Publications by authors named "Paul R Kunk"

8 Publications

  • Page 1 of 1

Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies.

Am J Clin Pathol 2020 04;153(5):598-604

Departments of Pathology, University of Virginia, Charlottesville.

Objectives: Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability.

Methods: We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing.

Results: We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome.

Conclusions: Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.
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http://dx.doi.org/10.1093/ajcp/aqz199DOI Listing
April 2020

Risk of Major Bleeding with Ibrutinib.

Clin Lymphoma Myeloma Leuk 2018 11 1;18(11):755-761. Epub 2018 Aug 1.

Division of Hematology-Oncology, Department of Medicine and Cancer Center, University of Virginia Health System, Charlottesville, VA.

Background: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater.

Materials And Methods: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications.

Results: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01).

Conclusion: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.
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http://dx.doi.org/10.1016/j.clml.2018.07.287DOI Listing
November 2018

Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time?

Cancer Immunol Immunother 2018 02 20;67(2):161-174. Epub 2017 Oct 20.

Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, 450 Brookline Avenue, M1B13, Boston, MA, 02215, USA.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver's inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions.
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http://dx.doi.org/10.1007/s00262-017-2082-zDOI Listing
February 2018

Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature.

J Immunother Cancer 2016 20;4:94. Epub 2016 Dec 20.

Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, PO Box 800716, Charlottesville, 22908 VA USA.

Background: We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.

Case Presentation: A 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration.

Conclusions: Tissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.
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http://dx.doi.org/10.1186/s40425-016-0199-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5168862PMC
December 2016

Current debate in the oncologic management of rectal cancer.

World J Gastrointest Oncol 2016 Oct;8(10):715-724

Trish Millard, Paul R Kunk, Erika Ramsdale, Division of Hematology-Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, United States.

Despite the considerable amount of research in the field, the management of locally advanced rectal cancer remains a subject to debate. To date, effective treatment centers on surgical resection with the standard approach of total mesorectal resection. Radiation therapy and chemotherapy have been incorporated in order to decrease local and systemic recurrence. While it is accepted that a multimodality treatment regimen is indicated, there remains significant debate for how best to accomplish this in regards to order, dosing, and choice of agents. Preoperative radiation is the standard of care, yet remains debated with the option for chemoradiation, short course radiation, and even ongoing studies looking at the possibility of leaving radiation out altogether. Chemotherapy was traditionally incorporated in the adjuvant setting, but recent reports suggest the possibility of improved efficacy and tolerance when given upfront. In this review, the major studies in the management of locally advanced rectal cancer will be discussed. In addition, future directions will be considered such as the role of immunotherapy and ongoing trials looking at timing of chemotherapy, inclusion of radiation, and non-operative management.
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http://dx.doi.org/10.4251/wjgo.v8.i10.715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064049PMC
October 2016

Direct oral anticoagulants in hypercoagulable states.

J Thromb Thrombolysis 2017 Jan;43(1):79-85

Division of Hematology-Oncology, Department of Medicine, University of Virginia Health System, PO Box 800716, Charlottesville, VA, 22908-0716, USA.

Direct oral anticoagulants have been shown safe and effective in the treatment of pulmonary emboli and deep vein thrombi. Their role in the treatment of patients with hypercoagulability is uncertain. We designed a retrospective exploratory analysis of all patients with definite heparin induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS) that were treated with either apixaban or rivaroxaban from September 2011 through November 2015. Patients were reviewed for several clinico-pathologic features, including efficacy and safety. 23 patients were identified (12 patients with HIT and 11 patients with APS). Sixteen patients (70 %) were treated with apixaban and seven patients (30 %) were treated with rivaroxaban over a median follow up of 7 months (range 2-39). Zero patients developed recurrent thrombi. Two patients being treated for HIT developed major bleeding leading to discontinuation of all anticoagulation. Therefore, apixaban and rivaroxaban appear safe and effective for treatment of patients with HIT and APS in this small retrospective cohort and should be considered on an individual basis for patients who refuse, fail or are intolerant of warfarin. There were no sources of funding.
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http://dx.doi.org/10.1007/s11239-016-1420-xDOI Listing
January 2017

Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors.

Immunotherapy 2016 05;8(5):583-600

Division of Hematology-Oncology, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA.

Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers. This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.
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http://dx.doi.org/10.2217/imt-2015-0029DOI Listing
May 2016

From bench to bedside a comprehensive review of pancreatic cancer immunotherapy.

J Immunother Cancer 2016 15;4:14. Epub 2016 Mar 15.

Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, UVA Box 800716, Charlottesville, VA 22908 USA.

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.
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http://dx.doi.org/10.1186/s40425-016-0119-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791889PMC
March 2016