Nonfunctional Pancreatic Neuroendocrine Tumors <2 cm on Preoperative Imaging are Associated with a Low Incidence of Nodal Metastasis and an Excellent Overall Survival

Background

The optimal surgical management of small nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial. We sought to identify (1) clinicopathologic factors associated with survival in NF-PNETs and (2) preoperative tumor characteristics that can be used to determine which lesions require resection and lymph node (LN) harvest.

Methods

The records of all 116 patients who underwent resection for NF-PNETs between 1989 and 2012 were reviewed retrospectively. Preoperative factors, operative data, pathology, surgical morbidity, and survival were analyzed.

Results

The overall 5- and 10-year survival rates were 83.9 and 72.8 %, respectively. Negative LNs (p?=?0.005), G1 or G2 histology (p?=?0.033), and age <60 years (p?=?0.002) correlated with better survival on multivariate analysis. The 10-year survival rate was 86.6 % for LN-negative patients (n?=?73) and 34.1 % for LN-positive patients (n?=?32). Tumor size ≥2 cm on preoperative imaging predicted nodal positivity with a sensitivity of 93.8 %. Positive LNs were found in 38.5 % of tumors ≥2 cm compared to only 7.4 % of tumors <2 cm.

Conclusions

LN status, a marker of systemic disease, was a highly significant predictor of survival in this series. Tumor size on preoperative imaging was predictive of nodal disease. Thus, it is reasonable to consider parenchyma-sparing resection or even close observation for NF-PNETs <2 cm.     

CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer

Background

Compared to the widely adopted 2–4 months of pre-operative therapy for patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC), our institution tends to administer a longer duration before considering surgical resection. Using this unique approach, the aim of this study was to determine pre-operative variables associated with survival.

Methods

Records from patients with BR/LA PDAC who underwent attempt at surgical resection from 1992–2014 were reviewed.

Results

After a median duration of 6 months of pre-operative treatment, 109 patients with BR/LA PDAC (BR 63, LA 46) were explored; 93 (85.3 %) underwent pancreatectomy. Those who received at least 6 months of pre-operative treatment had longer median overall survival (OS) than those who received less (52.8 vs. 32.1 months, P?=?0.044). On multivariate analysis, pre-operative treatment duration was the strongest predictor of survival (hazard ratio (HR) 4.79, P?=?0.043). However, OS was similar in those whose CA19-9 normalized regardless of whether they received more or less than 6 months of chemotherapy (71.4 vs. 101.8 months, P?=?0.930).

Conclusions

Pre-operative CA19-9 decline can guide treatment duration in patients with BR/LA PDAC. We endorse 6 months of therapy except in those patients whose values normalize, where surgery can be considered after a shorter course.

     

Chondroitin sulfate proteoglycan but not hyaluronic acid is the receptor for the adherence of Plasmodium falciparum-infected erythrocytes in human placenta, and infected red blood cell adherence up-regulates the receptor expression

A low-sulfated chondroitin sulfate proteoglycan (CSPG) has been shown to be the receptor for the adherence of Plasmodium falciparum-infected red blood cells (IRBCs) in human placenta. Recently, hyaluronic acid (HA) has been suggested as an additional receptor even though IRBC binding to HA and the presence of HA at locations where IRBCs adhere in the placenta have not been established. In this study, we investigated whether HA is also a receptor for IRBC binding. IRBCs from infected placentas as well as those from different laboratory strains could bind to CSPG but not to HA. In a cell depletion assay, IRBCs from infected placentas could bind quantitatively to CSPG. Although CSPG is present both in the intervillous space and on the syncytiotrophoblast surface, HA is absent in these locations. These data conclusively demonstrate that CSPG, but not HA, is a receptor for IRBC adherence in the placenta. Our data also show, for the first time, that the IRBC-binding CSPG in the placenta is of fetal origin and that, in P. falciparum-infected placentas, the CSPG level is significantly increased, which could exacerbate IRBC adherence and placental pathogenesis. These results have important implications for the development of anti-IRBC adhesion-based vaccine for pregnancy-associated malaria.     

The effects of long and bulky aromatic pendent groups with flexible linkages on the thermal,mechanical and electrical properties of the polyimides and their nanocomposites with functionalized silica

A novel diamine bis(4-aminophenyl)bis{3,4[(4-(8-quinolyloxymethyl carbonyl)]}methane, containing two long/bulky aromatic pendent chains was synthesized by incorporating aromatic and hetero aromatic groups with flexible linkages. Flexible, stretchable, thermally stable and processable polyimides were prepared by reacting this newly synthesized diamine with commercial tetracarboxylic acid dianhydrides like 3,3′,4,4′-benzophenone tetra carboxylic acid dianhydride (BTDA) and 4,4′-(4,4′-isopropylidenediphenoxy)diphthalic Anhydride (BPADA). Nanocomposites of polyimides were prepared using aromatic amine functionalized silica as a filler by solution casting method. The current work investigates the effects of incorporating long/bulky aromatic side chains and flexible linkages on the thermal, mechanical, electrical and optical properties of the polyimides and nanocomposites. The polyimides showed good thermal stability (T_10% = 364 & 388), high flame resistance, low glass transition temperatures (T_g = 130 °C & 156 °C), very low dielectric constants (2.5 & 2.8 at 1 MHz) and good optical transparency. The neat polyimides displayed good elongation at break (133–155%) but possessed low tensile strength. The chemically imidized polyimides showed good solubility in low and high boiling solvents. Nanocomposites of polyimides based on aromatic amine functionalized silica exhibited enhanced properties with T_10% values varying between 409–482 °C, T_g between 165–280 °C and higher dielectric constants (3–5.7 at 1 MHz).

Novel polyimides containing two long/bulky aromatic pendent chains and their nanocomposites with aromatic amine functionalized silica were prepared from a new diamine bis(4-aminophenyl)bis{3,4[(4-(8-quinolyloxymethyl carbonyl)phenoxy)]}methane.     

MK-2206 Causes Growth Suppression and Reduces Neuroendocrine Tumor Marker Production in Medullary Thyroid Cancer Through Akt Inhibition

Background

Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials. We explored the antitumor effects of this compound in MTC.

Methods

Human MTC-TT cells were treated with MK-2206 (0–20 μM) for 8 days. Assays for cell viability were performed at multiple time points with MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). The mechanism of action, mechanism of growth inhibition, and production of neuroendocrine tumor markers were assessed with Western blot analysis.

Results

MK-2206 suppressed MTC cell proliferation in a dose-dependent manner (p ≤ 0.001). Levels of Akt phosphorylated at serine 473 declined with increasing doses of MK-2206, indicating successful Akt inhibition. The apoptotic proteins cleaved poly (ADP-ribose) polymerase and cleaved caspase-3 increased in a dose-dependent manner with MK-2206, while the apoptosis inhibitor survivin was markedly reduced. Importantly, the antitumor effects of MK-2206 were independent of RET inhibition, as the levels of RET protein were not blocked.

Conclusions

MK-2206 significantly suppresses MTC proliferation without RET inhibition. Given its high oral bioavailability and low toxicity profile, phase II studies with this drug alone or in combination with RET inhibitors are warranted.     

The PtdIns 3-Kinase/Akt Pathway Regulates Macrophage-Mediated ADCC against B Cell Lymphoma

Macrophages are important effectors in the clearance of antibody-coated tumor cells. However, the signaling pathways that regulate macrophage-induced ADCC are poorly defined. To understand the regulation of macrophage-mediated ADCC, we used human B cell lymphoma coated with Rituximab as the tumor target and murine macrophages primed with IFNγ as the effectors. Our data demonstrate that the PtdIns 3-kinase/Akt pathway is activated during macrophage-induced ADCC and that the inhibition of PtdIns 3-kinase results in the inhibition of macrophage-mediated cytotoxicity. Interestingly, downstream of PtdIns 3-kinase, expression of constitutively active Akt (Myr-Akt) in macrophages significantly enhanced their ability to mediate ADCC. Further analysis revealed that in this model, macrophage-mediated ADCC is dependent upon the release of nitric oxide (NO). However, the PtdIns 3-kinase/Akt pathway does not appear to regulate NO production. An examination of the role of the PtdIns 3-kinase/Akt pathway in regulating conjugate formation indicated that macrophages treated with an inhibitor of PtdIns 3-kinase fail to polarize the cytoskeleton at the synapse and show a significant reduction in the number of conjugates formed with tumor targets. Further, inhibition of PtdIns 3-kinase also reduced macrophage spreading on Rituximab-coated surfaces. On the other hand, Myr-Akt expressing macrophages displayed a significantly greater ability to form conjugates with tumor cells. Taken together, these findings illustrate that the PtdIns 3-kinase/Akt pathway plays a critical role in macrophage ADCC through its influence on conjugate formation between macrophages and antibody-coated tumor cells.     

Mitral valve repair in a developing country

Out of 454 patients who underwent mitral valve surgery, 210 (46.2%) had isolated mitral valve disease and the rest had mixed valvular disease. Repair was considered for 393 (86.6%) patients but was feasible in only 269 (59.3%) valves. Commissurotomy was performed in 177 (65.8%), leaflet plasty in 25(9.3%), chordal repair in 93(34.6%), papillotony 116(43.1%) and annuloplasty in 210 (78.0%) patients. The hospital mortality for the repair group was 1.49 per cent. There were 2(0.75%) late dealts. Twenty-seven (10.05%) patients underwent reoperation over 20 months, out of which four could be repaired again. Amongst the survivors, 95.5 per cent are in functional class I and II. The techniques of repairs undertaken have been described and its importance in the setting of a developing country has been highlighted.