Expression of invasion markers CD44v6/v3, NM23 and MMP2 in laryngeal and hypopharyngeal carcinoma

Twelve laryngeal squamous cell carcinoma cases (7 laryngeal and 5 hypopharyngeal cancer; 15 samples) were analysed by immunohistochemistry for the expression of invasion markers CD44v6/v3, NM23 and matrix metalloproteinase, MMP2. The laryngeal epithelium showed CD44v6⁺v3⁺NM23^- /MMP2^- phenotype. When tumors were grouped into TNM categories the phenotype of the T2 and T3 tumors was similar, characterised by decreased CD44v3⁺ and lack of MMP2 expressions. Meanwhile the NM23 expression was more frequent in T3 tumors. In T4 stage the frequency of NM23 and MMP2 positive cases increased (5/6 and 4/6, respectively) but there was no correlation with the appearence of lymph node metastasis. Comparison of the phenotype of laryngeal and hypopharyngeal tumors, irrespective of the TNM stages, revealed characteristic differences: T2 stage laryngeal tumors showed decreased CD44v3 and occasional NM23 and MMP2 positivity, while in T3 stage these tumors were characterised by increased frequency of NM23 positivity. The phenotype of the hypopharyngeal tumors was significantly different with a high frequency of MMP2 positive cases (5/6) and NM23⁺1ow CD44v3⁺ phenotype. The sharp differences in the phenotypes of laryngeal and hypopharyngeal carcinomas were connected to the differences in their invasive capacity unlike to the size of the tumors, since the T4 stage hypopharyngeal tumors had a significantly smaller size than laryngeal ones, even at lower stages. This work was supported by the Hungarian Ministry of Welfare: ETT No: T-11-100/93     

Combinedin vitro effect of marijuana and retrovirus on the activity of mouse natural killer cells

Both marijuana and retroviruses impair natural killer (NK) cell functions, but no data on their simulataneous effects are available. Similarities to human AIDS induced by Friend leukemia complex (FLO and its helper Rowson-Parr virus (RPV) provides a mouse model to study drug-virus action. Leukemia susceptible BALB/c and resistant C57BL/6 mice were infected, then at time intervals their nylon wool-separated splenocytes were exposed to tetrahydrocannabinol (THC) for 3h. Natural killer cell activity against Yac-1 cells was assayed by 51Cr-release for 4 and 18h. Recovery of splenocytes was found to be suppressed by FLC, but in BALB/c only by RPV. After a transient enhancement in C57BL/6 by FLC, NK cell activity of both mice became suppressed early (2 to 4 days), normalized subsequently and enhanced late (11 to 14 days) postinfection. A moderate increase in BALB/c, no change in C57BL/6 were induced by low (1-2.5 g/ml) THC doses. NK cell activity of BALB/c became suppressed exponentially by higher (5-10 g/ ml) THC doses in 18h as compared to 4h assays, while its proportional and moderate impairment was seen in C57BL/6. The magnitude of NK cell activity of infected mice was determined by THC: enhancement or impairment followed those of untreated, infected counterparts on the level of THC-treated cells. Low doses hardly, high doses additively influenced NK cells of infected BALB/c. THC slightly affected very early and late enhancement in NK cell activity of FLC infected C57BL/6, but augmented RPV induced suppression late in 18h assays. Genetic factors similar to endotoxin resistance, altered cytokine profile might determine these effects. Similar phenomena in humans might result in earlier manifestation of AIDS.     

Phase II trial of fortnightly irinotecan (CPT-11) in the treatment of colorectal cancer patients resistant to previous fluoropyrimidine-based chemotherapy

Introduction This phase II study investigated the anti-tumour activity and toxicity of CPT-11 (250 mg/m2 i.v. infusion over 60 minutes) administered every 2 weeks as second-line chemotherapy in patients with advanced colorectal cancer (CRC). Material and methods Patients (n=63) with histology diagnosis of advanced CRC and proven resistance to previous fluoropyrimidine therapy were enrolled. Results A total of 510 CPT-11 cycles were administered, with a mean of 8 cycles per patient (range: 1–32). The median relative dose intensity was 93%. Partial response (PR) was obtained in 11 patients (17.5%; 95%CI: 8.1%–26.7%) and 29 patients (46.0%) showed stable disease (clinical benefit of 63.5%). The median duration of response was 6.8 months (95%CI: 6.1–7.5 months), median survival was 8.8 months (95%CI: 6.3–11.5 months) and median time to disease progression was 4.5 months (95%CI: 3.9–5.0 months). Overall, this schedule of CPT-11 chemotherapy was well tolerated by the patient. Neutropenia was the most frequent grade 3/4 haematological toxicity (20.6% of patients and 4.1% of cycles). Neutropenia with concurrent fever or infection occurred in 7 patients (11.1%). Late onset diarrhoea was the most frequent grade 3/4 non-haematological toxicity (19.0% of patients and 2.3% of cycles). Other, lower-incidence, toxicities were anaemia, fever, infection, mucositis, nausea and vomiting. There were no toxic deaths. Conclusions We found that CPT-11, administered as 250 mg/m² i.v. infusion over 60 minutes every 2 weeks, was active and well tolerated schedule in the second-line chemotherapy of advanced CRC patients. This bi-weekly scheme could be used as an alternative to the weekly or the every-three-week schedule as well as in combined therapies with other chemotherapeutic agents for the treatment of advanced, metastatic, CRC.     

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non‐endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low‐grade, non‐ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE‐positive endometrioid endometrial carcinomas (EECs). We performed exome‐sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling‐related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA‐repair‐related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co‐occurrence (RAD50‐KMT2D and RAD50‐SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.     

Non-Hodgkin’s lymphoma in the elderly. Age is not always an adverse prognostic factor

A retrospective study analyzing non-Hodgkin's lym-phoma (NHL) diagnosed in patients in our center above 65 years of age between the years 1977–1991 is reported. Histological classification has been completed following the criteria of the Working Formulation. Of 521 patients, 427 were candidates for evaluation. Those above 65 years of age comprised the subject of our study, with a total of 95 cases. Population: 43/52 male/female, 47 intermediate-grade NHL, 38 low-grade NHL, Ann Arbor stages I–II/III–IV 36/59, performance status (PS) 0-1/2-3 39/56, B symptoms yes/no 47/48, lactic dehydrogenase (LDH) normal/high 33/62, albumin normal/low 75/20, Cu normal/high 44/37 (the rest not available), B2 microglobuline normal/high 17/11 (the rest not available), tumor burden (MD Anderson) high/intermediate/low 41/28/26. The median range of cause specific survival was 30 months (50 for the low-grade NHL, 17 for the intermediate-grade). Significant prognostic factors: Histological grade (low versus high and intermediate), PS 0/1 versus 2/3, presence versus absence of B symptoms, normal versus high LDH, tumor burden (low versus high and intermediate). There is no significant statistical difference between elderly patients and young patients with a poor PS, phases I and IV, low albumin level and high and low tumor burden. Age as an adverse prognostic factor is evident in patients with a strong PS, phases II and III, normal albumin and intermediate tumor burden. The characteristics and prognostic factors of elderly patients with NHL are similar to those of the young. Age does not always function as an independent prognostic factor; age has no effect on groups with favorable or unfavorable prognostic factors and it is in the intermediate prognostic groups in which age plays a part in survival.     

Regulation of differentiation, proliferation and drug-induced apoptosis in HT58 lymphoma cells

Recently, it has been suggested, that differentiated cells are more resistant to the apoptotic effect of DNA damaging agents possibly due to the decreased activity of “damage detecting/apoptosis triggering” mechanism. Previously, we have shown, that PMA pretreatment reduced etoposide-(ETO) but enhanced staurosporine- (STA) -induced apoptosis in HT58 cells. Data presented here show that the HT58 human, “mature” B-lymphoma cells exposed to PMA secrete more IgM into the supernatant indicating commitment of cells to perform differentiated function. The sensitivity of HT58 cells to ETO- or STA-induced apoptosis is influenced diversely with PMA pre- or posttreatment. Interestingly, the DNA damage (gamma radiation, bleomycin, ETO) or okadaic acic (30 nM) reduced the [PMA+STA] - induced apoptosis.     

Evaluation of the multimorbidity network and its relationship with clinical phenotypes in chronic obstructive pulmonary disease: The GALAXIA study

BackgroundChronic obstructive pulmonary disease (COPD) is a complex and heterogeneous condition, in which taking into consideration clinical phenotypes and multimorbidity is relevant to disease management. Network analysis, a procedure designed to study complex systems, allows to represent connections between the distinct features found in COPD.MethodsNetwork analysis was applied to a cohort of patients with COPD in order to explore the degree of connectivity between different diseases, taking into account the presence of two phenotypic traits commonly used to categorize patients in clinical practice: chronic bronchitis (CB⁺/CB⁻) and the history of previous severe exacerbations (Ex⁺/Ex⁻). The strength of association between diseases was quantified using the correlation coefficient Phi (ɸ).ResultsA total of 1726 patients were included, and 91 possible links between 14 diseases were established. Although the four phenotypically defined groups presented a similar underlying comorbidity pattern, with special relevance for cardiovascular diseases and/or risk factors, classifying patients according to the presence or absence of CB implied differences between groups in network density (mean ɸ: 0.098 in the CB⁻ group and 0.050 in the CB⁺ group). In contrast, between‐group differences in network density were small and of questionable significance when classifying patients according to prior exacerbation history (mean ɸ: 0.082 among Ex⁻ subjects and 0.072 in the Ex⁺ group). The degree of connectivity of any given disease with the rest of the network also varied depending on the selected phenotypic trait. The classification of patients according to the CB⁻/CB⁺ groups revealed significant differences between groups in the degree of conectivity between comorbidities. On the other side, grouping the patients according to the Ex⁻/Ex⁺ trait did not disclose differences in connectivity between network nodes (diseases).ConclusionsThe multimorbidity network of a patient with COPD differs according to the underlying clinical characteristics, suggesting that the connections linking comorbidities between them vary for different phenotypes and that the clinical heterogeneity of COPD could influence the expression of latent multimorbidity. Network analysis has the potential to delve into the interactions between COPD clinical traits and comorbidities and is a promising tool to investigate possible specific biological pathways that modulate multimorbidity patterns.     

Birth outcomes of patients with isolated anorectal malformations: A population‐based case‐control study

In most patients affected by isolated anorectal malformation (IARM) the etiology is largely unknown. Thus, the aim of our project was to analyze possible risk factors for IARM. In the first step, birth outcomes of cases with IARM were analyzed on the basis of maternal socio‐demographic variables, and these data are presented in this paper. Gestational age at delivery, birthweight, preterm birth, low birthweight and small for gestational age of cases with IARM were evaluated in the function of maternal age, birth/pregnancy order, marital and employment status of mothers in the population‐based large dataset of the Hungarian Case‐Control Surveillance of Congenital Abnormalities, 1980–1996. The study samples included 231 live‐born cases with IARM, 361 matched and 38 151 population controls without any defect. IARMs are more frequent in males, twins and newborn infants with low birthweight and small‐for‐gestational‐age, the latter being the consequence of intrauterine growth restriction. In addition, mothers of cases were younger but with higher birth order, and had lower socio‐economic status. These maternal variables are characteristic for the gypsy population in Hungary. The higher proportion of gypsy women among the mothers of cases with IARM was confirmed during the home visits of the study. Male sex and intrauterine growth restriction of cases, in addition to low socioeconomic status and gypsy origin of mothers may have a role in the risk of IARMs.