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.

Comparison of different VO2max scaling models in male and female non-obese and obese adults.

BACKGROUND: The aim of this paper was to identify the most appropriate allometric scaling model for expressing aerobic fitness, determined by maximal oxygen consumption (VO2max), that would allow comparisons across differing body types. METHODS: VO2max and body composition data were collected from untrained non-obese and obese participants (N.=126). Allometric models were created using body mass (BM), fat-free mass (FFM), and leg FFM (LFFM) to determine the goodness-of-fit using the Akaike Information Criterion (AIC). RESULTS: Allometric scaled exponents adjusted for BM, FFM and LFFM were 0.67, 0.68 and 0.55, respectively. VO2max scaled to BM was 22% higher in non-obese individuals. Scaled to LFFM, V VO2max was only 7.5% higher in non-obese individuals as compared to obese individuals. Data showed a positive correlation (r=0.28; P=0.009) between VO2max and BM for non-obese participants and a negative correlation (r=-0.39; P=0.014) for obese participants. AIC values showed the LFFM model as the best fit (AICc = 0 "substantial support) and the AIC differences for FFM and BM were both >10 "no support" for the model (12.1 and 28.2, respectively). CONCLUSIONS: Interpretation of aerobic power and comparisons would be most appropriate when allometrically scaled to the metabolically active tissue (LFFM). Bias is introduced when scaling to BM and comparing individuals of various body compositions.

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.

Measuring the Submucosal Depth of Invasion in Endoscopic Mucosal Resections for Barrett-associated Adenocarcinoma: Practical Issues and Relevance for the Decision for Esophagectomy.

CONTEXT.­: Endoscopic mucosal resection (EMR) has made it possible for Barrett esophagus patients with superficial cancers to be treated without esophagectomy. Recent guidelines recommend measuring depth of invasion (DOI) in submucosal cancers based on reports that in low-risk cancers, submucosal invasion 500 µm or less is associated with low nodal metastasis rates. However, pathologists face challenges in reproducibly measuring DOI. OBJECTIVE.­: To determine how often DOI measurements could impact treatment and to evaluate reproducibility in measuring submucosal DOI in EMR specimens. DESIGN.­: Consecutive adenocarcinoma EMR cases were identified, including cases of "low histologic risk" submucosal cancer, as follows: those with negative deep margins, no high-grade histology (G3), and no lymphovascular invasion. Submucosal DOI was measured by 7 pathologists according to guidelines. RESULTS.­: Of 213 cancer EMR cases, 46 were submucosa invasive and 6 cases were low histologic risk submucosal cancers for which measurement could impact decision-making. Of these low histologic risk cases, 3 were categorized as superficial, indicating that measurement would be a clinically actionable decision point in only 1.4% of adenocarcinoma EMRs. Interobserver agreement for in-depth categorization between 7 pathologists was moderate (κ = 0.42), and the range of measurements spanned the 500-µm relevant threshold in 40 of 55 measured samples (72.7%). CONCLUSIONS.­: While therapeutic decisions would rarely have depended on DOI measurements alone in our cohort, interobserver variability raises concerns about their use as a sole factor on which to offer patients conservative therapy. Responsibly reporting and clinically using submucosal DOI measurements will require practical experience troubleshooting common histologic artifacts, as well as multidisciplinary awareness of the impact of variable specimen-handling practices.

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.

Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells.

BACKGROUND & AIMS: Barrett's esophagus (BE) can progress to dysplasia and esophageal adenocarcinoma (EAC), accompanied by mutations in TP53 that increase the stability of its product, p53. We analyzed BE tissues for messenger RNAs (mRNAs) that associate with BE progression and identified one that affects the stabilization of p53. METHODS: We obtained 54 BE samples collected from patients with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), from 1992 through 2015, and performed RNA sequence analyses, including isoform-specific analyses. We performed reverse-transcription polymerase chain reaction analyses of 166 samples and immunohistochemical analyses of tissue microarrays that contained BE tissues from 100 patients with HGD or EAC and normal esophageal squamous mucosa (controls). Proteins were expressed from transfected plasmids or knocked down with small interfering RNAs in BE cells and analyzed by immunoblots and in immunoprecipitation and ubiquitin ligase assays. Athymic nude mice bearing EAC xenograft tumors (grown from OE-33 cells) were given intraperitoneal injections of simvastatin; tumor growth was monitored and tumors were collected and analyzed by immunoblotting for levels of RNF128, p53, and acetylated p53. RESULTS: Progression of BE to HGD or EAC associated with changes in expression of mRNAs that encoded mucins and promoted inflammation and activation of ATM and the DNA damage response. As tissues progressed from BE to HGD to EAC, they increased expression of mRNAs encoding isoform 1 of RNF128 (Iso1) and decreased expression of Iso2 of RNF128. RNF128 is an E3 ubiquitin ligase that targets p53 for degradation. Incubation of BE cells with interferon gamma caused them to increase expression of Iso1 and reduce expression of Iso2. Iso1 was heavily glycosylated with limited ubiquitin ligase activity for p53, resulting in p53 stabilization. Knockdown of Iso1 in BE and EAC cells led to degradation of the mutant form of p53 and reduced clonogenic survival. In contrast, Iso2 was a potent ligase that reduced levels of the mutant form of p53 in BE cells. In BE cells, Iso2 was hypoglycosylated and degraded, via ATM and GSK3ß-mediated phosphorylation and activation of the beta-TrCP1-containing SCF ubiquitin ligase complex. Simvastatin, which degrades the mutant form of p53, also degraded RNF128 Iso1 protein in BE cells and slowed growth of EAC xenograft tumors in mice. CONCLUSIONS: We found that isoform 2 of RNF128 is decreased in BE cells, resulting in increased levels of mutant p53, whereas isoform 1 of RNF128 is increased in BE cells, further promoting the stabilization of mutant p53.

Hyperandrogenism associated with an ovarian remnant in a spayed female cat.

CASE SUMMARY: An 11-year-old female, reportedly spayed, domestic shorthair cat was examined for a 4-month history of weight loss, aggression, urine spraying, malodorous urine and estrus-like behavior. Physical examination revealed thickened skin, a mildly prominent vulva and confirmed malodorous urine. On abdominal ultrasonography, a 6 mm hypoechoic nodule was found in the left cranial abdomen. An adrenocorticotropic hormone (ACTH) stimulation test with adrenal panel revealed elevated serum concentrations of androstenedione and testosterone pre- and post-cosyntropin stimulation, mildly decreased cortisol pre- and post-cosyntropin stimulation, and decreased resting aldosterone. Exploratory laparotomy was performed and a cystic, nodular mass was found in the region of the left ovary. The mass was surgically removed and submitted for histopathology; results were conclusive for an ovarian remnant with an intact corpus luteum and non-neoplastic parovarian cysts. Previously observed clinical signs resolved within two weeks of ovariectomy. A follow-up ACTH stimulation test with adrenal panel 6 weeks postoperatively revealed normalization of serum androstenedione, testosterone and cortisol concentrations. Four years postoperatively, at the time of writing, the cat remains free of clinical signs. RELEVANCE AND NOVEL INFORMATION: We are unaware of any previously reported cases of non-neoplastic ovarian remnants associated with clinically relevant hyperandrogenism. A non-neoplastic ovarian-dependent hyperandrogenism should be included as a differential diagnosis of spayed female cats showing aggression and urine spraying behavior.

The use of columns of the zeolite clinoptilolite in the remediation of aqueous nuclear waste streams.

Mud Hills clinoptilolite has been used in an effluent treatment plant (SIXEP) at the Sellafield nuclear reprocessing site. This material has been used to remove 134/137Cs and 90Sr successfully from effluents for 3 decades. Samples of the zeolite have been tested in column experiments to determine their ability to remove radioactive Cs+ and Sr2+ ions under increasing concentrations of competing ions, Ca2+, Mg2+, Na+ and K+. These ions caused increased elution of Cs+ and Sr2+. Ca2+, Mg2+ and K+ were more effective competitors than Na+. For Na+, it was found that if concentration was reduced, then column performance recovered rapidly.

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.

Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth.

Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.

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.

A Prospective Study Comparing Distance-based vs. Time-based Exercise Prescriptions of Walking and Running in Previously Sedentary Overweight Adults.

Prior work has reported that the declines observed in body mass index (BMI) and circumference measurements in their cross-sectional data were twice as large when calculated from distance energy expenditure estimations compared to energy expenditure estimations based on time and intensity. The primary purpose of this study was to compare walking/running for distance to walking/running for time as part of an exercise intervention. This study followed a between-subjects, repeated measures design. Fifteen overweight, but otherwise healthy participants completed the study. The time-based group walked/ran for self-reported time while the distance-based group walked/ran for self-reported distance. A mixed-factor repeated-measures ANOVA was used to compare all dependent variables both within-subjects and between-subjects. Weekly adherence rates to the exercise program did not exhibit a significant difference (p > 0.05). Significant interactions were shown for mean body mass loss between groups as well as mean blood glucose level (p < 0.05). Distance-based group exhibited a decline in body mass and blood glucose while the time-based group exhibited an increase in both variables. To the best of the authors' knowledge, the present study is the first to directly compare a distance-based vs. a time-based exercise program for walking and running for improvement of risk factors of cardiovascular disease. The results of this study would suggest that a distance-based exercise prescription of walking or running should provide a clinician or researcher with a closer estimation of overall accumulated exercise and resultant weight loss.

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.