia longipalpis Salivary Protein Induces Cross-Reactive Antibodies to Pemphigus Autoantigen Desmoglein 1.

J Invest Dermatol 2020 12 29;140(12):2332-2342.e10. Epub 2020 Apr 29.

Vector Molecular Biology Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.

Fogo selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P < 0.001 for both). The levels of IgG anti-DSG1 and IgG4 anti-LJM17 and anti-LJM11 antibodies correlated positively in normal settlers and patients with FS. Mice immunized with recombinant LJM17 produced IgG1 antibodies (human IgG4 homolog) that strongly cross-reacted with recombinant DSG1; these IgG1 antibodies were inhibited by LJM17, LJM11, and DSG1 in a dose-dependent manner. However, they did not bind human or mouse epidermis by indirect immunofluorescence. Lastly, we identified short-sequence homologies of surface-exposed residues within the human DSG1 ectodomain and LJM17. Inoculation by LJM17 from L. longipalpis-elicited DSG1-cross-reactive IgG4 antibodies may lead to FS in genetically predisposed individuals.
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http://dx.doi.org/10.1016/j.jid.2020.02.041DOI Listing
December 2020

Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

Clin Cancer Res 2020 07 6;26(13):3271-3279. Epub 2020 Mar 6.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.

Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.

Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline and mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (, 57% vs 36%; , 17% vs 9%; < 0.003).

Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348681PMC
July 2020
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