Fatal Moans and Bones in Crohn's: A Case of Heterotopic Mesenteric Ossification.

ABSTRACT: Heterotopic mesenteric ossification (HMO) represents a rare reactive condition characterized by abnormal bone formation within the mesentery. HMO's etiology remains enigmatic, with proposed triggers including trauma-induced metaplasia or bone fragment dislodgment from other sites during abdominal surgery. With fewer than 100 documented cases in the literature, much about this condition remains unknown. In this report, we present a notable case of HMO in a 43-year-old man with a history of severe Crohn's disease and multiple abdominal surgeries. Following a period of unresponsiveness at home, he was admitted to the intensive care unit, where he received palliative care due to a poor prognosis. An autopsy revealed mature, benign bone fragments within the mesentery, alongside severe dehydration, likely exacerbated by decreased oral intake and medication cessation related to his ostomy. Although antemortem imaging revealed HMO, it was misattributed to contrast versus calcification. This case underscores the importance of clinician awareness regarding HMO, particularly its potential implications in inflammatory bowel disease. Early recognition and interdisciplinary collaboration among radiologists, pathologists, and clinicians are paramount in optimizing patient outcomes. Further research is warranted to elucidate this intriguing pathology's pathogenesis and best management strategies.

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.

Intravascular Large B-cell Lymphoma Presenting as Sudden Death.

ABSTRACT: Intravascular large B-cell lymphoma is a rare subset of non-Hodgkin lymphoma composed of mature B lymphoma cells confined to the intravascular space. This disease remains elusive because it lacks a discrete tumor mass, can affect any part of the body, and has vague symptoms paired with heterogeneous clinical findings resulting in delayed or missed accurate diagnosis, even at postmortem examination. This is a case of a woman who died within hours of presenting to the emergency department with a diagnosis of intravascular large B-cell lymphoma made through autopsy examination, adding to the knowledge of this rare disease and bringing it to the attention of practicing autopsy and forensic pathologists.

Smoking Cessation Interventions.

In the United States, 1 in 5 adults uses tobacco products. Cigarette smoking is the leading cause of preventable disease and death in the United States despite its known health effects. Although nearly one-half of people who smoke try to quit each year, only up to 1 in 20 who quit without support achieve abstinence for at least six months. All patients, including school-aged children and adolescents, should be asked if they smoke and offered evidence-based treatments for smoking cessation. Use of the 5 A's framework (ask, advise, assess, assist, arrange) can help clinicians promote smoking cessation. Clinical studies have demonstrated that combining pharmacotherapy with effective behavior strategies is significantly more effective than either approach alone. Pharmacotherapies approved by the U.S. Food and Drug Administration for smoking cessation include nicotine replacement therapy, bupropion, and varenicline. Extended use (greater than 12 weeks) of a controller therapy (varenicline, bupropion, or nicotine patch) is associated with significantly higher sustained quit rates and lower relapse rates than standard use (six to 12 weeks). e-Cigarettes are not approved by the U.S. Food and Drug Administration for smoking cessation, and evidence supporting their benefit is inconclusive. Lung cancer screening is recommended for adults 50 to 80 years of age who have a 20-pack-year smoking history and currently smoke or have quit within the past 15 years. Lung cancer screening should be combined with smoking cessation tools and treatment.

Surgical intervention for vertebral osteomyelitis in a calf.

OBJECTIVE: To report the surgical treatment and outcome of a non-ambulatory calf with cervical vertebral ostoeomyelitis. STUDY DESIGN: Clinical report. SAMPLE POPULATION: One 3.5-month-old female mixed-breed calf with tetraparesis of 3 months duration. METHODS: After computed tomography-guided bone biopsy, a bacterial osteolytic lesion within the body of the fourth cervical vertebrae (C4) and resultant pathologic compression fracture clinically resulting in full tetraparesis was diagnosed in the calf. Culture results from the lesion within C4 confirmed a diagnosis of Trueperella pyogenes. RESULTS: Poor response to medical management justified surgical debridment of the lesion in C4 and subsequent stabilization of the cervical vertebral column. A three-part procedure was performed including (1) debridement of the C4, (2) bilateral ventral vertebral stabilization from C3 to C5, and (3) placement of ampicillin-impregnated plaster of Paris beads within the body of C4. With postoperative physical rehabilitation, the calf regained full ambulatory function. At 1-month follow-up, the calf remained ambulatory with mild proprioceptive ataxia and no evidence of implant failure. At annual recheck, the calf had gained 208 kg and remained fully ambulatory with no residual neurologic deficits. CONCLUSION: Surgical intervention and use of antibiotic-impregnated implants offered a viable alternative to long-term medical management of vertebral osteomyelitis in the calf reported here. CLINICAL SIGNIFICANCE: This case identifies surgical intervention as a potential means for improving outcomes in a historically fatal condition of production animals.

EGFR-mediated apoptosis via STAT3.

The Epidermal Growth Factor Receptor (EGFR) is a cell surface receptor with primary implications in cell growth in both normal and malignant tissue. Paradoxically, cell lines that hyperexpress the EGFR have been documented to undergo receptor-mediated apoptosis. The underlying mechanism by which EGF-induced apoptosis occurs however remains inexplicit. In an attempt to identify this mechanism, we assessed downstream effectors of EGFR in MDA-MB-468 cells during conditions of EGF-induced apoptosis. The effector assessment revealed STAT3 as a potential mediator of EGF-induced apoptosis. Alternative strategies for activating STAT3, independent of EGFR stimulation, resulted in the induction of the apoptotic pathways. A reduction in STAT3 expression via RNAi resulted in a significant attenuation of EGF-induced PARP cleavage. Our findings support STAT3 as a positive mediator of EGF-induced apoptosis in MDA-MB-468 cells.

Pathology Image Of the Month: Rapidly Progressive Hemorrhagic Cellulitis of Bilateral Lower Extremities with Subsequent Septic Shock and Death.

A 51-year-old man presented to a community based emergency department with bilateral lower extremity swelling that began four days prior and that had evolved into recent blister formation on the left lower extremity. Medical history was significant only for hypertension and a recent self-described episode of "food poisoning" five days earlier characterized by diarrhea, nausea, and vomiting that quickly resolved. Physical exam revealed marked bilateral lower extremity edema and an ecchymotic rash below the knee. In addition to the rash, there were large flaccid bullae on the left leg, mostly intact but some notable for draining of scanty serosanguinous fluid. The patient was tachycardic with a rate of 114 bpm and initial labs showed thrombocytopenia (platelets 56 x 103/uL [140-440 x 103/uL]), hypoglycemia (15mg/dl [70-105mg/dl]), an elevated creatinine (2.7mg/dL [0.7- 1.25mg/dL]), and aspartate aminotransferase (AST 156U/L [5- 34U/L]). Two sets of blood cultures were drawn, broad spectrum antibiotics including doxycycline were empirically initiated and then he was subsequently transported to a tertiary care hospital for escalation of care. Within hours of presentation to the tertiary care facility, the rash appeared progressively hemorrhagic and bullous, lactic acidosis and coagulopathy developed and hemodynamic instability and septic shock necessitated endotracheal intubation and vasopressors. He was taken to the operating room for skin debridement but was emergently converted to bilateral above the knee lower extremity amputations due to the extent of the soft tissue necrosis. The patient remained intubated and in critical condition following surgery and the ecchymotic rash reappeared at the amputation sites. A newly developed ecchymotic rash with bullae formation was noted on the right upper extremity forearm. At that time, the clinicians were notified that four out of four blood culture bottles from admission were rapidly growing a microorganism. The family elected for withdrawal of care, and the patient died approximately 72 hours following presentation. A full and unrestricted autopsy was authorized by the Coroner's Office.

Protein Kinase G facilitates EGFR-mediated cell death in MDA-MB-468 cells.

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase with critical implications in cell proliferation, migration, wound healing and the regulation of apoptosis. However, the EGFR has been shown to be hyper-expressed in a number of human malignancies. The MDA-MB-468 metastatic breast cell line is one example of this. This particular cell line hyper-expresses the EGFR and undergoes EGFR-mediated apoptosis in response to EGF ligand. The goal of this study was to identify the kinases that could be potential intermediates for the EGFR-mediated induction of apoptosis intracellularly. After identifying Cyclic GMP-dependent Protein Kinase G (PKG) as a plausible intermediate, we wanted to determine the temporal relationship of these two proteins in the induction of apoptosis. We observed a dose-dependent decrease in MDA-MB-468 cell viability, which was co-incident with increased PKG activity as measured by VASPSer239 phosphorylation. In addition, we observed a dose dependent decrease in cell viability, as well as an increase in apoptosis, in response to two different PKG agonists, 8-Bromo-cGMP and 8-pCPT-cGMP. MDA-MB-468 cells with reduced PKG activity had attenuated EGFR-mediated apoptosis. These findings indicate that PKG does not induce cell death via transphosphorylation of the EGFR. Instead, PKG activity occurs following EGFR activation. Together, these data indicate PKG as an intermediary in EGFR-mediated cell death, likely via apoptotic pathway.

Recurrence and Survival After Segmentectomy in Patients With Prior Lung Resection for Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: Lobectomy is the standard of care for patients with early-stage non-small cell lung cancer (NSCLC). However, the treatment of choice for patients with prior lung resection and a second primary NSCLC has not been established. We compared rates and patterns of recurrence and survival in patients with and without prior lung resection treated by segmentectomy and determined predictors of recurrence. METHODS: This was a retrospective cohort study of 90 patients who underwent 91 consecutive segmentectomies for early-stage NSCLC between April 2004 and December 2014. Logistic regression was used to determine predictors of recurrence, and Kaplan-Meier curves were used to determine survival. RESULTS: Of the 91 segmentectomies, 21 (23%) had a prior lung cancer resection and 70 (77%) were primary resections. There were 18 recurrences (20%): 9 of 21 (43%) in those with prior lung resection and 9 of 70 (13%) in those without. The 90-day mortality was 0%. The recurrence-free survival and 5-year survival were 61% and 55% in those with prior lung resection (p = 0.09) and 84% and 65% in those without (p = 0.4). Close parenchymal margin and number of lymph nodes examined were significant modifiable predictors of recurrence. CONCLUSIONS: Segmentectomy is a reasonable option for patients with early-stage NSCLC who have had a prior lung resection. It results in similar survival but trends toward lower recurrence-free survival compared with patients undergoing primary resection.

The safety and efficacy of approaches to liver resection: a meta-analysis.

BACKGROUND: The aim of this study is to compare the safety and efficacy of conventional laparotomy with those of robotic and laparoscopic approaches to hepatectomy. DATABASE: Independent reviewers conducted a systematic review of publications in PubMed and Embase, with searches limited to comparative articles of laparoscopic hepatectomy with either conventional or robotic liver approaches. Outcomes included total operative time, estimated blood loss, length of hospitalization, resection margins, postoperative complications, perioperative mortality rates, and cost measures. Outcome comparisons were calculated using random-effects models to pool estimates of mean net differences or of the relative risk between group outcomes. Forty-nine articles, representing 3702 patients, comprise this analysis: 1901 (51.35%) underwent a laparoscopic approach, 1741 (47.03%) underwent an open approach, and 60 (1.62%) underwent a robotic approach. There was no difference in total operative times, surgical margins, or perioperative mortality rates among groups. Across all outcome measures, laparoscopic and robotic approaches showed no difference. As compared with the minimally invasive groups, patients undergoing laparotomy had a greater estimated blood loss (pooled mean net change, 152.0 mL; 95% confidence interval, 103.3-200.8 mL), a longer length of hospital stay (pooled mean difference, 2.22 days; 95% confidence interval, 1.78-2.66 days), and a higher total complication rate (odds ratio, 0.5; 95% confidence interval, 0.42-0.57). CONCLUSION: Minimally invasive approaches to liver resection are as safe as conventional laparotomy, affording less estimated blood loss, shorter lengths of hospitalization, lower perioperative complication rates, and equitable oncologic integrity and postoperative mortality rates. There was no proven advantage of robotic approaches compared with laparoscopic approaches.

Robotic versus laparoscopic colorectal surgery.

BACKGROUND: Robotic approaches have become increasingly used for colorectal surgery. The aim of this study is to examine the safety and efficacy of robotic colorectal procedures in an adult population. STUDY DESIGN: A systematic review of articles in both PubMed and Embase comparing laparoscopic and robotic colorectal procedures was performed. Clinical trials and observational studies in an adult population were included. Approaches were evaluated in terms of operative time, length of stay, estimated blood loss, number of lymph nodes harvested, and perioperative complications. Mean net differences and odds ratios were calculated to examine treatment effect of each group. RESULTS: Two hundred eighteen articles were identified, and 17 met the inclusion criteria, representing 4,342 patients: 920 robotic and 3,422 in the laparoscopic group. Operative time for the robotic approach was 38.849 minutes longer (95% confidence interval: 17.944 to 59.755). The robotic group had lower estimated blood loss (14.17 mL; 95% confidence interval: -27.63 to -1.60), and patients were 1.78 times more likely to be converted to an open procedure (95% confidence interval: 1.24 to 2.55). There was no difference between groups with respect to number of lymph nodes harvested, length of stay, readmission rate, or perioperative complication rate. CONCLUSIONS: The robotic approach to colorectal surgery is as safe and efficacious as conventional laparoscopic surgery. However, it is associated with longer operative time and an increased rate of conversion to laparotomy. Further prospective randomized controlled trials are warranted to examine the cost-effectiveness of robotic colorectal surgery before it can be adopted as the new standard of care.

Safety of robotic thyroidectomy approaches: meta-analysis and systematic review.

BACKGROUND: This study compared the efficacy of robotic thyroidectomy via a gasless, axillary approach with conventional cervical and endoscopic techniques by meta-analysis. METHODS: Articles were identified from the following keyword searches: robotic/robot-assisted thyroidectomy/thyroid surgery. Outcomes included operative time, hospital stay, complications, and cosmetic satisfaction after surgery. Between-group outcome differences were calculated using random-effects models. RESULTS: In all, 87 publications were identified and 9 studies met inclusion criteria, totaling 2881 patients, 1122 of whom underwent robotic thyroidectomy. Those who underwent robotic surgery reported greater cosmetic satisfaction, with a pooled net mean difference of -1.35 (95% confidence interval [CI]: -1.69, -1.09). Robotic approach operative time was longer than that of the conventional approach (95% CI: 29.23, 54.87), with a trend to be shorter than the endoscopic approaches. Robotic surgery had similar risks to open and endoscopic approaches. CONCLUSIONS: Our meta-analysis suggests that robotic thyroidectomy is as safe, feasible, and efficacious as conventional cervical and endoscopic thyroidectomy, showing superior cosmetic satisfaction than that of conventional thyroidectomy.

A comparative North American experience of robotic thyroidectomy in a thyroid cancer population.

PURPOSE: This study seeks to explore the efficacy of robotic thyroidectomy in treating a North American population with differentiated thyroid cancer (DTC) as compared with the conventional cervical approach. METHODS: A retrospective analysis of our prospectively collected thyroid surgery database was performed. We included all consecutive patients that underwent thyroidectomy for the treatment of well-differentiated thyroid cancer, performed by a single surgeon. RESULTS: Twenty-four robotic transaxillary and 35 conventional thyroidectomy procedures were performed. Average size of the tumor was 1.1 ± 0.2 cm in the robotic group and 1.7 ± 0.3 cm in the cervical group (p = 0.16). Average total operative time for the robotic group was 133 ± 65.4 and 119.7 ± 22.5 min in the cervical group (p = 0.34). No robotic cases required conversion. One patient required reoperation for recurrent disease at 24 months follow-up. Both groups had similar blood loss (p = 0.37) and all margins were negative for malignancy on permanent pathology. All patients were discharged home within 24 h. Postoperative stimulated thyroglobulin levels were similar for the two groups (p = 0.82). CONCLUSIONS: Our experience with robotic transaxillary thyroidectomy confirms this technique is feasible. It is possible to achieve a safe and effective oncologic result in a select group of North American patients with DTC.

MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets.

PURPOSE: While the molecular basis of hereditary medullary thyroid cancer (HMTC) has been well defined, little is known about the molecular pathogenesis of sporadic medullary thyroid cancer (SMTC). In addition, microRNAs (miRNAs) have been shown to be important diagnostic and prognostic markers in cancer but have not been defined in MTC. Our aim was to study the miRNA profile of MTC to identify prognostic biomarkers and potential therapeutic targets. EXPERIMENTAL DESIGN: MiRNA microarray profiling was carried out in fresh frozen tissues from patients with SMTC (n = 12) and HMTC (n = 7). Differential expression of three miRNAs was confirmed in a validation cohort of SMTC and HMTC samples (n = 45) using quantitative reverse transcriptase-PCR and correlated with clinical outcomes. The functional role of a selected miRNA was investigated in vitro in the human medullary thyroid carcinoma cell line (TT cells) using cell proliferation assays and Western blotting analysis. RESULTS: MiRs-183 and 375 were overexpressed (P = 0.001; 0.031) and miR-9* was under-expressed (P = 0.011) in SMTC versus HMTC. Overexpression of miRs-183 and 375 in MTC predicted lateral lymph node metastases (P < 0.001; P = 0.001) and was associated with residual disease (P = 0.001; 0.003), distant metastases (P = 0.003; 0.001), and mortality (P = 0.01; 0.011). Knock down of miR-183 expression in the TT cell line induced a significant decrease in the viable cell count and upregulation of the protein LC3B, which is associated with autophagy. CONCLUSIONS: Our data indicate that miRNAs play a pivotal role in the biology of MTC and represent an important class of prognostic biomarkers and therapeutic targets warranting further investigation.

Medullary thyroid carcinoma: long-term outcomes of surgical treatment.

BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths. METHODS: We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009. RESULTS: We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort. CONCLUSIONS: A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.

MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets.

MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.

Synthesis and activity of quinolinyl-methylene-thiazolinones as potent and selective cyclin-dependent kinase 1 inhibitors.

A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.

Human mast cell-derived gelatinase B (matrix metalloproteinase-9) is regulated by inflammatory cytokines: role in cell migration.

Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-alpha significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-gamma inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-alpha significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-gamma, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage.