Case Report: Hypertriglyceridemia-Induced Pancreatitis after Lenvatinib and Pembrolizumab Use.

Introduction: Lenvatinib and Pembrolizumab together are used as a chemotherapy regimen for patients with metastatic endometrial carcinoma. Lenvatinib is a vascular endothelial growth factor (VEGF) receptor inhibitor, fibroblast growth factor inhibitor and an inhibitor that acts on platelet derived growth factor receptor alpha, ret oncogene and c-KIT oncogene. Pembrolizumab is an immune checkpoint inhibitor that acts against programmed-death one (PD-1) receptors and programmed-death ligand one (PD-L1) receptors. In combination, this regimen has proven to be efficacious in the setting of advanced endometrial carcinoma, but this must be weighed against its' side effect profile, most specifically their individual side effects. Pembrolizumab has been associated with pancreatitis. Lenvatinib has been associated with hypertriglyceridemia. However, little has been published with hypertriglyceridemia-induced pancreatitis in the setting of the combination of Lenvatinib and Pembrolizumab and its' management. Case Presentation: This case presentation discusses a 57-year-old female with history of stage IV uterine cancer with metastasis to the liver status post total abdominal hysterectomy/bilateral salpingo-oophrectomy (on Lenvatinib 8 mg PO daily/Pembrolizumab 200 mg IV every three weeks) presenting with epigastric pain, nausea, vomiting and decreased appetite; her symptoms were due to hypertriglyceridemia-induced pancreatitis with CT findings consistent with pancreatitis as well as a serum lipase of 1,508, and serum triglyceride level of 2,052; she was treated with IV insulin, resulting in resolution of her hypertriglyceridemia-induced pancreatitis. Conclusion: This case demonstrates a unique presentation of the hypertriglyceridemia induced pancreatitis in the setting of Lenvatinib and Pembrolizumab use and the need for future research to better understand the pathophysiology of the pancreatitis induced by this chemotherapy regimen.

Thermal boundary layer analysis of MHD nanofluids across a thin needle using non-linear thermal radiation.

An analysis of steady two-dimensional boundary layer MHD (magnetohydrodynamic) nanofluid flow with nonlinear thermal radiation across a horizontally moving thin needle was performed in this study. The flow along a thin needle is considered to be laminar and viscous. The Rosseland estimate is utilized to portray the radiation heat transition under the energy condition. Titanium dioxide (TiO$ _2 $) is applied as the nanofluid and water as the base fluid. The objective of this work was to study the effects of a magnetic field, thermal radiation, variable viscosity and thermal conductivity on MHD flow toward a porous thin needle. By using a suitable similarity transformation, the nonlinear governing PDEs are turned into a set of nonlinear ODEs which are then successfully solved by means of the homotopy analysis method using Mathematica software. The comparison result for some limited cases was achieved with earlier published data. The governing parameters were fixed values throughout the study, i.e., $ k_1 $ = 0.3, $ M $ = 0.6, $ F_r $ = 0.1, $ \delta_\mu $ = 0.3, $ \chi $ = 0.001, $ Pr $ = 0.7, $ Ec $ = 0.5, $ \theta_r $ = 0.1, $ \epsilon $ = 0.2, $ Rd $ = 0.4 and $ \delta_k $ = 0.1. After detailed analysis of the present work, it was discovered that the nanofluid flow diminishes with growth in the porosity parameter, variable viscosity parameter and magnetic parameter, while it upsurges when the rate of inertia increases. The thermal property enhances with the thermal conductivity parameter, radiation parameter, temperature ratio parameter and Eckert number, while it reduces with the Prandtl number and size of the needle. Moreover, skin friction of the nanofluid increases with corresponding growth in the magnetic parameter, porosity parameter and inertial parameter, while it reduces with growth in the velocity ratio parameter. The Nusselt number increases with increases in the values of the inertia parameter and Eckert number, while it decliens against a higher estimation of the Prandtl number and magnetic parameter. This study has a multiplicity of applications like petroleum products, nuclear waste disposal, magnetic cell separation, extrusion of a plastic sheet, cross-breed powered machines, grain storage, materials production, polymeric sheet, energy generation, drilling processes, continuous casting, submarines, wire coating, building design, geothermal power generations, lubrication, space equipment, biomedicine and cancer treatment.

Co-stimulatory and co-inhibitory immune markers in solid tumors with MET alterations.

The implication of MET alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring MET alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a MET missense mutation, four had an exon 14 splice site mutation and six had MET amplification. CD6, CCL19, CD40LG, XCR1, MAGEA1, ATM and CCL19 genes were significantly differentially expressed in MET-altered cancers. MET alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors.

I1171 missense mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC patients who have progressive disease while on alectinib and is sensitive to ceritinib.

OBJECTIVES: Acquired resistance mutations to anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been documented in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangement (ALK+). Of note I1171T/N/S mutations in the ALK kinase domain have recently been described by several groups to confer resistance to alectinib, a second-generation ALK inhibitor. Additionally one of these reports demonstrated one ALK+ NSCLC patient harboring an I1171T acquired mutation has responded to ceritinib, another second-generation ALK inhibitor. MATERIALS AND METHODS: We reported the presence of an ALK I1171N resistance mutation from comprehensive genomic profiling from a liver biopsy of a progressing metastatic lesion in an ALK+ patient on alectinib after an initial partial response. The patient then responded to ceritinib 750 mg orally once daily but required dose reduction to 600 mg once daily. She initially had grade 3 elevation of liver enzymes from crizotinib necessitating the original switch to alectinib but experienced no transaminase elevations with alectinib or ceritinib. CONCLUSIONS: This is the fifth patient case to date demonstrating that ALK I1171 mutation confers resistance to alectinib and the second reported case of ALK I1171 mutation being sensitivity to ceritinib. Substitutions of isoleucine at amino acid 1171 in the ALK kinase domain may distinguish which second generation ALK inhibitor will be effective after crizotinib failure. This case also provides evidence that transaminase elevations is likely a unique adverse event associated with crizotinib and unlikely a "class" effect involving all ALK inhibitors.

Outcome of allogeneic hematopoietic stem cell transplantation in patients with low left ventricular ejection fraction.

A high risk of regimen-related toxicity with allogeneic hematopoietic stem cell transplantation (allo-HSCT) limits this potentially curative treatment for patients with a left ventricular ejection fraction (LVEF) of > or =50%. We evaluated the frequency of cardiac complications and 100-day nonrelapse mortality (NRM) in 56 patients with a LVEF of < or =45%, who received allo HCT at our institution. The results were retrospectively compared with a matched control group with LVEF of > or =50%, which received an allogeneic stem cell transplantation (allo-SCT). After a median follow-up of 29 months in the study group, grade > or =2 cardiac complications were seen in 7 of 56 (12.5%) patients and cumulative incidence of 100-day NRM was 12.5% with no deaths from cardiac causes. In contrast, after a median follow-up of 49 months in the control group, grade >2 cardiac complications were seen in 19 of 161 patients (11.8%; P = 1.00) and cumulative incidence of 100-day NRM was 14.9% (P = .82). The presence of at least 1 of the 7 pretransplant cardiac risk factors (past history of smoking, hypertension, hyperlipidemia, coronary artery disease, arrhythmia, prior myocardial infarction, and congestive heart failure) was associated with a higher cardiac complication rate in the study group (P = .03). In conclusion, selected patients with a LVEF of < or =45% can safely receive allo-HCT without a significant increase in cardiac toxicity or NRM.

Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma.

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

The DNA sequence, annotation and analysis of human chromosome 3.

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.