Evaluation of endoscopic gastrojejunostomy revision after Roux-en-Y gastric bypass for treatment of dumping syndrome.

BACKGROUND AND AIMS: Gastrojejunostomy stomal dilation is a frequent cause of weight regain after Roux-en-Y gastric bypass and may be a contributing cause of dumping syndrome. This study aims to evaluate the long-term durability of endoscopic gastrojejunostomy revision (EGJR) to resolve dumping syndrome. METHODS: A retrospective chart review was performed of patients undergoing EGJR at a single institution from January 1, 2013 to December 1, 2018. The primary endpoint, dumping symptom resolution, was measured at 1 month and at the most recent postoperative follow-up. Continuous data are reported as mean and standard deviations and categorical data as percentages. The Fisher exact test was used to assess associations between categorical variables. RESULTS: Ninety-eight patients underwent EGJR for dumping syndrome. Mean patient age was 51 years (standard deviation [SD], 9.9), and mean body mass index (BMI) was 36.2 kg/m2 (SD, 7.1), with most patients (53%) presenting with BMIs ≥35 kg/m2. Thirty-two patients (32%) reported severe dumping (≥3 symptoms). All patients were followed-up for 1 month, and 83% had a long-term follow-up at a mean of 3.45 years (SD, 1.7) after EGJR. In addition, 88% had initial symptom resolution at 1 month, and 85% reported symptom resolution 3 years postoperatively. Patients with GERD had a statistically significant improvement in dumping syndrome at 3 years compared with those without GERD (69% vs 62%, P = .03). Long-term weight loss averaged 2.1 pounds after EGJR. CONCLUSIONS: EGJR is associated with effective and durable resolution of dumping syndrome at 3 years postoperatively, with a minimal long-term impact on weight loss. The presence of GERD preoperatively correlates with a statistically significant resolution of dumping syndrome.

Prognostic Factors in Gastrointestinal Leiomyosarcomas: An Analysis Using the Surveillance, Epidemiology, and End Results (SEER) Database.

Background Gastrointestinal leiomyosarcomas (LMSs) from intramural smooth muscle are extremely rare, with limited literature. This paper evaluates the epidemiology and survival and prognostic factors in LMSs of the gastrointestinal tract. Methods Clinical data from the Surveillance, Epidemiology and End Results (SEER) 18 registry from 2001 to 2016 with additional treatment fields were compared between primary tumor sites using the chi-squared test for categorical variables and ANOVA for continuous variables. A five-year survival rate analysis was performed for overall and cancer-specific survival. Hazard ratios (HRs) were calculated using univariate and multivariate Cox proportional models using the variables age group, tumor location, grade, stage, surgery, and chemotherapy. Results We identified a total of 523 patients diagnosed with LMSs of the gastrointestinal tract. The median age of diagnosis was 66 years, with no significant difference between tumor sites for age, sex, and race. The five-year overall survival was 77.3%, and the cancer-specific survival was 90.3%. In the multivariate analysis, grade and stage of tumor were the only factors significantly affecting survival in this cohort. Conclusion While surgical status significantly affected survival in the univariate analysis, when adjusted for other factors, the HR for death was not significantly different by surgical therapy. Grade 3 tumors and tumors with distant metastasis at diagnosis were associated with worse survival among these patients.

Vertical Plate for Flail Chest Repair.

Operative treatment of rib fractures in the context of flail chest and respiratory failure is a well-established approach. In-line rib osteosynthesis with plates is the standard treatment sufficient to eliminate flail, achieve sufficient stability, and create chest rigidity to improve the respiratory cycle and maintain reduction. However, bridging large skeletal defects with missing portion of ribs is very challenging, particularly in the absence of suitable anchoring rib fragments. We describe an unusual use of vertical plate rib osteosynthesis in a patient with traumatic flail chest, exacerbated by a prior thoracoplasty and severe osteoporosis.

Integrin α4ß1 and TLR4 Cooperate to Induce Fibrotic Gene Expression in Response to Fibronectin's EDA Domain.

Alternative splicing of fibronectin increases expression of the EDA+ isoform of fibronectin (EDA+Fn), a damage-associated molecular pattern molecule, which promotes fibro-inflammatory disease through the activation of toll-like receptors. Our studies indicate that the fibronectin EDA domain drives two waves of gene expression in human dermal fibroblasts. The first wave, seen at 2 hours, consisted of inflammatory genes, VCAM1, and tumor necrosis factor. The second wave, evaluated at 24 hours, was composed of the fibrosis-associated cytokines IL-10 and IL-13 and extracellular matrix genes fibronectin and osteopontin. Gene expression was coordinately regulated by the α4ß1 integrin and the innate immune receptor toll-like receptor 4. Additionally, we found a significant toll-like receptor 4/α4ß1-dependent enrichment in the ratio of EDA+Fn to total fibronectin in response to EDA, consistent with EDA+Fn initiating further production of EDA+Fn. Our data also suggest that the EDA/α4ß1 integrin interaction primes the cell for an enhanced response to toll-like receptor 4 ligands. Our studies provide evidence that remodeling of the fibronectin matrix in injured or diseased tissue elicits an EDA-dependent fibro-inflammatory response in dermal fibroblasts. The data suggest a paradigm of damage-associated molecular pattern-based signaling whereby damage-associated molecular pattern binding integrins cooperate with innate immune receptors to stimulate inflammation and fibrosis.

Targeting c-Met in melanoma: mechanism of resistance and efficacy of novel combinatorial inhibitor therapy.

Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active ß-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.

hnRNP C1/C2 and Pur-beta proteins mediate induction of senescence by oligonucleotides homologous to the telomere overhang.

BACKGROUND: Experimental disruption of the telomere overhang induces a potent DNA damage response and is the target of newly emerging cancer therapeutics. Introduction of T-oligo, an eleven-base oligonucleotide homologous to the 3'-telomeric overhang, mimics telomere disruption and induces DNA damage responses through activation of p53, p73, p95/Nbs1, E2F1, pRb, and other DNA damage response proteins. ATM (ataxia telangiectasia mutated) was once thought to be the primary driver of T-oligo-induced DNA damage responses; however, recent experiments have highlighted other key proteins that may also play a significant role. METHODS: To identify proteins associated with T-oligo, MM-AN cells were treated with biotinylated T-oligo or complementary oligonucleotide, cell lysates were run on SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), and the protein bands observed after treatment of cells with T-oligo or complementary oligonucleotide were analyzed using mass spectrometry. To study the effect of T-oligo on expression of hnRNP C1/C2 (heterogeneous nuclear ribonucleoprotein C1 and C2) and purine-rich element binding proteins (Pur proteins), cells were treated with T-oligo, and immunoblotting experiments were performed. To determine their role in senescence, cells were treated with shRNA (short hairpin ribonucleic acid) against these proteins, and senescence was studied using the senescence associated beta-galactosidase assay. RESULTS: Using mass spectrometry, RNA-binding hnRNP C1/C2 and DNA-binding Pur proteins were found to associate with T-oligo. hnRNP C1/C2 exhibited increased expression (3.6-12.0-fold) in non-small-cell lung cancer (NSCLC) and in melanoma cells (4.5-5.2-fold), and Pur proteins exhibited increased expression of 2.2-fold in NSCLC and 2.0-fold in melanoma cells after T-oligo treatment. Experimental knockdown of hnRNP C1/C2 and Pur-beta completely abrogated T-oligo induced senescence in both MU melanoma and H358 NSCLC cells. Additionally, knockdown of Pur-beta prevented T-oligo-induced phosphorylation of p53, hypophosphorylation of pRb, and upregulation of E2F1, p21, and p53. CONCLUSION: These novel findings highlight proteins essential to T-oligo's anticancer effects that may be of interest in telomere biology and cancer therapeutics.