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Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48–94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8–47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9–42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5–52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8–57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

Background The Centers for Disease Control and Prevention and New York State Department of Health recently identified the Capital District of New York (CDNY) as an emerging endemic area for blastomycosis. However, no clinical or epidemiological description of blastomycosis in the CDNY has been published. Methods We performed a retrospective analysis of blastomycosis cases at Albany Medical Center (AMC) and Albany Stratton Veterans Affairs Medical Center (VAMC) from January 1, 2000, through June 1, 2019. Patients were identified via an institution-approved informatics system at the hospital's microbiology laboratory. Results We identified 20 patients diagnosed with blastomycosis over the past 2 decades. There was a nearly 9-fold increase in the annual number of cases in 2016–2019 compared with 2000–2015. The majority of patients resided in the CDNY (90%), and 65% lived within the Mohawk River valley. Most cases (85%) were assumed to be malignancies or non-mycotic infections prior to diagnosis, with median time between presentation and diagnosis of 53 days. Conclusions Our data support recent reports that blastomycosis is an emerging disease in the CDNY. Most patients were misdiagnosed as malignancy or non-mycotic infection, which led to treatment delays.

Dermatomyositis (DM) is an idiopathic inflammatory disorder that presents with proximal muscle weakness and typical DM skin changes. DM can involve other organs such as the lung, esophagus, and heart. Diaphragmatic muscle paralysis is an unrecognized clinical presentation of acute DM exacerbation. A 58-year-old man with a history of DM presented to the hospital after sustaining a cardiorespiratory arrest. Before arrest, he had been suffering from progressive dyspnea and muscle weakness. Immunosuppressive therapy of tacrolimus for DM was recently discontinued due to renal toxicity. Bedside ultrasound of the diaphragm while intubated revealed evidence of bilateral diaphragmatic paralysis. After extubation, supine and upright pulmonary function tests (PFT) and sniff test results strengthened the diagnosis of diaphragmatic paralysis. The patient was worked up for an acute DM exacerbation as the likely etiology of the severe diaphragmatic muscle weakness (diaphragmatic paralysis) and ventilatory failure. Skin and muscle biopsy confirmed the diagnosis of active DM. The patient was treated with high dose steroids and mycophenolate mofetil, following which he soon recovered.

Purpose The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. Methods AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts. Results AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates. Conclusions AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials.

AimsRoutine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC).MethodsPD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR-proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined.ResultsPD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, pPD-L1 or PD-L2 genes by CGP.ConclusionsPD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR-D. PD-L1 amplification is extremely uncommon in CRC. Evaluation of whole tissue section and incorporation of IC staining enhance the sensitivity to screen patients who may benefit from ICPI therapy.

Background Genomic fusions of the anaplastic lymphoma kinase gene (ALK) are a well-established therapy target in non-small cell lung cancer (NSCLC). From a survey of 114,200 clinical cases, we determined the prevalence of ALK rearrangements (rALK) in non-NSCLC tumors and report their responsiveness to therapies targeting ALK. Materials and Methods Comprehensive genomic profiling of 114,200 relapsed and metastatic malignancies, including both solid tumors and hematolymphoid cancers, was performed using a hybrid-capture, adaptor ligation-based next-generation sequencing assay. Results Of 114,200 clinical samples, 21,522 (18.8%) were NSCLC and 92,678 (81.2%) were other tumor types. Of the 876 (0.8%) cases with ALK fusions (fALK) or rALK, 675 (77.1%) were NSCLC and 201 (22.9%) were other tumor types. ALK fusions were significantly more frequent in NSCLC (3.1%) than non-NSCLC (0.2%; p Conclusion ALK rearrangements can be identified in a wide variety of epithelial and mesenchymal malignancies beyond NSCLC. Anti-ALK therapies can be effective in non-NSCLC tumors driven by fALK, and further study of therapies targeting ALK in clinical trials involving a wider variety of cancer types appears warranted.

» Assessment of chondral lesions begins with a clinical evaluation and radiographs. » Longitudinal follow-up with serial radiographs is appropriate in cases without evidence of aggressive radiographic features. » Concerning radiographic features include periosteal reaction, soft-tissue extension, cortical destruction, endosteal scalloping of greater than two-thirds of the native cortex, larger lesion size (≥5 cm), and location in the axial skeleton. » Biomarkers such as IMP3, SOX4, microRNA, and periostin may be used as an adjunct in histologic assessment to help differentiate benign enchondroma from a low-grade chondrosarcoma. » Advanced-imaging studies, such as computed tomography (CT), bone scans, magnetic resonance imaging (MRI), dynamic contrast-enhanced MRI, and fluorodeoxyglucose positron emission tomography (FDG-PET), may be considered for borderline cases. » Aggressive or concerning radiographic features should prompt evaluation with advanced imaging or referral to an orthopaedic oncologist.

Timely diagnosis and care are major determinants of the outcome in acute promyelocytic leukaemia (APL), a malignancy whose incidence may be increasing. The Canadian Cancer Registry (CCR) and health system represent valuable settings to study APL epidemiology. We analysed the CCR, which contains data on all Canadians with APL. To provide clinical information lacking in the CCR, we obtained data from five leukaemia referral centres during a similar time period. Between 1993 and 2007, there were 399 APL in Canada. Age-standardized incidence was 0·083/100,000 and was stable over time. The early death (ED) rate was 21·8% (10·6% in patients50 years old and 35·5% for those aged50 years), with no improvement over time. Five-year overall survival (OS) was 54·6% (73·3% in patients50 years; 29·1% older patients). In the referral cohort, 131 patients were diagnosed between 1999 and 2010. ED was 14·6% and 2-year OS was 76·5%. Within this cohort, ED and OS improved over time, although advanced patient age remained an adverse determinant of OS. In Canada, APL incidence is unexpectedly low and temporally stable. ED was higher than reported in clinical trials, but similar to reports from other registries. In contrast, ED was lower in referral centres and improved with time.

Large-scale diversion of controlled substances (CS) from within a hospital or heath system pharmacy is a rare but growing problem. It is the responsibility of pharmacy leadership to scrutinize control processes to expose weaknesses. This article reviews examples of large-scale diversion incidents and diversion techniques and provides practical strategies to stimulate enhanced CS security within the pharmacy staff. Large-scale diversion from within a pharmacy department can be averted by a pharmacist-in-charge who is informed and proactive in taking effective countermeasures.

Recent studies have pointed to changes in tissue mechanics as a contributory element to the development of malignancies. Increased tissue rigidity is associated with the unfolding of the Type III domains of fibronectin within the extracellular matrix. The consequences of this unfolding on cellular functions within the lung are not well understood. In the present study, we evaluated the effect of a peptide representing a partially unfolded intermediate of the first Type III repeat of fibronectin (FnIII-1c) on inflammatory gene expression in adult human lung fibroblast cells. FnIII-1c induced expression of cytokines, CXCL1-3, IL-8 and TNF-α, by lung fibroblast cells. The increase in IL-8 expression was dependent on Toll-like receptor 2 and NFκB. Immunohistochemistry of tissue arrays representing squamous cell carcinoma of the lung revealed extensive stromal staining for IL-8 and fibronectin fibrils which were co-aligned with myofibroblasts. These data suggest a model in which unfolding of FnIII domains secondary to myofibroblast-generated tension may induce the release of cytokines by stromal fibroblasts present within the lung tumor.

The diagnosis and management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive single genes and proteins have been discovered that are designed to reflect sensitivity and/or resistance to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical extirpation. More recently, a number of biomarkers tested by a variety of methods have been proposed as specific predictors of chemotherapy and radiotherapy response. Other markers have been successfully used to predict toxic effects of standard therapies. In this review, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome.

Background Carcinoma-associated calcifications (Ca(2+)) are a common phenomenon. In the skin, basal cell carcinomas (BCC) can be associated with Ca(2+). Objective To examine the prevalence, characteristics, and clinicopathologic correlations of BCC associated with Ca(2+). Material and methods Eighty-three BCC with Ca(2+) were retrieved, 27 (11.1%) of which were identified from a review of 243 consecutive BCC. Ca(2+) were classified into 4 types: type 1, Ca(2+) within BCC epithelium; type 2, Ca(2+) in BCC keratocysts; type 3, BCC tumor necrosis with Ca(2+); and type 4, free Ca(2+) adjacent to BCC. Clinical and pathologic features were assessed and compared with BCC without Ca(2+). Expression of hair-associated proteins (hair keratins (K31, K32, and K35) and matrical transcription factors (LEF1, HOXC13, and β-catenin) were examined in a subset of BCC with Ca(2+) and compared with matched controls without Ca(2+). Results Compared with BCC without Ca(2+), BCC with Ca(2+) were significantly more likely to show a nodular keratinizing phenotype with keratocyst formation, background solar elastosis, active regression, and areas of tumor necrosis (all P ≤ 0.03). Comparing all BCC, high-risk BCC (mostly infiltrative) had significantly higher frequency of Ca(2+) than low-risk (mostly nodular) BCC (44% vs. 25%; P = 0.009). The median and mean number of Ca(2+) deposits per specimen were 2 and 3 ± 4, range 1-30. In decreasing frequency, type 2 Ca(2+) (58%), type 4 (53%), type 3 (14%), and type 1 (10%) were found. In 9 cases (11%), type 2 and type 4 Ca(2+) were linearly arranged, ostensibly after a follicular or eccrine duct tract. In 5 cases (6%), initial histologic sections showed type 4 dermal Ca(2+) without evidence of BCC; level sections revealed BCC in the adjacent tissue. Neither BCC with nor BCC without Ca(2+) showed evidence of matrical differentiation by immunophenotypic analysis. Conclusions A minority of BCC exhibits Ca(2+) that are associated with BCC-related keratin and/or necrosis. Like other follicular-derived tumors (trichilemmal cyst, pilomatricoma, and trichoepithelioma), BCC produce keratins that are ostensibly predisposed to calcification but are not related to matrical differentiation (mature hair keratin formation). Either due to transtumor elimination or due to tumor regression, Ca(2+) are frequently found free in solar elastotic or fibrotic dermis: a histologic clue in sun-damaged skin to the presence of BCC in the surrounding dermis.

Background: Lymphedema typically affects a whole limb. Rarely, lymphedema can present as a circumscribed plaque or an isolated skin tumor. Objective: To describe the clinical and pathologic characteristics and etiologic factors of localized lymphedema. Methods: Case–control study of skin biopsy and excision specimens histologically diagnosed with lymphedema and presenting as a localized skin tumor identified during a 4-year period. Results: We identified 24 cases of localized lymphedema presenting as solitary large polyps (11), solid or papillomatous plaques (7), pendulous swellings (4), or tumors mimicking sarcoma (2). Patients were 18 females and 6 males with a mean age of 41 years (range 16–74). Anogenital involvement was most frequent (75%) – mostly vulva (58%), followed by eyelid (13%), thigh (8%) and breast (4%). Causative factors included injury due to trauma, surgery or childbirth (54%), chronic inflammatory disease (rosacea, Crohn’s disease) (8%), and bacterial cellulitis (12%). Eighty-five percent of these patients were either overweight (50%) or obese (35%). Compared with a series of 80 patients with diffuse lymphedema, localized lymphedema patients were significantly younger (41 vs. 62 years old, p = 0.0001), had no history of cancer treatment (0% vs. 18%, p = 0.03), and had an injury to the affected site (54% vs. 6%, p = 0.0001). Histologically, all cases exhibited dermal edema, fibroplasia, dilated lymphatic vessels, uniformly distributed stromal cells and varying degrees of papillated epidermal hyperplasia, inflammatory infiltrates and hyperkeratosis. Tumor size significantly and positively correlated with history of cellulitis, obesity, dense inflammatory infiltrates containing abundant plasma cells, and lymphoid follicles (p

Volar melanotic macules are asymptomatic, tan-brown to brownish-black macules found on the palms, fingers, soles, and/or toes of dark-skinned individuals and are infrequently reported in light-skinned individuals. Herein, we report the acquisition of multiple, brownish-black volar digital macules in a 63-year-old white woman and avid gardener that were noted after the onset of pruritic, chronic hand dermatitis over a 10-month period. She was healthy without any medical conditions or medications. No family history of intestinal polyposis or mucosal melanosis existed. At presentation, she had less than 20 brownish-black, 2- to 10-mm irregular macules over the volar aspect of the thumbs and index fingers, left greater than right hand, associated with erythema, scale, and a negative potassium hydroxide examination. In addition, she had melanotic macules of her lips, buccal mucosa, and conjuctiva. No nail or anogenital macules were found. Biopsy demonstrated a region of epidermal hyperplasia, hyperkeratosis, and interface dermatitis associated with melanophages and sparse lymphocytic infiltrate. Melanin staining revealed diffuse pan-epidermal hypermelanization, dermal melanin, and dendritic melanocytes, which expressed HMB-45. After 1-year follow-up and treatment with topical corticosteroid, the volar macules have faded to tan brown. Based on the location, avocation, and coexisting mucosal melanotic macules, an irritant phytodermatitis with postinflammatory hyperpigmentation was diagnosed in the setting of Laugier-Hunziker syndrome-a disorder denoted by macular hyperpigmentation of nail, volar, and/or mucosal surfaces in healthy adults. Volar melanotic macules can also complicate 5-flourouracil therapy, tinea pedis, and other inflammatory disorders; be associated with acral melanomas; or represent a cutaneous manifestation of systemic disease such as Addison disease, Peutz-Jegher syndrome, Leopard syndrome, Carney syndrome, AIDS, and neurofibromatosis.

To describe severe lymphedema of the eyelids, known as Morbihan disease, a previously characterized but infrequently reported and poorly understood entity related to rosacea that features solid mid-facial and eyelid lymphedema. Retrospective chart review, histopathologic and immunohistochemical analysis, and pertinent literature consideration. Five cases of Morbihan disease were identified. Histopathologic examination revealed pleomorphic perivascular and perilymphatic inflammation with profound lymphangiectasis and lymph stasis, thus suggesting elements of both rosacea and localized, chronic lymphedema. Multiple therapeutic interventions were performed including systemic anti-inflammatory therapy, surgical debulking, and corticosteroid injection. Extreme eyelid edema associated with characteristic skin changes and histopathologic findings represents an entity known as Morbihan disease which is rare and difficult to treat. While multiple modalities have been employed with variable results, future therapeutic considerations may include the use of targeted biologic agents.

AimWe queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy.MethodsComprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma.ResultsThere were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0–13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified.ConclusionsComprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies.

Objectives: To construct and validate a frailty index (FI) that is clinically sensible and practical for geriatricians by basing it on a routinely used comprehensive geriatric assessment (CGA) instrument. Design: Secondary analysis of a 3-month randomized, controlled trial of a specialized mobile geriatric assessment team. Setting: Rural Nova Scotia. Participants were seen in their homes. Participants: Frail older adults, of whom 92 were in the intervention group and 77 in the control group. Measurements: A standard CGA form that accounts for impairment, disability, and comorbidity burden was scored and summed as a frailty index (FI-CGA). The FI-GCA was stratified to describe three levels of frailty. Patients were followed for up to 12 months to determine how well the index predicted adverse outcomes (institutionalization or mortality, whichever came first). Results: The three levels of frailty were mild (FI-CGA 0–7), moderate (FI-CGA 7–13), and severe (FI-CGA>13). Demographic and social traits were similar across groups, but greater frailty was associated with worse function (r=0.55) and mental status (r=0.33). Those with moderate and severe frailty had a greater risk of adverse outcomes than those with mild frailty (unadjusted hazard ratio=1.9 and 5.5, respectively). There was no difference between frailty groups in mean 3-month goal-attainment scaling scores. Intrarater reliability was 0.95. Conclusion: The FI-CGA is a valid, reliable, and sensible clinical measure of frailty that permits risk stratification of future adverse outcomes.

National assault injury surveillance has identified major seasonal variation, but it is not clear whether assault injury is a seasonal problem in large cities. Relationships between community violence, calendar events and ambient conditions were investigated with reference to prospective, Accident and Emergency (A&E) derived information obtained from people injured in assaults in Cardiff between 1 May 1995 and 30 April 2000. Records of daily local ambient conditions included data relating to temperature, rainfall and sunshine hours and data of major local sporting events and annual holidays were studied. Pearson correlation coefficients were used to evaluate associations between variables. Overall, 19,264 assault-related A&E attendances were identified over the 5-year period. Almost three-quarters were males. Violence was clustered predominantly on Saturdays and Sundays, New Year and rugby international days. Temperature, rainfall and sunlight hours did not correlate significantly with violence (P > 0.05). The findings indicate that injury reduction effort should be intensified at the known risk times for violence and that in a capital city/regional centre violence cannot be predicted on the basis of ambient conditions.

Craniopharyngioma is a histologically benign intracranial neoplasm. Although it may be locally aggressive and frequently recur, frank malignant transformation of craniopharyngioma is very rare, with only 20 cases being well-documented in the literature. Most of these occur as recurrences within 10 years following initial surgery, while in rare cases malignancy can develop de novo. The majority of these malignant tumors are either squamous cell carcinomas transformed from craniopharyngiomas, or histological malignant features which have developed in otherwise typical craniopharyngiomas. The outcome after malignant transformation is generally poor, with most patients succumbing within 7 months. The underlying mechanism for malignant transformation is unclear, but radiation is suggested as a contributing factor. The Wnt/beta-catenin signaling pathway has been implicated in the tumorigenesis of craniopharyngiomas, but its role(s) in the carcinogenesis of craniopharyngiomas needs to be further explored.

A patient with an intracranial skull base alveolar soft-part sarcoma, thought on preoperative imaging to be a meningioma, is presented. The mass was removed and identified by pathological evaluation to be an alveolar soft-part sarcoma. Postoperative investigation revealed widespread systemic disease. The histologic and clinical characteristics of this unusual tumor and the implications for prognosis and treatment are discussed.

Eosinophilic myocarditis (EM) is a rare myocardial disease that results from various eosinophilic diseases, such as idiopathic hypereosinophilic syndrome, helminth infection, medications and vasculitis. Patients with EM may present with different severities, ranging from mild symptoms to a life-threatening condition. Diagnosis of EM is a challenge and requires an extensive workup, including endomyocardial biopsy. Treatment options are limited because EM is rare and there is a lack of randomised controlled trials. We report a case of EM that presented as cardiac tamponade, which was initially treated with high-dose prednisone and immunosuppressant medications without significant improvement. Mepolizumab (anti-interleukin (IL)-5 antibody) was then applied, leading to an increased ejection fraction and stabilised cardiac function. This case report shows, for the first time, that mepolizumab has novel effects in treating EM. Our findings suggest that mepolizumab can be used as a steroid-sparing agent for treating EM.

Background. Intrahepatic cholangiocarcinoma (ICC) is a subtypeofprimarylivercancerthatisrarelycurablebysurgeryand is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonlyextrapolatedfromthose used in othergastrointestinalmalignancies.Wehypothesizedthat genomic profiling of clinicalICCsampleswouldidentifygenomicalterationsthatare linked to targeted therapies and that could facilitate a personalized approach totherapy. Methods. DNA sequencing of hybridization-capturedlibraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 mm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage. Results.Themostcommonlyobservedalterationswerewithin ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%).Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1(4%),PIK3CA(4%),PTCH1(4%),andTSC1(4%).Four(14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1). Conclusion.Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients. The Oncologist 2014; 19:235–242 Implications for Practice:The recenttranslation of next-generation DNA sequencingtechnology fromthe researchlaboratory to clinical practice has enabled oncologists to personalize therapy decisions for each patient by targeting the genomic alterations driving the disease. For tumors such as primary cholangiocarcinoma of the liver, this new ability to determine all of the major genomic alterations (base substitutions, short insertions and deletions, copy number changes, homozygous deletions, and gene fusions)onverysmallformalin-fixedparaffinembeddedclinicalsamplesholdsgreatpromisethatlesstoxictargetedtherapiesmay be available for patients currently being treated with conventional “one size fits all” approaches.

Deoxyribonucleic acid ploidy correlates with the biological behavior of prostate carcinoma. However, the usefulness of ploidy on needle biopsies that show prostate cancer has not been established to our knowledge.We retrospectively determined ploidy on needle biopsies of 159 men with prostate carcinoma treated surgically at Johns Hopkins Hospital. Ploidy was determined by image analysis of Feulgen stained slides. Needle ploidy and Gleason score were compared as prognostic tools in the prediction of grade and stage of subsequent prostatectomy.Of the 159 cases 98 (62%) were diploid, 16 (10%) tetraploid and 45 (28%) aneuploid. Of the diploid, tetraploid and aneuploid tumors 69, 50 and 44%, respectively, proved to be organ confined. Tetraploid and aneuploid tumors were grouped for the remaining analysis. Needle ploidy correlated significantly with pathological stage (p = 0.003). However, needle Gleason score correlated even more strongly (p0.001), and on multivariate analysis ploidy was not further predictive of pathological stage once Gleason score was considered. Needle ploidy and Gleason score were predictive of prostatectomy Gleason score (6 or less versus 7 or greater), and on multivariate analysis ploidy was an independently significant predictor of this parameter (p = 0.04). In 13 cases (8%) there was an important grading discrepancy, in which needle ploidy would have accurately predicted prostatectomy grade. However, in 33 cases (21%) needle and prostatectomy Gleason scores were congruent, and needle ploidy did not accurately predict prostatectomy Gleason score.With accurate needle Gleason grading, ploidy is not helpful in predicting prostatectomy findings. However, ploidy correlates with prostatectomy stage and grade, and may be useful if accurate Gleason grading is a concern.

Minority women are gaining more weight than recommended during pregnancy. This study aimed to determine the risk of excessive gestational weight gain (GWG) in Hispanic and Black women compared to non-Hispanic women in Colorado. A retrospective cohort study of all birth records from 2007 to 2010 in Colorado was conducted. The primary outcome was GWG, and the exposure was race/ethnicity. Covariates were marital status, education, intensity of prenatal care, age, parity, tobacco use, alcohol use and years in the US. Chi square and multiple logistic regression was performed. 230,698 records were analyzed. Half of the Hispanic and Black women began their pregnancy overweight or obese. Hispanic women had a 0.84 (95 % CI 0.8–0.9) and Black women had a 0.95 (95 % CI 0.9–1.0) risk of excessive GWG than NHW women. Pre-pregnancy weight is an independent risk for adverse outcomes. The study findings provide healthcare providers focal points in preconception health care and programming.

The authors present a patient with fever of unknown origin and vague loin pain. Baseline investigations revealed elevated inflammatory markers and imaging eventually identified a renal mass. Radical nephrectomy was performed at a collaborative surgical list involving both the urology and vascular surgical teams. Histological examination confirmed a retroperitoneal paraganglioma and the patient made a rapid recovery and remains well at follow-up. This case draws attention to the rare diagnosis of retroperitoneal paraganglioma and the potential for diagnostic delay. Furthermore, the vital multi-disciplinary approach to the optimum management of patients with such tumours is highlighted.

Candida parapsilosis is an uncommon cause of invasive endocarditis. This pathogen induces severe complications and carries a high mortality rate. We describe a case of C. parapsilosis endocarditis in a 54-year-old man with a history of HIV and Hepatitis C infection who previously underwent prosthetic valve replacement due to bacterial endocarditis. The patient presented with prolonged febrile episodes and fungemia with repeat blood cultures positive for C. parapsilosis. The patient failed multiple regimens of antifungal therapy and the C. parapsilosis isolate progressively acquired resistance to a number of drugs. Due to the multidrug resistant nature of the isolate, replacement of the infected valve was required to resolve his fungemia, and the patient remained asymptomatic for two years. This case is unusual due to the multidrug resistant nature of the isolate requiring both combined medical and surgical intervention. A review of published reports indicates that endocarditis due to C. parapsilosis responds well to a combination of medical and surgical interventions; the latter is particularly suitable for immunocompromised hosts.

Six years after kidney-pancreas transplant, a 47-year-old white man developed multiple subcutaneous and tenosynovial nodules of hands and wrists, limiting mobility. Biopsy of multiple nodules showed fibrosing, sarcoidal granulomas, some of which contained pigmented material. Microbiology, immunohistochemistry, scanning electron microscopy with backscattered electron imaging and energy dispersive X-ray analysis and polymerase chain reaction assays failed to show any infectious agents or foreign material. There was no historical, clinical or laboratory evidence of systemic sarcoidosis. It is not known whether the donor had sarcoidosis. Despite empiric antimycobacterial therapy and ongoing immunosuppressive therapy (corticosteroids, mycophenolate, cyclosporine), the man has progressively developed more nodules, limiting hand function. Sarcoidosis occurring in non-donor tisssue post-transplantation is an exceedingly rare complication of transplantation. We discuss this case and review the literature on sarcoidal tenosynovitis and sarcoidosis occurring post-transplantation.

Dermatofibroma (DF) or cutaneous fibrous histiocytoma is a common benign skin tumor that exhibits multiple, distinct histologic variants. Although clear cell DF has been described in the literature, balloon cell degeneration causing a clear cell DF phenotype has been not been reported to date. Herein, we describe the clinicopathologic findings of balloon cell DF arising on the heel of a 43-year-old man. Clinically, it presented as enlarging tan-white, ulcerated, firm 1.5 cm nodule, clinically suspected to be pyogenic granuloma. Excisional biopsy revealed a circumscribed fibrous tumor populated by mostly clear and spindle cells. A zonal arrangement separated the varied tumor cells where the most superficial, polypoid area showed large, clear polygonal balloon cells; the mid-dermal zone demonstrated a transition between balloon cells, epithelioid cells, and spindle cells; and the deep dermal zone had storiform arrangement of spindle cells, with the fascicles separated by coarse collagen bundles. A CD10+ > CD68+ > Factor XIIIa+ immunophenotype was identified with negative immunolabeling for S-100 protein, HMB-45, cytokeratin AE1/AE3, desmin, smooth muscle actin, lysozyme, and leukocyte common antigen (LCA). Ultrastructurally, the clear tumor cells were filled with multiple, empty, nonmembrane bound vacuoles of varying size. No recurrence has been described after complete excision and 7 months of follow up. DF with balloon cell change, likely secondary to persistent irritation, should be added to the differential diagnosis of cutaneous primary and metastatic neoplasms showing balloon cell degeneration such as balloon cell melanocytic nevi and renal cell carcinoma, respectively.

Background: RUNX2, a member of the RUNX family of transcription factors, regulates normal bone, cartilage and skeletal muscle morphogenesis. Aberrant RUNX2 expression has correlated with malignant cell migration, invasion and bone metastases. In the following study, we evaluated the prognostic significance of RUNX2 protein expression in a large cohort of tumors from each of three sites of origin - prostate, colon and breast. Design: Formalin-fixed paraffin-embedded tissue sections from 121 PAC, 104 CRC and 82 invasive BC [64 ductal (IDC); 18 lobular (ILC)] were immunostained by a manual method (DAKO LSAB+ System-HRP) using mouse monoclonal RUNX2 (Santa Cruz). Nuclear and/or cytoplasmic immunoreactivity was scored based on intensity and percentage of positive cells in both the tumor (T) and adjacent benign (B) epithelium in each case. Cases were assessed as tumor>benign (T>B), tumor = benign (T = B), tumor Results: RUNX2 immunoreactivity was predominately nuclear in PAC, CRC and BC and noted as follows: in PACs: T>B 58%, T = B 31%, T = Gleason grade 7] vs low [< = Gleason grade 6] tumor grade (p = 0.001), advanced [stage III, IV] vs early [stage I, II] tumor stage (p = 0.039) and biochemical disease recurrence (p = 0.008). In CRCs, immunoreactivity was noted as: T>B 61%, T = B 22%, TB 65% and T = B 35%; and correlated overall with early [stage I, II] vs advanced [stage III, IV] tumor stage (p = 0.05); ER positive status (p = 0.028); and on Cox univariate analysis, correlated with both lengthened recurrence free (p = 0.033) and overall (p = 0.042) survival; and showed a trend toward association with PR positive status (p = 0.075). Within the ER negative BC subgroup, RUNX2 immunoreactivity correlated with early tumor stage (p = 0.008) and PR positive status (p = 0.033). Conclusion: While RUNX2 protein expression correlates with adverse prognostic variables in prostate and colon cancers, RUNX2 immunoreactivity portends favorable prognosis in breast cancer. Further study of RUNX2 expression and its potential role as a therapeutic target particularly in PAC and CRC appear warranted. Citation Format: Bhaskar V.S. Kallakury, Albert Huho, Ann B. Boguniewicz, David M. Jones, Tipu Nazeer, Hwa Jeong Lee, Christine E. Sheehan, Jeffrey S. Ross. Prognostic significance of RUNX2 protein expression in carcinomas of the prostate (PAC), colon (CRC), and breast (BC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2015-4355

Background: Allografting of adult patients remains a widely utilized strategy but rates of treatment-related morbidity and mortality are still high. Granulocyte colony stimulating factor (G-CSF)-stimulated peripheral blood (G-PB) is now the most common source of clinically used hematopoietic allografts. G-PB grafts provide faster rates of neutrophil and platelet recovery compared to unstimulated bone marrow (BM), but G-PB is also associated with an increased risk of graft versus host disease (GVHD). More recently plerixafor has been demonstrated to be an effective hematopoietic cell mobilizing agent, and plerixafor is also now widely used alongside G-CSF to procure PB cells for clinical allografting. However, little is known as to whether plerixafor treatment alone or in combination with G-CSF might have an effect (positive or negative) on the repopulating activity of a BM harvest. Methods: In this study we have evaluated the affect over time of plerixafor ± G-CSF on the hematopoietic activity of the BM and PB of 10 normal adult donors. Donors received one treatment of plerixafor alone (240 μg/kg) vs plerixafor after 4 days of prior G-CSF (5 μg/kg/day). BM and PB samples were taken pre-treatment, post-G-CSF/pre-plerixafor, 4 hrs post-plerixafor, and 24 hours post plerixafor/48 hours post G-CSF. These samples were then analyzed for total nucleated cells (TNCs), CD34+ cells, in vitro colony-forming cells (CFCs), and cells capable of regenerating mature (TNCs) and CD34+ cells in 3-week stroma-containing cultures (LTC-ICs-3 wks) and in short-term (3-week) repopulating cell (STRC) assays in immunodeficient mice. The STRC assessment took advantage of a modified assay with improved sensitivity recently developed by our group, which utilizes NOD/Rag1-/--IL2Rγc-/- mice that constitutively produce human IL-3, GM-CSF and Steel factor (NRG-3GS mice) as the transplant recipients. Results: The G-CSF+plerixafor treatment protocol produced the largest increase in hematopoietic cells in the PB of the donors, as compared to either G-CSF or plerixafor alone. All counts reached peak values 4 hours after administration of plerixafor and 24 hrs after the last administration of G-CSF resulting in maximum increases at that time of 6-fold above baseline for TNCs, 15 for CD34+ cells and 25 for LTC-ICs-3 wks based on absolute measurements of each cell type per µL of PB. In the BM, where corresponding absolute values are not possible, there was a relative decrease in each of these parameters compared to BM TNC values. To assess in vivo STRC activity, collection time-points and sample types were pooled, depleted of CD3+ cells (using diptheria-conjugated OKT3), and 3x106 total cells transplanted IV into each of 2-3 replicate NRG-3GS mice. Four days of G-CSF reduced the STRC activity in donor BM asprates below baseline levels which was rescued by 4 hours after administration of plerixafor to the same donors. This restored human STRC activity included progenitor (CD34+) cells as well as maturing erythroid (glycophorin A+), granulopoietic (CD33+) cells and circulating SSClow human CD41+/CD61+ platelets. Conclusions: A time course study of plerixafor ± G-CSF administration in normal volunteers aligns with previous findings showing that G-CSF+plerixafor treatment induces a transiently higher output of multiple primitive hematopoietic cell types compared to G-CSF or plerixafor alone. These findings suggest an optimal time for harvesting PB and BM for a future clinical trial to determine which may serve as the superior allograft in patients. Disclosures No relevant conflicts of interest to declare.

Background: Tumor necrosis factor alpha induced protein 8 (TNFAIP8) is a transcription factor NF-kB inducible antiapoptotic and oncogenic molecule. This gene was initially discovered by comparison of expression profiles of primary and metastatic head and neck squamous cell carcinoma (hence earlier referred to as SCC-S2). Positive correlation between TNFAIP8 expression and cancer progression/poor prognosis has been suggested in a few human solid cancers including pancreatic and esophageal primaries. We were the first to publish the adverse prognostic implication of TNFAIP8 expression in prostatic adenocarcinomas. In this study, we evaluated the significance of this protein in normal, inflamed and neoplastic pancreatic tissues. Design: A total of 184 formalin-fixed, paraffin-embedded pancreatic tissues were analyzed; 151 samples in tissue microarray format [79 primary ductal carcinomas (PDC), 5 ductal adenocarcinomas from distant metastatic sites not matched to primary tumors (MDAC), 9 islet cell tumors (ICT) (one carcinoma), 2 chronic pancreatitis (CP), 29 normal adjacent to cancer, 8 normal adjacent to inflammation, and 19 normal pancreatic tissues] and 19 primary tumor resections [19 primary ductal adenocarcinomas (PDAC), 14 of these with normal tissue adjacent to the cancer]. All samples were immunostained by a manual method using a custom made anti-TNFAIP8 antibody as described earlier (Zhang et al., Int J Cancer, 133: 31-42, 2013). The staining pattern was semiquantitatively assessed based on staining intensity and distribution and the results were correlated with clinicopathologic variables. Results: Immunoreactivity for TNFAIP8 was predominantly cytoplasmic. TNFAIP8 protein overexpression was noted in 44/184 (24%) samples and correlated with tumor type [9/98 (9%) PDC/PDAC 2/5 (40%) unmatched distant MDAC, 5/9 (56%) (ICT) (1/1 carcinoma), 1/2 (50%) (CP), 15/43 (35%) normal adjacent to cancer, 5/8 (63%) normal adjacent to inflammation, and 7/19 (37%) normal pancreatic tissues, p Conclusion: TNFAIP8 immunohistochemical expression correlates with endocrine phenotype and portends poor prognosis in pancreatic ductal carcinomas. This protein may represent both a novel pathway in endocrine differentiation and a therapeutic target in the management of aggressive PDC, warranting further study. Citation Format: Jeffrey S. Ross, Bhaskar VS Kallakury, Hwa Jeong Lee, David M. Jones, Sanaz Ainechi, Gregory M. Sheehan, Christine E. Sheehan, Usha N. Kasid. TNFAIP8 protein expression in normal, inflammatory and neoplastic pancreatic tissues: Correlation with endocrine phenotype and advanced stage in ductal adenocarcinomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3836. doi:10.1158/1538-7445.AM2014-3836

The post mortem in an adult male gorilla (Gorilla gorilla gorilla) aged approximately 33 years revealed very small testes, and the cut surface of the left testis appeared nodular. Microscopic examination showed a marked atrophy of seminiferous tubules and fibrosis together with a diffuse interstitial cell hyperplasia. Two interstitial cell adenomas were identified in the left testis.

• Upper gastrointestinal (GI) tract complications have been a substantial cause of death following renal transplantation. Cimetidine, an H 2 receptor antagonist, has been used in the posttransplant period to decrease this hazard. However, H 2 receptor antagonists may enhance the immune response and be deleterious for the graft. The magnitude of the hazard of upper GI tract complications after renal transplantation was determined by reviewing 200 renal transplants. The effect of cimetidine treatment on the survival of canine renal allografts was investigated. The upper GI tract complication rate was 1.5% with one related death (0.5%). Treatment of dogs with cimetidine shortened the survival time of renal allografts (18.2 ± 5.5 [SE] days to 12.5 ± 2.2 days). Because upper GI tract complications are not a major hazard and H 2 receptor antagonist therapy may decrease the survival of dog renal allografts, we believe prophylactic use of cimetidine is not indicated. ( Arch Surg 1982;117:933-935.

Background Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer. Methods Immunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria. Results Although expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (rs = 0.49, p