Gigaxonin Suppresses Epithelial-to-Mesenchymal Transition of Human Cancer Through Downregulation of Snail.

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail. SIGNIFICANCE: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.

Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.

The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012).

A Rare Case of Spontaneous Fungal Peritonitis Caused by Candida lusitaniae in a Patient With Necrotizing Pancreatitis.

Candida lusitaniae is a rare cause of peritonitis most commonly associated with peritoneal dialysis patients. Pancreatitis is one possible cause of ascites with a low serum ascites albumin gradient. Herein, we present a case of spontaneous fungal peritonitis caused by Candida lusitaniae in a patient with necrotizing pancreatitis. The patient was treated with antifungal medication, while her pancreatitis was managed endoscopically with necrosectomy. She improved clinically and was discharged in stable condition.

High prevalence of pre-existing sarcopenia in critically ill patients with hematologic malignancies admitted to the intensive care unit for sepsis or septic shock.

BACKGROUND & AIMS: We aimed to evaluate body composition (BC) by computed tomography (CT) in hematologic malignancy (HM) patients admitted to the intensive care unit (ICU) for sepsis or septic shock. METHODS: We retrospectively assessed BC and its impact on outcome of 186 patients at the 3rd lumbar (L3) and 12th thoracic vertebral levels (T12) using CT-scan performed before ICU admission. RESULTS: The median patient age was 58.0 [47; 69] years. Patients displayed adverse clinical characteristics at admission with median [q1; q3] SAPS II and SOFA scores of 52 [40; 66] and 8 [5; 12], respectively. The mortality rate in the ICU was 45.7%. Overall survival rates at 1 month after admission in the pre-existing sarcopenic vs. non pre-existing sarcopenic patients were 47.9% (95% CI [37.6; 61.0]) and 55.0% (95% CI [41.6; 72.8]), p = 0.99), respectively, at the L3 level and 48.4% (95% CI [40.4; 58.0]) vs. 66.7% (95% CI [51.1; 87.0]), p = 0.062), respectively, at the T12 level. CONCLUSIONS: Sarcopenia is assessable by CT scan at both the T12 and L3 levels and is highly prevalent in HM patients admitted to the ICU for severe infections. Sarcopenia may contribute to the high mortality rate in the ICU in this population.

Case report: CAR-T cell therapy-induced cardiac tamponade.

CD19-specific chimeric antigen receptor T (CAR-T) cell therapy has recently been shown to improve the prognosis of refractory diffuse large B-cell lymphoma (DLBCL). However, CAR-T cells may induce numerous adverse events, in particular cytokine release syndrome (CRS) which is frequently associated with cardiovascular manifestations. Among the latter, acute pericardial effusion represents less than 1% of cases and cardiac tamponade has only been reported once. The management and outcome of these severe complications are not well established. We report here, a case of cardiac tamponade associated with CRS in a context of CAR-T cell therapy, which required urgent pericardiocentesis. Case summary: A 65-year-old man with refractory DLBCL was treated with CAR-T cell therapy. He had a history of dilated cardiomyopathy with preserved ejection fraction and transient atrial fibrillation. A pericardial localization of the lymphoma was observed on the second relapse. One day after CAR-T cell infusion the patient was diagnosed with grade 1 CRS. Due to hypotension, he was treated with tocilizumab and dexamethasone, and then transferred to intensive care unit (ICU). Echocardiography performed at ICU admission showed acute pericardial effusion with signs of right ventricular heart failure due to cardiac tamponade. It was decided to perform pericardiocentesis despite grade IV thrombocytopenia in a context of aplasia. Analysis of pericardial fluid showed a large number of lymphoma cells and 73% of CAR-T cells amongst lymphocytes, a level that was similar in blood. Hemodynamic status improved after pericardiocentesis, and no recurrence of pericardial effusion was observed. The presence of a high count of activated CAR-T cells in the pericardial fluid as well as the short interval between CAR-T cells injection and the symptoms appear as potential arguments for a direct action of CAR-T cells in the mechanism of this adverse event. The patient was discharged from ICU after two days and initially exhibited a good response to DLBCL treatment. Unfortunately, he died fifty days after starting CAR-T cell therapy due to a new DLBCL relapse. Conclusion: Patients with a pericardial localization of DLBCL should be assessed for a risk of cardiac tamponade if receiving CAR-T cell therapy and presenting CRS. In this case, cardiac tamponade seems directly related to CAR-T cell expansion. Pericardiocentesis should be considered as a feasible and effective treatment if the risk of bleeding is well controlled, in association with anti-IL6 and corticosteroids.

Anabolic Steroid-Induced Cholestatic Liver Injury: A Case Report.

Owing to performance-enhancing and cosmetic effects, illicit use of anabolic-androgenic steroids (AAS) has been well-described and can be associated with significant complications. We report a 27-year-old Caucasian male who self-medicated with AAS in the form of intramuscular injections and oral testosterone for a one-year duration. He complained of persistent jaundice and moderate generalized itching for one month. On admission, his total bilirubin level was 11.4 mg/dl (normal: 0-1.2 mg/dl), and liver enzymes were slightly elevated. On follow-up, the patient stated complete resolution of symptoms and near-normalization of lab results after one month of conservative management.

Retrospective analysis of the safety of peripherally inserted catheters versus implanted port catheters during first-line treatment for patients with diffuse large B-cell lymphoma.

OBJECTIVES: Both peripherally inserted central catheters (PICCs) and implanted port catheters (PORTs) are commonly used for the delivery of immunochemotherapy. We compared the safety of the two types of devices in a homogeneous and monocentric population of diffuse large B-cell lymphoma (DLBCL) patients who were treated with first-line immunochemotherapy by evaluating the numbers of catheter-related venous thromboses (VTs) and infections that occurred in the six months after implantation according to the type of device. METHODS: Using a propensity score, the adjusted relative risk (ARR) between the type of catheter and the occurrence of catheter-related complications (infection and/or VT) of interest was retrospectively determined. RESULTS: 479 patients were enrolled (266 PORTs/213 PICCs), and 26 VTs (5.4%) and 30 infections (6.3%) were identified in the period following PICC/PORT implantation. The adjusted relative risk (ARR) of catheter-related complications (infection and/or VT) according to the type of device was 2.6 (95% CI =1.3-5.9, p = .0075). This risk increase associated with the PICC device was significant for both infections (ARR = 3.2; 95% CI = 1.3-10.9) and thrombosis (ARR = 4; 95% CI = 1.5-11.6). CONCLUSION: Our study supports the preferential use of PORTs for the first line of treatment for DLBCL patients.

Coaxial Double-Pigtail Stent Placement: A Simple Solution to Decrease Bleeding Risk Associated With Lumen-Apposing Metal Stent?

Endoscopic cystogastrostomy using lumen-apposing metal stent (LAMS) is considered the first-line therapy for symptomatic pancreatic fluid collections (PFCs). Routine coaxial placement of a double-pigtail stent (DPS) through LAMS is debated. We report the case of a patient with delayed massive gastrointestinal bleed eight weeks after LAMS placement due to splenic artery pseudoaneurysm leading to a complicated hospitalization. Theoretically, coaxial placement of DPS through LAMS can prevent the relatively sharp LAMS from eroding into the mucosa of the collapsed cavity of PFCs, decreasing the risk of bleeding. Our case adds to the growing need to further explore the utility of this combined intervention.

Utility of Transjugular Intrahepatic Portosystemic Shunt Placement for Maintaining Portal Vein Patency in Candidates on Wait Lists Who Develop Thrombus.

OBJECTIVES: Although no longer a contraindication to liver transplant, portal vein thrombosis may lead to longer operative time and complexities in venous reconstruction. Strategies to maintain preoperative patency include systemic anticoagulation and/or transjugular intrahepatic portosystemic shunt placement. The former may not be ideal in cirrhotic patients prone to luminal gastrointestinal tract bleeding, and factors that predict improvements in portal vein thrombosis with the latter have not been well defined. Our goal was to evaluate the effectiveness of transjugular intrahepatic portosystemic shunt placement as monotherapy to improve and/or resolve portal vein thrombosis in otherwise eligible liver transplant candidates with partial or complete portal vein thrombosis and to identify factors predicting success. MATERIALS AND METHODS: We identified 30 patients from 2010 to 2015 who had transjugular intrahepatic portosystemic shunt placementfor primary indication to maintain portal vein patency. RESULTS: The main portal vein was completely thrombosed in 5 of 30 (16.6%), nearly completely thrombosed in 9 of 30 (30%), and partially thrombosed in 16 patients (53.3%). Twenty-four patients (80%) had improvement and/or resolution of portal vein thrombosis after transjugular intrahepatic portosystemic shunt placement, with 18 of these (75%) having complete resolution. All 5 patients (20.8%) with complete thrombosis had improvement/resolution of portal vein thrombosis. Nine patients (30%) required hospitalization within 3 months for hepatic encephalopathy. There were 3 deaths (10%) not related to transjugular intrahepatic portosystemic shunt placement (10%). Nine patients underwent liver transplant after shunt placement (median 2.9 mo; range, 0.3-32 mo); all 9 received endto-end anastomosis without need for intraoperative thrombectomy. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt placement may be effective as monotherapy for maintaining or restoring portal vein patency in selected livertransplant candidates, even in those with complete portal vein thrombosis. Further studies are needed to define potential responders to this approach.

Impact of the relative dose intensity on survival of patients with high-risk myelodysplastic syndromes treated with Azacitidine.

We performed a retrospective analysis of 93 myelodysplastic syndromes (MDS) patients with intermediate 2 or high-risk IPSS score to study the impact of Azacitidine (AZA) relative dose intensity (RDI) <80% on the overall survival (OS). There were 51.6% of patients who had full dose and 48.4% had dose reduction or delayed with a RDI <80%. Nineteen patients (20.4%) had RDI <80% before getting objective response. Overall and progression-free survivals (OS, PFS) probabilities for the whole population were 58% (95% CI: 48-69) and 47% (95% CI: 38-58) at 1 year; 35% (95% CI: 26-47) and 31% (95% CI: 23-43) at two years, respectively. When analyzing the outcomes according to the response to AZA, median OS was 32 months (range: 26-55) for responders and 8 months (range: 7-12) for nonresponders, with a respective 1-year and 2-year OS probabilities of 91% vs 28% and 66% vs 6%, respectively (P < 0.001). Interestingly, there was no impact of dose reduction on OS nor on PFS, however, when analyzing the timing of dose reduction as time-dependent variable, we found that patients who had dose reduction before achieving the objective response, had significantly lower OS (P = 0.02) and PFS (P = 0.01) compared to patients who had dose reduction after achieving the objective response. In multivariate analysis, acute myeloid leukemia with 21%-30% blasts in BM and poor and very poor karyotype significantly impacted OS, (HR = 2.09, 95% CI: 1.27-3.44, P = 0.004, and HR = 2.73, 95% CI: 1.6-4.6, P < 0.001 respectively), as well as PFS (HR = 1.84, 95% CI: 1.07-3.17, P = 0.028, and HR = 3.03, 95% CI: 1.7-5.39, P < 0.001, respectively).

[Lymphoplasmacytic lymphoma or multiple myeloma: immunoglobulins may lead to misdiagnosis]. / Lymphome lymphoplasmocytaire ou myélome multiple : quand les immunoglobulines induisent en erreur.

We report here a case of lymphoplasmacytic lymphoma with IgA paraproteinemia and a case of concomitant Waldenström macroglobulinemia and monoclonal gammapathy of unknown significance. These rare cases show that the isotype of a monoclonal immunoglobulin does not allow to foresee every time the underlying pathology. Clinical data and medical imaging are essential. From a biological point of view, additional analysis such as immunophenotyping, cytogenetics and molecular biology are required in addition to the cytological features in order to make an accurate differential diagnosis between lymphoid and plasma cell malignancy.

Human papillomavirus in oropharyngeal cancer: The changing face of a disease.

The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial.

BACKGROUND: To date, evidence for the efficacy of fecal microbiota transplantation (FMT) in recurrent Clostridium difficile infection (CDI) has been limited to case series and open-label clinical trials. OBJECTIVE: To determine the efficacy and safety of FMT for treatment of recurrent CDI. DESIGN: Randomized, controlled, double-blind clinical trial. (ClinicalTrials.gov: NCT01703494). SETTING: Two academic medical centers. PATIENTS: 46 patients who had 3 or more recurrences of CDI and received a full course of vancomycin for their most recent acute episode. INTERVENTION: Fecal microbiota transplantation with donor stool (heterologous) or patient's own stool (autologous) administered by colonoscopy. MEASUREMENTS: The primary end point was resolution of diarrhea without the need for further anti-CDI therapy during the 8-week follow-up. Safety data were compared between treatment groups via review of adverse events (AEs), serious AEs (SAEs), and new medical conditions for 6 months after FMT. Fecal microbiota analyses were performed on patients' stool before and after FMT and also on donors' stool. RESULTS: In the intention-to-treat analysis, 20 of 22 patients (90.9%) in the donor FMT group achieved clinical cure compared with 15 of 24 (62.5%) in the autologous FMT group (P = 0.042). Resolution after autologous FMT differed by site (9 of 10 vs. 6 of 14 [P = 0.033]). All 9 patients who developed recurrent CDI after autologous FMT were free of further CDI after subsequent donor FMT. There were no SAEs related to FMT. Donor FMT restored gut bacterial community diversity and composition to resemble that of healthy donors. LIMITATION: The study included only patients who had 3 or more recurrences and excluded those who were immunocompromised and aged 75 years or older. CONCLUSION: Donor stool administered via colonoscopy seemed safe and was more efficacious than autologous FMT in preventing further CDI episodes. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases.

Limited Fibrosis Progression but Significant Mortality in Patients Ineligible for Interferon-Based Hepatitis C Therapy.

BACKGROUND: Individuals ineligible for interferon-based hepatitis C therapy may have a worse prognosis than patients who have failed or not received treatment. AIMS: To provide information about the limitations of medical treatment of hepatitis C in real-world patients. METHODS: We studied 969 treatment-ineligible patients and 403 treated patients enrolled between 1/1/01 and 6/30/06; data were collected until 3/31/13. Treatment barriers were grouped into five categories and classified as health-related or health-unrelated. Fibrosis stage was assessed initially and at the end of follow-up. Mortality was determined by search of the Social Security database. Death certificates of treatment-ineligible patients were reviewed. RESULTS: Initially, 288 individuals had advanced fibrosis and compensated disease; 87 untreated patients developed advanced fibrosis during follow-up. Health-related treatment barriers were more commonly associated with fibrosis progression and worse survival. During follow-up, 247 untreated patients died: 47% of liver-related and 53% of liver-unrelated causes. Patients with significant comorbid illness had the worst five- (70%) and ten-year (50.5%) survival. Despite high mortality (47%) in persons with decompensated liver disease, no treatment barrier was associated with a greater incidence of liver-related death. Only significant comorbid medical illness was an independent predictor of disease progression; however, it was not associated with a greater incidence of liver-related death. Furthermore, treated patients had better 10-year survival than untreated patients on Kaplan-Meier analysis (80.3% vs. 74.5%, P = 0.005). CONCLUSION: Many patients with hepatitis C will die of non-liver-related causes and may not be helped by anti-viral treatment.

Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population.

We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted.