Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection

The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-gamma)-mediated resolution of replicative Legionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (10(6) L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-gamma mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior to L. pneumophila infection inhibited induction of intrapulmonary IFN-gamma production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-gamma and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-gamma in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.     

Radiotherapy is not indicated in patients with vulvar squamous cell carcinoma and only one occult intracapsular groin node metastasis

ObjectiveMost guidelines advise no adjuvant radiotherapy in vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis. However, several recent studies have questioned the validity of this recommendation. The aim of this study was to analyze the groin recurrence rate in patients with a single intracapsular positive lymph node treated without adjuvant radiotherapy.MethodsPatients with a single clinically occult intracapsular lymph node metastasis, treated without adjuvant radiotherapy, formed the basis for this study. Groin recurrences, and the risk of death, were analyzed in relation to the size of the metastasis in the lymph node and the lymph node ratio. Data were analyzed using SPSS, version 26.0 for Windows.ResultsAfter a median follow-up of 64 months, one of 96 patients (1%) was diagnosed with an isolated groin recurrence and another two (2.1%) were diagnosed with a combination of a local and a groin recurrence. The only isolated groin recurrence occurred in a contralateral lymph node negative groin. Size of the metastasis and lymph node ratio had no impact on the groin recurrence risk, nor on survival. The 5-year actuarial disease-specific and overall survivals were 79% and 62.5% respectively. The 5-year actuarial groin recurrence-free survival was 97%.ConclusionBecause of the low risk of groin recurrence and the excellent groin recurrence-free survival, we recommend that adjuvant radiotherapy to the groin in patients with vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis can be safely omitted to prevent unnecessary toxicity and morbidity.     

Validation of tissue microarray technology in endometrioid cancer of the endometrium

AIM: To validate tissue microarray (TMA) for endometrial cancer by comparing immunohistochemical staining results of triplicate core biopsies on TMA with the results of full-section analysis. METHODS: The study material consisted of slides and selected tissue blocks of 41 patients with endometrioid cancer of the endometrium. A TMA was constructed. Both the TMA and the slides were stained with the same antibodies against progesterone receptor (PR), oestrogen receptor, p53 and epithelial membrane antigen (EMA). Concordance between results was expressed as the kappa statistic. RESULTS: Concordance between the staining results of TMA and whole slides was good for PR (kappa = 0.69), oestrogen receptor (kappa = 0.78), p53 (kappa = 0.81) and EMA (kappa = 0.72). Concordance between the results on TMA and slides depends on the number of assessable cores per tumour. Three assessable cores per case result in outcomes that are at least 94% similar to those achieved using conventional tissue sections with a two-class scoring system. This is independent of focal or diffuse staining patterns. CONCLUSION: TMA is a useful tool for further analysis of the molecular pathways in endometrial cancer. The effect of selection has to be taken into account when the prognostic value of protein expression on TMA is determined.     

Four human breast cancer cell lines with biallelic inactivating <Emphasis Type="Italic">α-catenin</Emphasis> gene mutations

Mutations of E-cadherin have been identified in half of lobular breast cancers and diffuse-type gastric cancers, two tumor subtypes with remarkably similar pathological appearances including small rounded cells with scant cytoplasm and a diffuse growth pattern. A causal role for E-cadherin gene mutations in the lobular breast cancer phenotype was recently demonstrated in E-cadherin knock-out mice. These observations suggested that another gene in the E-cadherin tumor suppressor pathway might be mutated in lobular breast cancers with wild-type E-cadherin genes. Here, we identified E-cadherin gene mutations exclusively in human breast cancer cell lines that grow with a rounded cell morphology. Using expression analyses and gene mutation analyses, we have identified four biallelic inactivating α-catenin mutations among 55 human breast cancer cell lines. All four α-catenin mutations predicted premature termination of the encoded proteins, and concordantly, none of the four mutant cell lines expressed α-catenin proteins. Importantly, three of the α-catenin mutant cell lines had the rounded cell morphology and all 14 cell lines with the rounded cell morphology had mutations of either E-cadherin or α-catenin. As anticipated, loss of α-catenin protein expression was associated with the lobular subtype in primary breast cancers. Together, our observations suggest that α-catenin may be a new tumor suppressor gene that operates in the E-cadherin tumor suppressor pathway.     

Parotidectomy for parotid tumours: 19-year experience from The Netherlands.

A total of 150 patients were treated for parotid tumours over a period of 19 years. In 94 per cent superficial or total parotidectomy was performed. Histological diagnosis of the resected specimen revealed pleomorphic adenoma in 92 patients (61 per cent), Whartin's tumour in 30 (20 per cent), various benign neoplasms in 11 (7 per cent) and malignant tumour in 17 (11 per cent). After a mean follow-up of 7.7 years, no recurrence of a benign tumour was seen. Malignant tumours recurred in five patients. Permanent partial facial paralysis was seen in 4 per cent of patients after surgery for benign lesions. Frey's syndrome was observed in 43 per cent of patients, and was not prevented by resection of the auriculotemporal nerve.     

Involvement of inhibin in the regulation of follicle-stimulating hormone concentrations in prepubertal and adult, male and female rats

Administration of steroid-free bovine follicular fluid (bFF), containing inhibin-like activity, depressed levels of FSH measured 4 h after injection in intact adult and 35-day-old female rats, but not in younger females. Suppression of FSH was also observed in intact male rats, aged 55 days, but not in older and younger male rats. Eight hours after injection of bFF, FSH levels were depressed in 15-day-old and older immature and adult rats of both sexes. Male and female rats, gonadectomized 2 days earlier, responded similarly to bFF treatment as did the intact animals. In a second experiment it was found that the rise of FSH levels, occurring within 8 h of gonadectomy, decreased with age in male and increased with age in female rats. Steroid treatment was found to prevent the rise in FSH levels partially in 15-day-old male and completely 25-day-old female rats, whereas treatment with bFF was fully effective in blocking the FSH rise in both immature and adult rats of both sexes. It is concluded that inhibin might be a major physiological factor in a fast-acting control of FSH concentrations from at least the age of 25 days onwards in female rats. In male rats its physiological significance might be limited to the prepubertal period, despite the fact that pituitary secretion of FSH is suppressed by exogenous inhibin-like activity at all ages studied.