Inflammatory Myofibroblastic Tumor After Receiving Treatment for Non-small Cell Carcinoma.

Inflammatory pseudotumor encompasses a spectrum of both neoplastic and non-neoplastic conditions characterized by a histological pattern featuring a proliferation of cytologically bland spindle cells, accompanied by a prominent chronic inflammatory infiltrate. Within this spectrum, inflammatory myofibroblastic tumor (IMT) has emerged as a distinct entity over the past two decades, marked by unique clinical, pathological, and molecular characteristics. Typically affecting the visceral soft tissues of children and adolescents, IMT exhibits a propensity for local recurrence while posing a minimal risk of distant metastasis. They are extremely rare in adults, constituting less than 1% of adult lung tumors. Our patient, a 63-year-old female, has an intricate medical background, encompassing chronic obstructive pulmonary disease (COPD), a previous history of smoking (35 pack-years, quit a year before admission), coronary artery disease, non-obstructive hypertrophic cardiomyopathy, and obstructive sleep apnea. Presenting with a diagnostic dilemma, she recently received treatment for non-small cell carcinoma with radiation therapy, which has evolved into a swiftly advancing case of IMT.

Loss of RAB25 Cooperates with Oncogenes in the Transformation of Human Mammary Epithelial Cells (HMECs) to Give Rise to Claudin-Low Tumors.

The loss of RAB25 expression-RAS superfamily of GTPase characteristic of numerous breast cancers-corresponds with H-RAS point mutations, particularly in triple-negative breast cancers (TNBC), a subtype associated with a poor prognosis. To address the poorly understood factors dictating the progression of TNBC tumors, we examine the cooperative effects that loss of RAB25 expression in human mammary epithelial cell (HMEC) lines with H-RAS mutations confers in tumorigenesis. HMECs were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, a catalytic subunit of the telomerase enzyme. We found that with the loss of RAB25 and overexpression of mutant H-RAS61L, immortal HMECs transformed toward anchorage-independent growth and acquired an increased ability to migrate. Furthermore, cells express low CD24, high CD44, and low claudin levels, indicating stem-like properties upon transformation. Besides, loss of RAB25 and overexpression of H-RAS61L resulted in increased expression of transcription factors Snail and Slug that drive these cells to lose E-cadherin and undergo epithelial-mesenchymal transition (EMT). This study confirms that loss of RAB25 and overexpression of mutant H-RAS can drive HMECs toward a mesenchymal stem-like state. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker of the claudin-low type of TNBC.

Streamlining orthopaedic trauma surgical care: do all patients need medical clearance?

INTRODUCTION: Preoperative medical optimization is necessary for safe and efficient care of the orthopaedic trauma patient. To improve care quality and value, a preoperative matrix was created to more appropriately utilize subspecialty consultation and avoid unnecessary consults, testing, and operating room delays. Our study compares surgical variables before and after implementation of the matrix to assess its utility. METHODS: A retrospective review of all orthopaedic trauma cases 6 months before and after the use of the matrix (2/2021-8/2021) was conducted an urban, level one trauma centre in collaboration with internal medicine, cardiology, anaesthesia, and orthopaedics. Patients were separated into two cohorts based on use of the matrix during the initial orthopaedic consultation. Logistic regressions were performed to limit significant differences in comorbidities. Independent samples t-tests and Chi-squared tests were used to compare means and proportions, respectively, between the two cohorts. RESULTS: In total, 576 patients were included in this study (281 pre- and 295 post-matrix implementation). Use of the matrix resulted in no significant difference in time to OR, LOS, readmissions, or ER visits; however, it resulted in 18% fewer overall preoperative consults for general trauma, and 25% fewer pre-operative consults for hip fractures. Older patients were more likely to require a consult regardless of matrix use. When controlling for comorbidities, patients with renal disease were at higher risk for increased LOS. CONCLUSION: Use of an orthopaedic surgical matrix to predict preoperative subspecialty consultation is easy to implement and allows for better care utilization without a corresponding increase in complications and readmissions. Follow-up studies are needed to reassess the relationships between matrix use and a potential decrease in ER to OR time, and validate its use.

AKR1B10 as a Potential Novel Serum Biomarker for Breast Cancer: A Pilot Study.

Background: Aldo-keto reductase 1B10 (AKR1B10) is a secretory protein that is upregulated in breast cancer. Objective: This case-controlled pilot study evaluated the serum level of AKR1B10 in healthy women and patients with a localized or metastatic breast cancer. Methods: AKR1B10 levels were measured by ELISA and IHC in several patient cohorts. Results: Our data showed that serum AKR1B10 was significantly elevated in patients with localized (6.72 ± 0.92 ng/ml) or metastatic (7.79 ± 1.13 ng/ml) disease compared to cancer-free healthy women (1.69 ± 0.17 ng/ml) (p<0.001); the serum AKR1B10 was correlated with its expression in tumor tissues, but not with the tumor burden, molecular subtypes or histological stages. After surgical removal of primary tumors, the serum AKR1B10 was rapidly decreased within 3 days and plateaued at a level similar to that of healthy controls in most patients. ROC curve analysis suggested the optimal diagnostic cut-off value of serum AKR1B10 at 3.456 ng/ml with AUC 0.9045 ± 0.0337 (95% CI 0.8384 - 0.9706), sensitivity 84.75% (95% CI 73.01% to 92.78%), and specificity 93.88% (95% CI 83.13% to 98.72%). Conclusions: These data indicate the potential value of serum AKR1B10 as a biomarker of breast cancer.

P-ANCA negative eosinophilic granulomatosis with polyangiitis.

Vasculitis refers to inflammation of the systemic vessels. Eosinophilic granulomatosis with polyangiitis (EGPA) is a medium and small vessel vasculitis characterized by hypereosinophilia, pulmonary infiltrates, difficult to treat asthma and polyneuropathies. Diagnosis can often be challenging. In this article, we present a case of a young lady who was diagnosed ANCA negative EGPA.

Transcatheter Mitral Valve Therapy With Novel Supra-Annular AltaValve: First Experience in the United States.

This case demonstrates the feasibility and procedural success of a novel supra-annular transcatheter mitral valve, the AltaValve via transapical approach in a patient with severe symptomatic mitral regurgitation who was a prohibitive surgical risk candidate. (Level of Difficulty: Advanced.).

Hepatic Involvement in Systemic Sarcoidosis.

BACKGROUND Sarcoidosis is a systemic disease that can affect any organ, including the liver. It is manifested by the presence of non-caseating granulomas within involved organs, most commonly the pulmonary, lymphatic, and hepatic system. Unlike pulmonary or lymphatic involvement, hepatic involvement is usually asymptomatic and it is underdiagnosed. Here, we report a case of a patient with a history of pulmonary sarcoidosis who developed hepatic sarcoidosis. CASE REPORT 68-year-old female with pulmonary sarcoidosis with a 2-week history of severe abdominal pain and epigastric tenderness presented to our center. Abdominal magnetic resonance imaging (MRI) demonstrated mild hepatic fibrosis and cirrhosis. A thorough workup was performed including a liver biopsy which showed chronic non-necrotizing granulomas consistent with sarcoidosis. She was started on prednisone and subsequently improved. The patient was symptom-free on follow-up 1 month later. CONCLUSIONS The majority of patients with hepatic sarcoidosis are usually asymptomatic, with only 5-30% presenting with abdominal pain, jaundice, nausea, vomiting, and hepatosplenomegaly. In rare cases, hepatic sarcoidosis can lead to cholestasis, portal hypertension, cirrhosis, or Budd-Chiari syndrome. Treatment with steroids is the mainstay of therapy; however, in severe cases, patients may require liver transplantation. This case report demonstrates that hepatic sarcoidosis is a serious condition, and if not treated, can lead to portal hypertension and cirrhosis. In patients with sarcoidosis, early detection and longitudinal follow-up is important in preventing overt liver failure.

Severe metabolic alkalosis-a diagnostic dilemma.

BACKGROUND: Cushing's syndrome due to ectopic ACTH secretion has been associated with many cancers; most commonly small cell carcinoma of the lung and bronchial carcinoid tumors. Usually, patients who confer this diagnosis have poor prognosis. CASE PRESENTATION: A 66-year-old female presented with worsening shortness of breath and weakness over three days. Initial laboratory derangements included severe hypokalemia and metabolic alkalosis. Treatment included high amounts of potassium chloride and acetazolamide. Imaging studies revealed anterior medial right upper lobe lung mass as well as suspicion for many liver metastases. Liver biopsy was sought and was positive for small cell carcinoma. CONCLUSION: We describe a case of severe metabolic alkalosis and hypokalemia in a patient with Cushing's syndrome due to ectopic ACTH secretion from small cell lung cancer. To our knowledge, this is the first case identified which exhibited such significant metabolic derangements in the form of serum and arterial blood bicarbonate. As prognosis is quite poor, we recommend swift diagnosis and management.

Effects of rapamycin on growth hormone receptor knockout mice.

It is well documented that inhibition of mTORC1 (defined by Raptor), a complex of mechanistic target of rapamycin (mTOR), extends life span, but less is known about the mechanisms by which mTORC2 (defined by Rictor) impacts longevity. Here, rapamycin (an inhibitor of mTOR) was used in GHR-KO (growth hormone receptor knockout) mice, which have suppressed mTORC1 and up-regulated mTORC2 signaling, to determine the effect of concurrently decreased mTORC1 and mTORC2 signaling on life span. We found that rapamycin extended life span in control normal (N) mice, whereas it had the opposite effect in GHR-KO mice. In the rapamycin-treated GHR-KO mice, mTORC2 signaling was reduced without further inhibition of mTORC1 in the liver, muscle, and s.c. fat. Glucose and lipid homeostasis were impaired, and old GHR-KO mice treated with rapamycin lost functional immune cells and had increased inflammation. In GHR-KO MEF cells, knockdown of Rictor, but not Raptor, decreased mTORC2 signaling. We conclude that drastic reduction of mTORC2 plays important roles in impaired longevity in GHR-KO mice via disruption of whole-body homeostasis.

A Case Report Describing a Rare Presentation of Simultaneous Occurrence of MPO-ANCA-Associated Vasculitis and Rheumatoid Arthritis.

Background. Renal-limited myeloperoxidase vasculitis with simultaneous rheumatoid arthritis is reported as a rare occurrence. Review of literature suggests that most patients had a diagnosis of rheumatoid arthritis for several years prior to presenting with renal failure from myeloperoxidase vasculitis. Case Presentation. A 58-year-old Caucasian male presented to the hospital experiencing malaise, fevers, decreased oral intake, nausea, and vomiting for one week duration. His past medical history consisted of newly diagnosed but untreated rheumatoid arthritis, hypertension, and non-insulin-dependent diabetes mellitus. He was found to have acute renal failure, proteinuria, and hypoglycemia. Standard therapy, including intravenous fluids, did not improve his acute renal failure. A vasculitis workup resulted in a positive myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Renal biopsy revealed crescentic glomerulonephritis (GN) pauci-immune type, suggestive of MPO-ANCA-associated vasculitis (MPO-AAV). Treatment consisted of prednisone, cyclophosphamide, and seven cycles of plasmapheresis, in addition to hemodialysis for uremia. Upon discharge, he received hemodialysis for another week and continued treatment with cyclophosphamide and prednisone. Conclusion. Patients with longstanding rheumatoid arthritis may develop renal failure due to nonsteroidal anti-inflammatory medication use and AA type amyloidosis; however, necrotizing glomerulonephritis with crescent formation has been rarely reported. This stresses the importance of early recognition and swift initiation of treatment.

Development and Validation of a Rome III Functional Gastrointestinal Disorders Questionnaire for Infants and Toddlers.

OBJECTIVE: Functional gastrointestinal disorders (FGIDs) in infants and toddlers are common, but no questionnaire is available for use in clinic and research. The purpose of the present study was to develop and validate a questionnaire assessing symptoms associated with FGIDs in infants and toddlers. METHODS: Questions were developed based on the Rome III diagnostic criteria for FGIDs. A group of parents of children with FGIDs and experts in FGID reviewed the questionnaire for content, understandability, and completeness (face validity). Initial content validity was established by comparing physician and questionnaire diagnoses in a group of 332 consecutive new patients at a tertiary care clinic. RESULTS: Ten parents and 8 experts identified no major problems, indicating good face validity. Of 332 consecutive new patients, age 1 month to 4 year of age, 172 subjects (52% of the sample) qualified for a FGID by parent responses to the questionnaire (mean age = 1.23 year, 53% girls). All of these subjects also received an FGID diagnosis by their physician. Agreement between parent and doctor was fair to substantial (κ = 0.18-0.76), except for infant rumination and functional diarrhea in infants, which showed poor overlap. CONCLUSIONS: The newly developed Rome III questionnaire for infants and toddlers had good initial face and content validity. This questionnaire will be an important addition to clinical care and research of infant/toddler FGIDs. Replication of these findings in primary care is needed.

Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice.

PURPOSE: Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC. EXPERIMENTAL DESIGN: Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8(-/-)) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors. RESULTS: AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8(-/-) mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8(-/-) mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8(-/-) mice than in wild-type mice. Palpable masses were seen in the AKR1B8(-/-) mice only, not in wild-type. CONCLUSIONS: AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases.

Gastrointestinal CMV in an elderly, immunocompetent patient.

An 83-year-old male with a history of diabetes but with an otherwise intact immune system presented with melena. Upper endoscopy showed gastric and duodenal ulcers. Colonoscopy showed colonic ulcers. Biopsies revealed cytomegalovirus (CMV). Therapy with an antiviral such as ganciclovir should be considered even in an immunocompetent patient if male and over the age of 55, or if they have chronic diseases such as diabetes or chronic kidney disease.

AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker.

Aldo-keto reductase 1B10 (AKR1B10) is a secretory protein that is upregulated with tumorigenic transformation of human mammary epithelial cells. This study demonstrated that AKR1B10 was overexpressed in 20 (71.4%) of 28 ductal carcinomas in situ, 184 (83.6%) of 220 infiltrating carcinomas and 28 (87.5%) of 32 recurrent tumors. AKR1B10 expression in breast cancer was correlated positively with tumor size (p = 0.0012) and lymph node metastasis (p = 0.0123) but inversely with disease-related survival (p = 0.0120). Univariate (p = 0.0077) and multivariate (p = 0.0192) analyses both suggested that AKR1B10, alone or together with tumor size and node status, is a significant prognostic factor for breast cancer. Silencing of AKR1B10 in BT-20 human breast cancer cells inhibited cell growth in culture and tumorigenesis in female nude mice. Importantly, AKR1B10 in the serum of breast cancer patients was significantly increased to 15.18 ± 9.08 ng/ml [n = 50; 95% confidence interval (CI), 12.60-17.76], with a high level up to 58.4 ng/ml, compared to 3.34 ± 2.27 ng/ml in healthy donors (n = 60; 95% CI, 2.78-3.90). In these patients, AKR1B10 levels in serum were correlated with its expression in tumors (r = 0.8066; p < 0.0001). Together our data suggests that AKR1B10 is overexpressed in breast cancer and may be a novel prognostic factor and serum marker for this deadly disease.

Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation.

Undifferentiated or medullary carcinoma is characterized by its distinct histologic appearance and relatively better prognosis compared to poorly differentiated colonic carcinoma. These 2 entities may be difficult to differentiate by light microscopy alone. Only limited immunohistochemical studies investigating medullary carcinoma have been reported. These studies suggest a loss of intestinal differentiation, exemplified by a high percentage of CDX2 negativity. Our aim was to further characterize the immunohistochemical profile of medullary carcinoma, with particular emphasis on intestinal markers. Paraffin blocks from 16 cases of medullary carcinoma and 33 cases of poorly differentiated colonic carcinoma were retrieved, and tissue microarrays were constructed and stained with an immunohistochemical panel including CDX2, CK7, CK20, p53, intestinal trefoil factor 3, chromogranin, synaptophysin, MLH-1, MUC-1, MUC-2, and calretinin. A significantly higher proportion of medullary carcinomas, as opposed to poorly differentiated colonic carcinomas, showed loss of staining for MLH-1 and for the intestinal transcription factor CDX2, in accordance with previous studies. MLH-1 staining was present in only 21% of medullary carcinoma cases compared with 60% of the poorly differentiated colonic carcinoma cases (P = .02), whereas CDX2 was positive in 19% of medullary carcinomas and 55% of poorly differentiated colonic carcinomas (P = .03). Interestingly, calretinin staining was strongly positive in 73% of medullary carcinomas compared to only 12% of poorly differentiated colonic carcinomas (P < .0001). Evidence of intestinal differentiation by MUC-1, MUC-2, and TFF-3 staining was seen in 67%, 60%, and 53% of the medullary carcinomas, respectively. These 3 markers were frequently positive in many of the CDX2-negative medullary carcinoma cases. Medullary carcinoma of the colon retains a significant degree of intestinal differentiation as evidenced by its high percentage of staining for MUC-1, MUC-2, and TFF-3. Calretinin, MLH-1, and CDX2 may help to differentiate medullary carcinoma from poorly differentiated colonic carcinoma of the colon.

Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis.

PURPOSE: Transcriptional profiling showed decreased expression of gastrokine 1 (GKN1) and the related trefoil factor interacting protein (TFIZ1/GKN2) in Helicobacter pylori infection. Decreased GKN1 and GKN2 mRNA expression has been reported in gastric adenocarcinoma. We have examined GKN1 and GKN2 protein expression in a large gastric cancer series, correlated expression with tumor subtype, and evaluated their utility as prognostic biomarkers. EXPERIMENTAL DESIGN: GKN1, GKN2, and the trefoil factors TFF1 and TFF3 were examined in tissue microarrays from 155 distal gastric adenocarcinomas. Immunohistochemical expression was correlated with clinical outcome. GKN1 and GKN2 expression was measured by real-time PCR and Western analysis in samples of gastric cancer and adjacent nonneoplastic mucosa. RESULTS: GKN1 was lost in 78% of diffuse and 42% of intestinal cancers (P < 0.0001, diffuse versus intestinal). GKN2 expression was lost in 85% of diffuse and 54% of intestinal type cancers (P < 0.002). GKN1 and GKN2 down-regulation were confirmed by Western and real-time PCR analysis. Loss of either protein was associated with significantly worse outcome in intestinal-type tumors by univariate analysis; and GKN2 loss remained a predictor of poor outcome in multivariate analysis (P < 0.033). TFF1 was lost in >70%, and TFF3 was expressed in approximately 50% of gastric cancers. CONCLUSIONS: Loss of GKN1 and GKN2 expression occurs frequently in gastric adenocarcinomas, especially in the diffuse subtype. GKN1 and GKN2 loss are associated with shorter overall survival in the intestinal subtype.

Dedifferentiated liposarcoma arising from the sigmoid mesocolon: a case report.

Dedifferentiated liposarcoma is a variant of liposarcoma with a more aggressive course. It occurs most commonly in the retroperitoneum and rarely in other anatomic locations. In the present report, we describe a case of dedifferentiated liposarcoma that occurred in an unusual location, sigmoid mesocolon, which has not yet been documented.