Publications by authors named "Kimberly Perez"

49 Publications

Beyond the Front Line: Emerging Data for Maintenance Therapy in Pancreatic Cancer.

J Clin Oncol 2021 Oct 24;39(29):3199-3206. Epub 2021 Aug 24.

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

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http://dx.doi.org/10.1200/JCO.21.01510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500570PMC
October 2021

The complete mitochondrial genome of the strawberry aphid Cockerell, 1901 (Hemiptera: Aphididae) from California, USA.

Mitochondrial DNA B Resour 2021 19;6(8):2373-2375. Epub 2021 Jul 19.

Division of Mathematics, Science, and Engineering, Hartnell College, Salinas, CA, USA.

The aphid Cockerell, 1901 is an agricultural pest and known vector of strawberry viruses. To better understand its biology and systematics, we performed a genomic analysis on collected from Quinalt strawberry plants from Pacific Grove, Monterey county, California, USA using Oxford Nanopore and Illumina sequencing. The resulting data were used to assemble the aphids complete mitogenome. The mitogenome of is 16,108 bp in length and contains 2 rRNA, 13 protein-coding, and 22 tRNA genes (GenBank accession number LC590896). The mitogenome is similar in content and organization to other Aphididae. Phylogenetic analysis of the mitogenome resolved it in a fully supported clade in the tribe Macrosiphini. Analysis of the barcode sequence of from California found exact and nearly identical sequences to and Hille Ris Lambers, 1953, suggesting the two species are conspecific.
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http://dx.doi.org/10.1080/23802359.2021.1915206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291070PMC
July 2021

Correlation of 68Ga-DOTATATE uptake on PET/CT with pathologic features of cellular proliferation in neuroendocrine neoplasms.

Ann Nucl Med 2021 Sep 19;35(9):1066-1077. Epub 2021 Jun 19.

Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Avenue, DL203, Boston, MA, 02215, USA.

Objective: 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing and staging neuroendocrine neoplasms (NEN). Unlike other PET tracers like FDG, the meaningfulness and use of standardized uptake values (SUVs) of 68Ga-DOTATATE is not well-established. This study aimed to determine if a correlation exists between intensity of 68Ga-DOTATATE uptake and markers of cellular proliferation.

Methods: This retrospective study included 79 patients with positive 68Ga-DOTATATE PET/CT and Ki-67 and/or mitotic index (MI) available on pathology report. SUV of the most intense lesion and the most intense organ-matched lesion were determined. Demographics and pathology results for Ki-67 and MI were collected from the electronic medical record. Correlations and trends for correlations of SUV to Ki-67 and MI were performed using Kruskal-Wallis and Cuzick trend tests.

Results: A trend for an association between SUV and Ki-67 grade was found; median SUV of Ki-67 < 3%, 3-20%, and > 20% was 35.2, 31.8, and 12.8 (p = 0.077), respectively. There was also a trend between SUV and Ki-67 categories in organ-matched lesions (p = 0.08). The median organ-matched SUV of MI < 2, 2-20, and > 20 lesions was 34.2, 18, and 21.7, respectively, (Cuzick trend test p = 0.066). The median SUV for small bowel, pancreatic, and other primary locations was 27.6, 46.9, and 9.3 (p < 0.01), respectively.

Conclusions: The association between 68Ga-DOTATATE SUV, histologic grade, and primary site of NEN demonstrates its potential use for prognostication, or potentially as a surrogate for histologic grading when biopsy is not possible.
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http://dx.doi.org/10.1007/s12149-021-01642-3DOI Listing
September 2021

Pancreatic acinar cell carcinoma: A multi-center series on clinical characteristics and treatment outcomes.

Pancreatology 2021 May 15. Epub 2021 May 15.

Division of Gastroenterology, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA, USA. Electronic address:

Background: Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series.

Methods: This is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test.

Results: Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p < 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006).

Conclusion: Pancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.
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http://dx.doi.org/10.1016/j.pan.2021.05.011DOI Listing
May 2021

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

Pancreas 2021 04;50(4):469-493

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001792DOI Listing
April 2021

Prediagnostic Inflammation and Pancreatic Cancer Survival.

J Natl Cancer Inst 2021 Sep;113(9):1186-1193

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

Background: Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before diagnosis and pancreatic cancer survival.

Methods: We prospectively examined the association of prediagnostic plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 with survival among 492 participants from 5 large US prospective cohort studies who developed pancreatic cancer. Using an empirical dietary inflammatory pattern (EDIP) score, we evaluated whether long-term proinflammatory diets were associated with survival among 1153 patients from 2 of the 5 cohorts. Cox proportional hazards regression was used to estimate hazard ratios for death with adjustment for potential confounders. All statistical tests were 2-sided.

Results: Higher prediagnostic levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 were individually associated with reduced survival (Ptrend = .03, .01, and .04, respectively). Compared with patients with a combined inflammatory biomarker score of 0 (all 3 marker levels below medians), those with a score of 3 (all 3 marker levels above medians) had a hazard ratio for death of 1.57 (95% confidence interval = 1.16 to 2.12; Ptrend = .003), corresponding to median overall survival times of 8 vs 5 months. Patients consuming the most proinflammatory diets (EDIP quartile 4) in the prediagnostic period had a hazard ratio for death of 1.34 (95% confidence interval = 1.13 to 1.59; Ptrend = .01), compared with those consuming the least proinflammatory diets (EDIP quartile 1).

Conclusion: Prediagnostic levels of inflammatory biomarkers and long-term proinflammatory diets were inversely associated with pancreatic cancer survival.
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http://dx.doi.org/10.1093/jnci/djab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522350PMC
September 2021

Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors.

Endocr Relat Cancer 2021 Apr;28(4):237-246

Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The mammalian target of rapamycin inhibitor everolimus is an established therapy for well-differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a 1 week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.
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http://dx.doi.org/10.1530/ERC-20-0446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428776PMC
April 2021

Bortezomib for treatment of anti-NMDA receptor encephalitis in a pediatric patient refractory to conventional therapy.

Am J Health Syst Pharm 2021 02;78(5):395-400

St. Joseph's Children's Hospital, Tampa, FL.

Purpose: The case of a pediatric patient with treatment refractory anti-N-methyl-d-aspartate (NMDA) receptor encephalitis treated with the plasma cell-depleting therapy bortezomib is reported.

Summary: A 5-year-old female presented to the hospital with a 1-week history of altered mental status, agitation, and possible seizure-like activity. She was admitted to the hospital for suspected meningitis or meningoencephalitis and an extensive workup was completed, including sending blood and cerebrospinal fluid (CSF) for testing for NMDA receptor antibodies. While test results were pending, the patient was treated initially with intravenous immunoglobulin (IVIG) for 4 days followed by high-dose methylprednisolone for 5 days. The patient's serum and CSF studies were positive for NMDA receptor antibodies, confirming the diagnosis of anti-NMDA receptor encephalitis. She was then treated with plasmapheresis therapy every other day for 5 treatments, without any clinical improvement. The patient then received rituximab once weekly for 6 weeks. Three weeks after completion of rituximab therapy, the patient was started on her first cycle of bortezomib therapy. She received a total of 6 cycles, with improvement in her clinical status beginning with the third cycle. Upon completion of 6 cycles, the patient's mental status and level of functioning had greatly improved. She was discharged to an inpatient rehabilitation facility and ultimately able to return home to her family.

Conclusion: A 5-year-old female with anti-NMDA receptor encephalitis was successfully treated with bortezomib after having shown no clinical improvement during treatment with IVIG, high-dose methylprednisolone, plasmapheresis, and rituximab.
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http://dx.doi.org/10.1093/ajhp/zxaa415DOI Listing
February 2021

Implementing Systematic Genetic Counseling and Multigene Germline Testing for Individuals With Pancreatic Cancer.

JCO Oncol Pract 2021 02 13;17(2):e236-e247. Epub 2021 Jan 13.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: National guidelines recommend genetic counseling and multigene germline testing (GC/MGT) for all patients with pancreatic ductal adenocarcinoma (PDAC). This study's aim was to assess real-world effectiveness of implementing systematic GC/MGT for all patients with PDAC at a high-volume academic institution.

Methods: An iterative process for systematizing GC/MGT was developed in which gastrointestinal oncology providers at the Dana-Farber Cancer Institute were recommended to refer all patients with PDAC for GC/MGT (clinician-directed referral). Workflows were subsequently changed such that patients with PDAC were automatically offered GC/MGT when scheduling their initial oncology consultation (automated referral). Clinical and germline data were collected on a consecutive cohort of patients with PDAC undergoing GC/MGT during a 25-month enrollment period (19-month clinician-directed referrals; 6-month automated referrals).

Results: One thousand two hundred fourteen patients with PDAC were seen for initial oncologic evaluation, 266 (21.9%) of whom underwent GC/MGT. Compared with baseline clinician-directed referrals, implementation of automated referrals led to a significant increase in patients with PDAC undergoing GC/MGT (16.5% 38.0%, < .001), including those undergoing multigene germline testing (MGT) ≤ 7 days of initial oncology evaluation (14.7% 60.3%, < .001), with preserved pathogenic variant detection rates (10.0% 11.2%, = 0.84). 16 of 28 (57.1%) pathogenic variant carriers had relatives who pursued cascade germline testing, and 13 of 26 (50.0%) carriers with incurable disease received targeted therapy based on MGT results.

Conclusion: Implementation of systematic GC/MGT in patients with PDAC is feasible and leads to management changes for patients with PDAC and their families. GC/MGT workflows that bypass the need for clinician referral result in superior uptake and time to testing. Further investigation is needed to identify other barriers and facilitators of universal GC/MGT.
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http://dx.doi.org/10.1200/OP.20.00678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257923PMC
February 2021

Chromatin Landscape Underpinning Human Dendritic Cell Heterogeneity.

Cell Rep 2020 09;32(12):108180

Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Human dendritic cells (DCs) comprise subsets with distinct phenotypic and functional characteristics, but the transcriptional programs that dictate their identity remain elusive. Here, we analyze global chromatin accessibility profiles across resting and stimulated human DC subsets by means of the assay for transposase-accessible chromatin using sequencing (ATAC-seq). We uncover specific regions of chromatin accessibility for each subset and transcriptional regulators of DC function. By comparing plasmacytoid DC responses to IFN-I-producing and non-IFN-I-producing conditions, we identify genetic programs related to their function. Finally, by intersecting chromatin accessibility with genome-wide association studies, we recognize DC subset-specific enrichment of heritability in autoimmune diseases. Our results unravel the basis of human DC subset heterogeneity and provide a framework for their analysis in disease pathogenesis.
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http://dx.doi.org/10.1016/j.celrep.2020.108180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546547PMC
September 2020

Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1586-1595. Epub 2020 May 28.

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes.

Methods: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors.

Results: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; = 0.032). -mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, < 0.001).

Conclusions: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC.

Impact: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415636PMC
August 2020

Treatment of Gastroenteropancreatic Neuroendocrine Tumors.

Surg Pathol Clin 2019 Dec;12(4):1045-1053

Program in Carcinoid and Neuroendocrine Tumors, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.

Neuroendocrine tumors (NETs) represent a group of biologically and clinically heterogeneous neoplasms arising from the diffuse neuroendocrine system. Although NETs may develop in almost any organ, they commonly arise in the gastrointestinal tract and pancreas and are referred to as gastroenteropancreatic (GEP)-NETs when they arise from these sites. In recent years, advances in understanding of the biology of NETs have resulted in an expansion in treatment options and improved survival for patients. This review focuses on treatment of GEP-NETS and highlights factors that govern the therapeutic approach.
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http://dx.doi.org/10.1016/j.path.2019.08.011DOI Listing
December 2019

Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk.

Br J Cancer 2019 04 14;120(8):848-854. Epub 2019 Mar 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.

Background: Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types.

Methods: We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models.

Results: During 1.1 million person-years (1986-2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28-6.07) or breast cancer (HR, 1.40; 95% CI, 1.01-1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95-1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94-1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41-4.82] and 1.92 [95% CI, 1.05-3.49], respectively).

Conclusion: Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.
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http://dx.doi.org/10.1038/s41416-019-0426-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474278PMC
April 2019

Survival of Staphylococcus epidermidis in Fibroblasts and Osteoblasts.

Infect Immun 2018 10 21;86(10). Epub 2018 Sep 21.

Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

is a leading cause of infections associated with indwelling medical devices, including prosthetic joint infection. While biofilm formation is assumed to be the main mechanism underlying the chronic infections causes, we hypothesized that also evades immune killing, contributing to its pathogenesis. Here, we show that prosthetic joint-associated isolates can persist intracellularly within human fibroblasts and inside human and mouse osteoblasts. We also show that the intracellularly persisting bacteria reside primarily within acidic phagolysosomes and that over the course of infection, small-colony variants are selected for. Moreover, upon eukaryotic cell death, these bacteria, which can outlive their host, can escape into the extracellular environment, providing them an opportunity to form biofilms on implant surfaces at delayed time points in implant-associated infection. In summary, the acidic phagolysosomes of fibroblasts and osteoblasts serve as reservoirs for chronic or delayed infection.
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http://dx.doi.org/10.1128/IAI.00237-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204734PMC
October 2018

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.

Genet Med 2019 01 2;21(1):213-223. Epub 2018 Jul 2.

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

Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses.

Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression.

Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5-13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30-0.99; P = 0.05).

Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.
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http://dx.doi.org/10.1038/s41436-018-0009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666401PMC
January 2019

Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.

Cancer Discov 2018 09 14;8(9):1096-1111. Epub 2018 Jun 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192263PMC
September 2018

Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer.

Int J Radiat Oncol Biol Phys 2018 04 31;100(5):1175-1178. Epub 2018 Jan 31.

The Department of Medicine, The Brown University Oncology Research Group, Providence, Rhode Island.

Purpose: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer.

Patients And Methods: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 10 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation.

Results: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months.

Conclusions: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.004DOI Listing
April 2018

Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor.

EBioMedicine 2017 Nov 16;25:50-57. Epub 2017 Oct 16.

Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.

Background: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs.

Methods: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR.

Findings: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set.

Interpretation: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.
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http://dx.doi.org/10.1016/j.ebiom.2017.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704062PMC
November 2017

When, What, and Why of Perioperative Treatment of Potentially Curable Pancreatic Adenocarcinoma.

J Clin Oncol 2017 Feb 28;35(5):485-489. Epub 2016 Dec 28.

Kimberly Perez, Thomas E. Clancy, Joseph D. Mancias, Michael H. Rosenthal, and Brian M. Wolpin, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 64-year-old woman with a history of hypertension and type 2 diabetes had been in her usual state of health until she developed symptoms of diarrhea, abdominal bloating, and discomfort in the midepigastrium. Evaluation with a contrast-enhanced abdominopelvic computed tomography (CT) scan demonstrated a mass in the pancreatic body that was approximately 3.1 cm × 2 cm × 2.1 cm in size with abutment of the portal vein-superior mesenteric vein confluence for less than 180°. The confluence was narrowed but without thrombosis. No tumor-vessel interface was noted at the superior mesenteric artery, celiac artery, or common hepatic artery. Several peripancreatic lymph nodes were observed that measured up to 11 mm × 5 mm. No evidence for distant spread of disease was identified. An upper endoscopy with endoscopic ultrasound was performed and fine-needle aspirates of the pancreas mass were positive for malignant cells that were consistent with adenocarcinoma. Chest CT scan without intravenous contrast demonstrated no evidence of metastatic disease. The patient came to the clinic to discuss management of her newly diagnosed malignancy.
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http://dx.doi.org/10.1200/JCO.2016.70.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455317PMC
February 2017

Staphylococcusepidermidis Small-Colony Variants Are Induced by Low pH and Their Frequency Reduced by Lysosomal Alkalinization.

J Infect Dis 2017 02;215(3):488-490

Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, and.

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http://dx.doi.org/10.1093/infdis/jiw503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853244PMC
February 2017

Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute-Designated Cancer Program.

J Oncol Pract 2016 Apr 23;12(4):e396-404. Epub 2016 Feb 23.

Rhode Island Hospital; The Miriam Hospital, Providence; Memorial Hospital of Rhode Island, Pawtucket; and Newport Hospital, Newport, RI.

Purpose: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)-designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non-NCI-designated cancer programs.

Materials And Methods: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board-approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers.

Results: Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physician's choice of a different therapy (6.8%), or stable disease (11%).

Conclusion: This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.
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http://dx.doi.org/10.1200/JOP.2015.008433DOI Listing
April 2016

Pitfalls of Personalizing Cancer Treatment.

Authors:
Kimberly Perez

Am J Clin Oncol 2016 Feb;39(1):107

Warren Alpert School of Medicine Brown University, Providence, RI.

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http://dx.doi.org/10.1097/COC.0000000000000173DOI Listing
February 2016

FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.

Am J Clin Oncol 2016 12;39(6):619-622

The Brown University Oncology Research Group, Providence, RI.

Background: The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel.

Methods: Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity.

Results: Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months.

Conclusions: The maximum tolerated dose of nab-paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.
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http://dx.doi.org/10.1097/COC.0000000000000246DOI Listing
December 2016

Updates in Tumor Profiling in Gastrointestinal Cancers.

R I Med J (2013) 2015 Oct 1;98(10):21-4. Epub 2015 Oct 1.

Research Director of the Comprehensive Cancer Center at Rhode Island, The Miriam and Newport hospitals and the medical director for the Brown University Oncology Group. He is a Professor of Medicine at The Warren Alpert Medical School of Brown University.

In the last decade there has been a focus on biomarkers that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression of cancers. Characterization of genomes by next-generation sequencing (NGS) has permitted significant advances in gastrointestinal cancer care. These discoveries have fueled the development of novel therapeutics and have laid the groundwork for the development of new treatment strategies. Work in colorectal cancer (CRC) has been in the forefront of these advances. With the continued development of NGS technology and the positive clinical experience in CRC, genome work has begun in esophagogastric, pancreatic, and hepatocellular carcinomas as well.
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October 2015

Advances in the Molecular Profiling of Tumor Tissue.

R I Med J (2013) 2015 Oct 1;98(10):15. Epub 2015 Oct 1.

Assistant Professor of Medicine, Division of Hematology/ Oncology, at The Warren Alpert Medical School of Brown University.

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October 2015

Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells.

BMC Cancer 2015 Aug 1;15:571. Epub 2015 Aug 1.

Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Coro West, Suite 5.01, One Hoppin St, Providence, RI, 02903, USA.

Background: Extracellular vesicles (EVs) are secreted from many cells, carrying cargoes including proteins and nucleic acids. Research has shown that EVs play a role in a variety of biological processes including immunity, bone formation and recently they have been implicated in promotion of a metastatic phenotype.

Methods: EVs were isolated from HCT116 colon cancer cells, 1459 non-malignant colon fibroblast cells, and tumor and normal colon tissue from a patient sample. Co-cultures were performed with 1459 cells and malignant vesicles, as well as HCT116 cells and non-malignant vesicles. Malignant phenotype was measured using soft agar colony formation assay. Co-cultures were also analyzed for protein levels using mass spectrometry. The importance of 14-3-3 zeta/delta in transfer of malignant phenotype was explored using siRNA. Additionally, luciferase reporter assay was used to measure the transcriptional activity of NF-κB.

Results: This study demonstrates the ability of EVs derived from malignant colon cancer cell line and malignant patient tissue to induce the malignant phenotype in non-malignant colon cells. Similarly, EVs derived from non-malignant colon cell lines and normal patient tissue reversed the malignant phenotype of HCT116 cells. Cells expressing an EV-induced malignant phenotype showed increased transcriptional activity of NF-κB which was inhibited by the NF--κB inhibitor, BAY117082. We also demonstrate that knock down of 14-3-3 zeta/delta reduced anchorage-independent growth of HCT116 cells and 1459 cells co-cultured with HCT derived EVs.

Conclusions: Evidence of EV-mediated induction of malignant phenotype, and reversal of malignant phenotype, provides rational basis for further study of the role of EVs in tumorigenesis. Identification of 14-3-3 zeta/delta as up-regulated in malignancy suggests its potential as a putative drug target for the treatment of colorectal cancer.
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http://dx.doi.org/10.1186/s12885-015-1568-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522096PMC
August 2015

Biofilm-like aggregation of Staphylococcus epidermidis in synovial fluid.

J Infect Dis 2015 Jul 23;212(2):335-6. Epub 2015 Feb 23.

Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1093/infdis/jiv096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566000PMC
July 2015

Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study.

Am J Clin Oncol 2017 Jun;40(3):283-287

Brown University Oncology Research Group, Providence, RI.

Purpose: Following preoperative chemoradiation and surgery, many patients with stage II to III rectal cancer are unable to tolerate full-dose adjuvant chemotherapy. BrUOG R-224 was designed to assess the impact of COmplete Neoadjuvant Treatment for REctal cancer (CONTRE), primary chemotherapy followed by chemoradiation and surgery, on treatment delivery, toxicities, and pathologic response at surgery.

Methods: Patients with clinical stage II to III (T3 to T4 and/or N1 to N2) rectal cancer received 8 cycles of modified FOLFOX6 followed by capecitabine 825 mg/m bid concurrent with 50.4 Gy intensity-modulated radiation therapy. Surgery was performed 6 to 10 weeks after chemoradiation.

Results: Thirty-nine patients were enrolled between August 2010 and June 2013. Median age was 61 years (30 to 79 y); 7 patients (18%) were clinical stage II and 32 (82%) stage III. Thirty-six patients (92%) received all 8 cycles of mFOLFOX6, of whom 35 completed subsequent chemoradiation; thus 89% of patients received CONTRE as planned. No unexpected toxicities were reported. All patients had resolution of bleeding and improvement of obstructive symptoms, with no complications requiring surgical intervention. Pathologic complete response (ypT0N0) was demonstrated in 13 patients (33%; 95% CI, 18.24%-47.76%).

Conclusions: CONTRE seems to be a well-tolerated alternative to the current standard treatment sequence. Evaluating its impact on long-term outcomes would require a large randomized trial, but using pathologic response as an endpoint, it could serve as a platform for assessing the addition of novel agents to preoperative treatment in stage II to III rectal cancer.
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http://dx.doi.org/10.1097/COC.0000000000000149DOI Listing
June 2017

New therapeutic strategies for squamous cell cancer and adenocarcinoma.

Ann N Y Acad Sci 2013 Oct;1300:213-225

FMUSP and Nucleus of General and Specialized Surgery, Sao Paulo, Brazil.

This paper presents commentaries on neoadjuvant treatment esophagectomy; the prognostic and predictive effects of single nucleotide polymorphisms (SNP) in the multimodality therapy of esophageal cancer; optimal preoperative treatment prior to surgery for esophageal cancer; a possible role for trastuzumab in treating esophageal adenocarcinoma or any esophageal dysplasia/intra-epithelial neoplasia; surgery after chemoradiation in resectable esophageal cancer; whether para-aortic lymph node dissection should be performed in esophagogastric junction (EGJ) tumors; and transhiatal esophagectomy in treatment of the esophageal cancer.
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http://dx.doi.org/10.1111/nyas.12247DOI Listing
October 2013

RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients.

BMC Cancer 2013 Oct 8;13:463. Epub 2013 Oct 8.

Department of Medicine, Rhode Island Hospital and The Alpert Medical School of Brown University, Providence, RI 02903, USA.

Background: A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients.

Methods: HCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients.

Results: We demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients.

Conclusions: In the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional treatments were detected. The phosphorylation of pRKIP and STAT3 are induced by the cytokine IL-6 and suppressed by the chemotherapeutic drugs CPT and OXP. Therefore, these results suggest that STAT3 and pRKIP may serve as prognostic biomarkers in stage II colon cancer patients and may improve chemotherapy.
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http://dx.doi.org/10.1186/1471-2407-13-463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856511PMC
October 2013
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