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.

Evaluation of acute renal colic: a comparison of non-contrast CT versus 3-T non-contrast HASTE MR urography.

With the introduction of a 3-T scanner, magnetic resonance urography (MRU) may be an alternative imaging modality for evaluation of acute renal colic. We performed a prospective study to compare the performance of computed tomography (CT) with half-Fourier single shot turbo spin-echo (HASTE) MRU in the evaluation of patients with suspected renal colic. Patients presenting to the emergency department with acute renal colic were eligible for inclusion. Following a standard CT stone evaluation, patients underwent a non-contrast HASTE MRU study with a 3-T scanner. The presence of perinephric fluid, hydronephrosis, ureteral obstruction, and calculus was assessed. A total of 22 patients completed the study. Twenty (91 %) were diagnosed with an upper tract stone by radiographic findings. MRU detected a discrete stone in 50 % of the patients with stones detected by CT. Perinephric fluid was noted in 12 MRUs, compared to 7 CTs. Using CT as the reference standard, the combination of stone or perinephric fluid and ureteral dilation gave MRU a sensitivity of 84 %, specificity of 100 %, and accuracy of 86 % (95 % CI 0.72-1.0). HASTE MRU with a 3-T MR scanner can reliably detect the presence of upper urinary tract obstruction. Although CT imaging remains the superior modality with which to detect calculi, MRU detects a greater number of secondary signs of upper tract obstruction. For situations in which the use of ionizing radiation is undesirable, MRU is a reasonable imaging alternative.

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.

Breast cancer: dietary and environmental oestrogens.

Breast cancer is among the most common of the cancers that occur in women living in western societies. It is a much-feared disease and the risks are confusing and often badly reported. Oestrogen levels are a known risk factor. But is it possible to lower the risk? And where are all the oestrogens coming from?

Proteomic patterns of nipple aspirate fluids obtained by SELDI-TOF: potential for new biomarkers to aid in the diagnosis of breast cancer.

Nipple aspirate fluid (NAF) has been used for many years as a potential non-invasive method to identify markers for breast cancer risk or early detection. Because individual markers have not been optimal, we are exploring the use of surface enhanced laser desorption and ionization time of flight (SELDI-TOF) mass spectrometry to identify patterns of proteins that might define a proteomic signature for breast cancer. SELDI-TOF was used to analyze a study set of NAF samples that included 12 women with breast cancer and 15 healthy controls (the latter included three women with an abnormal mammogram but subsequent normal biopsy). In this preliminary report, we present data showing that SELDI analysis of NAF is rapid, reproducible, and capable of identifying protein signatures that appear to differentiate NAF samples from breast cancer patients and healthy controls, including those with an abnormal mammogram who were later proven to be biopsy normal.

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.

Predictive value of cathepsin-D for cervical lymph node metastasis in head and neck squamous cell carcinoma.

BACKGROUND: Prognosis of head and neck squamous cell carcinoma (HNSCC) is strongly associated with cervical lymph node metastasis. Cathepsin-D is a lysosomal protease expressed in all cells. Its role in extracellular matrix degradation is postulated to promote tumor invasion and metastasis. Increased cathepsin-D has been demonstrated in cervical lymph node metastasis in HNSCC. METHODS: Formalin fixed tumor biopsy samples from 34 patients with HNSCC of the oral cavity, oropharynx, or hypopharynx were analyzed for the presence of cathepsin-D by immunohistochemistry (1:8000, Calbiochem, Cambridge, MA). Tumors were considered positive if >50% of cells showed strong cytoplasmic staining. RESULTS: All patients had T1 or T2 lesions ranging in size from 1-4 cm and 19 (56%) had cervical metastasis. Eight (24%) were well differentiated and 26 (76%) were moderately or poorly differentiated. Thirteen tumors (38%) had high cathepsin-D expression that was strongly associated with cervical lymph node metastasis (p = 0.008). When adjusted for tumor stage and grade, cathepsin-D positivity was nearly twice as likely to be associated with node metastasis (p = 0.011). CONCLUSIONS: We demonstrated cathepsin-D expression in biopsies from a subset of patients with HNSCC and a strong association between this protease and cervical lymph node metastases. Cathepsin-D is a potential independent predictor of cervical lymph node metastasis in HNSCC and merits additional study.

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.

Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer.

Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. We examined the expression of a series of tumor markers that have been associated with chemotherapy resistance in pretreatment biopsies from 68 patients who received cisplatin-based neoadjuvant chemotherapy at either of two institutions. Patients received either cisplatin/5-fluorouracil (n = 49) or cisplatin/paclitaxel (n = 19). Expression of p53, glutathione S-transferase pi (GSTpi), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST pi and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GSTpi score group, compared to 46% in the high GSTpi score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GSTpi, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.

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.