LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Predictors and outcomes of perioperative blood transfusions in classic bladder exstrophy repair: A single institution study.

BACKGROUND: Primary bladder closure of classic bladder exstrophy (CBE) is a major operation that occasionally requires intraoperative or postoperative (within 72 h) blood transfusions. OBJECTIVE: This study reported perioperative transfusion rates, risk factors for transfusion, and outcomes from a high-volume exstrophy center in primary bladder closure of CBE patients. STUDY DESIGN: A prospectively maintained, institutional exstrophy-epispadias complex database of 1305 patients was reviewed for primary CBE closures performed at the authors' institution (Johns Hopkins Hospital) between 1993 and 2017. Patient and surgical factors were analyzed to determine transfusion rates, risk factors for transfusions, and outcomes. Patients were subdivided into two groups based upon the time of closure: neonatal and delayed closure. RESULTS: A total of 116 patients had a primary bladder closure during 1993-2017. Seventy-three patients were closed in the neonatal period, and 43 were delayed closures. In total, 64 (55%) patients received perioperative transfusions. No transfusion reactions were observed. Twenty-five transfusions were in the neonatal closure group, yielding a transfusion rate of 34%. In comparison, 39 patients were transfused in the delayed closure group, giving a transfusion rate of 91%. Pelvic osteotomy, delayed bladder closure, higher estimated blood loss (EBL), larger pubic diastasis, and longer operative time were all associated with blood transfusion. In multivariable logistic regression, pelvic osteotomy (OR 5.4; 95% CI 1.3-22.8; P < 0.001), higher EBL-to-weight ratio (OR 1.3; 95% CI 1.1-1.6; P = 0.029), and more recent years of primary closure (OR 1.1; 95% CI 1.0-1.2; P = 0.018) remained independent predictors of receiving a transfusion (Summary Table). No adverse transfusion reactions or complications were observed. DISCUSSION: This was the first study from a single high-volume exstrophy center to explore factors that contribute to perioperative blood transfusions. Pelvic osteotomy as a risk factor was unsurprising, as the osteotomy may bleed both during and immediately after closure. However, it is important to use osteotomy for successful closure, despite the increased transfusion risk. The risks accompanying contemporary transfusions are minimal and osteotomies are imperative for successful bladder closure. CONCLUSIONS: More than half of CBE patients undergoing primary closure at a single institution received perioperative blood transfusions. While there was an association between transfusions and osteotomy, delayed primary closure, larger diastasis, increased operative time, and increased length of stay, only the use of pelvic osteotomy, higher EBL-to-weight ratio, and recent year of closure independently increased the odds of receiving a transfusion on multivariate analysis.

Efficacy of post-operative radiation in a prostatectomy cohort adjusted for clinical and genomic risk.

BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n=111), minimal residual disease (MRD) SRT (n=70) and SRT (n=83) were defined by PSA levels of <0.2, 0.2-0.49 and ⩾0.5 ng ml(-1), respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P<0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P=0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

Pelvic lymph node dissection is associated with symptomatic venous thromboembolism risk during laparoscopic radical prostatectomy.

PURPOSE: Venous thromboembolism is a potentially catastrophic complication of radical prostatectomy. It is unknown whether pelvic lymph node dissection is related to the development of venous thromboembolism. We hypothesized that omitting pelvic lymph node dissection may be associated with a decreased incidence of venous thromboembolism. MATERIALS AND METHODS: The records of 773 consecutive patients who underwent laparoscopic radical prostatectomy by a single surgeon from 2001 to 2009 were reviewed for postoperative venous thromboembolism. All patients underwent laparoscopic radical prostatectomy with or without pelvic lymph node dissection and had at least 3 months of followup. Generally only patients at increased risk for lymph node metastasis received pelvic lymph node dissection. Diagnostic studies were not routinely performed but were initiated for clinical symptoms of venous thromboembolism. Separately a meta-analysis of radical prostatectomy studies with or without pelvic lymph node dissection was performed to evaluate associations with venous thromboembolism. RESULTS: Of the 773 patients 468 (60.8%) underwent laparoscopic radical prostatectomy plus pelvic lymph node dissection, 302 (39.2%) underwent laparoscopic radical prostatectomy without pelvic lymph node dissection, and 3 were missing preoperative data and were excluded from study. Patients in the laparoscopic radical prostatectomy plus pelvic lymph node dissection and laparoscopic radical prostatectomy only groups were similar in age, body mass index and prostate volume, although they differed in pathological characteristics and operative time. Venous thromboembolism occurred in 7 of 468 (1.5%) patients who underwent laparoscopic radical prostatectomy plus pelvic lymph node dissection and in 0 of 302 (0%) who underwent laparoscopic radical prostatectomy only (p = 0.047). Patients in whom venous thromboembolism developed had greater body mass index (30.8 vs 27.1 kg/m(2), p = 0.015) than those in whom venous thromboembolism did not develop. No patient had a symptomatic lymphocele. Meta-analysis of the literature demonstrated a significant association between venous thromboembolism and radical prostatectomy plus pelvic lymph node dissection compared to radical prostatectomy only (RR 2.15, CI 1.14-4.04, p = 0.018). CONCLUSIONS: Pelvic lymph node dissection during radical prostatectomy increases the risk of venous thromboembolism. In carefully selected low risk patients omitting pelvic lymph node dissection may decrease the incidence of venous thromboembolism.

Potential biomarker for early risk assessment of prostate cancer.

BACKGROUND: Catechol estrogen quinones (CEQ) derived from 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2) react with DNA to form depurinating--N7Gua and--N3Ade adducts. This damage leads to mutations that can initiate breast and prostate cancer. To determine whether this damage occurs in humans, urine samples from men with prostate cancer and benign urological conditions, and healthy controls were analyzed. The objective was determining whether any of the cancer patients had formed the depurinating 4-OHE1(E2)-1-N3Ade adducts. METHODS: The adducts were extracted from samples by using affinity columns equipped with a monoclonal antibody developed for detecting 4-OHE1(E2)-1-N3Ade adducts. Eluted extracts were separated by capillary electrophoresis with field-amplified sample stacking and/or ultraperformance liquid chromatography. Absorption/luminescence spectroscopies and mass spectrometry were used to identify the adducts. RESULTS: 4-OHE1-1-N3Ade was detected at higher levels in samples from subjects with prostate cancer (n = 7) and benign urological conditions (n = 4) compared to healthy males (n = 5). CONCLUSION: This is the first demonstration that CEQ-derived DNA adducts are present in urine samples from subjects with prostate cancer.

The effect of hospital volume on cancer control after radical prostatectomy.

PURPOSE: For complex oncological procedures, hospital volume affects short and long-term patient outcome. We examined the association of hospital volume and long-term cancer control after radical prostatectomy. MATERIALS AND METHODS: With a cohort study design, we used the Surveillance, Epidemiology and End Results-Medicare linked files to identify a population based sample of men with newly diagnosed prostate cancer treated primarily with radical prostatectomy. Failure of cancer control was defined as the use of postoperative medical or surgical hormone ablation or treatment with radiation therapy more than 6 months after surgery. RESULTS: A total of 12,635 men underwent radical prostatectomy for incident prostate cancer. After adjusting for age, comorbidity, histological grade and clinical stage, the risk of adjuvant therapy was greater among those treated at low (1 to 33 cases) and medium (34 to 61 cases) volume hospitals than at very high (more than 108 cases) volume hospitals (HR 1.25, p <0.001 and HR 1.11, p =0.023 respectively). CONCLUSIONS: Patients treated at lower volume institutions are at increased risk of initiation of subsequent adjuvant therapy with radiation therapy, medical hormone ablation or orchiectomy. Noted differences in cancer control provide additional evidence regarding issues surrounding the debate over surgical volume standards for the surgical treatment of prostate cancer.

New approaches to proteomic analysis of breast cancer.

Proteomic based approaches are beginning to be utilized to study the natural history and treatment of breast cancer. A variety of proteomics approaches are under study, and are summarized herein. Two-dimensional gel electrophoresis (2D-PAGE) is still the foundation of most proteomics studies. We present an analysis of 2D-PAGE studies reported to date in breast cancer, including those examining normal/tumor differences and selected populations of breast cells. Newer technologies such as laser capture microdissection and highly sensitive mass spectrometry methods are currently being used together to identify greater numbers of lower abundance proteins that are differentially expressed between defined cell populations. Novel technologies still in developmental phases will enable identification of validated targets in small biopsy specimens, including high density protein arrays, antibody arrays and lysate arrays. Surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) analysis enables the high throughput characterization of lysates from very few tumor cells and may be best suited for clinical biomarker studies. We present SELDI-TOF data herein to show the accuracy of the method in a small cohort of breast tumors, as well as its potential discriminatory capability. Such technologies are expected to supplement our armamentarium of mRNA-based assays, and provide critical information on protein levels and post-translational modifications.

Does capsular incision at radical retropubic prostatectomy affect disease-free survival in otherwise organ-confined prostate cancer?

OBJECTIVES: To evaluate the influence of isolated, histologically identified capsular incision (CI) (exposure of benign or malignant glands to the inked surgical margin in the setting of organ-confined disease) on disease progression after anatomic radical retropubic prostatectomy (RRP) for clinically localized prostate cancer. METHODS: Between March 1993 and September 1999, 4747 men underwent RRP at the Johns Hopkins Hospital; 107 men (2.3%) were diagnosed with CI in otherwise organ-confined disease; 92 (86%) had at least 6 months (mean 30) of follow-up. We matched these CI cases (based on surgeon, age, clinical stage, final pathologic Gleason grade, and preoperative serum prostate-specific antigen level) one-for-one with controls in three additional pathologically defined groups and compared the freedom from disease progression (prostate-specific antigen level greater than 0.2 ng/mL and/or local palpable recurrence) after RRP. RESULTS: The actuarial 3-year likelihood of freedom from disease progression was 87.8% for the CI group, 96.4% for men with organ-confined disease (P = 0.10), 91.3% for men with extraprostatic extension and negative surgical margins (P = 0.99), and 73.9% for men with positive surgical margins resulting from extraprostatic extension (P <0.01). No statistically significant difference was found in the actuarial likelihood of freedom from disease progression between men with CI into benign glands (n = 22) and men with CI into tumor (n = 70) (P = 0.93). CONCLUSIONS: No statistically significant difference was found in the likelihood of early recurrence between patients with isolated CI and other specimen-confined disease. Patients with isolated CI have a significantly lower likelihood of early recurrence than patients with positive surgical margins due to extraprostatic extension, regardless of whether the CI is into benign glands or tumor. Long-term follow-up is necessary to confirm these findings.

Age and survival from squamous cell carcinoma of the oral tongue.

BACKGROUND: A worse outcome for young patients with head and neck squamous cell carcinoma has been previously suggested in the literature. This issue has been investigated with respect to squamous cell carcinoma of the oral tongue. METHODS: The Surveillance, Epidemiology and End Results (SEER) program tumor registries were used. Cases of squamous cell carcinoma of the oral tongue (ICD-9 codes 141.1-141.5) diagnosed from 1988-1993 in which this cancer was the one and only cancer were included (n = 749). Disease-specific survival was evaluated with respect to age, type of surgical treatment, and radiotherapy while stratifying for stage using Cox proportional hazards analysis. A secondary analysis included the additional variables, tumor size and nodal status. (These fields were recorded in SEER for only about half of the cases in the primary analysis.) RESULTS: Analysis revealed that increasing age predicted worse disease-specific survival. A 10-year increase in age was associated with an 18% increase in risk of death. Surgical therapy with excision of the primary tumor alone or excision plus neck dissection predicted improved survival, whereas the use of radiotherapy was associated with worse survival. (The latter may reflect bias associated with positive surgical margins or premorbid conditions.) In the secondary analysis, age, tumor size, and positive lymph node status were associated with significantly worse disease-specific survival, whereas surgical excision plus neck dissection was associated with improved survival. CONCLUSION: The SEER database shows increased disease-specific mortality with increasing age in patients with cancer of the oral tongue. Surgical therapy is associated with improved survival, whereas the use of radiotherapy, increasing tumor size, and positive lymph node status are associated with worse outcome.

Validation of surrogate endpoint biomarkers in prostate cancer chemoprevention trials.

Phase 2 cancer chemoprevention trials are designed to provide estimates of the efficacy of an agent at a specified dose, and the expected size of the risk reduction that may be achieved in a subsequent phase 3 randomized trial. To allow these trials to be rapid and efficient, the study outcome is modulation of a surrogate endpoint biomarker (SEB), that is, a molecular event assumed to be on the causal pathway between the chemopreventive agent and the desired reduction in cancer incidence. However, SEBs commonly used in prostate cancer chemoprevention studies, such as prostate-specific antigen, high grade prostatic intraepithelial neoplasia, proliferation, and apoptosis, have not been validated by documenting that changes in the SEBs ultimately translate to decreased prostate cancer risk. Because of uncertainty in the pathway from SEBs to cancer, additional considerations are necessary to permit valid inferences from phase 2 trial data. This article considers the framework underlying validation and use of SEBs in specific chemoprevention models and methodologic issues in quantifying the effect of an agent. In particular, inferences depend on whether a single pathway involving the SEBs is assumed to mediate the effect of the agent on cancer incidence. If there are competing pathways of equal or greater importance than the one involving the candidate SEB, then the estimate of chemopreventive efficacy will be biased and may greatly underestimate the magnitude of the achievable risk reduction. Strategies for validating biomarkers and minimizing the degree of bias in the risk reduction estimate are discussed. Finally, problems associated with phase 2 study designs commonly used for prostate cancer chemoprevention are discussed, along with possible solutions.

C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance.

Data from basic research suggests that amplification of the proto-oncogene c-myc is important in breast cancer pathogenesis, but its frequency of amplification and prognostic relevance in human studies have been inconsistent. In an effort to clarify the clinical significance of c-myc amplification in breast cancer, we conducted a comprehensive literature search and a meta-analysis in which 29 studies were evaluated. The weighted average frequency of c-myc amplification in breast tumours was 15.7% (95% CI = 12.5-18.8%), although estimates in individual studies exhibited significant heterogeneity, P<0.0001. C-myc amplification exhibited significant but weak associations with tumour grade (RR = 1.61), lymph-node metastasis (RR = 1.24), negative progesterone receptor status (RR = 1.27), and postmenopausal status (RR = 0.82). Amplification was significantly associated with risk of relapse and death, with pooled estimates RR = 2.05 (95% CI = 1.51-2.78) and RR = 1.74 (95% CI = 1.27-2.39), respectively. This effect did not appear to be merely a surrogate for other prognostic factors. These results suggest that c-myc amplification is relatively common in breast cancer and may provide independent prognostic information. More rigorous studies with consistent methodology are required to validate this association, and to investigate its potential as a molecular predictor of specific therapy response.

Genetic testing in families with hereditary nonpolyposis colon cancer.

CONTEXT: Genetic testing for hereditary nonpolyposis colon cancer (HNPCC) is available, but the rates of acceptance of testing or barriers to participation are not known. OBJECTIVE: To investigate rates and predictors of utilization of genetic testing for HNPCC. DESIGN: Cohort study conducted between July 1996 and July 1998. SETTING: Hereditary nonpolyposis colon cancer family registry. PARTICIPANTS: Adult male and female members (n = 208) of 4 extended HNPCC families contacted for a baseline telephone interview. INTERVENTIONS: Family education and individual genetic counseling. MAIN OUTCOME MEASURE: Participant acceptance of HNPCC test results. RESULTS: Of the 208 family members, 90 (43%) received test results and 118 (57%) declined. Of 139 subjects (67%) who completed a baseline telephone interview, 84 (60%) received test results and 55 (40%) declined. Of the 84 subjects who received test results, 35 (42%) received information indicating that they had HNPCC-associated mutations and 49 (58%) that they did not. Test acceptors had higher education levels (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.49-5.61) and were more likely to have participated in a previous genetic linkage study (OR, 4.30; 95% CI, 1.84-10.10). The presence of depression symptoms significantly reduced rates of HNPCC test use (OR, 0.34; 95% CI, 0.17-0.66). Although rates of test use were identical among men and women, the presence of depression symptoms resulted in a 4-fold decrease in test use among women (OR, 0.25; 95% CI, 0.08-0.80) and a smaller, nonsignificant reduction among men (OR, 0.49; 95% CI, 0.19-1.27). CONCLUSIONS: Despite having significantly elevated risks of developing colon cancer, a relatively small proportion of HNPCC family members are likely to use genetic testing. Barriers to test acceptance may include less formal education and the presence of depression symptoms, especially among women. Additional research is needed to generalize these findings to different clinical settings and racially diverse populations.

Serendipity in diagnostic imaging: magnetic resonance imaging of the breast.

BACKGROUND: Magnetic resonance imaging (MRI) of the breast has been proposed as a noninvasive diagnostic test for evaluation of suspicious ("index") lesions noted on mammography and/or clinical breast examination (CBE). However, women may have incidental ("serendipitous") lesions detected by MRI that are not found on mammography or CBE. To understand better whether or not biopsy procedures should be performed to evaluate serendipitous lesions, we estimated the breast cancer risk for women with this type of lesion. METHODS: A decision analysis model was used to estimate the positive predictive value (i.e., the chance that a woman with a serendipitous lesion has cancer) of MRI for serendipitous lesions in women who had an abnormal mammogram and/or CBE suspicious for cancer (where a biopsy procedure is recommended). We restricted the analysis to data from women whose index lesions were noncancerous and used meta-analysis of published medical literature to determine the likelihood ratios (measures of how test results change the probability of having cancer) for MRI and the combination of CBE and mammography. The positive predictive value of MRI was calculated using the U.S. population prevalence of cancer (derived from registry data) and the likelihood ratios of the diagnostic tests. RESULTS: Under a wide variety of assumptions, the positive predictive value of MRI was extremely low for serendipitous lesions. For instance, assuming sensitivity and specificity values for MRI of 95.6% and 68.6%, respectively, approximately four of 1000 55- to 59-year-old women with serendipitous lesions would be expected to have cancer (positive predictive value = 0.44%, 95% confidence interval = 0.24%-0.67%). CONCLUSION: In women with a suspicious lesion discovered by mammography and/or CBE that is found to be benign, serendipitous breast lesions detected by MRI are extremely unlikely to represent invasive breast cancer. Immediate biopsy of such serendipitous lesions may, therefore, not be required.

Association between expression of glutathione-associated enzymes and response to platinum-based chemotherapy in head and neck cancer.

We examined the correlation between response to platinum-based chemotherapy and expression of glutathione S-transferase (GST), gamma-GGT (both by immunohistochemistry) and gamma-GCS (by in situ hybridization) in 51 patients with head and neck cancer, who received a total of 56 courses of chemotherapy. The overall response rate for the 56 chemotherapy treatment courses was 48%. The overall response rate (CR, PR) for patients with low GST scores was 88% (21 of 24), while among the patients with high GST scores, the overall response rate was 19% (6 of 32, P = 0.001). Patients with a low GST score were 4.7 times more likely to respond to chemotherapy than patients with high GST scores. GST scores corresponded to response in 84% of cases. Among 33 patients treated with chemotherapy for relapsed disease, the overall response rate for patients with low GST score was 70% (7 of 10), while among the patients with high GST scores, the overall response rate was 8.7% (2 of 23), P < 0.001). In contrast, both gamma-GCS and gamma-GGT showed a range of expression in these samples, but there was no significant correlation with treatment response. We conclude that GST expression correlates well with response to platinum based chemotherapy in head and neck cancer.

Tamoxifen-resistant fibroblast growth factor-transfected MCF-7 cells are cross-resistant in vivo to the antiestrogen ICI 182,780 and two aromatase inhibitors.

Although the antiestrogen tamoxifen has been the mainstay of therapy for estrogen receptor (ER)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxifen resistance. Subsequently, only 30-40% of patients have a positive response to second hormonal therapies. This lack of response might be explained by mechanisms for tamoxifen resistance that sensitize ER pathways to small amounts of estrogenic activity present in tamoxifen or that bypass ER pathways completely. To elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen ICI 182,780 or one of two aromatase inhibitors, 4-OHA or letrozole. These treatments did not slow estrogen-independent growth or prevent metastasis of tumors produced by FGF-transfected MCF-7 cells in ovariectomized nude mice. FGF-transfected cells had diminished responses to ICI 182,780 in vitro, suggesting that autocrine activity of the transfected FGF may be replacing estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF transfectants were not down-regulated, and basal levels of transcripts for estrogen-induced genes or of ER-mediated transcription of estrogen response element (ERE) luciferase reporter constructs in the FGF expressing cells were not higher than parental cells, implying that altered hormonal responses are not due to down-regulation of ER or to FGF-mediated activation of ER. These studies indicate that estrogen independence may be achieved through FGF signaling pathways independent of ER pathways. If so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of antiestrogen treatment.

Heat shock protein and p53 expression in head and neck squamous cell carcinoma.

BACKGROUND: Heat shock proteins have been associated with the mutant form of the tumor suppressor gene, TP53, and with resistance to cancer chemotherapy. METHODS: Archival tissues from 50 patients with head and neck squamous cell carcinoma who received primary surgical resection were examined for p53, HSP27, and HSP70 by immunohistochemistry and correlated with tumor stage, grade, and 5-year survival (alive or deceased). RESULTS: Both heat shock proteins were strongly expressed in normal mucosa and in small (T1 and T2) tumors. Thirty (60%) of tumors were positive for p53, 43 (86%) for HSP27, and 34 (68%) for HSP70, with no association between p53 and heat shock protein expression. Twenty-five patients were alive (4 with disease), and 25 patients were deceased (9 from other causes). p53 Protein overexpression correlated with low-grade tumors. Only primary tumor site (i.e., oral cavity > larynx > oropharynx/base of tongue) and N stage were significantly associated with survival. CONCLUSIONS: Heat shock proteins are expressed in normal upper respiratory tract squamous mucosa, and their role in carcinoma remains unclear. None of the markers, p53, HSP27, or HSP70, demonstrated prognostic significance for 5-year survival. We confirm the recognized association of cervical lymph node metastases with decreased survival.

Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance.

BACKGROUND: P-glycoprotein (gp170; encoded by the MDR1 gene [also known as PGY1]) is a membrane protein capable of exporting a variety of anticancer drugs from cells. MDR1/gp170 expression has been studied in breast cancer, but the prevalence of this expression and its role in breast tumor drug resistance are unclear. PURPOSE: We conducted a critical review and meta-analysis of studies examining MDR1/gp170 expression in breast cancer to estimate the likely prevalence and clinical relevance of this expression. We also explored reasons for differences in the findings from individual studies. METHODS: Published papers on MDR1/gp170 expression in breast cancer were identified by searching several literature databases and reviewing the bibliographies of identified papers. Variability across the studies in the proportion of tumors expressing MDR1/gp170 was assessed by use of chi-squared tests of homogeneity, weighted means, and weighted linear regression. Pooled relative risks (RRs) for the association between the induction of MDR1/gp170 expression and prior chemotherapy and associations between MDR1/gp170 expression and several clinical outcomes were estimated by use of Mantel-Haenszel methods. Heterogeneity among the pooled RRs was explored by use of chi-squared tests. Reported P values are two-sided. RESULTS: Thirty-one studies were identified and evaluated. The proportion of breast tumors expressing MDR1/gp170 in all of the studies was 41.2%, but there was substantial heterogeneity in the values across individual studies (P<.0001). Regression analyses demonstrated that a considerable portion of the observed heterogeneity was a consequence of the change, over time, from RNA hybridization-based assays to immunohistochemistry-based assays of MDR1/gp170 expression. Measuring MDR1/gp170 expression before versus after chemotherapy and use of cytotoxic drugs that are not substrates for gp170 also contributed to the heterogeneity. Treatment with chemotherapeutic drugs or hormonal agents was associated with an increase in the proportion of tumors expressing MDR1/gp170 (RR = 1.77; 95% confidence interval [CI] = 1.46-2.15). Patients with tumors expressing MDR1/gp170 were three times more likely to fail to respond to chemotherapy than patients whose tumors were MDR1/gp170 negative (RR = 3.21; 95% CI = 2.28-4.51); this RR increased to 4.19 (95% CI = 2.71-6.47) when considering only patients whose tumor expression of MDR1/gp170 was measured after chemotherapy. MDR1/gp170 expression was not associated with lymph node metastases, estrogen receptor status, tumor size, tumor grade, or tumor histology. CONCLUSIONS AND IMPLICATIONS: MDR1/gp170 expression in breast tumors is associated with treatment and with a poor response to chemotherapy. The data are consistent with a contributory role for MDR1/gp170 in the multidrug resistance in some breast tumors.

Immunohistochemical staining for glutathione S-transferase predicts response to platinum-based chemotherapy in head and neck cancer.

The glutathione S-transferases (GSTs) play an important role in the cell's defense against toxic substances. The GSTs are a family of enzymes produced by several genes that interact with distinct but overlapping substrates and that may play a role in resistance of tumor cells to several chemotherapeutic agents. We examined the correlation between expression of GSTs determined by immunohistochemistry and clinical response to platinum-based chemotherapy in 51 patients with head and neck cancer, who received a total of 56 courses of chemotherapy. The overall response rate for the 56 chemotherapy treatment courses was 48%. The overall response rate (complete response + partial response) for patients with low GST scores was 88% (21 of 24), whereas among the patients with high GST scores, the overall response rate was 19% (6 of 32; P = 0.001). Patients with a low GST score were 4.7 times more likely to respond to chemotherapy than patients with high GST scores. GST scores corresponded to response in 84% of cases. Among 23 patients treated with neoadjuvant chemotherapy, the overall response rate for patients with low GST scores was 100% (14 of 14), whereas among the patients with high GST scores, the overall response rate was 44% (4 of 9; P = 0.002). Among 33 patients treated with chemotherapy for relapsed disease, the overall response rate for patients with low GST scores was 70% (7 of 10), whereas among the patients with high GST scores, the overall response rate was 8.6% (2 of 23; P < 0.001). We conclude that GST expression correlates well with response to platinum-based chemotherapy in head and neck cancer.

A prognostic model for predicting 10-year survival in patients with primary melanoma. The Pigmented Lesion Group.

OBJECTIVE: To develop a prognostic model, based on clinical and pathologic data that are routinely available to the clinician, that would estimate the chance for survival of a patient with primary cutaneous melanoma after definitive surgical therapy. DESIGN: Cohort analytical study. SETTING: University medical center. PATIENTS: 488 patients with primary cutaneous melanoma who had no apparent metastatic disease. Patients were followed prospectively for at least 10 years. An independent validation sample of 142 patients was used to assess the stability of the model. MEASUREMENTS: Six clinical and pathologic variables that predict survival and are readily available to the clinician were used to develop a prediction model. The variables were tested for their association with death by using a univariate logistic regression model. Point estimates were generated for the probability of surviving melanoma at 10 years. Variables that were statistically significantly associated with survival were retained for testing in a logistic regression model. RESULTS: 488 patients were followed prospectively for a median of 13.5 years (minimum, 10.0 years; maximum, 20.5 years). The overall 10-year survival of the study group was 78%. Four variables were found to be independent predictors of survival. Presented as adjusted odds ratios, from strongest to weakest relative predictive strength, these variables were tumor thickness (odds ratio, 50.8), site of primary melanoma (odds ratio, 4.4), age of the patient (odds ratio, 3.0), and sex of the patient (odds ratio, 2.0). The four-variable model was significantly more accurate than tumor thickness alone, particularly for predicting death. Overall, use of the model reduced the error rate of the prediction of death by 50%. CONCLUSIONS: A prognostic model that uses four readily accessible variables more accurately predicts outcome in patients with primary melanoma than does tumor thickness alone. This four-variable model can identify patients at high risk for the recurrence of disease, an identification that becomes increasingly important as adjuvant therapies are developed for treatment of melanoma.

Effects of AGM-1470 and pentosan polysulphate on tumorigenicity and metastasis of FGF-transfected MCF-7 cells.

Previously, we described FGF-1- or FGF-4-transfected MCF-7 breast carcinoma cells which are tumorigenic and metastatic in untreated or tamoxifen-treated ovariectomised nude mice. In this study, we have assessed the effects of AGM-1470, an antiangiogenic agent, and pentosan polysulphate (PPS), an agent that abrogates the effects of FGFs, on tumour growth and metastasis produced by these FGF-transfected MCF-7 cells. Untreated or tamoxifen-treated ovariectomised mice were injected with FGF-transfected cells, treated with AGM-1470 or PPS, and tumour growth and metastasis analysed. The sensitivity of FGF-transfected and parental MCF-7 cells to AGM-1470 or PPS was also determined in vitro. Both AGM-1470 and PPS inhibited tumour growth in otherwise untreated or tamoxifen-treated mice injected with either FGF- or FGF-4-transfected MCF-7 cells. This effect was more reliably seen in tamoxifen-treated animals. AGM-1470 was about 10(5) times less potent in inhibiting the anchorage-dependent growth of parental MCF-7 or FGF-transfected MCF-7 cells than in inhibiting the growth of human umbilical vein endothelial cells. PPS did not affect the in vitro growth of the transfectants or parental cells. Thus, the growth-inhibitory effect on tumours was in excess of the effect of either drug on the same cells in tissue culture, implying that stromal elements are important determinants of the effects of these drugs. There was a positive correlation between tumour size and the extent of proximal lymph node metastasis. However, neither drug had a significant effect on the extent of metastasis to proximal or distal lymph nodes or lungs. AGM-1470 or PPS may be helpful in cases of breast carcinoma in which angiogenesis is due to expression of FGFs by the tumour cells and may be more effective when combined with tamoxifen.