Perioperative Immunotherapy for Non-Small Cell Lung Cancer: Practical Application of Emerging Data and New Challenges.

Immune checkpoint inhibition, with or without chemotherapy, is an established standard of care for metastatic non-small cell lung cancer (NSCLC). For locally advanced NSCLC treated with chemoradiotherapy, consolidation immunotherapy has dramatically improved outcomes. Recently, immunotherapy has also been established as a valuable component of treatment for resectable NSCLC with pembrolizumab, atezolizumab, and nivolumab all approved for use in this setting. As more results read out from ongoing perioperative clinical trials, navigating treatment options will likely become increasingly complex for the practicing oncologist. In this paper, we distill key outcomes from major perioperative trials and highlight current knowledge gaps. In addition, we provide practical considerations for incorporating perioperative immunotherapy into the clinical management of operable NSCLC.

INI-1 (SMARCB1)-Deficient Undifferentiated Sinonasal Carcinoma: Novel Paradigm of Molecular Testing in the Diagnosis and Management of Sinonasal Malignancies.

Sinonasal tumors consist of a group of rare heterogeneous malignancies, accounting for 3%-5% of all head and neck cancers. Although squamous cell carcinomas make up a significant portion of cancers arising in the sinonasal tract, there are a variety of aggressive tumor types that can present with a poorly differentiated morphology and continue to pose diagnostic challenges. Accurate classification of these unique malignancies has treatment implications for patients. Recent discoveries have allowed more detailed molecular characterization of subsets of these tumor types, and may lead to individualized treatments. INI-1 (SMARCB1)-deficient sinonasal carcinoma is a recently identified subtype of sinonasal malignancy, which is characterized by deletion of the INI-1 tumor suppressor gene. Loss of INI-1 expression has emerged as an important diagnostic feature in several human malignancies including a subset of sinonasal carcinomas. In this article, we present a case of INI-1 (SMARCB1)-deficient sinonasal carcinoma, provide an overview of recent advances in histological and molecular classification of sinonasal malignancies, and discuss challenges of caring for patients with these rare malignancies, as well as potential treatment implications. KEY POINTS: Clinicians and pathologists should recognize that a variety of sinonasal tumors can present with a poorly differentiated morphology that warrants further workup and molecular classification. Routine workup of poorly or undifferentiated sinonasal tumors should include testing for INI-1/SMARCB1, SMARCA4, and NUT. Patients with these molecularly defined subsets of tumors may benefit from clinical trials that seek to exploit these molecular alterations. The EZH2 inhibitor, tazemetostat, has demonstrated some antitumor activity in INI-1-deficient tumors, and is currently under investigation.

Primary ductal adenocarcinoma of the lacrimal gland with changing genetic analysis mutations.

Primary ductal adenocarcinoma of the lacrimal gland is a rare but highly aggressive epithelial malignancy with a poor prognosis. Early diagnosis, along with genetic testing of these tumors, is imperative for proper management. We present a case of a 54-year-old man with decreasing vision over the past three years and increasing proptosis in his right eye over the past three months, secondary to a lacrimal gland mass diagnosed as primary ductal adenocarcinoma. The diagnosis was made using histological and immunohistochemical profiles (positivity for cytokeratin AE1/3, CAM5.2, androgen receptor, human epidermal growth factor receptor 2, and gross cystic disease fluid protein 15) seen in previous cases, alongside a tumor genetic profile that showed actionable mutations. Uniquely in this case, after failing traditional chemotherapy, repeat biopsy revealed a change in genetics with the malignancy no longer showing actionable mutations. These findings show that these immunohistochemical findings can act as diagnostic biomarkers, while genetic testing can reveal actionable mutations for targeted therapy.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E-positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases.

Methods for Developing Patient-Reported Outcome-Based Performance Measures (PRO-PMs).

OBJECTIVE: To recommend methods for assessing quality of care via patient-reported outcome-based performance measures (PRO-PMs) of symptoms, functional status, and quality of life. METHODS: A Technical Expert Panel was assembled by the American Medical Association-convened Physician Consortium for Performance Improvement. An environmental scan and structured literature review were conducted to identify quality programs that integrate PRO-PMs. Key methodological considerations in the design, implementation, and analysis of these PRO-PM data were systematically identified. Recommended methods for addressing each identified consideration were developed on the basis of published patient-reported outcome (PRO) standards and refined through public comment. Literature review focused on programs using PROs to assess performance and on PRO guidance documents. RESULTS: Thirteen PRO programs and 10 guidance documents were identified. Nine best practices were developed, including the following: provide a rationale for measuring the outcome and for using a PRO-PM; describe the context of use; select a measure that is meaningful to patients with adequate psychometric properties; provide evidence of the measure's sensitivity to differences in care; address missing data and risk adjustment; and provide a framework for implementation, interpretation, dissemination, and continuous refinement. CONCLUSION: Methods for integrating PROs into performance measurement are available.

A framework for describing health care delivery organizations and systems.

Describing, evaluating, and conducting research on the questions raised by comparative effectiveness research and characterizing care delivery organizations of all kinds, from independent individual provider units to large integrated health systems, has become imperative. Recognizing this challenge, the Delivery Systems Committee, a subgroup of the Agency for Healthcare Research and Quality's Effective Health Care Stakeholders Group, which represents a wide diversity of perspectives on health care, created a draft framework with domains and elements that may be useful in characterizing various sizes and types of care delivery organizations and may contribute to key outcomes of interest. The framework may serve as the door to further studies in areas in which clear definitions and descriptions are lacking.

Ki 67 is an independent predictive biomarker of cancer specific and local recurrence-free survival after lung tumor ablation.

BACKGROUND: The objective of this work was to evaluate the feasibility of histopathological analysis of tissue extracted on multitined electrodes and assess whether tissue characteristics can be used as biomarkers of oncologic outcomes after lung tumor radiofrequency (RF) ablation. METHODS: Treatment-related data regarding RF ablation of lung malignancies at our institution was collected using a Health Insurance Portability and Accountability Act-compliant ablation database. Institutional review board waiver was obtained for this study. Immunohistochemical analysis of tissue extracted from the electrodes after lung tumor RF ablation was performed for proliferation (Ki-67) and apoptosis (caspase-3). Patient, tumor demographics, and ablation parameters were recorded. Local tumor progression-free survival (LPFS), disease-specific survival (DSS), and overall survival (OS) were assessed using Kaplan-Meier methodology. Multivariate analysis determined factors affecting these oncological outcomes. RESULTS: A total of 47 lung tumors in 42 patients were ablated; 30 specimens were classified as coagulation necrosis (CN) and 17 as Ki-67-positive (+) tumor cells (viable). Tumor sizes were similar in the CN and Ki-67+ groups (P = 0.32). Median LPFS was 10 versus 16 months for Ki-67+ and CN groups, and 1-year LPFS was 34 and 75 %, respectively (P = 0.003). Median OS was 20 and 46 months (P = 0.12), and median DSS was 20 and 68 months (P = 0.01) for the Ki-67 + and CN groups, respectively. Identification of Ki-67+ tumor cells more than tripled the risk of death from cancer [hazard ratio (HR) = 3.65; 95 % confidence interval (95 % CI), 1.34-9.95; P = 0.01] and tripled the risk of local tumor progression (LTP) (HR = 3.01; 95 % CI, 1.39-6.49; P = 0.005). CONCLUSIONS: Ki-67+ tumor cells on the electrode after pulmonary tumor RF ablation is an independent predictor of LTP, shorter LPFS, and DSS.

Endotracheal myoepithelioma.

Myoepitheliomas have been described most commonly in salivary glands and have been reported elsewhere but are rare in the lung, with only six previously reported cases. To our knowledge, this represents the first endotracheal myoepithelioma. These tumors have characteristic features that distinguish them from other tumors, and the diagnosis is a pathologic one, based on the morphology and supported by immunohistochemistry. Myoepitheliomas should be considered in the diagnosis of any pulmonary nodule.

Ethical issues in clinical neuroscience research: a patient's perspective.

A patient-centered paradigm for clinical research and medical care is presented as a solution to the problem of declining innovation and increasing costs and development time in the pipeline for new therapies. Fundamental differences in values and motivations among scientists, clinicians, industry sponsor, and patients in neurotherapeutics provide a framework for analysis of ethical conflicts and the loss of public confidence in medical research. Parkinson advocates' views on clinical trial participation, perceived risks and benefits, placebo controls, and sham surgery are presented. These views reflect the sense of urgency and the unique perspective that comes from living with this progressive, debilitating condition full time. A patient-centered paradigm that includes authentic voices of patients as collaborators at every stage of development will help to resolve conflicts, build trust, recruit trial participants, and accelerate new therapies. Key elements are adaptive clinical trial methods and the development of information technology for the assessment of outcomes and surveillance of safety over the life cycle of a medical product. Supported by the Parkinson's Disease Foundation, the Parkinson Pipeline Project is a grassroots group of Parkinson's patients whose goal is to represent an authentic voice for patients in the treatment development process. This group promotes education and communication between members of the Parkinson's community and active stakeholders in medical research, industry, and regulatory agencies. Its members are an example of a new breed of knowledgeable consumers, armed with first-hand access to research findings and reinforced by on-line connections to like-minded peers throughout the world.

Comorbidity of depression with other medical diseases in the elderly.

A major factor in the context of evaluating depression in the elderly is the role of medical problems. With aging there is a rapid increase in the prevalence of a number of medical disorders, including cancer, heart disease, Parkinson's disease, Alzheimer's disease, stroke, and arthritis. In this article, we hope to bring clarity to the definition of comorbidity and then discuss a number of medical disorders as they relate to depression. We evaluate medical comorbidity as a risk factor for depression as well as the converse, that is, depression as a risk factor for medical illness. Most of the disorders that we focus on occur in the elderly, with the exception of HIV infection. This review focuses exclusively on unipolar disorder. The review summarizes the current state of the art and also makes recommendations for future directions.