Prognostic Factor For Clinical Outcome Research Articles

Clinical Outcomes by Age in Men With Hormone Refractory Prostate Cancer: A Pooled Analysis of 8 Cancer and Leukemia Group B (CALGB) Studies

We determined if age is a prognostic factor of clinical outcomes, specifically overall survival, disease-free survival and progression-free survival in men with hormone refractory prostate cancer. Data from 8 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive adenocarcinoma of the prostate after androgen ablation, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate hematological, renal and hepatic function. The proportional hazards model stratified by study was used to assess the prognostic importance of age for predicting clinical outcomes. Of 1,194 men 132 (11%) were 50 to 60 years old and 120 (10%) were 80 to 89 years old. Median survival was 12.2 months (95% CI 10.6 to 13.8) in men 50 to 59 years old, 15.9 months (95% CI 14.2 to 17.6) in men 60 to 69 years old, 15.6 months (95% CI 13.8 to 16.9) in men 70 to 79 years old and 8.9 months (95% CI 6.6 to 12.1) in men 80 to 89 years old. Compared to 70 to 79-year-old men the HR for death in octogenarians was 1.3 (95% CI 1.0 to 1.6, p = 0.015). Furthermore, the HR for prostate cancer death in octogenarians was 1.3 (95% CI 1.1 to 1.7, p = 0.010) and in 50 to 59-year-old men it was 1.3 (95% CI 1.0 to 1.6, p = 0.042) compared to men 70 to 79 years old. Black men were at lower risk for death than white men (HR 0.77, 95 CI% 0.65 to 0.92, p = 0.004). Octogenarians and white men are at increased risk for death compared to other men with hormone refractory prostate cancer.

Micrometastases detected by cytokeratin 19 expression in sentinel lymph nodes of patients with early-stage cervical cancer

The purpose of this study was to detect micrometastases in sentinel lymph nodes (SLNs) by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) analyses for cytokeratin 19 (CK19) expression in early-stage cervical cancer. One hundred twenty-five SLNs were collected from 46 patients with early-stage cervical cancer. Conventional histopathologic techniques revealed 14 metastatic SLNs from 11 out of 46 patients. CK19 expression was detected by RT-PCR and IHC in all the 125 SLNs. Cervical cancer tissues from nine patients and five pelvic lymph nodes from the patients without tumor were utilized as positive and negative controls, respectively. All the metastastic SLNs on conventional histopathologic techniques were positive by either RT-PCR or IHC analyses, while all the positive controls were positive and all the negative controls were negative as expected. Of 35 patients without metastatic SLNs on conventional histopathologic techniques, the detection rate of micrometastases was 42.85% by RT-PCR and 20% by IHC analyses. RT-PCR and IHC were more sensitive to identify micrometastases in SLNs of patients with early-stage cervical cancer than routine pathology. These findings demonstrated that micrometastasis could be identified by molecular technique such as RT-PCR and IHC analyses for CK19 expression. RT-PCR was more sensitive to detect micrometastases in SLNs than IHC in patients with early-stage cervical cancer. Therefore, molecular assessment of the SLNs may be a valuable tool to complement routine histologic examination of cervical cancer. The importance of micrometastases in SLNs is under close clinical observation to determine whether it can be used as a predicting factor to help us make decision whether to proceed with whole-pelvic lymph node dissection or as a prognostic factor for clinical outcome.

The T393C Polymorphism of the Gαs Gene (GNAS1) Is a Novel Prognostic Marker in Bladder Cancer

The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.

Immunohistochemical Detection of CD95L (Fas Ligand) in Mantle Cell Lymphoma: A Prognostic Factor for Clinical Outcome.

Mantle cell lymphoma is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. Proliferation indices are important prognostic factors in the clinical outcome. We investigated immunohistochemically the expression of the apoptotic marker CD95L (Fas Ligand) in relation to the clinical course. Biopsy specimen from 69 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, CD95L. The CD95L expression was analyzed into three groups: negative, weak positive and strong positive. The expression was compared with the overall survival data analysed according to Kaplan and Meier. Patients with mantle cell lymphoma that had negative and weak positive CD95L expression had a median overall survival time of 32.0 months compared to 18.3 months for patients with a strong CD95L expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time between the patients with strong CD95L expression and the group of patients with negative or weak positive tumor cells (p<0.0038). Based on these findings, the immunohistochemical detection of CD95L in mantle cell lymphoma is a prognostic factor.

Evaluation of sICAM-1, sVCAM-1, and sE-Selectin levels in patients with metastatic breast cancer receiving high-dose chemotherapy.

Soluble forms of some cell adhesion molecules (CAM), sICAM-1, sVCAM-1, and sE-selectin, are elevated in the sera and plasma of patients with inflammation, arthritis, diabetes, and cancer. Increased levels of these soluble molecules in patients with cancer have been shown to correlate with disease progression and survival. This suggests that increased expression of the soluble forms of CAMs may play an important role in cancer cell growth and metastasis and may be prognostic and/or predictive of malignant disease. In this retrospective study, we assessed the clinical significance of sICAM-1, sVCAM-1, and sE-selectin in 95 patients with metastatic breast cancer enrolled in clinical trials of high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). The significance of soluble HER-2 (sHER-2) and sFAS status, determined in previous studies for this group of patients, was also included in this analysis. Univariate analysis showed that sICAM-1, sVCAM-1, sFas, sHER-2 positive status, and the presence of liver metastases were significant prognostic factors for both progression-free survival (PFS) and overall survival (OS) in the total patient group. In multivariable analysis, HER-2 and sFAS were shown to be independent prognostic factors for PFS and OS. Within the various treatment groups examined, sICAM-1 was a prognostic factor for clinical outcome for patients with metastatic breast cancer enrolled in trials with cyclophosphamide- and carboplatin-based or vinblastine-based HDC, but not in trials with paclitaxeland cyclophosphamide-based HDC.

Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P<0.001) and Ki-67 (P<0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P<0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

Complicated acute myocardial infarction requiring mechanical ventilation in the intensive care unit: Prognostic factors of clinical outcome in a series of 157 patients*

To determine prognostic factors associated with death in patients with complicated acute myocardial infarction requiring mechanical ventilation. Retrospective chart-based analysis. A 22-bed medical intensive care unit in a university hospital. A total of 157 consecutive patients with acute myocardial infarction requiring endotracheal intubation and mechanical ventilation admitted to an intensive care unit during a 6-yr period. Coronary reperfusion strategy within 12 hrs following symptom onset. Clinical characteristics at admission of survivors (n = 77) and nonsurvivors (n = 80) were similar regarding demographics, medical history, and Glasgow Coma Scale score. Twenty-eight-day intensive care unit mortality rate was 51%. The following criteria were higher for nonsurvivors: Simplified Acute Severity Score II, 79 +/- 18 vs. 64 +/- 17 (p <.0001); Acute Physiology and Chronic Health Evaluation (APACHE) II, 33 +/- 13 vs. 25 +/- 6 (p <.0001); incidence of cardiogenic shock (p =.0085) and failing organs (p <.0001); coronary artery disease extension (p =.045); and delay between symptom onset and coronary reperfusion (p =.0348). Nonsurvivors also had higher serum urea and creatinine and lower urine output, arterial pH, and left ventricular ejection fraction (p <.05). Mortality rate was higher in patients with PaO2/FiO2 ratio <200 than in patients with PaO2/FiO2 ratio >200 at admission (log-rank, 5.016; p =.0251). By multivariate analysis, only three factors were independently associated with death: APACHE II >29 (odds ratio, 1.132; 95% confidence interval, 1.013-1.265, p =.0287), serum creatinine >180 micromol/L (odds ratio, 6.151; 95% confidence interval, 1.446-26.166, p =.0139), and initial left ventricular ejection fraction <0.4 (odds ratio, 1.121; 95% confidence interval, 1.049-1.347, p =.0316). Overall, good discrimination was achieved for the risk score model (c-index, 0.852). We confirmed the high mortality rate of patients admitted to an intensive care unit with acute myocardial infarction requiring mechanical ventilation. In these patients, the main risk factors for death found, namely high APACHE II, early development of acute renal failure, and low resting left ventricular function, reflected the severity of the myocardial infarction.

CME Test Answers treatment options for chronic obstructive pulmonary disease

Nearly 800,000 strokes occur in the United States each year, and stroke is the leading cause of preventable permanent disability. Timely recognition and treatment are imperative to reduce stroke-related morbidity and mortality. Given the evidence supporting intravenous thrombolysis and mechanical thrombectomy for ischemic stroke, stroke symptoms must be rapidly identified and mimics quickly excluded prior to therapeutic decisions. Intravenous tissue plasminogen activator is recommended for all qualified patients and patients with presentations suggesting large vessel occlusion should be evaluated for mechanical thrombectomy. Time to treatment is the most important prognostic factor for clinical outcome, highlighting the importance of reliable and efficient local and regional systems of care.

Neurophysiological Evidence May Predict the Outcome of Sacral Neuromodulation

Chronic stimulation of the sacral nerves has now become one of the most accepted stimulation therapies for functional lower urinary tract symptoms refractory to conservative treatment. Despite the existence of a large amount of literature on sacral neuromodulation (SNM) showing a fairly high percent of significant improvement in clinical outcome there are few experimental studies of SNM stimulus parameters and/or neurophysiological monitoring. We evaluated the specific action of SNM on the primary sensory cortical area. Somatosensory evoked potentials (SEPs) of the pudendal and posterior tibial nerves were evaluated in patients implanted with a monolateral permanent quadripolar electrode. A total of 24 patients underwent stage 1 monolateral sacral nerve implantation. Three SEP patterns were evaluated; namely before implantation, 1 month after stage 1 with stimulation set at 21 Hz and again with a pulse rate of 40 Hz. In all patients SNM produced a significant decrease in pudendal SEP latency of the first positive deflection between baseline SNM stimulation at different pulse rates at the ipsilateral and contralateral implant sites. This finding was evidence of the effect of S3 SNM on the cortical sensory area and the specificity of pudendal SEPs in measuring how SNM modulates the afferent pathway from the spinal nerve to the cortical sensory area. Our study confirms previous observations that SNM acts by the afferent pathway at the cortical site level and it sheds light on so-called idiopathic lower urinary tract symptoms. A modification of SEPs induced by SNM seems to be a prognostic factor of clinical outcomes. The action of SNM on the afferent pathway from the sacral area to the somatosensory cortex is specific and neurophysiological evaluation via pudendal SEPs provides evidence to this effect.

Nuclear receptor DAX-1 in human common epithelial ovarian carcinoma: an independent prognostic factor of clinical outcome.

DAX-1 is a member of the nuclear receptor superfamily and is thought to be involved in the regulation of steroidogenesis. Its expression has been detected primarily in endocrine neoplasms such as adrenocortical as well as pituitary tumors in human, but its biological roles have not been examined well in sex steroid-dependent neoplasms. The aim of this study is to detect the expression of DAX-1 in common epithelial ovarian carcinomas in order to evaluate its possible biological significance. DAX-1 immunoreactivity was examined using immunohistochemistry. The correlation between the status of DAX-1 immunoreactivity and clinicopathological parameters and disease-free survival of the patients in a series of 60 cases of common epithelial ovarian carcinoma was examined. The status of DAX-1 immunoreactivity was evaluated using H score. DAX-1 immunoreactivity was widely detected in the nuclei of common epithelial ovarian carcinoma cells. There was a significant positive correlation between DAX-1 immunoreactivity and clinical staging (P = 0.0241), tumor grade (P = 0.0115), the residual size of the tumor (P = 0.0014) and Ki-67 labeling index (P = < 0.0001). In univariate survival analysis, a significant association was detected between DAX-1 immunoreactivity and shortened patient survival (P = 0.0157). Other significant prognostic parameters were clinical stage, residual size of tumor and Ki-67. In multivariate analysis, DAX-1 immunoreactivity, clinical stage, residual size of tumor and Ki-67 all turned out to be independent prognostic factors for shortened survival. In conclusion, DAX-1 immunoreactivity is considered to be a new independent marker of poor prognosis or adverse clinical outcome in patients with epithelial ovarian carcinoma, possibly through altering in situ steroids production.

Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases.

We have undertaken this retrospective study to determine factors associated with in-hospital mortality and morbidity in 80 adult patients with severe Streptococcus pneumoniae meningitis. Clinical characteristics at admission of patients infected with susceptible (n = 54) and nonsusceptible (n = 17) strains to penicillin G were similar: age: 51 +/- 19 versus 58 +/- 15 yr (p = 0.16); Simplified Acute Severity Score (SAPS II): 39 +/- 14 versus 41 +/- 11 (p = 0.68); and Glasgow Coma Score: 8 +/- 3 versus 9.5 +/- 3 (p = 0.21), respectively. In-hospital mortality was 25% (20/80), with one death among the 17 patients (6%) infected with a nonsusceptible strain (p = 0.03). High-dose dexamethasone was used in 22 cases. By multivariate analysis, three factors were independently associated with death: platelet count < 100 G/L (adjusted odds ratio [aOR] = 32.7; 95% CI = 3.2 to 332.5; p = 0.0032), arterial pH > 7.47 (aOR = 33.1; 95% CI = 3.4 to 319.7; p = 0.0025), and mechanical ventilation (aOR = 48.8; 95% CI = 2.6 to 901.5; p = 0.009). When adjusting for the identified prognostic factors, corticosteroids significantly reduced the risk of death (aOR = 0.069; 95% CI = 0.005 to 0.9; p = 0.048). Only SAPS II was predictive of adverse outcome (death or neurologic deficit). We conclude that in intubated patients with S. pneumoniae meningitis, hyperventilation should be used with caution. Nonsusceptibility to penicillin G is not associated with a worse outcome. High-dose corticosteroids may be beneficial in the most severely ill patients.

Urinary levels of cyclic guanosine monophosphate (cGMP) in patients with cancer of the uterine cervix: a valuable prognostic factor of clinical outcome?

Changes in urinary cyclic nucleotide levels have been reported in patients with various types of cancers. The present study was conducted to relate changes in urinary levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) to the clinical outcome of 11 patients treated for cancer of the uterine cervix. Urine was sampled for 24 h before and 3 months after primary treatment. The levels of cGMP increased in all the patients (n = 5) who relapsed within the observation period of 39 months. 4 of these patients showed an increased cGMP/cAMP ratio. In the patients without relapse (n = 6), the cGMP levels decreased, whereas the cGMP/cAMP ratios were unchanged. No marked changes in the levels of cAMP were observed for either of the groups. The measurement of urinary cGMP levels seems to be a valuable tool in the follow-up of patients with cancer of the uterine cervix.

Urokinase-type plasminogen activator in epithelial ovarian cancer: A poor prognostic factor, associated with advanced stage

Chambers SK, Ivins CM,Carcangiu ML. Urokinase-type plasminogen activator in epithelial ovarian cancer: A poor prognostic factor, associated with advanced stage. Int J Gynecol Cancer 1998; 8: 242–250. Objective: Expression of urokinase-type plasminogen activator (uPA), a CSF-1 (macrophage colony stimulating factor) inducible gene, has been associated with invasion and metastatic properties, as well as with poor prognosis in a variety of epithelial cancers. In ovarian cancer metastases, co-expression of CSF-1 and CSF-1 receptor has been shown to be an independent poor prognostic factor for clinical outcome. Moreover, CSF-1 stimulated invasion of ovarian cancer cells in vitro is mediated by uPA activity. Ovarian cancers contain a higher concentration of uPA and its receptor, uPAR, than benign ovarian tumors. Reports, however, on the prognostic value of uPA content in ovarian cancer tissue extracts, which contain tumor epithelium, stroma, and infiltrating inflammatory cells, have been conflicting. The objectives of this study are to determine: (1) the prognostic value of uPA or uPAR expression in ovarian cancer epithelium, (2) the level of uPA or uPAR staining in the stromal cells, and (3) if there is an association between expression of uPA/uPAR and CSF-1/CSF-1 receptor in ovarian cancers. Methods: Immunohistochemistry was used to study the primary and metastatic tissues from 131 epithelial ovarian carcinomas, which included all stages of disease. The intensity and extent of staining for uPA and uPAR in the tumor epithelium was scored. Kaplan-Meier curves of survival were compared with the log-rank test. The Cox regression model was used for multivariate analysis. The Chi square test was used to study the association between uPA/uPAR immunohistochemical positivity and clinicopathologic parameters, as well as with CSF-1 and CSF-1 receptor expression. Results: For the invasive cases, 66% of the primary tumors and 57% of the metastases expressed uPA, while only 32 % of the primary tumors and 23% of the metastases expressed uPAR. There was low level staining for uPA or uPAR in the stromal cells surrounding the tumor. Tumor cell expression of uPA in the invasive primary tumors was strongly predictive of a shorter overall survival; the median survival of 29 months for the 76 patients whose primary tumors expressed uPA was extended to 53 months for the 40 patients whose primary tumors did not express uPA. The prognostic value of uPA expression was retained in the subgroup of patients with residual disease ≥ 2 cm, but not among patients with minimal or no residual disease. Urokinase expression was, however, significantly associated with advanced stage and older age, and was not an independent factor for survival on multivariate analysis. Expression of uPAR alone, or in combination with uPA, had no prognostic value in this study. Co-expression of uPA and uPAR was strongly associated with co-expression of CSF-1 and CSF-1 receptor. Conclusions: The current study is the first to describe the prognostic significance of uPA/uPAR expression localized to ovarian cancer epithelium. Two previous studies on ovarian cancer, as well as studies on breast, lung, gastric, colon, and cervical cancers, examined the prognostic value of uPA content in tissue extracts. We demonstrate that uPA expression in the primary tumor epithelium is a common finding which is significantly predictive of a shorter overall survival, but is not an independent factor, most likely due to its close association with advanced stage. On the other hand, ovarian cancer stromal staining for uPA was of a low level and was not a prominent feature. In this study, a significant association was found between co-expression of uPA/uPAR and of CSF-1/CSF-1 receptor; thus components of the uPA system may act as a mediator of the invasive, poor prognosis phenotype conferred by CSF-1 in epithelial ovarian cancers.

Overexpression of p53 Protein Does Not Predict Local-Regional Control or Survival in Patients With Early-Stage Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiotherapy

Purpose: Nonfunctional or mutated p53 protein (m-p53) is found in a myriad of solid tumors in humans. m-p53 is believed to confer radioresistance through inhibition of radiation-induced apoptosis. This study was carried out to determine if the overexpression of p53 in squamous cell carcinomas (SCC) of the glottic larynx treated with radiation therapy alone carried a poorer prognosis than normal wild-type p53 (w-p53) and could, therefore, be used as a marker of radioresistance in glottic SCC. Methods & Materials: Eighty-six patients with early-stage glottic SCC (64 T1N0, 25 T2N0 by TMN stage) treated with contemporary radiotherapy techniques to doses of 50–70 Gy were analyzed. Aberrant p53 protein was detected by immunohistochemical (IHC) staining on archival tissue samples containing original tumor specimens. Analysis of prognostic factors and treatment outcome to expression of p53 was performed. All patients were carefully selected to have comparable sites of disease, histology, early-stage disease, and treatment delivered, thus increasing the power of this study by controlling for other independent factors affecting outcome. Results: Sixty percent of patients demonstrated overexpression of p53 in tissue samples. Accumulation of p53 was not predictive of tumor grade, stage, or smoking status prior to diagnosis. p53 status was not predictive of treatment outcome parameters including local-regional failure rate and disease-free survival rate. Factors significantly affecting treatment outcome were stage and dose of radiotherapy in T2 patients (50 Gy vs. > 62 Gy). Conclusion: m-p53 protein detected by IHC staining was not predictive as a prognostic factor for clinical outcome following radiation therapy for early-stage glottic SCC. This is in general agreement with other recently published studies of laryngeal carcinoma patients treated with radiation or surgery. At the present time, p53 status should not be used as a marker for prognosis and clinical outcome in laryngeal SCC.

Molecular Mechanisms of Multidrug Resistance in Cancer Chemotherapy

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.

PATHOBIOLOGICAL CHARACTERISTICS OF THE 1ST PRIMARY AND RISK OF METACHRONOUS CONTRALATERAL INVASIVE BREAST-CARCINOMA - CLINICAL IMPLICATIONS

The study was undertaken to determine the clinico-pathobiological characteristics in a series of 49 patients who developed metachronous breast carcinoma. Possible differences between the two tumours of conventional clinico-pathological features and of some biological markers such as DNA ploidy, c-erbB-2 oncoprotein overexpression and tumour angiogenesis were evaluated. The McNemar's test for independence showed that all the characteristics analyzed between the two tumours, in the same case, were not significantly different. After a median follow-up time of 69 months the overall survival of the series was 87.5% and the only significant prognostic factor for clinical outcome was peritumoural lymphatic vessel invasion (PLVI). The median second tumour-free interval was of 32 months ( 13 to 160 months) and none of the variables analyzed on the first primary was predictive of the timing of appearance of the second tumour. To assess the association between the characteristics of the first tumour and the odds of developing a metachronous carcinoma a case-control analysis was conducted. For each woman of the present series who developed bilateral cancer (case) a woman who had unilateral breast cancer (control) was matched for the length of the follow-up. A log-logistic regression model for matched sets was also performed to assess the risk of developing the second tumour. Applying multivariate analysis we found that progesterone receptor (PgR) status was the most important prognostic factor for the odds of bilateral tumour (odds ratio 0.22, p=0.013) followed by histological grade (odds ratio 0.20, p=0.063) and presence of PLVI (odds ratio 3.13, p=0.067). These findings suggest that the knowledge on the initial primary of PgR, grading and PLVI could be important to assess the individual risk of developing metachronous breast cancer. The determination of these factors could improve our ability to identify subsets of patients operated for breast cancer with different risks for bilateral tumour, allowing for a better selection of those patients who need intensive surveillance of their contralateral breast, and eligible for chemoprevention.

Association of genetic alterations of c-myc, c-fos, and c-Ha-ras proto-oncogenes in colorectal tumors

Using Northern and dot-blot analysis we examined normal and tumor tissue from 29 patients with colorectal carcinomas for the expression and amplification of c-myc, c-fos and c-Ha-ras proto-oncogenes. Overexpression of c-myc (6/24), c-fos (4/24), and c-Ha-ras (9/23) was found. For the c-fos proto-oncogene we also have observed decreased levels of expression in 13 percent (3/24) of the cases analyzed. Gene amplification appeared to be a rare event in these tumors and was found in 3/29 (10 percent) tumors for c-myc and in 1/29 (3 percent) for c-fos proto-oncogene. Curves for overall survival and for disease-free survival failed to show a significant tendency in these parameters to be poorer in tumors with alterations of gene expression for any of the proto-oncogenes analyzed. Despite the biologic importance of these genetic alterations in the etiology of colorectal tumors, levels of c-myc, c-fos, and c-Ha-ras gene expression separately or together cannot be considered as prognostic factors for clinical outcome of the disease.