Publications by authors named "PauL Swiecicki"

45 Publications

Implementation of human papillomavirus circulating tumor DNA to identify recurrence during treatment de-escalation.

Oral Oncol 2021 Jun 14:105332. Epub 2021 Jun 14.

University of Michigan, Department of Otolaryngology- Head and Neck Surgery, United States; University of Michigan, Rogel Cancer Center, United States; University of Michigan, Department of Pharmacology, United States. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2021.105332DOI Listing
June 2021

Tumor-Infiltrating Lymphocytes in Patients With Advanced Laryngeal Cancer Undergoing Bioselection.

Otolaryngol Head Neck Surg 2021 May 25:1945998211013765. Epub 2021 May 25.

Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Objective: Bioselection to assess tumor response after induction chemotherapy has been introduced as an alternative treatment strategy to total laryngectomy for patients with advanced larynx squamous cell carcinoma (LSCC). Tumor-infiltrating lymphocytes (TILs) have proven to serve as prognostic biomarkers in head and neck cancer but have not been evaluated as a way to select patients for treatment paradigms. The aim of this study is to evaluate the role of pretreatment TILs in patients with advanced LSCC undergoing the bioselection paradigm.

Study Design: Retrospective study.

Setting: Tertiary care hospital.

Methods: Patients with advanced LSCC treated with bioselection and available tissue were included (N = 76). Patients were stratified into CD8-low and CD8-high cohorts by using the median TIL count. Kaplan-Meier survival analysis and multivariate cox regression were performed with SPSS version 26 (IBM).

Results: After controlling for tobacco use, tumor site, and stage, a high CD8 TIL count was an independent predictor of improved 5-year disease-specific survival (hazard ratio, 0.17 [95% CI, 0.03-0.84]; = .03). CD8 TIL counts did not predict response to induction chemotherapy; however, subgroup analysis of patients treated with chemoradiation therapy revealed that CD8 TIL count was significantly associated with degree of response ( = .012).

Conclusion: These findings support prior data published by our group showing that TILs are predictive of disease-specific survival in patients with head and neck cancer. CD8 TIL counts were significantly associated with degree of clinical response after induction chemotherapy. These results suggest that pretreatment assessment of tumor-infiltrating CD8 cells could be useful in selecting patients.
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http://dx.doi.org/10.1177/01945998211013765DOI Listing
May 2021

Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial.

Lancet Oncol 2021 06 11;22(6):883-892. Epub 2021 May 11.

Moores Comprehensive Cancer Center, University of California, San Diego, La Jolla, CA, USA.

Background: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC.

Methods: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m intravenously followed by 250 mg/m intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants.

Findings: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred.

Interpretation: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00136-4DOI Listing
June 2021

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

Oncologist 2021 May 14. Epub 2021 May 14.

Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

Background: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC).

Materials And Methods: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists.

Results: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins.

Conclusion: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408.

Implications For Practice: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.
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http://dx.doi.org/10.1002/onco.13820DOI Listing
May 2021

Management of Salivary Gland Malignancy: ASCO Guideline.

J Clin Oncol 2021 Jun 26;39(17):1909-1941. Epub 2021 Apr 26.

University of California San Francisco, San Francisco, CA.

Purpose: To provide evidence-based recommendations for practicing physicians and other healthcare providers on the management of salivary gland malignancy.

Methods: ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, neuroradiology, pathology, and patient advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2020. Outcomes of interest included survival, diagnostic accuracy, disease recurrence, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.

Results: The literature search identified 293 relevant studies to inform the evidence base for this guideline. Six main clinical questions were addressed, which included subquestions on preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate radiotherapy techniques, the role of systemic therapy, and follow-up evaluations.

Recommendations: When possible, evidence-based recommendations were developed to address the diagnosis and appropriate preoperative evaluations for patients with a salivary gland malignancy, therapeutic procedures, and appropriate treatment options in various salivary gland histologies.Additional information is available at www.asco.org/head-neck-cancer-guidelines.
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http://dx.doi.org/10.1200/JCO.21.00449DOI Listing
June 2021

Patient Burden with Current Surveillance Paradigm and Factors Associated with Interest in Altered Surveillance for Early Stage HPV-Related Oropharyngeal Cancer.

Oncologist 2021 Apr 6. Epub 2021 Apr 6.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA.

Introduction: Optimal surveillance paradigms for survivors of early stage human papillomavirus (HPV)-related oropharyngeal cancer are not well defined. This study aimed to characterize patient interest in and factors associated with an altered surveillance paradigm.

Materials And Methods: We surveyed patients with Stage I or II HPV-related oropharyngeal cancer treated at a tertiary care institution from 2016 to 2019. Primary outcomes were descriptive assessment of patient knowledge, interest in altered surveillance, burdens of in-person appointments, and priorities for surveillance visits. Ordinal regression was used to identify correlates of interest in altered surveillance.

Results: Sixty-seven patients completed surveys from February to April 2020 at a median of 21 months since completing definitive treatment. A majority (61%) of patients were interested in a surveillance approach that decreased in-person clinic visits. Patients who self-identified as medical maximizers, had higher worry of cancer recurrence, or were in long-term relationships were less likely to be interested. Patients reported significant burdens associated with surveillance visits, including driving distance, time off work, and nonmedical costs. Patients were most concerned with discussing cancer recurrence (76%), physical quality of life (70%), mortality (61%), and mental quality of life (52%) with their providers at follow-up visits.

Conclusion: Patients with early stage HPV-related oropharyngeal cancers are interested in altered surveillance approaches, experience significant burdens related to surveillance visits, and have concerns that are not well addressed with current surveillance approaches, including physical and mental quality of life. Optimized surveillance approaches should incorporate patient priorities and minimize associated burdens.

Implications For Practice: The number of patients with HPV-related oropharyngeal cancers is increasing, and numerous clinical trials are investigating novel approaches to treating these good-prognosis patients. There has been limited work assessing optimal surveillance paradigms in these patients. Patients experience significant appointment-related burdens and have concerns such as physical and mental quality of life. Additionally, patients with early stage HPV-related oropharyngeal cancers express interest in altered surveillance approaches that decrease in-person clinic visits. Optimization of surveillance paradigms to promote broader survivorship care in clinical practice is needed.
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http://dx.doi.org/10.1002/onco.13784DOI Listing
April 2021

Prediction of Disease Free Survival in Laryngeal and Hypopharyngeal Cancers Using CT Perfusion and Radiomic Features: A Pilot Study.

Tomography 2021 Mar 5;7(1):10-19. Epub 2021 Feb 5.

Department of Radiology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (S.W.); (A.V.); (L.H.); (K.C.); (H.-P.C.).

(1) Purpose: The objective was to evaluate CT perfusion and radiomic features for prediction of one year disease free survival in laryngeal and hypopharyngeal cancer. (2) Method and Materials: This retrospective study included pre and post therapy CT neck studies in 36 patients with laryngeal/hypopharyngeal cancer. Tumor contouring was performed semi-autonomously by the computer and manually by two radiologists. Twenty-six radiomic features including morphological and gray-level features were extracted by an internally developed and validated computer-aided image analysis system. The five perfusion features analyzed included permeability surface area product (PS), blood flow (flow), blood volume (BV), mean transit time (MTT), and time-to-maximum (Tmax). One year persistent/recurrent disease data were obtained following the final treatment of definitive chemoradiation or after total laryngectomy. We performed a two-loop leave-one-out feature selection and linear discriminant analysis classifier with generation of receiver operating characteristic (ROC) curves and confidence intervals (CI). (3) Results: 10 patients (28%) had recurrence/persistent disease at 1 year. For prediction, the change in blood flow demonstrated a training AUC of 0.68 (CI 0.47-0.85) and testing AUC of 0.66 (CI 0.47-0.85). The best features selected were a combination of perfusion and radiomic features including training AUC of 0.68 (CI 0.5-0.85) and testing AUC of 0.69 (CI 0.5-0.85). The laryngoscopic percent change in volume was a poor predictor with a testing AUC of 0.4 (CI 0.16-0.57). (4) Conclusions: A combination of CT perfusion and radiomic features are potential predictors of one-year disease free survival in laryngeal and hypopharyngeal cancer patients.
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http://dx.doi.org/10.3390/tomography7010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934704PMC
March 2021

Obstructive sleep apnea in patients with head and neck cancer: a systematic review.

J Clin Sleep Med 2021 May;17(5):1109-1116

Division of Sleep Medicine, Department of Neurology, University of Michigan, Ann Arbor, Michigan.

Study Objectives: Head and neck cancers (HNCs) may modify the upper airway anatomy and thereby increase the risk for obstructive sleep apnea (OSA). If untreated, OSA is associated with adverse outcomes. Identification of risk factors for OSA in patients with HNC is essential to promote proper evaluation, treatment, and improvement of sleep-related outcomes. In this review, we assessed associations between tumor stage, cancer treatment, and OSA in the population with HNC.

Methods: A systematic search of PubMed, EMBASE (Embase.com), Cochrane Library (Cochranelibrary.com), Scopus, and Web of Science was conducted to identify articles related to OSA in patients with HNC. A total of 215 articles were identified, of which 14 were included in the qualitative synthesis. These studies included 387 participants.

Results: The most common cancer type, tumor location, and cancer therapy were squamous cell carcinoma, oropharynx, and surgery, respectively. Three of six articles reported an association between surgical treatment and OSA. Conversely, associations between tumor stage, radiotherapy, and OSA were found in only a minority of studies (15%). The prevalence of OSA was between 57% and 76% pre-cancer therapy and 12% and 96% afterward.

Conclusions: This review suggests a potential association between HNC surgery and OSA. An association between tumor stage, radiotherapy to the head and neck, and OSA is inconclusive. Further research is needed to examine the relationship between HNC and OSA.
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http://dx.doi.org/10.5664/jcsm.9134DOI Listing
May 2021

Surveillance and Monitoring Techniques for HPV-Related Head and Neck Squamous Cell Carcinoma: Circulating Tumor DNA.

Curr Treat Options Oncol 2021 Feb 8;22(3):21. Epub 2021 Feb 8.

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.

Opinion Statement: Human papilloma virus (HPV) related head and neck cancer is rising in prevalence, preferentially affecting young patients and imparting long term toxicities. Despite this, there are no screening tests or clinical biomarkers for treatment monitoring. HPV circulating tumor DNA (HPV ctDNA) represents a novel circulating biomarker which may provide real-time assessment of tumor response to therapy and recurrence. Early work suggests the promise of this assay as a predictive biomarker in numerous clinical settings, namely risk of recurrence after chemoradiation in locally advanced disease. Advancement of these findings to the clinic will require a collaborative effort in the field, including technical harmonization of assay testing characteristics, understanding of the normal kinetics in patients being treated with standard of care therapies, and appropriately designed phase III trials prior to implementation in the clinic. If successful, HPV ctDNA has the potential to revolutionize clinical trial treatment paradigms and transform patient care.
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http://dx.doi.org/10.1007/s11864-021-00821-8DOI Listing
February 2021

Prognostic Significance of Oxidation Pathway Mutations in Recurrent Laryngeal Squamous Cell Carcinoma.

Cancers (Basel) 2020 Oct 22;12(11). Epub 2020 Oct 22.

Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. Sixty-two patients were sequenced using a targeted panel, of which twenty-two also underwent transcriptome sequencing. Alterations were grouped based on biologic pathways and survival outcomes were assessed using Kaplan-Meier analysis and multivariate cox regression. Select pathways were evaluated against The Cancer Genome Atlas (TCGA) data. Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, = 0.02). Multivariate analysis showed mutations in the Oxidation pathway remained an independent predictor of disease specific survival (HR 3.2, 95% CI 1.1-9.2, = 0.03). Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity. Further, TCGA analyses demonstrated the prognostic value of oxidation pathway alterations in previously untreated disease. Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer. These prognostic genetic biomarkers may inform precision medicine protocols and identify putatively targetable pathways to improve survival in this cohort.
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http://dx.doi.org/10.3390/cancers12113081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690434PMC
October 2020

Efficacy of axitinib in metastatic head and neck cancer with novel radiographic response criteria.

Cancer 2021 Jan 20;127(2):219-228. Epub 2020 Oct 20.

Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Background: There are limited treatment options for unresectable recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Vascular endothelial growth factor is of significant interest for targeted therapy in R/M HNSCC because of its central role in tumorigenesis and immunosuppression. Axitinib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) 1 , VEGFR2, VEGFR3, platelet-derived growth factor receptor, as well as c-kit and offers such an approach.

Methods: This article reports the results of a phase 2 trial evaluating axitinib in R/M HNSCC according to the Choi criteria for radiographic response assessment. The primary endpoint of this trial was 6-month overall survival.

Results: Twenty-nine patients were enrolled, and 28 were evaluable for a response. Patients were heavily pretreated with 61% having had at least 1 previous systemic treatment in the metastatic setting (range, 0-5). The median overall survival of 9.8 months and the 6-month overall survival rate of 70% met the protocol-defined criteria for clinical efficacy. The best overall response rate was 42%. Correlative analyses demonstrated that PI3K signaling pathway alterations were associated with an increased response to therapy (75% vs 17%). A marked response to therapy was seen in a subgroup of patients who were treated with an immune checkpoint inhibitor after progression on axitinib.

Conclusions: Treatment with axitinib is associated with improved survival in patients with heavily pretreated head and neck cancer, and PI3K pathway alterations may serve as a biomarker for response. Further investigation is warranted to evaluate axitinib in biomarker-selected populations, especially in combination with immune checkpoint inhibitor therapy.

Lay Summary: Metastatic head and neck squamous cancer is an incurable disease with limited treatment options and a poor prognosis. This study is the first to demonstrate that the targeted oral drug axitinib improves survival in patients with heavily pretreated metastatic head and neck cancer. Furthermore, patients whose tumors have specific mutations derive the greatest benefit from therapy. The investigation of axitinib alone or in combination with immunotherapy in a genomic biomarker-selected population is warranted.
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http://dx.doi.org/10.1002/cncr.33226DOI Listing
January 2021

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

Radiother Oncol 2021 02 16;155:174-181. Epub 2020 Oct 16.

Department of Radiation Oncology, Michigan Medicine, Ann Arbor, United States.

Purpose: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT).

Methods: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA).

Results: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001).

Conclusions: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy.

Statement Of Translational Relevance: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.
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http://dx.doi.org/10.1016/j.radonc.2020.10.006DOI Listing
February 2021

Targeted Therapy and Traditional Chemotherapy in Melanoma and Cutaneous Squamous Cell Carcinoma.

Facial Plast Surg 2020 Apr 15;36(2):186-193. Epub 2020 May 15.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Cutaneous squamous cell carcinoma (cSCC) and melanoma encompass the majority of all malignant skin cancers. There has been an increase in their incidence globally in recent decades. In cases of high-risk, unresectable, or metastatic disease; or when patient factors or preferences limit the availability of conventional surgery or radiotherapy; or a systemic therapy is often warranted. Our improved understanding of the molecular and immune pathogenesis underlying tumor growth and development has been critical in advancing cancer therapeutics. Over the past several years, several new systemic agents have been approved for both diseases. The role of cytotoxic chemotherapy is gradually waning with the introduction of targeted therapy and immunotherapy. In this article, we review the current and relevant literature and evidence of cytotoxic chemotherapy, targeted therapy, and immune checkpoint inhibitors in the adjuvant and neoadjuvant settings for cSCC and melanoma. Additionally, we describe their role in the unresectable or metastatic disease setting.
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http://dx.doi.org/10.1055/s-0040-1709126DOI Listing
April 2020

Predictors of survival in patients undergoing oropharyngeal surgery for cancer recurrence after radiation therapy.

Eur Arch Otorhinolaryngol 2020 Jul 19;277(7):2085-2093. Epub 2020 Mar 19.

Department of Otolaryngology Head and Neck Surgery, University of Michigan, 1500 East Medical Center Dr., Ann Arbor, MI, 48109-5312, USA.

Purpose: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery.

Methods: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS).

Results: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04).

Conclusion: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.
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http://dx.doi.org/10.1007/s00405-020-05913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292755PMC
July 2020

Paired phase II trials evaluating cetuximab and radiotherapy for low risk HPV associated oropharyngeal cancer and locoregionally advanced squamous cell carcinoma of the head and neck in patients not eligible for cisplatin.

Head Neck 2020 08 27;42(8):1728-1737. Epub 2020 Jan 27.

Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

Background: Alternative therapeutic strategies are needed for localized oropharyngeal carcinoma. Cetuximab represents a potential option for those ineligible for cisplatin or, until recently, an agent for de-escalation in low risk HPV+ oropharyngeal carcinoma (OPSCC). Our objective was to define the toxicity and efficacy of cetuximab-radiotherapy.

Methods: We conducted paired phase II trials evaluating cetuximab-radiotherapy in two cohorts (a) low risk HPV+ OPSCC and (b) cisplatin ineligible. The mean follow-up was 48 months.

Results: Forty-two patients were enrolled in cohort A with a 2-year disease free survival (DFS) of 81%. Twenty-one patients were enrolled in cohort B prior to closure due to adverse outcomes with a 2-year DFS of 37%. Severe toxicities were seen in 60% of patients, 30% required enteral nutrition.

Conclusion: Among cisplatin ineligible patients, cetuximab treatment engendered poor outcomes. Rates of severe toxicities were on par with platinum-based regimens suggesting that cetuximab is not a benign treatment.
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http://dx.doi.org/10.1002/hed.26085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404812PMC
August 2020

A multi-center phase II trial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma.

Invest New Drugs 2020 10 24;38(5):1550-1558. Epub 2020 Jan 24.

Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, 300 N Ingalls St, SPC 5419, Ann Arbor, MI, 48109, USA.

Background Palbociclib is a selective inhibitor of CDK4/6 approved in metastatic breast cancer as well as evidence of activity in malignancies with CDK4-amplifications. Extensive preclinical evidence has demonstrated synergy of CDK4/6 inhibitors with platinum chemotherapy suggesting a potential role for clinical synthetic lethality. Given the sensitivity to platinum therapy as well as the landscape of genomic alterations, concurrent treatment with platinum chemotherapy and palbociclib is of significant interest as a novel treatment approach. Patients and Methods Patients with unresectable, recurrent, or metastatic head and neck cancer (R/M HNC) were enrolled. Eligible patients were required to have no previous treatment with cytotoxic chemotherapy in the recurrent/metastatic setting. This was a multicenter phase II trial in which patients were administered carboplatin in addition to concurrent palbociclib. The primary endpoint of this trial was 12-week disease control rate (DCR). Results Twenty-one patients were enrolled and 18 were evaluable for response. Grade 3/4 treatment related toxicities were seen in 79% of patients of which the most common were related to myelosuppression. 12-week DCR was 33% (5 patients with stable disease, 1 with a partial response). Median progression free survival was 2.9 months (range: 1.2-13.3) and overall survival was 4.6 months (range: 1.4-14.8). Conclusion The combination of carboplatin and palbociclib is associated with significant treatment related toxicity and insufficient anti-tumor activity.
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http://dx.doi.org/10.1007/s10637-020-00898-2DOI Listing
October 2020

Patient-reported financial toxicity and adverse medical consequences in head and neck cancer.

Oral Oncol 2020 02 23;101:104521. Epub 2019 Dec 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States; Department of Internal Medicine, Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, United States. Electronic address:

Objectives: Financial toxicity (FT) is a significant barrier to high-quality cancer care, and patients with head and neck cancer (HNCA) are particularly vulnerable given their need for intensive support, daily radiotherapy (RT), and management of long-term physical, functional, and psychosocial morbidities following treatment. We aim to identify predictors of FT and adverse consequences in HNCA following RT.

Materials And Methods: We performed a prospective survey study of patients with HNCA seen in follow-up at an academic comprehensive cancer center (CCC) or Veterans Affairs hospital between 05/2016 and 06/2018. Surveys included validated patient-reported functional outcomes and the COST measure, a validated instrument for measuring FT.

Results: The response rate was 86% (n = 63). Younger age and lower median household income by county were associated with lower COST scores (i.e., worse FT) on multivariable analysis (p = .045 and p = .016, respectively). Patients with worse FT were more likely to skip clinic visits (RR (95% CI) 2.13 (1.23-3.67), p = .007), be noncompliant with recommended supplements or medications (1.24 (1.03-1.48), p = .02), and require supportive infusions (1.10 (1.02-1.20), p = .02). At the CCC, patients with worse FT were more likely to require feeding tubes (1.62 (1.14-2.31), p = .007). Overall, 36% reported that costs were higher than expected, 48% were worried about paying for treatment, and 33% reported at least a moderate financial burden from treatment.

Conclusion: HNCA patients experience substantial FT from their diagnosis and/or therapy, with potential implications for medical compliance, QOL, and survivorship care.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008081PMC
February 2020

Predictive Values of MRI and PET Derived Quantitative Parameters for Patterns of Failure in Both p16+ and p16- High Risk Head and Neck Cancer.

Front Oncol 2019 14;9:1118. Epub 2019 Nov 14.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States.

FDG-PET adds to clinical factors, such tumor stage and p16 status, in predicting local (LF), regional (RF), and distant failure (DF) in poor prognosis locally advanced head and neck cancer (HNC) treated with chemoradiation. We hypothesized that MRI-based quantitative imaging (QI) metrics could add to clinical predictors of treatment failure more significantly than FDG-PET metrics. Fifty four patients with poor prognosis HNCs who were enrolled in an IRB approved prospective adaptive chemoradiotherapy trial were analyzed. MRI-derived gross tumor volume (GTV), blood volume (BV), and apparent diffusion coefficient (ADC) pre-treatment and mid-treatment (fraction 10), as well as pre-treatment FDG PET metrics, were analyzed in primary and individual nodal tumors. Cox proportional hazards models for prediction of LRF and DF free survival were used to test the additional value of QI metrics over dominant clinical predictors. The mean ADC pre-RT and its change rate mid-treatment were significantly higher and lower in p16- than p16+ primary tumors, respectively. A Cox model identified that high mean ADC pre-RT had a high hazard for LF and RF in p16- but not p16+ tumors ( = 0.015). Most interesting, persisting subvolumes of low BV (TV) in primary and nodal tumors mid-treatment had high-risk for DF ( < 0.05). Also, total nodal GTV mid-treatment, mean/max SUV of FDG in all nodal tumors, and total nodal TLG were predictive for DF ( < 0.05). When including clinical stage (T4/N3) and total nodal GTV in the model, all nodal PET parameters had a -value of >0.3, and only TV of primary tumors had a -value of 0.06. MRI-defined biomarkers, especially persisting subvolumes of low BV, add predictive value to clinical variables and compare favorably with FDG-PET imaging markers. MRI could be well-integrated into the radiation therapy workflow for treatment planning, response assessment, and adaptive therapy.
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http://dx.doi.org/10.3389/fonc.2019.01118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874128PMC
November 2019

Window of opportunity trials in head and neck cancer.

J Cancer Metastasis Treat 2019 18;5. Epub 2019 Mar 18.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Head and neck squamous cell carcinoma (HNSCC) has a large global burden of disease and poor survival outcomes. Recent targeted therapies and immunotherapies have been explored in HNSCC, but there has been limited translation to clinical practice outside of recurrent or metastatic cases. Window of opportunity settings, where novel agents are administered between cancer diagnosis and planned definitive therapy, have begun to be employed in HNSCC. Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, along with other biospecimens and radiographic exams. Thus, this study design can characterize the safety profiles, pharmacodynamics, and initial tumor responses to novel therapies in a treatment-naïve subject. Early window studies have also identified potential biomarkers to predict sensitivity or resistance to treatments. However, these early investigations have revealed multiple challenges associated with this trial design. In this review, we discuss recent window of opportunity trials in HNSCC and how they inform design considerations for future studies.
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http://dx.doi.org/10.20517/2394-4722.2018.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638557PMC
March 2019

Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer: ASCO Provisional Clinical Opinion.

J Clin Oncol 2019 06 25;37(18):1578-1589. Epub 2019 Apr 25.

13 Fox Chase Cancer Center, Philadelphia, PA.

Purpose: An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership after publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the role of treatment deintensification in the management of p16+ oropharyngeal cancer (OPC).

Clinical Context: For patients with p16+ OPC, current treatment approaches are well established. In the good-prognosis subset of nonsmoking p16+ patients with early-stage disease, these treatments have been highly successful, albeit with significant associated acute and late toxicity. Deintensification of surgical, radiation, and medical treatment in an effort to reduce toxicity while preserving high survival rates is an appropriate therapeutic objective currently being explored in patients who are experiencing the best treatment results. However, careful delineation of this good-risk subset is essential. While the current eighth edition of the American Joint Committee on Cancer staging system is prognostically robust, it should not be interpreted as reason to alter therapeutic decisions or justify treatment deintensification. The development of transoral surgical techniques and the adoption of intensity-modulated radiation therapy planning have been transformative in disease management and suggest potentially beneficial approaches. Recent advances in systemic treatments have been notable. The optimal integration and modification of these modalities to ameliorate toxicity has not been defined and remains an important focus of current investigation.

Provisional Clinical Opinion: The hypothesis that de-escalation of treatment intensity for patients with p16+ OPC can reduce long-term toxicity without compromising survival is compelling and necessitates careful study and the analysis of well-designed clinical trials before changing current treatment standards. Treatment deintensification for these patients should only be undertaken in a clinical trial. Additional information is available at www.asco.org/head-neck-cancer-guidelines .
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http://dx.doi.org/10.1200/JCO.19.00441DOI Listing
June 2019

Impact of American Joint Committee on Cancer Eighth Edition clinical stage and smoking history on oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Head Neck 2019 04 18;41(4):857-864. Epub 2019 Feb 18.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.

Background: The purpose of this study was to evaluate the AJCC eighth edition clinical staging system for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma and to further understand how clinical stage and smoking history affect oncologic outcomes. The purpose of this study was to present the understanding of how clinical stage and smoking history affect oncologic outcomes in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is critical for selecting patients for treatment deintensification.

Methods: Kaplan-Meier and Cox regression were used to evaluate overall survival (OS), locoregional recurrence-free survival (LRFS), and distant recurrence-free survival (DRFS). Concordance statistics (C-indices) were used to compare discriminating ability.

Results: The OS and DRFS but not LRFS were significantly distributed using the American Joint Committee on Cancer (AJCC) seventh and eighth editions criteria. The C-indices for OS, LRFS, and DRFS were 0.57, 0.54, and 0.60, respectively, using the AJCC seventh edition, and 0.63, 0.53, and 0.65, respectively, using the AJCC eighth edition. On multivariate analysis, 1 + pack-year smoking history correlated with OS (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.2-3.1; P < .01) but not LRFS or DRFS.

Conclusion: These results support implementation of the AJCC eighth edition for HPV-associated oropharyngeal SCC. Clinical stage may be more important than smoking history in selection for deintensification.
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http://dx.doi.org/10.1002/hed.25336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420360PMC
April 2019

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers.

Laryngoscope 2019 08 20;129(8):1836-1843. Epub 2018 Dec 20.

Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, U.S.A.

Head and neck squamous cell carcinomas are aggressive tumors that often present at advanced stage in difficult-to-biopsy regions of the head and neck. With the rapid move to analyze circulating tumor DNA (ctDNA) to either detect cancer or monitor disease progression and response to therapy, we have designed this article as a primer to understand the recent studies that support a transition to use these circulating biomarkers as a part of routine clinical care. Whereas some technical challenges still need to be overcome, the utility of ctDNA in cancer care is already evident from these early studies. Therefore, it is critical to understand recent advances in this area as well as emerging questions that need to be addressed as these biomarkers move closer to enhancing routine clinical care paradigms. Laryngoscope, 129:1836-1843, 2019.
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http://dx.doi.org/10.1002/lary.27725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586546PMC
August 2019

Mutational profiles of persistent/recurrent laryngeal squamous cell carcinoma.

Head Neck 2019 02 12;41(2):423-428. Epub 2018 Dec 12.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan.

Background: We sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene-specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA).

Methods: The tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene-specific alteration frequencies were compared (Chi-Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform.

Results: Persistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53.

Conclusions: Our results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.
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http://dx.doi.org/10.1002/hed.25444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431792PMC
February 2019

From VA Larynx to the future of chemoselection: Defining the role of induction chemotherapy in larynx cancer.

Oral Oncol 2018 11 1;86:200-205. Epub 2018 Oct 1.

Department of Otolaryngology - Head and Neck Surgery, United States; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, United States.

Organ preservation protocols utilizing induction chemotherapy as a selection agent have played a critical role in the treatment of advanced laryngeal squamous cell carcinoma (LSCC). The selection of patients who will have a good response to chemoradiation allows for organ preservation in a significant group of patients and minimizes the rate of surgical salvage. While there remains debate regarding its utility when compared to surgery or other organ preservation regimens, the data does suggest an important role for induction chemotherapy in LSCC. In addition, there are continued opportunities to identify pretreatment biomarkers for induction chemotherapy, whether genetic, epigenetic or cellular, that could predict response to treatment and select patients to therapy (whether organ preservation or surgery). As our understanding of the biology of larynx cancer advances, induction paradigms have utility for the development and adoption of novel agents and therapeutics. The background of induction chemotherapy as a selection agent and future directions of this approach are discussed.
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http://dx.doi.org/10.1016/j.oraloncology.2018.09.026DOI Listing
November 2018

Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma.

Cancer Immunol Immunother 2019 Feb 25;68(2):213-220. Epub 2018 Oct 25.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, Ann Arbor, 48109-0602, MI, USA.

Background: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4, CD8 and/or CD103 TIL status in patients with advanced LSCC.

Methods: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4, CD8, and CD103 TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4, CD8, and CD103 TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC.

Results: High tumor CD103 TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8 or CD4 TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103 and CD4 TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC.

Conclusions: An immune profile driven by CD103 TIL content, alone and in combination with CD4 TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.
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http://dx.doi.org/10.1007/s00262-018-2256-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375747PMC
February 2019

Palliative Head and Neck Cancer Treatment for Asymptomatic Disease.

Otolaryngol Head Neck Surg 2018 07 27;159(1):25-28. Epub 2018 Feb 27.

3 Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health Center, Ann Arbor, Michigan, USA.

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http://dx.doi.org/10.1177/0194599818761861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030473PMC
July 2018

Outcomes of Patients With Familial Transthyretin Amyloidosis After Liver Transplantation.

Prog Transplant 2017 09 4;27(3):246-250. Epub 2017 Jul 4.

7 Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis.

Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation.

Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed.

Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase.

Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.
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http://dx.doi.org/10.1177/1526924817715463DOI Listing
September 2017

Revisiting Expectations in an Era of Precision Oncology.

Oncologist 2018 03 20;23(3):386-388. Epub 2017 Nov 20.

Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA

As we enter an era of precision medicine and targeted therapies in the treatment of metastatic cancer, we face new challenges for patients and providers alike as we establish clear guidelines, regulations, and strategies for implementation. At the crux of this challenge is the fact that patients with advanced cancer may have disproportionate expectations of personal benefit when participating in clinical trials designed to generate generalizable knowledge. Patient and physician goals of treatment may not align, and reconciliation of their disparate perceptions must be addressed. However, it is particularly challenging to manage a patient's expectations when the goal of precision medicine-personalized response-exacerbates our inability to predict outcomes for any individual patient. The precision medicine informed consent process must therefore directly address this issue. We are challenged to honestly, clearly, and compassionately engage a patient population in an informed consent process that is responsive to their vulnerability, as well as ever-evolving indications and evidence. This era requires a continual reassessment of expectations and goals from both sides of the bed.
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http://dx.doi.org/10.1634/theoncologist.2017-0269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903918PMC
March 2018