Extended lymph node dissection in gastrointestinal cancer

We reviewed the literature concerning the effect of extended lymph node dissection on survival in patients with gastrointestinal cancer. Most retrospective and/or prospective nonrandomized comparative studies have claimed that extended lymph node dissection significantly improves survival rate in patients with esophageal cancer, gastric cancer, and colorectal cancer. However, it is difficult to interpret these results since specialized care provided in trials may itself improve survival. In gastric cancer, several prospective randomized trials have failed to demonstrate a survival advantage of extended dissection, while there are few well-done prospective randomized trials in esophageal or colorectal cancer. Therefore, the therapeutic value of extended lymph node dissection remains to be determined in gastrointestinal cancer. Randomized prospective studies within the bounds of the ethical treatment of patients can and should be done. J. Surg. Oncol. 1997;65:57-65. © 1997 Wiley-Liss, Inc.     

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Objective

To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Rationale

NMDA-RA-induced increased LA and impairment of NOR are widely used models of the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs (APDs), and the identification of novel treatments. Serotonin (5-HT) plays an important role in attenuating these effects of NMDA-RA.

Results

Selective 5-HT_2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT_2A than D₂ antagonists, e.g., clozapine and lurasidone, are more effective than selective D₂ receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT_2A inverse agonists alone are not effective to improve NMDA-RA-impaired NOR, but augment the effects of atypical, but not typical APDs, to improve NOR. The 5-HT_1A receptor partial agonist tandospirone alone and the 5-HT_1A agonist effects of atypical APDs may substitute for, or contribute to, the effects of D₂ and 5-HT_2A receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT₆ and 5-HT₇ receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT_2C receptor inverse agonist, but not neutral antagonists, block NOR in na?ve rats and the effects of atypical APDs to restore NOR in PCP-treated rats, suggesting the importance of the constitutive activity of 5-HT_2C receptors in NOR.

Conclusions

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.     

A possible mechanism for 2,2',4,4',5,5'-hexachlorobiphenyl-mediated decrease in serum thyroxine level in mice

Serum total thyroxine (T₄) level was markedly decreased, without significant increases in the levels of hepatic T₄-UDP-glucuronosyltransferase (T₄-UGT) and serum thyroid-stimulating hormone, 3 days after treatment with 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB153) (100 mg/kg, ip) in both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 and TCDD-resistant DBA/2 mice. Likewise, in either strain of mice, no CB153-mediated changes in the binding levels of [¹²⁵I]T₄ to serum proteins, such as transthyretin, albumin, and thyroxine binding globulin, were observed, while in CB153-pretreated C57BL/6 mice, but not in CB153-pretreated DBA/2 mice, the levels of biliary [¹²⁵I]T₄ and [¹²⁵I]T₄-glucuronide at 90-120 min after injection of [¹²⁵I]T₄ slightly increased, as compared with those in the corresponding control mice. Concerning tissue distribution of [¹²⁵I]T₄, liver-selective increases in the [¹²⁵I]T₄ accumulation by CB153-pretreatment were observed in both C57BL/6 and DBA/2 mice, and the hepatic levels of [¹²⁵I]T₄ in the C57BL/6 and DBA/2 mice became more than 44% and 34% of the [¹²⁵I]T₄ dosed, respectively. The present findings indicated that the CB153-mediated decreases in the level of serum total T₄ in C57BL/6 and DBA/2 mice occur mainly through an increase in the accumulation of T₄ in the liver.     

Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT(2A) receptors in promoting thrombosis in diabetes

To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT(2A) receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tube-induced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT(2A) receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.     

Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis

Endothelial cells and pericytes play critical role in angiogenesis, which is controlled, in part, by the angiopoietin (Ang)/Tie-2 system and vascular endothelial growth factor (VEGF). Here, we investigated Ang, Tie-2, and VEGF expression within endothelial cells and pericyte interdigitations (EPI), which consist of cytoplasmic projections of pericytes and corresponding endothelial indentations. After subcutaneous implantation of a thermoreversible gelation polymer disc in rats, the capillary density was low on day 5, increased to a peak on day 7, and then decreased on days 10-20. A small number of EPI were observed on day 5, then increased sharply to a peak on day 10, but had decreased on day 20. Light and electron microscopy immunohistochemical and RNA in situ hybridization analyses revealed that Tie-2 localized at endothelial cells, and Ang-2 localized at endothelial cells and pericytes, while Ang-1 and VEGF localized at pericytes, and Ang-1 was most intensely observed at EPI of pericytes. Conventional quantitative RT-PCR and Western blot analyses revealed that the level of Ang-1 was low on days 5-7, then increased on days 10-20, while the level of VEGF was high on days 5-10, but had decreased on day 20. The level of Ang-2 remained high and Tie-2 remained at the level of the control on days 5-20. The present study showed that the angiogenic phase might be initiated by increases in Ang-2 and VEGF, while the microvessel maturation phase might be initiated by a relative increase in Ang-1 and a decrease in VEGF. Moreover, EPI might serve as a pathway for the Ang-1/Tie-2 system, with VEGF promoting pericyte recruitment for microvascular integrity.     

Augmentation of 3‐methylcholanthrene‐induced bioactivation in the human hepatoma cell line HepG2 by the calcium channel blocker nicardipine

(Cancer Sci 2010; 101: 652–657) The abilities of the dihydropyridine calcium channel blocker nicardipine (Nic) to induce cytochrome P450 1 family enzymes (CYP1s) and to enhance the 3‐methylcholanthrene (MC)‐mediated induction of CYP1s and formation of MC‐DNA adduct were examined in the human hepatoma cell line HepG2. The results from real time RT‐PCR analysis demonstrated that Nic could induce CYP1 mRNAs and enhance the MC‐mediated induction of the CYP1 mRNAs. The luciferase‐reporter gene assay using the HepG2‐A10 cell line, which has been previously established for the screening of aryl hydrocarbon receptor (AhR) activators, also indicated the augmentation of MC‐mediated activation of AhR (induction of luciferase) by Nic, although Nic showed limited capacity for the activation of AhR. Furthermore, the results from the Western blot analysis of CYP1s, the enzyme activity assay, and the assay for MC‐DNA adduct formation indicated that Nic could enhance the MC‐mediated induction of CYP1s, especially CYP1A1. Furthermore, the intracellular accumulation level of [³H]MC after treatment of HepG2 cells with [³H]MC significantly increased in the presence of Nic. The present findings demonstrate that Nic can enhance the MC‐mediated induction of CYP1s, especially CYP1A1, and the formation of MC‐DNA adduct in HepG2 cells. Furthermore, the augmentation of the MC‐mediated bioactivation by Nic is demonstrated to occur mainly through an increase in intracellular accumulation of MC.     

The roles of <Superscript>18</Superscript>F-FDG-PET/CT and US-guided FNAC in assessment of axillary nodal metastases in breast cancer patients

Background

There is a need for less invasive techniques for preoperative identification of axillary lymph node (ALN) metastases.

Method

Patients underwent ultrasonography (US) and ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT), and then US-guided fine needle aspiration cytology (FNAC) and/or sentinel lymph node (SLN) biopsy were performed based on the US findings of the ALNs. Subsequently, patients with positive FNAC as well as those with positive SLN underwent axillary lymph node dissection (ALND). Postoperatively, removed SLNs and ALNs were examined histologically.

Results

Fifty (85 %) of 59 patients with positive ¹⁸F-FDG uptake in the axilla had axillary metastases, but ¹⁸F-FDG uptake results were false-positive in 9 (15 %) cases. On the other hand, 29 patients with positive FNAC underwent ALND without the need for SLN biopsy, while the remaining 20 patients with negative FNAC as well as 249 patients with negative US findings underwent SLN biopsy. Subsequently, 68 patients with positive SLN underwent ALND.

Conclusions

Positive FDG uptake in the axilla does not always indicate axillary metastasis. US-guided FNAC is useful to avoid unnecessary ALND in patients with positive ¹⁸F-FDG uptake. However, SLN biopsy is needed in patients with negative US findings of the ALNs and those with negative FNAC.

     

The changing role of axillary lymph node dissection for breast cancer

Currently, it is standard practice that patients with negative sentinel lymph nodes (SLNs) do not undergo axillary lymph node dissection (ALND), whereas ALND is mandated in those with positive SLNs. However, the Z0011 trial showed that ALND could be safely omitted in selected patients with positive SLNs. This article presents a review and discussion of the current role and practice of ALND in the surgical management of breast cancer. A review of the English-language medical literature was performed using the MEDLINE database and cross-referencing major articles on the subject. It may be concluded that ALND can be avoided not only in patients with negative SLNs but also in those with positive SLNs who undergo breast-conserving therapy with whole-breast irradiation and appropriate systemic therapy. However, the omission of ALND would be indicated only in patients with a low axillary tumor burden. On the other hand, ALND remains a standard method of treating regional disease not only in patients with clinically positive nodes but also in other SLN-positive patients who do not meet the above criteria. Although the role of ALND has been limited to the prevention of axillary recurrence, SLN biopsy with whole-breast irradiation and systemic therapy can replace ALND in patients with a low axillary tumor burden.