Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

Identifying oncogenic drivers associated with increased risk of late distant recurrence in postmenopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study.

BACKGROUND: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. PATIENTS AND METHODS: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. RESULTS: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20-0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30-9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51-19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. CONCLUSIONS: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.

Immunohistochemical versus molecular (BluePrint and MammaPrint) subtyping of breast carcinoma. Outcome results from the EORTC 10041/BIG 3-04 MINDACT trial.

PURPOSE: This study compares immunohistochemical (IHC) versus molecular subtyping (BluePrint and MammaPrint) in the population of patients enrolled in MINDACT and outcome based on molecular subtyping (MS) versus surrogate pathological subtyping (PS) as defined by the 2013 St. Gallen guidelines. METHODS: MS classified patients in the following subtypes: Luminal A, Luminal B, HER-2-, and Basal-type. IHC/FISH for pathological subtyping (ER, PgR, HER-2, and Ki67) was centrally assessed in the European Institute of Oncology (n = 5806). Hazard ratios for distant-metastasis-free survival (DMFS) by subtype were adjusted for chemotherapy and endocrine therapy administration and thus independent of adjuvant treatment allocation. RESULTS: PS Luminal cancers classified as HER-2+ or Basal-type by MS did not have a significantly lower DMFS than the Luminal-type cancers by MS (95.9%): HR = 1.40, 95% CI 0.75-2.60 (p = 0.294). More patients were identified with Luminal A disease by MS (63%) as compared with PS (47%) with comparable 5-year DMFS (≥96.0%). Among the 500 patients with PS TN cancers, MS identified 24 (5%) patients as Luminal-type with 5-year DMFS estimated at 100% versus 71.4% for MS HER-2+ or 90.1% for MS Basal-type. CONCLUSIONS: MS was able to re-stratify 54% of patients with a Luminal-B PS subtype to a low-risk Luminal A-type group with comparable outcome. Among TN EBC, 5% were classified as Luminal by MS with Luminal-like outcome. Molecular classification can help to identify a larger group of patients with low risk of recurrence compared with the more contemporarily used classification methodology including high-quality assessed Ki67.

High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial.

BACKGROUND: To investigate the correlation of TargetPrint with local and central immunohistochemistry/fluorescence in situ hybridization assessment of estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) in the first 800 patients enrolled in the MINDACT trial. PATIENTS AND METHODS: Data from local (N = 800) and central (N = 626) assessments of receptor status were collected and compared with TargetPrint results. RESULTS: For ER, the positive agreement (the percentage of central pathology positive assessments that were also TargetPrint/local laboratory positive) for TargetPrint in comparison to centralized assessment was 98% with a negative agreement (the percentage of central pathology negative assessments that were also TargetPrint/local laboratory negative) of 96%. For PgR, the positive agreement was 83% with a negative agreement of 92%. For HER2, the positive agreement was 75% with a negative agreement of 99%. Even though the local assessment showed higher positive agreement for PgR (89%) and higher positive agreement for HER2 (85%), the range of discordant local versus central assessments were as high as 6.7% for ER, 12.9% for PgR, and 4.3% for HER2. CONCLUSION: TargetPrint and local assessment of ER, PgR, and HER2 show high concordance with central assessment in the first 800 MINDACT patients. However, there are concerns about the higher discordance rates for some local sites. TargetPrint can improve the reliability of hormone receptor and HER2 testing for those centers with a lower rate of concordance with the reference laboratory, with the limitation of a positive agreement of 75% for HER2. TargetPrint consequently has important implications for treatment decisions in clinical practice and is a reliable alternative to local assessment for ER. CLINICAL TRIALS NUMBER: NCT00433589.

The effect of metformin on apoptosis in a breast cancer presurgical trial.

BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial.

BACKGROUND: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important. PATIENTS AND METHODS: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy. RESULTS: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk. CONCLUSION: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

Epidermal growth factor receptor serum (sEGFR) level may predict response in patients with EGFR-positive advanced colorectal cancer treated with gefitinib?

PURPOSE: Epidermal growth factor receptor-overexpression reported in colorectal cancer, justifies therapeutic use of EGFR-inhibitors. We have recently conducted a phase II study in 57 patients with EGFR-positive advanced colorectal cancer (ACC) who received gefitinib-FOLFOX6 followed by gefitinib-single agent as maintenance. Main biological objective was to assess sEGFR as surrogate marker of tyrosine kinase inhibition and as predictor of response. METHODS: sEGFR, evaluated by quantitative ELISA, was investigated as predictive factor both taking into account the basal value only, and its whole pattern over time. sEGFR was collected at baseline and at every 2-months assessment in 42 cases. Thirty-three patients reported CR/PR as best objective response (BOR), while nine showed SD/PD. RESULTS: Retrospectively, on average, the sEGFR values reported by both responders (CR/PR) and not responders (SD/PD) were already different at baseline (49.4 +/- 6.2 and 42.4 +/- 8.4 ng/ml respectively). This difference was statistically significant (p = 0.042). Although sEGFR trend over time confirmed the basal difference (p = 0.032), this result should be taken with caution, due to the small number of patients reporting EGFR values besides the basal one. CONCLUSIONS: Higher sEGFR at baseline was associated to BOR and may be considered a significant predictor of outcome in patients with ACC.

Restoration of posterior aspect of rhabdosphincter shortens continence time after radical retropubic prostatectomy.

PURPOSE: Prolonged postoperative incontinence is a major drawback of RRP. Age, scars in the rhabdosphincter, nonnerve sparing surgery and postoperative sphincter insufficiency can cause temporary or definitive urinary incontinence. We believe that sphincter deficiency is the main cause of early incontinence. Urinary leakage results from the shortening of anatomical and functional sphincter length due to caudal retraction of the urethral sphincteric complex and disruption of the median posterior fibrous raphe. We describe a modification of the Walsh RRP that overcomes caudal retraction, reconstructs the posterior fibrous raphe and decreases time to continence. The primary study end point was early continence rate assessment. Long-term continence (1 year) and erectile function assessment were secondary end points. MATERIALS AND METHODS: To avoid caudal retraction of the urethrosphincteric complex, before completing the vesicourethral anastomosis the posterior semicircumference of the sphincter is joined to the residuum of Denonvilliers' fascia and fixed to the posterior bladder wall 1 to 2 cm cranial and dorsal to the new bladder neck. Vesicourethral anastomosis is subsequently performed with care taken not to involve the neurovascular bundles. A total of 161 patients with clinically confined disease underwent modified RRP (group 1). They were compared with a historical series of 50 patients who underwent standard RRP (group 2). Early continence was defined as no pad use but patients using 1 diaper were also considered continent. Continence, assessed prospectively as the number of pads daily, was evaluated 3, 30 and 90 days, and 1 year after catheter removal. The continence state was assessed by a multivariate logistic model. Erectile function was evaluated using the International Index of Erectile Function questionnaire preoperatively and after 18 months in patients younger than 65 years who underwent nerve sparing surgery. RESULTS: In group 1, 116 (72%), 127 (78.8%) and 139 patients (86.3%) were continent 3, 30 and 90 days after catheter removal compared with 7 (14%), 15 (30%) and 23 (46%), respectively, in group 2. One-year continence rates were 96% and 90%, respectively. Erectile function was similar in groups 1 and 2 (46% and 42%, respectively). Multivariate analysis showed that continence was significantly influenced by operation type, stage and patient age. CONCLUSIONS: Careful reconstruction of the posterior aspect of the rhabdosphincter markedly shortens time to continence.

Reverse transcription-polymerase chain reaction assay for multiple mRNA markers in the detection of breast cancer metastases in sentinel lymph nodes.

The identification of specific tumor mRNA markers by reverse transcription-polymerase chain reaction might be a valuable diagnostic adjunct for the detection of breast cancer metastases in axillary sentinel lymph nodes (SLNs). In this study we have compared the diagnostic accuracy of an extensive histopathologic examination of 146 SLNs from 123 breast carcinoma patients with that of the evaluation of 5 mRNA markers. When analyzed individually, none of the different markers attained a sensitivity higher than 77.8%, and the general concordance with the histopathologic findings ranged from 78.8 to 83.6%. In a multiple-marker assay, taking into account the expression of at least 1 of the 5 tumor markers, the sensitivity of the test rose to 95.6%, with a specificity of 66.3% and a general concordance with the histopathologic status of 75.3%. Finally, when at least 2 of 3 markers (maspin, cytokeratin 19 and mammaglobin 1) were expressed, the concordance with either SLN or axillary lymph node status was highest (88.4% and 84.6%, respectively). The high prevalence of positive reverse transcription-polymerase chain reaction assays in histologically uninvolved SLNs, however, may hamper extensive application of these techniques in the clinical setting.

[Physiology of the urethral sphincteric vesico-prostatic complex]. / Fisiologia del complesso sfinterico vescico-prostatico uretrale.

We propose a review of the literature about innervation and physiology of the urethral sphincteric complex. Parasympathetic innervation of the pelvic viscera comes from ventral branches of the sacral nerves (S2-S4). The orthosympathetic component derives from superior hypogastric plexus and runs down the hypogastric nerves to form the right and left pelvic plexus together with the parasympathetic component. The pelvic plexus is situated inferolaterally with respect to the rectum and runs on the surface of the levator ani muscle down to the prostatic apex. The pelvic plexus gives innervation to the rectum, the bladder, the prostate and the urethral sphincteric complex. The pelvic muscular floor is innervated by the somatic component (pudendal nerve) derived from the sacral branches (S2-S4). Bladder neck and smooth muscle urethral sphincter innervation is given mostly by the orthosympathetic component. The rhabdosphincter innervation comes from the pudendal nerve and from the pelvic plexus; its role in the continence mechanism is probably to give steady tonic urethral compression. Levator ani muscle takes part in the sphincteric complex with its anteromedial pubococcygeal portion. It plays its role strengthening the sphincteric tone during increase of the abdominal pressure or during active quick stop cessation of the urinary stream.

[Personal research: reconstruction of the urethral striated sphincter]. / Ricerca personale: la ricostruzione dello sfintere striato uretrale.

OBJECTIVE: Incontinence is one of the drawbacks of radical prostatectomy. The causes of post-operative incontinence are sphincter deficiency (SD) and bladder dysfunction (BD). SD seems to be the main cause of incontinence and long time to continence. We present a surgical modification of the anatomical radical retropubic prostatectomy consisting in the reconstruction of the posterior aspect of the striated urethral sphincter in order to obtain a quick recovery of continence postoperatively. MATERIALS AND METHODS: Caudal retraction of the urethro-sphincteric complex after apical dissection of the prostate often occurs. Furthermore posterior fibrous raphe interruption can cause shortening of anatomical and functional urethral length and affect continence. In order to avoid caudal retraction of the sphincteric complex, after completing vesico-urethral anastomosis, the posterior emicircumference of the striated sphincter is fixed to the posterior aspect of the bladder one centimeter cranially and posteriorly to the urethro-vesical anastomosis. The rabdosphincter is sutured separately from the urethro-vesical suturing. This technical modification makes it possible to obtain an anatomical length of the urethra of about a centimeter more than with the standard technique, replacing it in a more anatomical position. Furthermore, this technique provides the new posterior platform for the urethro-sphincteric complex. Twenty-four patients with clinical organ confined disease and age range 54-74 years (mean 64 years) underwent Walsh's anatomical radical retropubic prostatectomy with reconstruction of the rabdosphincter (group A). Catheter was removed 7 to 11 days postoperatively. Early continence was assessed objectively with the number of pads per day as follows: 0-1 mini pad = continent; 1-2 pads per day = mild incontinence; 2 or more pads per day = severe incontinence. Continence was evaluated at 3 days and one month after catheter removal. Group A compared to 21 patients (group B) who underwent standard anatomical RPP (historical control group). RESULTS: In group A 16/24 patients (66.7%) and 19/24 patients (79.2%) were continent respectively at three days after removal of the catheter and after one month; mild incontinence (1-2 pads/day) was present in 6/24 patients (25%) and 3/24 (12.5%) respectively, 2/24 patients (8.3%) suffered from severe incontinence after 3 days and one month. In group B 7/21 patients (33%) were continent at hospital discharge, 11/21 (52%) after one month. CONCLUSIONS: Careful reconstruction of the posterior aspects of the rabdosphincter shortens time to continence after RRP.

Immunoreactivity for latent membrane protein 1 of Epstein-Barr virus in nevi and melanomas is not related to the viral infection.

Epstein-Barr virus (EBV) is a human herpes virus with oncogenic potential, associated with several malignancies. The EBV-encoded latent membrane protein 1 (LMP1) is one of nine proteins regularly expressed in virally infected and immortalised B lymphocytes. We now document the consistent immunoreactivity for LMP1 in 90% of 65 nevi and melanomas, using the monoclonal antibody cocktail CS1-4. The immunocytochemical findings, however, were not confirmed using reverse-transcription polymerase chain reaction (RT-PCR) experiments, which failed to demonstrate any actual expression of LMP1 mRNA. In situ hybridisation for EBV-encoded RNAs (EBERs 1 and 2) and PCR amplification of EBV genomic sequences also failed to document any viral infection. Several normal and neoplastic human tissues have also been immunostained for LMP1, without any positive staining, with the exception of a minor percentage of skin melanocytes and of normal blasts of the myeloid and erythroid lineages. We conclude that the vast majority of nevi and melanomas express a still uncharacterised molecule, cross-reacting with anti-LMP1 (CS1-4) antibodies, which may be considered a consistent marker of melanocytic proliferations. The immunoreactivity of normal and neoplastic human tissues for the anti-LMP1 reagent should not be taken as evidence of EBV infection.

Down-regulation of beta(1C) integrin in breast carcinomas correlates with high proliferative fraction, high histological grade, and larger size.

beta(1C) integrin is an unspliced form of the integrin beta(1) subfamily, which has been shown to inhibit cell proliferation in vitro. Using an affinity-purified rabbit antibody, we have investigated 283 previously untreated breast carcinomas, with the aim of ascertaining the actual prevalence of beta(1C) expression in these tumors and of defining its pathological correlates. Immunoblotting and reverse transcriptase-polymerase chain reaction experiments have also been performed in selected cases, to confirm the immunocytochemical findings. Overall, beta(1C) immunoreactivity was down-regulated (ie, expressed in < 50% of the neoplastic cells) in 114 cases (40.3%). Down-regulation of beta(1C) expression in breast carcinomas correlated significantly with the tumor grade, the proliferative fraction (as evaluated by Ki-67 immunostaining with the MIB-1 monoclonal antibody), the estrogen and progesterone receptor status, and the tumor size (pT classification) and marginally with the node status. In a multivariate analysis with all available measures fitted simultaneously, tumor grade (P = 0.004), Ki-67 immunolabeling (P = 0.01), and pT categories (P = 0.04) were significantly associated with beta(1C) immunoreactivity. Although the short follow-up time (2-3 years) of the current series of patients does not allow the performance of survival analyses, the correlation of beta(1C) expression with tumor size, grade, and proliferative fraction and its alleged role as an upstream regulator of p27(kip1) make this integrin variant a likely novel prognostic parameter for invasive carcinomas of the breast.

RANTES is more prevalent in bacterial than in nonbacterial maxillary sinusitis: and P-selectin is preferentially up-regulated in diseased mucosae.

OBJECTIVE: To investigate the relationship of the clinical appearance, histological characteristics, bacterial culturing, and messenger RNA (mRNA) expression of RANTES, interleukin 6, and interleukin 12, as well as the occurrence of endothelial adhesion molecules, in inflammatory diseased maxillary sinus mucosa in critically ill patients. DESIGN: Prospective case series. SETTING: General intensive care unit and neurosurgical intensive care unit of a tertiary care hospital. SUBJECTS: Seven critically ill patients, nasotracheally intubated or tracheotomized, who received ventilator treatment for more than 7 days and treatment with antibiotics. INTERVENTIONS: Bilateral biopsy specimens of antral mucosa were obtained at sinoscopy. Reverse transcriptase-polymerase chain reaction was used to detect the cytokine mRNAs in situ on paraformaldehyde-fixed tissue, and intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were analyzed by immunochemistry on frozen sections. Sampling of secretion and tissue from the antra was performed for bacterial culturing. RESULTS: Macroscopic and histological appearance varied and showed moderate to pronounced inflammation in 6 antra. All 4 bacterially infected antra showed mRNA RANTES (P=.005). No correlation was found for interleukin 6 and interleukin 12. Up-regulation of P-selectin in all cases and sparse expression of vascular cell adhesion molecule 1 indicate that the inflammation is chronic but nonallergic in type. CONCLUSION: We find an indication that RANTES is more prevalent in bacterial sinusitis.

Bcl-2 immunoreactivity in salivary gland neoplasms is unrelated to the expression of mRNA for natural killer cell stimulatory cytokines interleukin (IL)-2 and IL-12.

Certain cytokines are involved in the generation of natural killer (NK) cells and participate in the regulation of the proto-oncogene bcl-2. We aimed to study the mRNA expression of interleukin (IL)-2, IL-4 and IL-5, the composition of the tumour infiltrating lymphocytes (TIL), and the expression of bcl-2 in 14 benign and malignant human parotid tumours. T IL were predominantly composed of T lymphocytes and NK cells. We found evidence for the homing of T cells, and for generation of NK cells in the vicinity of the tumours. mRNA for IL-2 and IL-12, were identified but IL-4 mRNA was not found. The cytokine profiles and the composition of TIL of the two tumour categories were indistinguishable, suggesting that these host-response variables do not explain the differences in biological behaviour of these particular tumours. The results support a shift towards Th 1 (T helper 1) cells and interferon-gamma production, and that IL-12 also in vivo may play an important role in the regulatory interaction between innate resistance and adaptive immunity in tumour diseases. Most infiltrating lymphocytes showed strong expression of bcl-2; an interesting observation with regard to lymphocytic apoptosis in neoplastic diseases. The immunoreactivity for the bcl-2 protein varied considerably between and within tumours, and almost all benign tumours showed strong bcl-2 positively whereas several of the malignant tumours showed weak or absent staining. The variable expression of bcl-2 protein suggests a different susceptibility of tumour cells to apoptosis. The results also indicate that bcl-2 cannot pla a major role as protective agent in the specific apoptotic pathway induced by NK cells.

Positive identification in situ of mRNA expression of IL-6, and IL-12, and the chemotactic cytokine RANTES in patients with chronic sinusitis and polypoid disease. Clinical relevance and relation to allergy.

Interleukins 6 (IL-6) and 12 (IL-12), and the chemoattractant chemokine RANTES were studied in ethmoidal mucosa, using reverse transcriptase polymerase chain reaction. The 49 patients had chronic sinusitis or nasal/paranasal polyposis, and some also allergy. To the best of our knowledge, this is the first study that demonstrates RANTES and IL-12 on mRNA level in human sinonasal mucosa in situ. mRNA for IL-6, IL-12 and RANTES were detected in 2, 8 and 6 patients with chronic sinusitis, respectively, and in mucosa from patients with polyposis a positive expression was observed in 4, 14 and 10 cases. There were no statistically significant differences. Analysing the entire group of 49 patients, disregarding type of mucosal disease, the number of patients with positive RANTES was significantly higher than that for IL-6. Similarly, IL-12 positivity was more frequently expressed than IL-6. mRNA for IL-6 was expressed in only 2 of the allergic patients. The cytokine production studied thus seems to be unrelated to the clinically defined entities. There is thus a local production in human diseased sinonasal mucosa of RANTES, as well as of IL-6 and IL-12. The local production of RANTES is an important prerequisite for recruitment and migration of inflammatory cells into the tissue. IL-12 is a co-stimulator of antigen-specific responses of established T helper 1 (Th1) clones, and regulates the responsiveness of the clones to a number of T cell growth factors. The study supports a shift towards Th1 cells in these disease entities.

[pT1G3 bladder carcinoma: parameters of a correct therapy]. / Carcinoma vescicale pT1G3: parametri per una corretta terapia.

Between 13.8% and 27% of all superficial bladder cancers are represented by pT1G3 neoplasm. In the Department of Urology of Policlinico S. Marco-Zingonia, between February 1988 and June 1994, we treated 22 patients suffering for pT1G3 bladder tumor. TUR-B has demonstrated to be a good approach for treatment of superficial bladder cancer, with low morbility; on the opposite side, we have to underline the high rate of recurrence and of progression of the urothelium disease. Now a day our best approach for the treatment of pT1G3 bladder tumor is represented by radical cystectomy supplied by chemotherapy.

[pT1G3 bladder carcinoma: our experience]. / Carcinoma vescicale pT1G3: nostra esperienza.

Approximately 6 to 23% of the patients with transitional cell carcinoma confined to the superficial mucosa of the bladder suffer for a pT1G3 tumor. Between 1984 and 1994, 12 patients were treated for high grade stage T1 tumores. Trans-urethral resection of the bladder cancer was performed in 8 patients, supported in two cases by immunotherapy with B.C.G. and in one case by endovesical chemotherapy. Radical cystectomy was carried out in 4 patients. Our results are similar to what reported by other Authors, but we didn't have any progression in all 8 patients treated with conservative therapy.

[PSA values before and after finasteride treatment in patients with benign prostatic hypertrophy]. / Valori di PSA prima e dopo trattamento con finasteride in pazienti con ipertrofia prostatica benigna.

A total of 21 patients with benign prostatic hyperplasia was treated with finasteride to evaluate the variation of prostatic volumes and PSA values. After 6 months prostatic volumes showed a decrease of 16% while PSA values of 27%. No variations of PSA density were observed.