Regenerative Medicine: Pharmacological Considerations and Clinical Role in Pain Management.

PURPOSE OF REVIEW: Low back pain affects at least 80% of individuals at some point in their lifetime and is the fifth most common reason for physician visits in the USA. Treatment of an acute episode of LBP generally includes rest, activity modification, physical therapy, NSAIDs, and patient education. RECENT FINDINGS: A small percentage of patients will develop chronic pain lasting > 6 months duration. Platelet-rich plasma (PRP) is one of the main pillars of regenerative medicine, as its release of bioactive proteins supports the aim of RM of restoring the anatomical function in degenerative conditions. Mesenchymal stem cells (MSCs) are multipotent stem cells, multipotent progenitor cells, or marrow stromal cells found in various body tissues, including bone marrow, lung, and adipose tissue. Evidence from well-designed case-control or cohort studies for the use of PRP and MSCs in lumbar facet joint, lumbar epidural, and sacroiliac joint injections is currently described as level IV evidence. PRP and MSCs are used autogenously to help facilitate the healing process, and their injection has been studied in the long-term management of discogenic low back pain. PRP has been compared to steroid injections in the sacroiliac joint for chronic low back pain, with favorable results. MSCs have also been shown to be useful in intervertebral disc regeneration and treatment of chronic low back pain associated with degenerative disc disease. Currently, the price for these treatments is extremely high, and thus the standard of care continues to be steroid injections and other treatments. This could change, however, with more robust data and research on the safety and long-term efficacy of biologics compared to other interventional management.

Pathology of Granulomatous Pulmonary Diseases.

CONTEXT.­: Because granulomas are represented in almost every disease category, the number of clinically and pathologically important granulomatous pulmonary diseases is large. Their diagnosis by pathologists is particularly challenging because of their nonspecificity. A specific diagnosis can be achieved only when a granuloma-inciting agent(s) (eg, acid-fast bacilli, fungi, foreign bodies, etc) are identified microscopically or by culture; this does not occur in most cases. Furthermore, a specific diagnosis cannot be reached in a high percentage of cases. Although sarcoidosis and infectious diseases account for approximately half of pulmonary granulomatous diseases worldwide, there is significant geographic variation in their prevalence. OBJECTIVES.­: To present updated information to serve as a guide to pathologic diagnosis of pulmonary granulomatous diseases, to address some commonly held misconceptions and to stress the importance of multidisciplinary coordination. Presentation of basic aspects of granulomas is followed by discussion of specific disease entities, such as tuberculous and nontuberculous Mycobacterial infections, fungal, bacterial, and parasitic infections, sarcoidosis, necrotizing sarcoid granulomatosis, berylliosis, hypersensitivity pneumonitis, hot tub lung, rheumatoid nodule, bronchocentric granulomatosis, aspirated, inhaled, and embolized foreign bodies, drug-induced granulomas, chronic granulomatous disease, common variable immunodeficiency, and granulomatous lesions associated with various types of cancer. DATA SOURCES.­: Review of pertinent medical literature using the PubMed search engine and the author's practical experience. CONCLUSIONS.­: Although the diagnosis of granulomatous lung diseases continues to present significant challenges to pathologists, the information presented in this review can be helpful in overcoming them. The importance of multidisciplinary coordination in cases where morphologic diagnosis is not possible cannot be overstated.

Pulse/hyaline ring granuloma revisited: etiologic role of seed-derived storage cells.

The objectives are to precisely identify the cells that incite the formation of lesions that are generally known as "pulse granuloma" or "hyaline ring granuloma" that occur mostly in the oral cavity, in the lungs, in and around the gastrointestinal tract, and other sites, and to suggest an alternative name for these lesions that accurately reflects their etiology. Critical review of the medical and dental literature was undertaken, and the microscopic appearances of granuloma-inciting cells depicted in the literature and seen in our practices were compared with seeds and their contents originating from a variety of leguminous and non-leguminous plants. Sections of selected seeds were examined microscopically before and after digestion with saliva and alpha amylase and subsequent routine processing and staining with H&E, PAS, and iodine. Pre- and post-digestion slides were examined with polarized light. The morphology of the granuloma-inciting cells is identical to the storage cells present in seeds from a variety of leguminous and non-leguminous plants. The cells that trigger the formation of "pulse granulomas"/"hyaline ring granulomas" are storage cells that are derived from ingested seeds of leguminous and non-leguminous plants. The terms "pulse," "legume," and "lentil," which have been applied to these cells, are misnomers. Our findings indicate that the terms "pulse granuloma" and "hyaline ring granuloma" are not appropriate descriptors of these lesions. We recommend that they be replaced by "seed storage cell granuloma," a term that now accurately reflects the etiology of these lesions.

Pulmonary neuroendocrine carcinomas in situ: do they exist?

Although precursor lesions of pulmonary squamous carcinoma, adenocarcinoma and carcinoid tumour are well known and accepted entities, precursor lesions of pulmonary neuroendocrine carcinomas, i.e. small-cell lung carcinoma and large-cell neuroendocrine carcinoma, have never been identified. A small body of literature documenting intraepithelial involvement in cases of pulmonary neuroendocrine carcinoma begs the question of whether the intraepithelial lesion represents de-novo intraepithelial neoplasia or invasion by underlying tumour. In this article, the literature on cases of invasive neuroendocrine carcinomas with an intraepithelial component showing a neuroendocrine immunophenotype is thoroughly and critically reviewed. The authors of the publications of cases of coexisting invasive and intraepithelial neuroendocrine carcinoma generally favour invasion as the explanation for the intraepithelial component. However, in practice, it is difficult or impossible to determine the direction of migration of tumour cells when there is both an invasive component and an intraepithelial component. Pulmonary neuroendocrine carcinomas in situ have been produced in genetically engineered mouse models. On the basis of the illustrations in the literature of human cases and the production of pulmonary neuroendocrine carcinomas in situ in genetically engineered mice, it seems likely that these tumours also exist in humans. However, their existence and acceptance require definitive proof. Studies should be undertaken to identify bronchial and other lung biopsies with in-situ carcinoma showing a neuroendocrine immunophenotype and a subsequent negative resection specimen and no follow-up evidence of invasive carcinoma. Documenting such cases would provide definitive proof for the existence of pulmonary neuroendocrine carcinomas in situ in humans.

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

Facebook Discussion Groups Provide a Robust Worldwide Platform for Free Pathology Education.

CONTEXT: - Facebook (Menlo Park, California) is one of many online sites that provide potential educational tools for pathologists. We have each founded Facebook groups dedicated to anatomic pathology, in which members can share cases, ask questions, and contribute to discussions. OBJECTIVES: - To report our experiences in founding and maintaining these Facebook groups and to characterize the contributed content. DESIGN: - We circulated a survey among the group founders, then compiled and analyzed the responses. RESULTS: - The groups varied in membership and in the quality of member contribution. Most posts were of pathology cases, although other topics (such as research articles) were also shared. All groups remained active and received posts from users all over the world, although all groups had many noncontributing members and received unwanted messages (which were screened and removed). Most founders were glad they had founded the groups because they provided an opportunity to both teach and learn. CONCLUSIONS: - Each analyzed Facebook group had a different character, and some downsides exist, but the groups all provided a no-cost way for pathologists and others across the world to interact online with many colleagues.

Four decades of necrotizing sarcoid granulomatosis: what do we know now?

CONTEXT: In the 4 decades since Dr Averill A. Liebow introduced necrotizing sarcoid granulomatosis, there have been publications of numerous cases, but its nature and possible relationship to classical and nodular sarcoidosis have been and remain controversial. Liebow introduced necrotizing sarcoid granulomatosis as a provisional diagnostic term and stated that "the problem is whether the disease represents necrotizing angiitis with sarcoid reaction, or sarcoidosis with necrosis of the granulomas and of the vessels." There has, as yet, been no definitive answer to the questions that he raised. OBJECTIVE: To determine whether there is a relationship between necrotizing sarcoid granulomatosis and nodular sarcoidosis in order to ascertain whether the current prevailing opinion that they are related is correct. DATA SOURCES: The world's literature on necrotizing sarcoid granulomatosis from 1973 to 2013 and nodular sarcoidosis from 1952 to 2013 was critically reviewed. One hundred three cases of necrotizing sarcoid granulomatosis and 111 cases of nodular sarcoidosis were found suitable for individual case analysis. CONCLUSIONS: The data showed a striking overlap in the clinical, radiologic, and pathologic features of both entities, strongly supporting the conclusion that necrotizing sarcoid granulomatosis is a previously unrecognized manifestation of sarcoidosis and is essentially the same as nodular sarcoidosis. It is proposed that use of necrotizing sarcoid granulomatosis as a diagnostic term be discontinued and replaced by sarcoidosis with necrotizing sarcoid granulomatosis pattern provided that an infectious etiology can be reasonably excluded. Our concept of sarcoidosis should now be expanded to recognize that there is a continuous spectrum of necrosis ranging from minimal to extensive.

Cryptococcus pneumonia presenting in an immunocompetent host with pulmonary asbestosis: a case report.

INTRODUCTION: Cryptococcal infections pose a diagnostic challenge in an immunocompetent host. Asbestos exposure has been associated with pulmonary aspergillosis. This case highlights an interesting presentation of cryptococcal lung inflammation with underlying asbestosis. CASE PRESENTATION: A 63-year-old Mediterranean Caucasian woman presented with progressive dry cough of nine months duration. A computed tomography (CT) scan of her chest revealed multiple foci in the right infra-hilar region, which were seen as hot lung masses on a positron emission tomography (PET) scan. These multiple foci appeared metastatic in nature throughout both lung fields with early mediastinal invasion. A computed tomography (CT)-guided core biopsy was obtained from a dominant right lower lobe lung mass. Histology showed chronic granulomatous inflammation with numerous budding yeast forms that were GMS-, PAS-, and mucin-positive, consistent with cryptococcosis together with asbestos bodies (ferruginous). She was managed with fluconazole (400mg (6mg/kg) per day orally) daily. At her six-month follow up, she had marked improvement in her general condition along with a diminution of the lower lobe lung mass. CONCLUSION: We report a clinical and radiological improvement in a patient treated for cryptococcal pneumonia. Asbestos exposure was likely to have been an important pathophysiological precursor to infection by environmental fungi.

Metallosis and pseudotumor after failed ORIF of a humeral fracture.

Metallosis following open reduction and internal fixation (ORIF) for fracture, usually presenting as a soft tissue mass, is barely discussed in the literature. In this case report, the imaging and pathological findings of metallosis after ORIF for a humeral fracture are presented and comprehensively discussed.

Small cell lung carcinoma with marked bronchial epithelial involvement.

Marked involvement of bronchial epithelium by malignant cells with a neuroendocrine immunophenotype was observed in a pulmonary lobectomy specimen containing combined small cell lung carcinoma (SCLC). Review of the medical literature reveals scant information on malignant neuroendocrine cells in bronchial epithelium accompanying SCLC and no documentation of an SCLC precursor. We discuss the possibility that the intraepithelial neoplastic lesion that we have described may be a primary lesion and possibly a precursor of SCLC and the alternative possibility that it represents invasion by underlying invasive SCLC. The need for further comprehensive study of the morphology and immunophenotype of bronchial mucosal abnormalities accompanying SCLC utilizing lung resection specimens is emphasized.

Pathology of sarcoidosis.

The role of pathology in the diagnosis of sarcoidosis is identification of granulomas in tissue specimens and performance of studies to exclude known causes of granulomatous inflammation. The granulomas of sarcoidosis are nonspecific lesions that, by themselves and in the absence of an identifiable etiologic agent, are not diagnostic of sarcoidosis or any other specific disease. Among the diseases to be excluded are mycobacterial, fungal, and parasitic infections, chronic beryllium disease and other pneumoconiosis, hypersensitivity pneumonitis, and Wegener's granulomatosis. Even after extensive workup a substantial number of granulomas will remain unclassified. Not every disease that features nonnecrotizing granulomas of undetermined etiology is sarcoidosis. The granulomas of sarcoidosis may exhibit focal necrosis of minimal amount. In cases with granulomas that exhibit a greater degree of necrosis an infectious or other nonsarcoid etiology should be strongly suspected. Strict clinical, radiological, and pathological criteria must be used for diagnosis. In cases that exhibit necrotizing granulomas with more than minimal, focal necrosis, extrathoracic involvement only, and/or incompatible clinical and radiological findings, the diagnosis of sarcoidosis should be approached with great caution. The diagnosis is most secure when compatible clinical and radiological findings are supported by the demonstration of microorganism-negative, nonnecrotizing granulomas in a biopsy specimen accompanied by biopsy evidence or strong clinical evidence of multisystem involvement, and negative cultures for bacteria, mycobacteria, and fungi. A positive Kveim-Siltzbach test provides strong support for the diagnosis of sarcoidosis.