A longitudinal mixed-methods study of pathology explanation clinics in patients with newly diagnosed localized prostate cancer.

OBJECTIVES: To characterize the role of pathology explanation clinics (PECs) in prostate cancer care and determine their impact on patients, urologic oncologists, and quality of care. METHODS: Semistructured interviews with 10 patients with newly diagnosed prostate cancer were conducted before and after a PEC pilot and at the 1- and 6-month follow-up visits. Information about participants' cancer knowledge and anxiety were collected quantitatively. Documented pathologist communications and proper review of outside biopsy slides were collected. Semistructured interviews were also completed with participating urologic oncologists following the pilot. RESULTS: Pathology explanation clinics improved participants' understanding of their diagnosis, cognitively and emotionally supporting them first in their urologic oncology visit and later in making an informed treatment decision. Mean knowledge scores were high, and a minority of participants had prostate cancer anxiety. Urologic oncologists noted improved understanding and reduced anxiety among participants, enabling nuanced conversations about prognosis and management during the visit. By ensuring review of outside biopsy slides and communication of clinically significant or unexpected diagnoses, PECs supported high-quality care and patient safety. CONCLUSIONS: In this small pilot, PECs positively affected patients with prostate cancer, their clinicians, and the overall care system. Additional studies in larger populations and diverse settings will be useful.

A Mixed-Methods Study of Clinicians' Attitudes Toward Pathology Explanation Clinics.

OBJECTIVES: To characterize the attitudes of treating clinicians toward pathology explanation clinics (PECs). METHODS: Clinicians from a tertiary care academic medical center were asked, "How interested would you be in having your patient meet with a pathologist to discuss their pathology report and see their tissue under the microscope?" Clinicians ranked their interest, then expanded on concerns and benefits in a semistructured interview. Audio recordings of interviews were transcribed and analyzed using a qualitative thematic approach. RESULTS: A total of 35 clinicians were interviewed, with 83% reporting some level of interest in PECs. Clinicians felt that highly educated and motivated patients were most likely to benefit from a PEC. Clinicians recognized that PECs could improve understanding and emotional processing but that the patient's information needs must be balanced with the potential for cognitive overload and emotional distress. When integrating the pathologist into the care team, clinicians worried about the pathologist's communication skills, care fragmentation, and increased clinician workload. If performed well, clinicians felt PECs had the potential to increase clinician efficacy and improve quality of care. CONCLUSIONS: Overall, clinicians are interested in PECs when they fulfill a patient's information needs and are optimally performed.

Gastrointestinal, hepatic, and pancreatobiliary involvement by plasma cell neoplasms: clinicopathologic correlations in a retrospective cohort of 116 cases.

AIMS: Plasma cell neoplasms (PCNs) may involve the gastrointestinal (GI) tract in two forms: plasmacytoma (PC), an isolated lesion that lacks marrow involvement, and extramedullary myeloma (EMM). However, previous literature on PCNs involving the GI tract, liver, and pancreas is limited. We evaluated the clinicopathologic features of the largest series of GI PCNs to date. METHODS AND RESULTS: Six institutional archives were searched for GI, liver, and pancreas cases involved with PCNs. Medical records were reviewed for clinical and imaging features. Histopathologic features evaluated included involved organ, tumor grade, and marrow involvement. Overall, 116 cases from 102 patients were identified. The tumors most presented as incidental findings (29%). The liver was most involved (47%), and masses/polyps (29%) or ulcers (21%) were the most common findings. Most cases had high-grade morphology (55%). The majority (74%) of GI PCNs were classified as EMM due to the presence of marrow involvement at some point during the disease course, occurring within a year of marrow diagnosis in 46% of patients. PC was classified in 26% of patients due to the lack of marrow involvement. Most (70%) patients died from disease within 10 years (median 14.1) of diagnosis and more than half (58%) died within 6 months. CONCLUSION: PC and EMM involving the GI tract, liver, and pancreas have a wide range of clinicopathologic presentations. Tumors may occur virtually anywhere in the GI tract or abdomen and may precede the diagnosis of marrow involvement. Both GI PC and EMM are associated with a poor prognosis.

Detection of Barrett's neoplasia with a near-infrared fluorescent heterodimeric peptide.

BACKGROUND: Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease with poor prognosis that is rising rapidly in incidence. We aimed to demonstrate specific binding by a peptide heterodimer to Barrett's neoplasia in human subjects. METHODS: Peptide monomers specific for EGFR and ErbB2 were arranged in a heterodimer configuration and labeled with IRDye800. This near-infrared (NIR) contrast agent was topically administered to patients with Barrett's esophagus (BE) undergoing either endoscopic therapy or surveillance. Fluorescence images were collected using a flexible fiber accessory passed through the instrument channel of an upper gastrointestinal endoscope. Fluorescence images were collected from 31 BE patients. A deep learning model was used to segment the target (T) and background (B) regions. RESULTS: The mean target-to-background (T/B) ratio was significantly greater for high grade dysplasia (HGD) and EAC versus BE, low grade dysplasia (LGD), and squamous epithelium. At a T/B ratio of 1.5, sensitivity and specificity of 94.1 % and 92.6 %, respectively, were achieved for the detection of Barrett's neoplasia with an area under the curve of 0.95. No adverse events attributed to the heterodimer were found. EGFR and ErbB2 expression were validated in the resected specimens. CONCLUSIONS: This "first-in-human" clinical study demonstrates the feasibility of detection of early Barrett's neoplasia using a NIR-labeled peptide heterodimer.

Broadening the Scope: A Qualitative Study of Pathologists' Attitudes Toward Patient-Pathologist Interactions.

OBJECTIVES: This study qualitatively explored and described pathologists' attitudes toward patient interaction. METHODS: In a survey to pathologists, we asked, "How interested would you be in meeting with patients to discuss their pathology report and show them microscopic images of their tissue?" Then, we asked "Why," followed by a free-text box. We asked pathologists to assume that their time would be adequately compensated and that patients' treating clinicians had already told them their diagnosis. Physician age, gender, rank, and type of practice were also collected. RESULTS: We surveyed 197 pathologists, 86% of whom were either definitely interested or interested in meeting with patients. Interest level did not differ by age, gender, or rank but was higher in academic practices than in community practices. Thematic analysis showed that pathologists believed that meeting with patients could impact (1) patients, through cognitive and emotional pathways; (2) pathologists, through patient contact and job satisfaction; and (3) the field of pathology, through quality of care and a redefined image of the specialty. CONCLUSIONS: Pathologists' interest level in meeting with patients was high. Potential impacts on patients, pathologists, and the field of pathology were identified.

The Patient-Pathologist Consultation Program: A Mixed-Methods Study of Interest and Motivations in Cancer Patients.

CONTEXT.­: There is a wide disconnect between patients and the pathologists who make their diagnoses. Recent literature highlights successful programs in which patients meet with pathologists to review their pathology reports and see their tissue under a microscope. We do not know how many patients are interested in such a service, nor do we understand what drives interested patients to want to meet with their pathologist and what specific value it may provide. OBJECTIVE.­: To quantify patient interest in a patient-pathologist consultation program and qualitatively assess motivations for patient interest or disinterest. DESIGN.­: Subjects were recruited from an academic cancer center and a local community cancer support group to respond to a survey about their interest in a patient-pathologist consultation program. Both online forms and paper surveys were available. The online survey was promoted via social media. RESULTS.­: There was a high level of patient interest, with 75% of respondents indicating they were definitely interested in a patient-pathologist consultation program. Key themes of interest were enhanced understanding of the diagnosis and disease, an opportunity to demystify the diagnostic process, and the perception that additional knowledge would empower the patient. CONCLUSIONS.­: In a select group of cancer patients, there is a very high level of interest in a patient-pathologist consultation program. Pathologists, clinicians, and hospital leadership should work together to pilot these programs in diverse settings. Additional quantitative work to scale interventions for the interested population and qualitative work to design effective, patient-centered consultation programs and to assess value are needed.

Update on Gastrointestinal Lymphomas.

Herein we review the following selection of gastrointestinal lymphomas: monomorphic epitheliotropic intestinal T-cell lymphoma; indolent T-cell lymphoproliferative disorder of the gastrointestinal tract; intestinal T-cell lymphoma, not otherwise specified; duodenal-type follicular lymphoma; and Epstein-Barr virus-positive mucocutaneous ulcer. Definitions reflect the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Clinical, morphologic, and immunophenotypic characteristics of each entity are emphasized.

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy.

Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.

Mid- and Deep-Zone Gastritis: A Histologic Pattern Associated With Autoimmune Disease but Distinct From Autoimmune Atrophic Gastritis.

OBJECTIVES: We sought to characterize a histologic pattern of mid- and deep-zone gastritis, distinct from the typical pattern of Helicobacter pylori or autoimmune gastritis and to see if it had any clinicopathologic association(s). METHODS: We analyzed inflammatory patterns and composition, excluded autoimmune gastritis using immunohistochemistry, and reviewed the medical record for demographics, medical/surgical history, presenting symptoms, endoscopic findings, and medications for 28 cases. RESULTS: All cases had inflammation in the middle and/or deep mucosal zones with sparing of the superficial/pit compartment. Subfeatures included corpus or antral predominance, pangastric involvement, prominence of a subset(s) of inflammatory cells, and degree of epithelial injury. Of 28 patients, 13 had autoimmune disease(s), autoantibodies, or both. There was no other unifying clinical feature. CONCLUSIONS: This unique pattern of gastritis should be distinguished from other entities such as H pylori and autoimmune gastritis. At least a subset may be an autoimmune condition different from classic autoimmune gastritis.

Lymphoproliferative Diseases of the Gut: A Survival Guide for the General Pathologist.

The gastrointestinal tract is the most common extranodal site of involvement by lymphoma, with B-cell tumors outnumbering T-cell tumors by a wide margin. Diffuse large B-cell lymphoma is the most common lymphoid neoplasm involving the gastrointestinal tract; but a variety of other B- and T-cell neoplasms occur in the gastrointestinal organs, often with characteristic associations and/or manifestations. Although the diagnosis of gastrointestinal lymphomas can sometimes seem daunting to general pathologists, a knowledge of the most commonly encountered entities, in combination with a reasoned and pragmatic approach to the diagnostic workup, makes it possible to approach most cases with confidence.

Ultrasmall Paramagnetic Iron Oxide Nanoprobe Targeting Epidermal Growth Factor Receptor for In Vivo Magnetic Resonance Imaging of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common worldwide cancer that is rising rapidly in incidence. MRI is a powerful noninvasive imaging modality for HCC detection, but lack of specific contrast agents limits visualization of small tumors. EGFR is frequently overexpressed in HCC and is a promising target. Peptides have fast binding kinetics, short circulatory half-life, low imaging background, high vascular permeability, and enhanced tissue diffusion for deep tumor penetration. We demonstrate a peptide specific for EGFR labeled with an ultrasmall paramagnetic iron oxide (UPIO) nanoparticle with 3.5 nm dimensions to target HCC using T1-weighted MRI. We modified the hydrophobic core with oleic acid and capped with PEGylated phospholipids DSPE-PEG and DSPE-PEG-Mal. The EGFR peptide is attached via thioether-mediated conjugation of a GGGSC linker to the maleimide-terminated phospholipids. On in vivo MR images of HCC xenograft tumors, we observed peak nanoprobe uptake at 2 h post-injection followed by a rapid return to baseline by ∼24 h. We measured significantly greater MR signal in tumor with the targeted nanoprobe versus scrambled peptide, blocked peptide, and Gadoteridol. Segmented regions on MR images support rapid renal clearance. No significant difference in animal weight, necropsy, hematology, and chemistry was found between treatment and control groups at one month post-injection. Our nanoprobe based on an EGFR specific peptide labeled with UPIO designed for high stability and biocompatibility showed rapid tumor uptake and systemic clearance to demonstrate safety and promise for clinical translation to detect early HCC.

Overexpressed Claudin-1 Can Be Visualized Endoscopically in Colonic Adenomas In Vivo.

BACKGROUND & AIMS: Conventional white-light colonoscopy aims to reduce the incidence and mortality of colorectal cancer (CRC). CRC has been found to arise from missed polypoid and flat precancerous lesions. We aimed to establish proof-of-concept for real-time endoscopic imaging of colonic adenomas using a near-infrared peptide that is specific for claudin-1. METHODS: We used gene expression profiles to identify claudin-1 as a promising early CRC target, and performed phage display against the extracellular loop of claudin-1 (amino acids 53-80) to identify the peptide RTSPSSR. With a Cy5.5 label, we characterized binding parameters and showed specific binding to human CRC cells. We collected in vivo near-infrared fluorescence images endoscopically in the CPC;Apc mouse, which develops colonic adenomas spontaneously. With immunofluorescence, we validated specific peptide binding to adenomas from the proximal human colon. RESULTS: We found a 2.5-fold increase in gene expression for claudin-1 in human colonic adenomas compared with normal. We showed specific binding of RTSPSSR to claudin-1 in knockdown and competition studies, and measured an affinity of 42 nmol/L and a time constant of 1.2 minutes to SW620 cells. In the mouse, we found a significantly higher target-to-background ratio for both polypoid and flat adenomas compared with normal by in vivo images. On immunofluorescence, we found significantly greater intensity for human adenomas (mean ± SD, 25.5 ± 14.0) vs normal (mean ± SD, 9.1 ± 6.0) and hyperplastic polyps (mean ± SD, 3.1 ± 3.7; P = 10-5 and 8 × 10-12, respectively), and for sessile serrated adenomas (mean ± SD, 20.1 ± 13.3) vs normal and hyperplastic polyps (P = .02 and 3 × 10-7, respectively). CONCLUSIONS: Claudin-1 is overexpressed in premalignant colonic lesions, and can be detected endoscopically in vivo with a near-infrared, labeled peptide.

In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft.

EGFR is a promising cell surface target for in vivo imaging that is highly overexpressed in hepatocellular carcinoma (HCC), a common cancer worldwide. Peptides penetrate easily into tumors for deep imaging, and clear rapidly from the circulation to minimize background. We aim to demonstrate use of an EGFR specific peptide to detect HCC xenograft tumors in mice with photoacoustic imaging. Nude mice implanted with human HCC cells that overexpress EGFR were injected intravenously with Cy5.5-labeled EGFR and scrambled control peptides respectively. Photoacoustic images collected from 0 to 24 h. Photoacoustic signal peaked in tumors at 3 h post-injection. Images from 0 to 1.8 cm beneath the skin revealed increased target-to-background (T/B) ratio from tumors. The T/B ratio was significantly greater for the EGFR versus control peptide. Clearance of signal was observed by ∼24 h. EGFR overexpression was validated with immunofluorescence and immunohistochemistry. A peptide specific for EGFR delivered systemically can detect HCC xenograft tumors in vivo with photoacoustic imaging.

Prostatic Adenocarcinoma With Hormone Exposure Related Changes in a Patient With Hepatic Cirrhosis - Value of Autopsy in a Case Report.

Hepatic cirrhosis is commonly associated with hyperestrogenism. Previous studies have reported morphologic changes in benign and malignant prostate tissue exposed to estrogen or anti-androgens. To our knowledge, histopathologic features of prostatic adenocarcinoma in patients with cirrhosis have not been well-reported. We present a case of incidental, but pathologically significant, prostatic adenocarcinoma detected on autopsy in a 67-year-old male patient with cirrhosis and spider angiomata. The morphologic and immunohistochemical features (including variable ERG expression) of the prostatic adenocarcinoma were consistent with hormone exposure related changes, suggesting that cirrhosis-induced elevated estrogen-to-testosterone ratio and exogenous hormone therapy might induce similar phenotypes.

Anti-TNFα alters the natural history of experimental Crohn's disease in rats when begun early, but not late, in disease.

Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% (P = 0.003), d7 = 57% (P = 0.18), d14 = no change (P = 0.99); histologic inflammation: d1 = 57% (P = 0.006), d7 = 50% (P = 0.019), d14 = no change (P = 0.99)]. This was also reflected in changes in IL-1ß, IL-6, TNF-α, IGF-I, TGF-ß1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.

Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia.

BACKGROUND AND STUDY AIMS: To demonstrate the clinical use of a multimodal endoscope with a targeted fluorescently labeled peptide for quantitative detection of Barrett's neoplasia. PATIENTS AND METHODS: We studied 50 patients with Barrett's esophagus using a prototype multimodal endoscope with a fluorescently labeled peptide. Co-registered fluorescence and reflectance images were converted to ratios to correct for differences in distance and geometry over the image field of view. The ratio images were segmented using a unique threshold that maximized the variance between high and low intensities to localize regions of high grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). RESULTS: Early neoplasia (HGD and EAC) was identified with 94 % specificity and 96 % positive predictive value at a threshold of 1.49. The mean results for HGD and EAC were significantly greater than those for squamous/Barrett's esophagus and low grade dysplasia by one-way analysis of variance (ANOVA). The receiver operator characteristic curve for detection of early neoplasia had an area under the curve of 0.884. No adverse events associated with the endoscope or peptide were found. CONCLUSION: A multimodal endoscope can quantify fluorescence images from targeted peptides to localize early Barrett's neoplasia. (ClinicalTrials.gov number NCT01630798.).

Interpretive Diagnostic Error Reduction in Surgical Pathology and Cytology: Guideline From the College of American Pathologists Pathology and Laboratory Quality Center and the Association of Directors of Anatomic and Surgical Pathology.

CONTEXT: Additional reviews of diagnostic surgical and cytology cases have been shown to detect diagnostic discrepancies. OBJECTIVE: To develop, through a systematic review of the literature, recommendations for the review of pathology cases to detect or prevent interpretive diagnostic errors. DESIGN: The College of American Pathologists Pathology and Laboratory Quality Center in association with the Association of Directors of Anatomic and Surgical Pathology convened an expert panel to develop an evidence-based guideline to help define the role of case reviews in surgical pathology and cytology. A literature search was conducted to gather data on the review of cases in surgical pathology and cytology. RESULTS: The panel drafted 5 recommendations, with strong agreement from open comment period participants ranging from 87% to 93%. The recommendations are: (1) anatomic pathologists should develop procedures for the review of selected pathology cases to detect disagreements and potential interpretive errors; (2) anatomic pathologists should perform case reviews in a timely manner to avoid having a negative impact on patient care; (3) anatomic pathologists should have documented case review procedures that are relevant to their practice setting; (4) anatomic pathologists should continuously monitor and document the results of case reviews; and (5) if pathology case reviews show poor agreement within a defined case type, anatomic pathologists should take steps to improve agreement. CONCLUSIONS: Evidence exists that case reviews detect errors; therefore, the expert panel recommends that anatomic pathologists develop procedures for the review of pathology cases to detect disagreements and potential interpretive errors, in order to improve the quality of patient care.