肿瘤微环境与炎症反应及溶瘤病毒治疗的关系

炎症反应在清除病原体、创伤愈合和抗肿瘤免疫中发挥重要作用,被肿瘤细胞劫持的炎性细胞和细胞因子也是肿瘤微环境重要的参与者;许多肿瘤起源于感染和慢性炎症,肿瘤微环境中炎症细胞和炎症介质的蓄积具有促进恶性细胞增殖和存活、促进血管生成和肿瘤转移,以及逆转获得性免疫反应的作用,也改变了肿瘤细胞对激素和化疗药物的敏感性。炎症反应在肿瘤的发生和消除中发挥的作用比较复杂。溶瘤病毒治疗肿瘤,是充分利用溶瘤病毒选择性感染和杀伤肿瘤细胞的特性。在肿瘤微环境中,溶瘤病毒所诱导的针对肿瘤细胞和病毒的天然免疫反应具有双重效应:既能引起肿瘤细胞的损伤,促进溶瘤病毒抗肿瘤的疗效,也能识别、清除隐藏于肿瘤组织内部的溶瘤病毒,降低溶瘤病毒的效应。     

Organ specificity, metabolism and reaction with DNA of aliphatic nitrosomethylalkylamines

Aliphatic nitrosomethylalkylamines are carcinogens with a remarkable organ specificity in rats, the principal targets being liver, oesophagus and bladder. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6-h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (NDMA, C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7- and O6-methylguanine; 7-meGua and O6-meGua) were determined by cation-exchange high-performance liquid chromatography with fluorescence detection. Highest levels of hepatic DNA methylation were found with NDMA (C1) and N-nitrosoethylmethylamine (NEMA, C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length from C1 to C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the most effective agents being the butyl and pentyl derivatives (C4 and C5). Levels of DNA methylation in bladder epithelium were close to the limit of detection (C6,C9,C10,C12) and there was no apparent correlation with carcinogenicity. It is concluded that initiation of malignant transformation by DNA methylation alone (through hydroxylation of the nitrosamine at the methylene alpha-carbon) could be operative for C1-C5. For the higher homologues, this type of DNA modification is insufficient to explain the complex pattern of tissue specificity.     

Indomethacin-induced, monocyte-dependent restoration of local graft-versus-host reaction among cells from cancer patients

Peripheral blood mononuclear cells from 16 of 17 cancer patients known to have a negative local graft-versus-host (GVH) reaction (T-cell function deficiency) were pharmacologically immunorestored by treatment with indomethacin. The restorative effect of the indomethacin was exerted directly on nonadherent lymphocytes. This process of desuppression required for its completion the presence of glass-adherent monocytes. The immune restorative effect of indomethacin in terms of local GVH reaction did not appear to be mediated by inhibition of prostaglandin synthesis. Pharmacologic immune restoration may be an important therapeutic modality in cancer patients.     

Amplotyping of microdissected, methanol-fixed lung carcinoma by arbitrarily primed polymerase chain reaction

The arbitrarily primed polymerase chain reaction (AP-PCR) was used to detect somatic genetic alterations in lung carcinomas. DNA fingerprints generated by a single arbitrary primer were compared between normal and tumor tissues of the same individuals. We adapted the technique to the use of tissue fixed with methanol, which allowed the analysis of small areas of tissue by microdissection. This improvement of the fingerprinting technique permitted the study of tumors at early stages of progression. Loss of sequences from chromosome 7 was detected in 41.7% of adenocarcinomas and from chromosome 22 in 84.6% of small-cell carcinomas. Gains of sequences from chromosomes 1, 8 and 13 were detected in more than 40% of adenocarcinomas and in chromosome 2 in 63.3% of squamous-cell carcinomas. Our results indicate that allelic imbalances at these chromosomal regions are common genetic abnormalities in lung carcinomas. Loss of sequences from chromosome 22q13.3, found in 11 of 13 small-cell carcinomas, were confirmed by microsatellite PCR analysis. We show that the use of our improved AP-PCR fingerprinting permits the detection of both losses and gains of novel chromosomal regions early during lung cancer development. Our results indicate that early-stage tumors tend to have more allelic imbalances than relatively advanced tumors, suggesting a high tumor genetic heterogeneity in the early stages of lung tumor progression.     

radiotherapy-induced ID reaction

To the authors' knowledge, there is a paucity of published accounts of radiotherapy-induced ID reaction. We report a case of generalized dermatitis pathologically defined as an ID reaction after a course of local radiotherapy.     

Acute phase reaction, heterogeneity, and microheterogeneity of serum proteins as nonspecific tumor markers in lung cancer

The acute phase proteins, orosomucoid, ceruloplasmin, antitrypsin, and haptoglobin were measured in serum from 54 patients with lung cancer, 16 patients with benign lung inflammation, and 30 healthy individuals. A statistical correlation was found between tumor size and acute phase protein level, which, however, was ascribed to nonspecific inflammation in the tissues surrounding the tumor. The patients who subsequently could not be radically treated by surgery had higher concentrations of orosomucoid and ceruloplasmin than the radically treated patients. No difference in acute phase protein concentration was found between benign and malignant disease. The glycan-dependent microheterogeneity of orosomucoid and ceruloplasmin was analyzed by crossed affinoimmunoelectrophoresis with lectins, and the patterns of the patients with benign inflammation and malignant disease were different. The heterogeneity of ceruloplasmin was also analyzed by crossed immunoelectrophoresis without lectin. This analysis, combined with the total serum concentration of ceruloplasmin, made it possible to discriminate the 54 cases of malignancy from the 46 cases of nonmalignancy with a sensitivity of 78% and a specificity of 93%. It is suggested that the simple electrophoretic analyses of (micro-)heterogeneity is a valuable supplement to the acute phase profile in isolating high-risk patients and in monitoring radically treated cancer patients for relapse.     

消化道反应、骨髓抑制对癌性疲劳的影响

目的：通过调查恶性肿瘤患者化疗前后疲劳状况，探讨化疗后消化道反应、骨髓抑制对疲劳评分的影响。方法：应用一般情况调查表及癌症疲劳量表，对150恶性肿瘤化疗患者进行问卷调查，采用SPSS 18.0软件统计数据分析。结果：恶性肿瘤患者化疗后疲劳评分较化疗前相比多有不同程度增加，差异有统计学意义（P<0.001）。化疗期间患者消化道反应越重，疲劳评分越高；有骨髓抑制患者相对无骨髓抑制者疲劳评分高（P<0.001），骨髓抑制程度与疲劳评分关系无统计学意义（P>0.05）。结论：恶性肿瘤患者化疗期间消化道反应和骨髓抑制是患者化疗后疲劳评分增加的影响因素。     

Adverse anaphilactoid reaction of oxaloplatin

Resumen El oxaloplatino (L-OHP) es un análogo de tercera generación del platino utilizado en pacientes con carcinoma colorrectal. Describimos el caso de un paciente varón de 50 a?os sin antecedentes de interés en estadio IV (pulmón e hígado) que recibió en 1999 6 ciclos de 5FU-LV, 6 ciclos de 5FU-oxaloplatino y 6 ciclos de 5FU-CPT11 sin respuesta. En febrero de 2001 por progresión pulmonar recibió quimioterapia con oxaloplatino y ratiltrexed. Tres semanas más tarde durante la administración del oxaloplatino presentó un cuadro de reacción anafilactoide que se resolvió con actocortina. A las 24 horas, previa protección con corticoides, al paso de escasas gotas de oxaloplatino inició un cuadro similar al descrito, por lo que se suspendió su administración. Los niveles de IgA (482 mg/dl) y de IgE total (647 UI/ml) se encontraban elevados, lo que indicó que se trataba de una reacción anafilactoide de hipersensibilidad tipo I mediada por IgE. Sin un tratamiento inmediato, el cuadro de anafilaxia avanza produciendo una gran morbilidad con shock, fallo multiórgano y muerte. El uso de esteroides antes de la administración de oxaloplatino previene este tipo de reacciones adversas.

     

Analysis of c-Ki-ras mutations in human colon carcinoma by cell sorting, polymerase chain reaction, and DNA sequencing

We have analyzed colon carcinomas by a combination of histological enrichment, cell sorting, polymerase chain reaction, and direct sequencing of the c-Ki-ras-2 gene. DNA was chemically extracted from 50-microns sections of paraffin-embedded colon carcinomas and amplified in vitro, and mutations were documented directly by DNA sequencing. Enrichment for tumor cells was obtained histologically and by sorting nuclei on the basis of DNA content differences. Mutations in codon 12 were present in both aneuploid and diploid subpopulations of sorted carcinomas, suggesting that these mutations precede ploidy alterations in the progression of these neoplasms. We have demonstrated the feasibility of utilizing DNA from tissues treated with different fixatives, including methyl carnoys, formalin, and Hollande's solution. This procedure allows one to retrospectively reconstruct the temporal relationship between the occurrence of mutations and sequential morphological changes during tumorigenic progression.     

Ductular reaction is helpful in defining early stromal invasion, small hepatocellular carcinomas, and dysplastic nodules

BACKGROUND: Stromal invasion is 1 of the main features used to distinguish high-grade dysplastic nodules (DNs) from well-differentiated hepatocellular carcinomas (HCCs). The authors hypothesized that ductular reaction (DR) takes place around noninvasive hepatocellular nodules but not within the stroma contiguous to invasive HCC. METHODS: DR/cytokeratin 7 (CK7)-positive patterns were evaluated in 105 resected small hepatic nodules according to the level of invasion. The nodules were classified histologically prior to immunostaining as noninvasive (large regenerative nodules, low-grade DNs, and high-grade DNs), minimally invasive (early HCCs with a vaguely nodular type), and overtly invasive (typical HCCs with a distinctly nodular type) in a review by expert pathologists, the current gold standard. Intranodular DR (inner DR) and DR around the nodule periphery (outer DR) were assessed separately on a semiquantitative scale from 0 to 4+. RESULTS: DR was 3 or 4+ in the majority of noninvasive nodules (inner DR, 81%; outer DR, 91%), whereas DR was 0 or 1+ in overtly invasive HCCs (inner DR, 96%; outer DR, 81%). Minimally invasive HCCs showed an intermediate DR pattern (2 or 3+ inner DR, 75%; 2+ outer DR, 67%). DR characteristically was absent at the stromal-invasive, leading edge of tumor cells in both minimally invasive HCCs (focal loss of DR/CK7) and overtly invasive HCCs (diffuse loss of DR/CK7). The DR patterns in 41 needle-biopsy samples were similar to the patterns observed in resected nodules. CONCLUSIONS: DR/CK7 immunostaining may help to identify small foci of invasion and to distinguish noninvasive, high-grade DNs from both minimally invasive and overtly invasive HCCs.     

Prevalence of HPV in cytomorphologically normal cervical smears,as determined by the polymerase chain reaction,is age-dependent

The prevalence of human papillomavirus (HPV) genotypes in relation to age was investigated by the polymerase chain reaction (PCR) method in cytologically normal smears from 4 different groups of women. Group A consisted of young women from a district population, aged 15–34 years, using oral contraceptives and visiting general practitioners for a check-up (n = 156); group B were asymptomatic women, aged 35–55, in a district population participating in a triennial screening program for cervical cancer (n = 1555); group C and D consisted of women, seen at the gynecological outpatient department for a wide spectrum of gynecological complaints or for control of their hormonal contraception, aged 15–34 years (n = 2320), and aged 35–55 years (n = 1826) respectively. An HPV (all types) prevalence of 14.1%, 4.1%, 13.9% and 6.6% and an HPV 16/18 prevalence of 3.8%, 0.9%, 3.3% and 1.5% were found in groups A, B, C and D respectively. Statistically significant differences (p value <0.001) in HPV prevalence were found between women aged 15–34 years and women aged 35–55 years in the district population and in the hospital population. No statistically significant differences in HPV 16/18 were observed after age-matching between women in corresponding age-classes of both populations. In a 5-year interval analysis a strong age-dependent relationship was demonstrated, with a maximum between 20 and 24 years. After the age of 35 a constant level of 1–2% HPV 16/18 was observed. These results indicate that genital HPV infections are age-dependent and suggest that HPV infections at young age can be transient. The implications of these findings in the context of cervical cancer screening are discussed.     

A severe,late reaction to radiological contrast media mimicking a sepsis syndrome

An unusual, severe delayed reaction to non-ionic intravenous contrast media was observed. A 44-year-old man underwent a computed tomogaphy scan with non-ionic contrast media. Four hours later the patient collapsed with hypotension and cardiovascular shock. Aggressive management (including inotropic support and fluid resuscitation) was instituted in the intensive care unit. Rigorous imaging and biochemical and microbiological investigation failed to identify a source of this man’s circulatory collapse. A rapid recovery ensued and at 3 months follow-up the patient was suffering no residual effects from this event. To our knowledge, this is only the second report of a severe delayed reaction to radiological contrast media and the first that manifested as a prolonged hypotensive syndrome.     

Infusion reaction and anaphylaxis

Infusion reactions and allergic reactions are common side effects of anti-cancer drugs, and are known as hypersensitivity reactions. Patients with these severe reactions require close attention because these reactions sometimes lead to critical conditions. Infusion reactions are caused by cytokine release, although the precise mechanisms involved are still obscure. Infusion reactions are often caused by rituximab, an anti-CD20 antibody, and other monoclonal antibodies. Allergic reactions, mediated by IgE, are observed with a variety of chemotherapeutic drugs, especially platinum compounds and taxanes. An acute severe allergic reaction is called anaphylaxis, and is often fatal unless treated appropriately. In this review, we describe the prevention of hypersensitivity reactions and their treatment based on our clinical experience.