Extended Lymphadenectomy in Gastric Cancer Is Debatable

Much debate still exists regarding the appropriate extent of lymphadenectomy for gastric adenocarcinoma. In high incidence countries in Eastern Asia, more extensive (e.g. D2) lymphadenectomies are standard, and these surgeries are generally done by experienced surgeons with low morbidity (<20 %) and mortality (<1 %). In United States and Western Europe, where the incidence of gastric adenocarcinoma is much lower, the majority of patients are treated at non-referral centers with less extensive (e.g. D1 or D0) lymphadenectomy. This symposium article first reviews early studies that led to recommendations for less extensive lymphadenectomy. Two large prospective, randomized trials performed in the United Kingdom and the Netherlands in the 1990s failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy, but these trials have been criticized for inadequate surgical training and high surgical morbidity (43–46 %) and high mortality rates (10–13 %) in the D2 group. We then discuss more contemporary studies that support more extensive lymphadenectomy with a minimum of 16 lymph nodes for adequate staging. The 15-year follow-up of the Netherlands trial now demonstrates an improved disease-specific survival and locoregional recurrence in the D2 group. A prospective, randomized trial from Taiwan found a survival benefit of more extensive lymphadenectomies, and another randomized trial from Japan found adding dissection of para-aortic nodes to a D2 lymphadenectomy did not improve survival. Western surgeons have increasingly accepted the importance of performing more than a D1 node dissection, and Eastern surgeons are accepting that more than a D2 node dissection does not improve survival and increases morbidity. Thus both Eastern and Western approaches are favoring D2 lymphadenectomy as a standard, and on this topic we appear to be harmonizing.     

Stability of Oxygen Transmissibility During Ischemia

Abstract

Simultaneous measurements of oxygen availability (O₂a) and partial pressure (PO₂) were made by the double noble metal electrode system designed by Erdmann and Krell in an attempt to monitor the oxygen transmissibility (Dk) with respect to time before and after ischemic episodes in the brain cortex. Available current equations can appropriately describe the performance of the electrode in a homogeneous nonconsuming medium, and with some experimental error this electrode system can be used to estimate oxygen transmissibility changes in the brain based on the different chararcteristics of the O₂a (rod-type, flush-ended bare tip) and the PO₂ (rod-type, recessed tip) cathodes. Our method monitors the oxygen transmissibility within the diffusion sphere of the bare tip as the ratio of the currents related to O₂a and PO₂. We find with this system that even prolonged global cerebral ischemia does not alter the oxygen transmissibility of the brain tissue. Therefore, alteration of the oxygen transmissibility can not be a contributing factor to postischemic cerebral malfunction.     

Enhanced creativity in bipolar disorder patients: a controlled study

OBJECTIVE: Associations between eminent creativity and bipolar disorders have been reported, but there are few data relating non-eminent creativity to bipolar disorders in clinical samples. We assessed non-eminent creativity in euthymic bipolar (BP) and unipolar major depressive disorder (MDD) patients, creative discipline controls (CC), and healthy controls (HC). METHODS: 49 BP, 25 MDD, 32 CC, and 47 HC (all euthymic) completed four creativity measures yielding six parameters: the Barron-Welsh Art Scale (BWAS-Total, and two subscales, BWAS-Dislike and BWAS-Like), the Adjective Check List Creative Personality Scale (ACL-CPS), and the Torrance Tests of Creative Thinking--Figural (TTCT-F) and Verbal (TTCT-V) versions. Mean scores on these instruments were compared across groups. RESULTS: BP and CC (but not MDD) compared to HC scored significantly higher on BWAS-Total (45% and 48% higher, respectively) and BWAS-Dislike (90% and 88% higher, respectively), but not on BWAS-Like. CC compared to MDD scored significantly higher (12% higher) on TTCT-F. For all other comparisons, creativity scores did not differ significantly between groups. CONCLUSIONS: We found BP and CC (but not MDD) had similarly enhanced creativity on the BWAS-Total (driven by an increase on the BWAS-Dislike) compared to HC. Further studies are needed to determine the mechanisms of enhanced creativity and how it relates to clinical (e.g. temperament, mood, and medication status) and preclinical (e.g. visual and affective processing substrates) parameters.     

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.Key Results: Sotalol attained C_max values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.     

Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells

BACKGROUND: The response of hepatocellular carcinoma (HCC) to therapy is often disappointing and new modalities of treatment are clearly needed. Active immunotherapy based on the injection of autologous dendritic cells (DC) co-cultured ex vivo with tumor antigens has been used in pilot studies in various malignancies such as melanoma and lymphoma with encouraging results. METHODS: In the present paper, the preparation and exposure of patient DC to autologous HCC antigens and re-injection in an attempt to elicit antitumor immune responses are described. RESULTS: Therapy was given to two patients, one with hepatitis C and one with hepatitis B, who had large, multiple HCC and for whom no other therapy was available. No significant side-effects were observed. The clinical course was unchanged in one patient, who died a few months later. The other patient, whose initial prognosis was considered poor, is still alive and well more than 3 years later with evidence of slowing of tumor growth based on organ imaging. CONCLUSIONS: It is concluded that HCC may be a malignancy worthy of DC trials and sufficient details in the present paper are given for the protocol to be copied or modified.     

Interleukin-3 treatment of rhesus monkeys leads to increased production of histamine-releasing cells that express interleukin-3 receptors at high levels

To understand the hematopoietic and nonhematopoietic responses to interleukin-3 (IL-3), expression of cell-surface IL-3 receptors (IL-3R) was examined on bone marrow (BM) cells and peripheral blood (PB) cells of rhesus monkeys during the course of in vivo IL-3 treatment. Whereas IL-3R expression is low in untreated monkeys, IL-3 administration led to a gradual increase in both low- and high-affinity binding sites for IL-3. This increase reflected the total number of cells expressing IL- 3Rs, as detected by flow cytometry using biotinylated IL-3. Most of these IL-3R+ cells in both BM and PB could be characterized as basophilic granulocytes that contained high levels of histamine. In contrast to the effect on these differentiated cells, IL-3 administration did not significantly alter the low level IL-3R expression on immature, CD34+ cells. Further flow cytometric analysis using biotinylated growth factors showed that the IL-3R+ basophils also expressed receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), but not for IL-6 or Kit ligand. These findings indicated that the IL-3R+ cells included neither monocytes, which express GM-CSFRs and IL-6Rs abundantly, nor mast cells, which express c- kit. By combining flow cytometric and Scatchard data, it was calculated that the basophils contain as many as 1 to 2 x 10(3) high-affinity IL- 3Rs and 15 to 30 x 10(3) low-affinity sites. The finding that in vivo IL-3 treatment leads to the production of large numbers of cells that express high levels of IL-3R and are capable of producing histamine provides an explanation for the often severe allergic reactions that occur during prolonged IL-3 administration. It also indicates that IL- 3, in addition to its direct effects on hematopoietic cells, may also stimulate hematopoiesis through the release of secondary mediators such as histamine by IL-3-responsive mature cells.     

In vivo release and turnover of secreted platelet antiheparin proteins in rhesus monkey (Macaca mulatta)

Human and rhesus monkey platelets secrete at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4). Neither of these proteins showed species-related antigenic differences. As determined by radioimmunoassay, the levels of PF4 and LA-PF4 antigen per 10(9) monkey platelets amounted to 10.7 and 20.3 microgram, respectively. One milliliter of monkey plasma prepared from blood collected into an anticoagulant composed of EDTA, prostaglandin E1, and theophylline solution contained 22.4 ng LA-PF4 and 8.0 ng PF4. Concentrations of these two platelet-specific proteins in monkeys closely resembled levels found in human platelets and plasma. Infusion of prostacyclin (PGI2) (100 or 300 ng/kg/min) into monkeys for 15 min resulted in a significant decrease of plasma levels of LA-PF4 antigen and of PF4 by 40%--60% (p < 0.0001). This decrease was related to the inhibitory effect of PGI2 on the secretion of platelets stimulated by a catheter or by venipuncture. Longer infusion of PGI2 did not produce further significant change. The supernate obtained after aggregation of human platelets stimulated by thrombin was injected into monkeys receiving PGI2 infusion. The disappearance of LA-PF4 antigen in monkey plasma followed a biphasic exponential curve with half-lives for the fast and slow components of 8.4 and 63 min. PF4 disappeared faster but followed the same pattern (half-lives for the fast and slow component of 2.1 and 70 min). Analysis of the experimental data suggests that the low levels of secreted platelet proteins in monkey plasma are related to their minimal in vivo release and to their rapid clearance.