Neoadjuvant Endocrine Therapy Versus Neoadjuvant Chemotherapy in Node-Positive Invasive Lobular Carcinoma.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is often recommended for patients with node-positive invasive lobular carcinoma (ILC) despite unclear benefit in this largely hormone receptor-positive (HR+) group. We sought to compare overall survival (OS) between patients with node-positive ILC who received neoadjuvant endocrine therapy (NET) and those who received NACT. METHODS: Women with cT1-4c, cN1-3 HR+ ILC in the National Cancer Data Base (2004-2014) who underwent surgery following neoadjuvant therapy were identified. Kaplan-Meier curves and Cox proportional hazards modeling were used to estimate unadjusted and adjusted overall survival (OS), respectively. RESULTS: Of the 5942 patients in the cohort, 855 received NET and 5087 received NACT. NET recipients were older (70 vs. 54 years) and had more comorbidities (Charlson-Deyo score ≥ 1: 21.1% vs. 11.5%), lower cT classification (cT3-4: 44.2% vs. 51.0%), lower rates of mastectomy (72.5% vs. 82.2%), lower rates of pathologic complete response (0% vs. 2.5%), and lower rates of postlumpectomy (73.2% vs. 91.0%) and postmastectomy (60.0% vs. 80.8%) radiation versus NACT recipients (all p < 0.001). NACT recipients had higher unadjusted 10-year OS versus NET recipients (57.9% vs. 36.0%), but after adjustment, there was no significant difference in OS between the two groups (p = 0.10). CONCLUSIONS: Patients with node-positive ILC who received NET presented with smaller tumors, older age, and greater burden of comorbidities versus NACT recipients but had similar adjusted OS. While there is evidence from clinical trials supporting efficacy of NET in HR+ breast cancer, our findings suggest the need for further, histology-specific investigation regarding the optimal inclusion and sequence of endocrine therapy and chemotherapy in ILC.

Prognostic significance of high-grade dysplasia in colorectal adenomas.

AIM: Colonoscopy to detect and remove polyps has contributed to a reduction in colorectal carcinoma. Three-year follow up is recommended for patients considered to be at high risk (at least three adenomas, adenoma ≥ 1 cm, villous or high-grade features). Our study focused on patients diagnosed with high-grade dysplasia with regard to initial management and follow up. METHOD: A search of patients who had had endoscopic removal of a high-grade adenoma was carried out. Patients with the following were excluded: follow up of < 1 year, polyposis syndromes, prior colon cancer and a diagnosis of adenocarcinoma within 6 months following initial diagnosis. RESULTS: Eighty-three patients treated between 1999 and 2007 for high-grade dysplasia (HGD) in a colorectal adenoma were identified. Over a median follow-up period of 4 years, 53 (64%) developed further adenomatous polyps. Among these, 7% had an adenoma with HGD or an adenocarcinoma. In all these patients, the initial high-grade adenoma was > 1 cm in diameter. Initial follow-up colonoscopy was performed on average 7 months following the initial diagnosis. Ten per cent of patients underwent prophylactic segmental resection, and 6% received argon laser therapy. CONCLUSION: The study demonstrates that patients who have a colorectal adenoma > 1 cm with HGD may be at high risk of developing further adenomas with HGD or carcinoma. Close follow up is warranted.

Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

BACKGROUND: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results. PATIENTS AND METHODS: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria. RESULTS: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33). CONCLUSION: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity. TRIALS REGISTRATION: ClinicalTrial.Gov NCT00545077 and NCT00601900.

Polymorphisms in adenosine receptor genes are associated with infarct size in patients with ischemic cardiomyopathy.

The goal of this experiment was to identify the presence of genetic variants in the adenosine receptor genes and assess their relationship to infarct size in a population of patients with ischemic cardiomyopathy. Adenosine receptors play an important role in protecting the heart during ischemia and in mediating the effects of ischemic preconditioning. We sequenced DNA samples from 273 individuals with ischemic cardiomyopathy and from 203 normal controls to identify the presence of genetic variants in the adenosine receptor genes. Subsequently, we analyzed the relationship between the identified genetic variants and infarct size, left ventricular size, and left ventricular function. Three variants in the 3'-untranslated region of the A(1)-adenosine gene (nt 1689 C/A, nt 2206 Tdel, nt 2683del36) and an informative polymorphism in the coding region of the A3-adenosine gene (nt 1509 A/C I248L) were associated with changes in infarct size. These results suggest that genetic variants in the adenosine receptor genes may predict the heart's response to ischemia or injury and might also influence an individual's response to adenosine therapy.

DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus.

Double-strand breaks (DSBs) can be efficiently removed from the DNA of higher eukaryotes by nonhomologous end-joining (NHEJ). Genetic studies implicate the DNA-dependent protein kinase (DNA-PK) in NHEJ, but the exact function of this protein complex in the rejoining reaction remains to be elucidated. We compared rejoining of DNA DSBs in a human glioma cell line, M059-J, lacking the catalytic subunit of DNA-PK (DNA-PKcs), and their isogenic but DNA-PK-proficient counterpart, M059-K. In both cell lines, rejoining of DNA DSBs was biphasic, with a fast and a slow component operating with a half-life of approximately 22 min and 12 h, respectively. Deficiency in DNA-PK activity did not alter the half-times of either of these components of rejoining but increased from 17 to 72% the proportion of DNA DSB rejoining with slow kinetics. DNA DSB rejoining was nearly complete in both cell lines, and there was only a small increase in the number of unrejoined breaks in M059-J as compared with M059-K cells after 30 h of incubation. Wortmannin radiosensitized to killing M059-K cells and strongly inhibited DNA DSB rejoining. Wortmannin did not affect the radiosensitivity to killing and produced only a modest inhibition in DNA DSB rejoining in M059-J cells, suggesting that, for these end points, DNA-PK is the principal target of the drug. These observations demonstrate that DNA-PK deficiency profoundly decreases the proportion of DNA DSB rejoining with fast kinetics but has only a small effect on the fraction remaining unrejoined. We propose that in higher eukaryotes, an evolutionarily conserved, independently active, but inherently slow NHEJ pathway is stimulated 30-fold by DNA-PKcs to rapidly remove DNA DSBs from the genome. The stimulation is expected to be of local nature and the presence of DNA-PKcs in the vicinity of the DNA DSB determines whether rejoining will follow fast or slow kinetics. Structural and regulatory functions of DNA-PKcs may mediate this impressive acceleration of DNA DSB rejoining, and regions of chromatin within a certain range from this large protein may benefit from these activities. We propose the term DNA-PK surveillance domains to describe these regions.

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism.

Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.

Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients.

PURPOSE: Metastatic deposits are the most common intraocular malignancies. We evaluated the efficacy of external-beam radiotherapy (EBRT) in the palliation of posterior uveal metastases in terms of clinically relevant outcomes: functional vision, tumor control, and globe preservation. PATIENTS AND METHODS: Four hundred eighty-three consecutive patients (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972 and 1995. Of these, 233 eyes (188 patients) had lesions of the posterior uveal tract and received EBRT. Best-corrected visual acuity (VA) was documented pre- and post-EBRT. Visual function was considered excellent if VA < or = 20/50, navigational if 20/60 to 20/200, and legally blind if > or = 20/400. Most patients received 30 to 40 Gy in 2- to 3-Gy fractions to the posterior or entire globe. RESULTS: Fifty-seven percent of all assessable eyes had improved visual function or maintained at least navigational vision following EBRT. Thirty-six percent of legally blind eyes regained useful vision. Ninety-three percent experienced no clinical evidence of tumor progression and the globe preservation rate was 98%. The following characteristics independently predicted improvement to or maintenance of excellent vision on multivariate analysis: excellent vision pre-EBRT (P = .001), age less than 55 years (P = .004), white race (v black/Hispanic) (P = .003), and tumor base diameter less than 15 mm (P < .001). CONCLUSION: EBRT effectively restores and maintains useful vision in patients with choroid metastases, with a globe preservation rate of 98%. Patients less than 55 years with pretreatment VA better than 20/60 and tumor diameter less than 15 mm are most likely to benefit from this therapeutic intervention.

Intention to be tested for prostate cancer risk among African-American men.

This study was conducted to identify factors associated with intention to be tested for prostate cancer risk among African-American men. Participants in this study included African-American men (n = 548) who were patients at the University Health Service at the University of Chicago, were 40 to 70 years of age, and did not have a personal history of prostate cancer. Baseline telephone survey data were collected for 413 (75%) men. Respondents were asked if they intended to have a blood test to assess prostate cancer risk. Univariate and multivariate analyses of intention to be tested for risk were performed. Eighty-six percent of the men said that they intended to be tested. Multivariate analysis results show that belief in the efficacy of prostate cancer screening [odds ratio (OR) = 3.6; 95% confidence interval (CI) = 1.4, 9.1] and intention to undergo a prostate cancer-screening (i.e., digital rectal examination and prostate-specific antigen testing; OR = 2.8; 95% CI = 1.3, 6.3) were positively associated with intention to be tested for prostate cancer risk. Being older (OR = 0.4; 95% CI = 0.2, 0.9), having had a prostate cancer-screening examination in the past year (OR = 0.5; 95% CI = 0.2, 1.0), perceiving one's prostate cancer susceptibility to be high (OR = 0.4; 95% CI = 0.2, 0.8), and being fatalistic about prostate cancer prevention (OR = 0.3; 95% CI = 0.2, 0.7) were negatively associated with intention to be tested for risk. Intention to be tested for prostate cancer risk was high among men in the study. Past screening, perceived susceptibility, and beliefs related to early detection might influence receptivity to genetic testing for prostate cancer risk.

Physician intention to recommend complete diagnostic evaluation in colorectal cancer screening.

Primary care physicians (PCPs) often do not recommend complete diagnostic evaluation (CDE; i.e., diagnostic colonoscopy or the combination of flexible sigmoidoscopy and barium enema X-ray procedures) for patients with an abnormal screening fecal occult blood test (FOBT+) result. Information is needed to understand why PCPs do not recommend CDE. In the spring of 1994, a telephone survey was carried out using a random sample of 520 PCPs in Pennsylvania or New Jersey who had patients that were targeted for an FOBT screening program. Survey data were obtained from 363 (70%) PCPs on physician practice characteristics; personal background; perceptions concerning FOBT screening, CDE performance, and patient behavior; social influence related to CDE; and intention to recommend CDE for FOBT+ patients. Physician CDE intention scores were distributed as follows: low (22%), moderate (51%), and high (27%). Multivariate analyses demonstrate that physician board certification status, time in practice, belief in CDE efficacy, and belief that CDE is standard practice were positively associated with CDE intention, whereas concern about CDE-related costs was negatively associated with CDE intention. Among physicians in larger practices, perceived FOBT screening efficacy was negatively associated with CDE intention, and belief in the benefit of CDE was positively associated with outcome. There is substantial variability in CDE intention among PCPs. Physician perceptions about FOBT screening and follow-up are associated with CDE intention, are likely to influence CDE performance, and may be amenable to educational intervention. Additional research is needed to evaluate the impact of educational interventions on CDE intention and performance.

External beam irradiation for choroid metastases: identification of factors predisposing to long-term sequelae.

PURPOSE: To improve overall quality of life, palliative treatments should attempt to minimize associated complications while effectively controlling specific symptoms. We reviewed our experience treating posterior uveal metastases with external beam radiotherapy (EBRT) to determine the complication rate and to identify the relationship between patient, tumor, or treatment-related factors and the development of ocular complications. METHODS AND MATERIALS: 483 consecutive patients (pts) (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972-1995. Of these, 233 eyes (188 pts) had lesions of the posterior uveal tract and received EBRT. Median follow-up time was 5.8 months (range: 0.7-170.0 months). Follow-up information regarding the development of complications was documented for 230 eyes. Complete EBRT details were available for 189 eyes. Seventy-two percent of the patients received 30.0-40.0 Gy in 2.0-3.0 Gy fractions. Biologically effective dose (BED) was calculated to allow meaningful comparisons between various fractionation regimens and total doses. Concurrent chemotherapy and/or hormonal therapy was used for 101 eyes (44%). RESULTS: Median BED was 61 Gy3 (range, 6.7-105 Gy3), and 80% of treated eyes received BED 50-70 Gy3. EBRT energies included photons (70%), 60Co (19%), electrons (6%), mixed energies (3%), and orthovoltage (2%). Lens-sparing techniques were used in 136 eyes (71%). At last follow-up 28 eyes (12%) developed one or more significant complications, including cataracts (16 eyes), radiation retinopathy (6 eyes), optic neuropathy (5 eyes), exposure keratopathy (5 eyes), and neovascularization of the iris (4 eyes). Two eyes developed narrow-angle glaucoma, and one of these required enucleation. On univariate analysis, Caucasian race (vs. Black/Hispanic, p = 0.03), increased intraocular pressure at diagnosis (>21 mmHg, p = 0.02), and diagnosis by biopsy (vs. no biopsy, p = 0.03) predisposed toward the development of complications. Factors not correlated with complications included BED (p = 0.18), energy type (p = 0.81), lens-sparing technique (versus whole globe, p = 0.57), and concurrent systemic treatment (p = 0.60). The small number of complications did not support a multivariate analysis. CONCLUSIONS: Despite the employment of a variety of EBRT treatment techniques and the proximity of choroidal metastases to radiosensitive structures, significant complications of palliative EBRT were infrequent. Although complications do occur, they are related to host factors and do not appear to be a function of irradiation parameters. We conclude that the potential benefits of vision and globe preservation after palliative EBRT outweigh the small risk of treatment induced complications.

Muscle sodium channel inactivation defect in paramyotonia congenita with the thr1313met mutation.

Mutations of the skeletal muscle sodium (Na) channel have been reported in families with paramyotonia congenita (PC), an autosomal dominant disorder with cold and/or exercise induced stiffness and myotonia. Functional consequences of specific Na channel mutations responsible for PC have not been described. Patch clamp recording of single Na channels were made in cultured myotubes at 22 and 34 degrees C from a PC patient with the thr1313met mutation. Cell-attached and outside-out recordings of mutant PC channels contained long duration and late openings. The mean open time was increased and the ensemble average showed a prolonged inward Na current. This membrane depolarization could cause repetitive action potentials and the clinical syndrome.

Overexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline ovarian tumors.

Ovarian epithelial tumors are classically divided into benign, malignant, and borderline or of low malignant potential. It is controversial whether this last group of tumors should be considered benign or malignant. Expression of cell cycle markers has recently been linked to tumor behavior and response to treatment. It has been shown that one of the pathways through which the p53 gene controls the cell cycle is by transactivating p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor. By inhibiting cdks, p21WAF1/CIP1 blocks the G-1 to S-phase transition in the cell cycle. p53 can be regulated by MDM2 (murine double minute-2) through direct inactivation or promotion of its cytoplasmic degradation. In an attempt to investigate the cell cycle checkpoint mechanisms of these tumors, we studied the expression of p53, Ki-67, MDM2, and p21WAF1/CIP1 by immunohistochemistry. We analyzed the expression of these proteins in 19 cystadenomas (8 serous and 11 mucinous), 40 borderline tumors (31 serous and 9 mucinous), and 18 serous carcinomas of the ovary. p21WAF1/CIP1 was expressed in 7 of 19 (37%) benign cystadenomas, 32 of 40 (80%) borderline tumors (93.5% of serous and 33% of mucinous), and in 9 of 18 (50%) serous carcinomas. Ki-67 was only weakly expressed in 8 of 19 (42%) benign cystadenomas, all borderline tumors showed Ki-67 staining in less than 50% of the cells, and 55% of serous carcinomas stained in more than 50% of tumor cells. p53 was absent in all but 1 of the cystadenomas, was expressed in 9 of 40 (22.5%) borderline tumors (25.8% of serous and 11% of mucinous), and in 10 of 18 (55%) carcinomas. All 11 implants of serous borderline tumors expressed p21WAF1/CIP1. Most serous borderline tumors expressed higher levels of MDM2 compared with the benign cystadenomas and carcinomas. Four of the serous borderline implants (40%) expressed MDM2. Coexpression of p21WAF1/CIP1 and MDM2 characterizes serous borderline tumors of the ovary and their implants, which suggests that these cell cycle control proteins are important in these tumors and may be related to tumor progression. Low expression of p53 protein in serous borderline tumors might be in part mediated by MDM2. This suggests that the p53 pathway is intact in most of these tumors, in contrast with carcinomas, in which high expression of p53 has been related to mutations of this gene.

Stage T3 prostate cancer: a nonrandomized comparison between definitive irradiation and induction hormonal manipulation plus prostatectomy.

OBJECTIVES: At our institution, a Phase II trial using androgen suppression followed by surgery was completed for men with Stage T3 disease and negative laparoscopic nodal dissection. We recently reported the unfavorable biochemical outcome of that experience. Because that analysis did not include a control group of irradiated patients, the current project was undertaken to compare that Phase II experience with clinical Stage T3 patients treated at our institution with definitive irradiation during an overlapping period of time. METHODS: The Phase II trial included 21 patients with T3 tumors and negative laparoscopic nodal dissections treated by 4 months of neoadjuvant hormonal treatment (leuprolide +/- flutamide) prior to radical prostatectomy. Patients who declined to participate in the study or those judged ineligible by virtue of poor surgical risk were treated with definitive irradiation (n = 29). Although the radiation portals were shaped with multileaf collimation, no attempt was made to design "conformal fields." The median dose was 68 Gy (range 66 to 72) delivered in conventional fractionation. Biochemical failure after prostatectomy was defined as prostate-specific antigen (PSA) levels exceeding 0.2 ng/mL. Biochemical failure after irradiation was defined as a rise in absolute level of PSA greater than 1.5 ng/mL, or two consecutive elevations of PSA on sequential measurements, even if the absolute level was less than 1.5 ng/mL. RESULTS: In univariate comparison, the freedom from biochemical relapse rate at 3 years was 41% for irradiated patients and 23% for those treated by hormones combined with surgery (P <0.05). In a multivariate regression model controlling for the prognostic factors of baseline PSA, age, clinical substage, Gleason score, and treatment modality (induction androgen suppression + prostatectomy versus radiotherapy), only low baseline PSA independently predicted improved freedom from biochemical recurrence (P = 0.04). CONCLUSIONS: The combination of induction hormonal treatment followed by radical prostatectomy offered no advantage over irradiation alone in this single institutional experience. Notwithstanding, the majority of men treated by definitive radiotherapy manifested biochemical failure. More innovative strategies such as conformal irradiation (either alone or combined with androgen ablation) and radiation dose escalation should be pursued to optimize outcome for this unfavorable group of patients.

African-American men and intention to adhere to recommended follow-up for an abnormal prostate cancer early detection examination result.

OBJECTIVES: To assess the intention of African-American men to have the recommended follow-up in the event of an abnormal prostate cancer early detection examination and to identify the variables that help to explain adherence intention. METHODS: In the spring of 1995, we selected a random sample of 548 African-American men who were patients at the University of Chicago Health Service. The sample included men who were 40 to 70 years of age, did not have a personal history of prostate cancer, and had a working telephone number. A total of 413 men who completed the telephone survey received an invitation to consider undergoing a prostate cancer early detection examination. The survey provided data on personal background characteristics, knowledge, attitudes, and beliefs related to prostate cancer and early detection. Respondents were asked whether they would choose to have the recommended follow-up in the event of an abnormal early detection examination result. Univariate and multivariate analyses of intention to have follow-up were performed. RESULTS: An intention to have the recommended follow-up was reported by 77% of the survey respondents. The results of multivariate analyses revealed that the intention to have the follow-up was positively associated with education beyond high school (odds ratio [OR] 1.9); perceived self-efficacy related to prostate cancer screening (OR 2.1); the belief that prostate cancer can be cured (OR 3.3); the belief that prostate cancer screening should be done in the absence of prostate problems (OR 2.3); and physician support for prostate cancer screening (OR 2.1). CONCLUSIONS: African-American men who have a high school education or less may be at risk of nonadherence to recommended follow-up. Adherence also may be low among men who do not have favorable views of early detection or do not perceive strong physician support for early detection. Research is needed to determine whether intention and other factors predict actual adherence to follow-up in this population group.

Induction androgen deprivation plus prostatectomy for stage T3 disease: failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial.

OBJECTIVES: There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations. METHODS: Of 26 patients, 21 had negative laparoscopic lymphadenectomy followed by 4 months of NHT (leuprolide +/- flutamide) prior to radical prostatectomy. eMRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3-month intervals. Prostatectomy specimens were evaluated by 3-mm whole-mount step sections. RESULTS: Prior to prostatectomy, biochemical response was documented in all patients and downsizing was observed by eMRI in 57%. Pathologic downstaging to a lower stage (T2c or lower) was achieved in 48%. However, the actuarial 3-year freedom from biochemical relapse rate was only 24%. CONCLUSIONS: Using laparoscopy to exclude node-positive patients and 4 months of NHT appears to result in pathologic and initial biochemical evidence of regression. These factors have not translated into improved freedom from biochemical relapse among patients with Stage T3 disease treated with NHT and prostatectomy. Recent data strongly suggest a beneficial effect in patients with clinical T2 disease treated with NHT and radical prostatectomy. The NGT and radical prostatectomy approach appeared to offer no clear advantage when compared with PSA-based benchmarks achieved with conformal irradiation or NHT followed by external beam treatment among patients with clinical T3 disease.

Prostate imaging may not be necessary in nonpalpable carcinoma of the prostate.

OBJECTIVES: Stage T1c carcinoma of the prostate is defined as a nonpalpable carcinoma (NPC-P) that is not visible by imaging and is identified by needle biopsy performed because of elevated prostate-specific antigen (PSA) concentrations. The purpose of this study was to define the incidence of normal findings on transrectal ultrasound (TRUS) and/or endorectal coil magnetic resonance imaging (EMRI) among patients with NPC-P, as well as to investigate the value of differentiating patients with Stage T1c disease from all other patients with NPC-P. METHODS: The records of 2211 patients diagnosed with prostate carcinoma between 1988 and 1995 were reviewed to identify 291 men with NPC-P. TRUS and EMRI reports were analyzed with regard to the presence and laterality of hypoechoic nodules or low-signal areas reported on T2-weighted images, respectively. Ninety percent of patients (n = 262) had at least six prostate biopsies, 185 patients (64%) underwent both TRUS and EMRI, 224 (77%) had TRUS, and 251 (86%) had an EMRI study. RESULTS: Results were considered normal in 101 (47%) of 214 patients undergoing TRUS, in 58 (23%) of 249 undergoing EMRI, and in 22 (12%) of 185 undergoing both TRUS and EMRI. For the side of the prostate with positive biopsy results, correlation with imaging abnormalities was better for EMRI than for TRUS (39% versus 24%). There was no significant difference in mean PSA value, distribution of Gleason score, or unilateral versus bilateral positive biopsy results among patients with normal versus abnormal findings on both TRUS and EMRI. CONCLUSIONS: (1) Only 12% of men with NPC-P have no TRUS or EMRI abnormalities, fulfilling the criteria for Stage T1c prostate carcinoma. (2) Those patients with Stage T1c disease do not differ from patients with NPC-P up-staged by TRUS or EMRI, with regard to pretreatment PSA levels, Gleason scores, and the probability of having bilateral rather than unilateral positive biopsy results. (3) The value of classifying patients with NPC-P into Stage T1c versus higher stages of prostate carcinoma on the basis of imaging should be questioned.

Long-term outcome following sympathectomy for complex regional pain syndrome type 1 (RSD).

We performed a retrospective study of 29 patients with CRPS1 (RSD) who were initially examined between 1983 and 1993, and had either transthoracic (lower third of stellate ganglia to T3) or lumbar (L2-L4) sympathectomy. The patients were followed from 24 to 108 months after surgery. Patients with unsuccessful surgical outcomes had significantly longer duration of symptoms before surgery (median, 36 months) than those with successful outcomes (median, 16 months) by Wilcoxon rank sum test (chi2=8.69, df=1, P<0.01). All seven patients (100%) who had sympathectomy within 12 months of injury, nine of 13 patients (69.2%) who had sympathectomy within 24 months of injury, and only four of nine patients (44.4%) who had sympathectomy after 24 months of injury obtained permanent (greater than 24 months) symptom relief. Patient age, sex, occupation, site of injury, type of injury, presence of trophic changes, and duration of follow-up were not significantly related (P>0.05) to surgical outcome.

Mean difference vs. variability reduction: tradeoffs in aggregate measures for individual bioequivalence. FDA Individual Bioequivalence Working Group.

Aggregate criteria for individual bioequivalence allow a tradeoff between difference in average bioavailability and reduction in within-subject variability. That is, a large difference in the average bioavailability between a test and a reference formulation can be offset by a sufficient reduction in variability of the test formulation. This offset could allow the test formulation to pass many individual bioequivalence criteria. We have identified 4 possible approaches for dealing with this tradeoff issue: say "No problem," since a reduction in variability is desirable; use disaggregate criteria; use general weighted forms of the individual bioequivalence criteria that weight the variance terms; and change the acceptable upper limits to reduce the impact of scaling to the reference formulation's within-subject variability. A dataset with a 14% increase in average bioavailability and a 48% reduction in within-subject standard deviation is used as an example of these issues.

Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells.

Expression of c-Myb is required for normal hematopoiesis and for proliferation of myeloid leukemia blasts and a subset of T-cell leukemia, but its role in B-cell leukemogenesis is unknown. We tested the role of c-Myb in p190(BCR/ABL)-dependent B-cell leukemia in mice transplanted with p190(BCR/ABL)-transduced marrow cells with a c-Myb allele (Myb(f/d)) and in double transgenic p190(BCR/ABL)/Myb(w/d) mice. In both models, loss of a c-Myb allele caused a less aggressive B-cell leukemia. In p190(BCR/ABL)-expressing human B-cell leukemia lines, knockdown of c-Myb expression suppressed proliferation and colony formation. Compared with c-Myb(w/f) cells, expression of Bmi1, a regulator of stem cell proliferation and maintenance, was decreased in pre-B cells from Myb(w/d) p190(BCR/ABL) transgenic mice. Ectopic expression of a mutant c-Myb or Bmi1 enhanced the proliferation and colony formation of Myb(w/d) p190(BCR/ABL) B-cells; by contrast, Bmi1 downregulation inhibited colony formation of p190(BCR/ABL)-expressing murine B cells and human B-cell leukemia lines. Moreover, c-Myb interacted with a segment of the human Bmi1 promoter and enhanced its activity. In blasts from 19 Ph(1) adult acute lymphoblastic leukemia patients, levels of c-Myb and Bmi1 showed a positive correlation. Together, these findings support the existence of a c-Myb-Bmi1 transcription-regulatory pathway required for p190(BCR/ABL) leukemogenesis.