This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The ...group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold ...particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients.
CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart.
Doses from 50 μg/m(2) to 600 μg/m(2) were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m(2), did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue.
These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers.
Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel ...gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, ...objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). We discussed the mechanism causing an elevated IFP and how it interferes with drug delivery. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and specifically targets tumors while the systemic toxicity is markedly reduced. The addition of cytotoxic agent by either directly conjugating to the gold nanoparticle or by systemic administration following gold nanoparticle carrying TNF resulted in significantly reduced tumor burden and increased survival in multiple mouse models with primary and metastatic endocrine cancer and pancreatic ductal carcinoma. A clinical trial in patients with advanced solid cancers is warranted based on the promising results in preclinical studies.
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for ...beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.
Background Sporadic, nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) are diagnosed with increasing frequency. We compared the risk of tumor growth, metastasis, and mortality between ...patients treated versus those treated expectantly. Method A retrospective study of patients seen at our institution with sporadic NF-PNETs, with ≥12 months of follow-up. Kaplan-Meier analysis was performed. Results Between 1999 and 2014, 35 patients with an incidentally discovered nonfunctional PNET were identified. Twenty underwent resection and 15 were followed with imaging. In the operative group, 8 had NF-PNETs < 2 cm, while 12 had NF-PNETs ≥ 2 cm. In the nonoperative expectant management by serial imaging group, 10 had NF-PNETs < 2 cm while 5 had NF-PNETs ≥ 2 cm. Small NF-PNETs (<2 cm) in either the operative or nonoperative groups demonstrated no evidence of progression or metastasis (median follow-up of 27.8 months). Morbidity in the operative group was 35% with pancreatic pseudocyst the most common. Conclusion Incidentally discovered NF-PNETs < 2 cm in size can be observed safely with serial imaging.
Amino Acids are not only major nutrient sources, but also serve as chemical signals to control cellular growth. Rab1A recently emerged as a key component in amino acid sensing and signaling to ...activate the mTOR complex1 (mTORC1). In a recently published study 1, we generated tamoxifen-inducible, conditional whole-body Rab1A knockout in adult mice. These mice are viable but develop hyperglycemia and glucose intolerance. Interestingly, Rab1A ablation selectively reduces insulin expression and pancreatic beta-cell population. Mechanistically, branched chain amino acids (BCAA), through the Rab1A-mTORC1 complex, promote the stability and nuclear localization of Pdx1, a master transcription factor that controls growth, function and identity of pancreatic beta-cells. These findings reveal a role and underlying mechanism by which amino acids control body’s glucose level through a beta-cell specific function by the Rab1A-mTORC1-Pdx1 signaling axis, which has implications in both diabetes and cancer.
•Rab1A deficiency impairs mTORC1 signaling specifically in beta-cells.•Rab1A deficiency blunts insulin expression and cause hyperglycemia in mice.•Rab1A expression is down-regulated in beta-cells of diabetes patients.•Amino acids regulate insulin transcription through mTORC1-Rab1A-PDX1 axis.•Amino acids regulate beta-cell proliferation and trans-differentiation through mTORC1-Rab1A-PDX1 axis.
A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose ...(MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy.
Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed.
DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia.
LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.
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