Curative Resection of Microgastrinomas Based on the Intraoperative Secretin Test

The intravenous secretin injection test (secretin test) has been used for the differential diagnosis of gastrinoma. In this study we report that the intraoperative secretin test (IOS test) is also useful for determining the extent of curability in patients with Zollinger-Ellison syndrome (ZES). Twelve patients with ZES underwent surgical exploration and the IOS test. The results of the IOS test were obtained by rapid radioimmunoassay of the serum gastrin level (IRG) within 60 minutes. The test was diagnosed as negative when the maximum increase of serum IRG was less than 80 pg/ml and also less than 20% of the basal serum IRG level. Three of the twelve patients underwent pancreatoduodenectomy (PD), and two patients underwent distal pancreatectomy. Extirpation of duodenal tumors with dissection of regional lymph nodes was performed in seven patients. In two of the seven patients the IOS test remained positive after extirpation of the duodenal tumors and the dissection of regional lymph nodes. In one patient PD was performed on the basis of the positive results, and the IOS test became negative after PD. In the other patient, two tiny metastatic liver tumors were identified and were resected, but the IOS test did not become negative. We closed the abdomen in 11 patients when we obtained negative results from the IOS test. The results of the IOS test were almost identical to the data obtained by the standard assay postoperatively. The serum IRG levels of all but one patient fell to the normal level, and the secretin test became negative postoperatively. The IOS test is thus useful and indispensable for curative resection of microgastrinomas in patients with ZES.     

Spinal coadministration of ketamine reduces the development of tolerance to visceral as well as somatic antinociception during spinal morphine infusion

This study was designed to investigate the effects of ketamine, an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to morphine and morphine antinociception during intrathecal infusion. Two intrathecal catheters were implanted in the subarachnoid space in male rats under pentobarbital anesthesia. One catheter was used for the intrathecal infusion with the following solutions: morphine 1 microg x kg(-1) x hr(-1)(M1) and 5 microg x kg(-1) x hr(-1) (M5);ketamine 250 microg x kg(-1) x hr(-1) (K250); morphine plus ketamine, 1 microg x kg(-1) x hr(-1) plus 250 microg x kg(-1) x hr(-1) (M1 + K250) and 5 microg x kg(-1) x hr(-1) + 250 microg x kg(-1) x hr(-1) (M5 + K250); or saline. The other catheter was used for morphine challenge tests. The responses to noxious somatic and visceral stimuli were measured by tail flick (TF) and colorectal distension (CD) tests, respectively. Measurements were performed once a day for 7 days. Challenge tests with intrathecal morphine were performed to assess the magnitude of tolerance on Day 5 and Day 7. The antinociceptive effect was evaluated by using the percent of maximal possible effect (%MPE). Morphine infusion produced significant increases in %MPEs in TF and CD tests, while the saline and K250 infusions did not show any changes. The M1 + K250 infusion significantly increased the %MPEs in TF and CD tests, although the M1 and K250 infusions alone showed no changes. M5 + K250 enhanced the increases of %MPEs in TF and CD tests compared with the M5 infusion alone. In the challenge tests, the M1 + K250 infusion showed no significant decrease in %MPEs and TF and CD tests. The M5 + K250 infusion significantly inhibited those decreases in %MPEs, although the M5 infusion showed significant decreases in TF and CD tests. We concluded that ketamine attenuated the development of morphine tolerance to antinociceptive effects and increased the somatic and visceral antinociception of morphine. IMPLICATIONS: Intrathecally coinfused ketamine attenuated morphine tolerance to somatic and visceral antinociception and increased morphine antinociception at the spinal level. These results suggest that a combination of morphine with ketamine may have an advantage in long-term use of opioids for controlling visceral as well as somatic pain.     

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

PURPOSE: To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS: We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS: EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION: EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.     

Thickened area of external granular layer and Ki-67 positive focus are early events of medulloblastoma in Ptch1+/− mice

Patched1 (Ptch1) encodes a receptor for Sonic hedgehog (Shh) and is major gene related to human medulloblastoma (MB) in the Shh subgroup. MB is thought to arise from residual granule cell precursors (GCPs) located in the external granular layer (EGL) of the developing cerebellum. As the detailed preneoplastic changes of MB remain obscure, we immunohistochemically clarified the derived cell, early events of MBs, and the cerebellar developmental processes of Ptch1^+/? (Ptch1) mice, an animal model of human MB of the Shh subgroup. In Ptch1 mice, the earliest proliferative lesions were detected at PND10 as focal thickened areas of outer layer of the EGL. This area was composed of GCP-like cells with atypia and nuclei disarrangement. In the latter cerebellar developmental period, GCP-like cell foci were detected at high incidence in the outermost area of the cerebellum. Their localization and morphological similarities indicated that the foci were derived from GCPs in the EGL. There were two types of the foci. A Ki-67-positive focus was found in Ptch1 mice only. This type resembled the GCPs in the outer layer of EGL characterized by having proliferating activity and a lack of neuronal differentiation. Another type of focus, Ki-67-negative, was observed in both genotypes and exhibited many of the same features of mature internal granule cells, suggesting that the focus had no preneoplastic potential. Due to morphological, immunohistochemical characteristics, our results indicate that the focal thickened area of EGL and Ki-67-positive foci are preneoplastic lesions of MB.     

Time-lapse Microscopy and DNA Double-strand Breakage of Chinese Hamster Cells Under Conditions Promoting or Preventing PLD Repair after Irradiation with 60Co γ Rays

Summary

We have confirmed previous time-lapse microscopic observations (Suzuki 1985) using Chinese hamster hai and V79 cells. The proportion of non-dividing to dividing cells was the same under conditions of potentially lethal damage (PLD) repair and non-PLD repair after irradiation with ⁶⁰Co γ-rays. This finding suggested that the radiation-induced damage to cellular DNA was similarly repaired so that cells undergo a first division to the same extent under both sets of conditions. In fact, direct measurement of double-strand breaks (dsb) in DNA from the two cell lines by the neutral elution technique showed no differences either in the initial amount of damage or in the time-course under conditions promoting or preventing PLD repair. These results indicate that PLD repair (i.e. an increase in cell survival) cannot be simply explained by a difference in the repair of dsb, but it can perhaps be explained by assuming that DNA damage is repaired with either fewer or more errors in the presence or absence of PLD repair respectively.     

Z‐ligustilide ameliorated ultraviolet B‐induced oxidative stress and inflammatory cytokine production in human keratinocytes through upregulation of Nrf2/HO‐1 and suppression of NF‐κB pathway

Ultraviolet B (UVB), a harmful environmental factor, is responsible for a variety of skin disorders including skin inflammation through reactive oxygen species (ROS) and inflammatory mediator production. Here, we investigated the effect of Z‐ligustilide (Z‐lig), an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on UVB‐induced ROS generation and inflammatory mediator production in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z‐lig significantly rescued UVB‐induced NHEKs damage in a dosage‐dependent manner. Pretreatment of NHEKs with Z‐lig inhibited UVB‐induced ROS production in NHEKs. Both silencing the nuclear factor E2‐related factor 2 (Nrf2) and the supplement of tin protoporphyrin IX (SnPP), a haeme oxygenase‐1 (HO‐1) inhibitor, cancelled the inhibitory effect of Z‐lig on UVB‐induced ROS upregulation in NHEKs. Moreover, pretreatment of NHEKs with Z‐lig reduced UVB‐induced nuclear factor kappa B (NF‐κB)‐dependent inflammatory mediators (IL‐6, IL‐8 and MCP‐1) production at both mRNA and protein level. In the presence of Z‐lig, UVB‐induced NF‐κB subunit p65 nuclear translocation was abolished, and the IκBα degradation was suppressed. Taken together, these findings suggest that Z‐lig can suppress UVB‐induced ROS generation through Nrf2/HO‐1 upregulation and inflammation by suppressing the NF‐κB pathway, suggesting that Z‐lig may be beneficial in protecting skin from UVB exposure.