A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC. METHODS: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. RESULTS: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%). CONCLUSIONS: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies.

Background: In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. Design: We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Results: Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. Conclusions: The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma.

Factors related to decision making and substance use in adolescent survivors of childhood cancer: a presenting clinical profile.

BACKGROUND: Adolescent survivors of childhood cancer are more vulnerable to the consequences of health risk behaviors because of the late effects of their disease and its treatment. Decision making related to risk behaviors is important as they have reached an age during which initiation of substance use risk behavior is common. OBJECTIVE: Factors associated with decision making and substance use behaviors (smoking, alcohol use, and illicit drug use) were identified among adolescent survivors of childhood cancer, the role of cognitive function was examined, and their rates of substance use behaviors were compared to a sample from the general population. METHODS: A cohort of 243 adolescent survivors, ages 14-19 years, participated who were recruited from three cancer centers (St. Jude Children's Research Hospital, Hackensack University, and Long Beach Medical Center). A cross-sectional survey was used to assess cognitive and psychosocial factors for a presenting clinical profile to predict quality decision making and substance use behaviors. Validated measures using online data entry were obtained at the time of their annual visit for evaluation of late effects of treatment. Cancer and treatment factors were abstracted from the medical record. Eight factors (nine for substance use risk behavior) were examined in two regression models, quality decision making and substance use. RESULTS: In the model to predict poor-quality decision making for this cohort, gender and risk motivation (a surrogate for resiliency to social influence) were each significant predictors, with male gender and less resiliency each associated with poor decision making. Significant predictors of lifetime substance use were older presenting age, lower resiliency to social influence, poorer abstract ability (representing executive function impairment), history of current school problems, and negative substance use risk behavior modeling by household members and closest friend; CNS-associated late effects were only marginally associated. For current substance use, three factors remained significant in this cohort: older presenting age, lower resiliency, and negative risk behavior modeling. IMPLICATIONS FOR CANCER SURVIVORS: Study results characterize a presenting clinical profile for adolescent survivors with poor-quality decision making regarding substance use risk behaviors that will be helpful to health professionals counseling teen survivors about the impact of risk behaviors on disease-and treatment-related late effects.

Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251.

PURPOSE: To define the activity and feasibility of brief-duration high-intensity chemotherapy for adults with small noncleaved, non-Hodgkin's lymphoma (SNC) and the L3 variant of acute lymphocytic leukemia (L3 ALL). PATIENTS AND METHODS: Seventy-five adults with either SNC or L3 ALL (median age, 44 years) were treated with an aggressive regimen that consisted of one cycle of cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide; high-dose methotrexate, vincristine, dexamethasone, and either doxorubicin or etoposide/cytarabine; or intrathecal triple therapy with prophylactic CNS irradiation. RESULTS: All 24 patients with L3 ALL and the 30 of 51 patients with SNC confirmed by central histologic review were included in this analysis. Forty-three of 54 patients achieved complete response (CR) (18 of 24 with ALL and 25 of 30 with SNC), and 28 are alive and in continuous CR with a median follow-up of 5.1 years. Hematologic toxicity was profound, and nonhematologic toxicity was notable, with 10 of 75 patients treated developing significant neurologic toxicity consisting of transverse myelitis in five patients, CNS toxicity in three, and severe peripheral neuropathy in two. All patients who did not achieve CR died of the disease, and all recurrences occurred within 16 months of the end of treatment. Responses and toxicities were similar in the patients with both lymphoma and leukemia. CONCLUSION: Aggressively delivered chemotherapy is potentially curative in as many as half of patients with SNC and the L3 ALL variant. This treatment regimen had considerable neurologic toxicity and has been modified.

Use of the aromatase inhibitor anastrozole in the treatment of patients with advanced prostate carcinoma.

BACKGROUND: Men with prostate carcinoma initially respond to therapies designed to inhibit androgen secretion or block its action. Later, the tumors in these patients become refractory to androgen-related therapies. Therefore, additional hormonal maneuvers that would benefit these men currently are needed. Reports of androgen receptor mutations and historic clinical observations raised the hypothesis that estrogens might be involved in the proliferation of androgen-refractory prostate carcinoma. METHODS: To explore this hypothesis, 14 men with advanced prostate carcinoma that was refractory to medical or surgical orchiectomy and antiandrogens were entered into a clinical Phase II trial involving suppression of estrogens. After complete evaluation, each patient received 1 mg daily of the third-generation aromatase inhibitor anastrozole until disease progression. Follow-up included serial determinations of prostate specific antigen (PSA), measurements of evaluable lesions, and assessment of intensity of pain. RESULTS: No patient experienced an objective response or disease stabilization as measured by PSA level or the greatest dimension of the lesion. Minimal improvement of bone pain was reported in two patients receiving intensive analgesic medication. CONCLUSIONS: It was concluded that the dependence of androgen-insensitive prostate carcinoma on estrogens for proliferation is uncommon and that aromatase inhibitors may not have a place in the treatment of prostate carcinoma at this stage of the disease.

Prostate specific antigen kinetics at tumor recurrence after radical prostatectomy do not suggest a worse disease prognosis in black men.

PURPOSE: It has been shown that black men with clinically localized prostate adenocarcinoma treated with radical prostatectomy have poorer disease-free and disease specific survival than white men with similar tumors. These findings suggest that a potentially more aggressive variant of prostate cancer exists in black men. Because prostate specific antigen (PSA) velocity at tumor recurrence is a good indicator of disease aggressiveness, we determine whether there was evidence that PSA velocity at biochemical recurrence after radical prostatectomy is faster in black men. MATERIALS AND METHODS: Our retrospective data search at 2 university centers resulted in 127 white and 37 black men with clinical stage cT1 to 2 prostate adenocarcinoma who underwent radical prostatectomy between 1990 and 1994 and had evidence of biochemical recurrence (PSA greater than 0.2 ng./ml.) on followup available for analysis. No neoadjuvant or adjuvant treatments were given before or after radical prostatectomy, and all PSA relapses and subsequent treatments were recorded. PSA velocity modeling was performed in patients before any form of treatment for PSA failure. Preoperative PSA, Gleason score and pathological stage were also included in the model to assess the impact on PSA velocity after recurrence. RESULTS: Our data suggested that PSA velocity at tumor recurrence was related to preoperative PSA on a continuous scale (p = 0.063). However, in our analysis there was little evidence that race had any effect on PSA velocity at tumor recurrence in our patient cohort (p = 0.58). Likewise, little difference in PSA velocity was seen in regard to Gleason score (p = 0.89) or pathological stage (p = 0.23) in these patients. With data on 37 black men available for analysis it was likely that only large or extreme trends could be detected. Results could be used to estimate required sample sizes for assessment of less extreme trends. CONCLUSIONS: Our data on tumor growth rate at recurrence, as reflected by PSA velocity kinetics, do not support the hypothesis that prostate tumors in black men are necessarily more aggressive due to enhanced growth. Further studies comparing the molecular and biological differences between prostate cancers in black and white males are needed to clarify reasons for the apparent differences in initial presentation, as compared to that at tumor recurrence in these 2 groups.

Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa.

BACKGROUND & AIMS: Barrett adenocarcinoma (BA+) and gastric adenocarcinoma comprise a related group of neoplasms that nevertheless have some distinct clinicopathologic characteristics. This study aimed at defining critical molecular abnormalities that may underlie differences between BA+ and gastric adenocarcinomas. METHODS: We used comparative genomic hybridization for the analyses of 34 xenografts of adenocarcinomas that arose from esophageal or gastric origin. RESULTS: All tumors, except one, exhibited DNA copy number alterations. Losses in 4q and 14q and gains at 2p and 17q were more frequent in proximal (esophageal, gastroesophageal junction [GEJ], and cardia) tumors than in distal (body and antrum) tumors (P

Cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) for advanced-stage Hodgkin's disease: CALGB 8856.

Successful treatment of advanced-stage Hodgkin's disease (HD) may critically depend on dose intensity. Because mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), and Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) are not suitable for major dose escalation, we evaluated the activity and toxicity of combined cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) in advanced HD, here used at conventional dose intensity, as a preparatory study prior to using this regimen at higher dose intensity. Ninety-two patients were treated with CHOPE (cyclophosphamide, 750 mg/m2, day 1; doxorubicin, 50 mg/m2, day 1; vincristine, 1.4 mg/m2, days 1 and 8; prednisone, 100 mg/day, days 1-5; and etoposide, 80 mg/m2, days 1, 2, and 3) every 21 days. All had advanced HD with no prior chemotherapy with 46% stage IV, 63% with B symptoms, and 57% with bulky disease (> 5 cm). Radiation and growth factor support were not permitted. Full-dose vincristine (not capped at maximum 2 mg/dose) was used in the first 33 patients. An initial cohort of 41 patients was treated with four cycles of CHOPE to evaluate safety and efficacy followed by four cycles of ABVD. A second cohort of 51 patients was treated with 6-8 cycles of CHOPE alone. Toxicity was generally acceptable and primarily hematologic, with neutrophils < 500 in 63% of cohort I and 90% of cohort II, and platelets < 25,000 in 7% of cohort I and 8% of cohort II. The long-term neurotoxicity of full-dose, high-intensity vincristine was acceptable and largely reversible. In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional cycles of ABVD. In cohort II, 77% achieved a CR with 6-8 cycles of CHOPE alone. FFS was 76% in cohort I and 59% in cohort II, with a median follow-up of 8.2 and 5.7 years, respectively. CHOPE, at conventional dose intensity as used here, is an effective first-line regimen for the treatment of advanced-stage HD and may warrant evaluation using higher doses of cyclophosphamide and etoposide with granulocyte colony stimulating factor (G-CSF) support.

Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854.

BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.

Prospective assessment of voiding and sexual function after treatment for localized prostate carcinoma: comparison of radical prostatectomy to hormonobrachytherapy with and without external beam radiotherapy.

BACKGROUND: Voiding and sexual function after treatment are major determinants of quality of life in prostate carcinoma patients. Erectile dysfunction, incontinence, and urinary symptoms, both obstructive and irritative, have a significant negative impact on patient quality of life. This prospective study was undertaken to evaluate voiding, sexual function, and their impact on patients with localized prostate carcinoma who were treated with radical retropubic prostatectomy (RP) and to compare these patients with patients who were undergoing hormonobrachytherapy with external bean radiotherapy (HBTC) and patients who were undergoing hormonobrachytherapy without external beam radiotherapy (HBT). METHODS: Patients treated for localized prostate carcinoma with either RP or interstitial palladium-103 (103Pd) HBTC or HBT were prospectively administered a voiding and sexual function questionnaire before any treatment was initiated and at posttreatment visits. Questionnaire components included the American Urological Association Symptom Score (AUASS) and specific items that addressed urinary control and sexual function from the University of California at Los Angeles Prostate Cancer Index. Questionnaire results were compiled, and differences among treatment groups were assessed over time. RESULTS: From January 1997 to November 1999, 127 consecutive patients were treated with either unilateral or bilateral nerve-sparing RP (42 patients), HBTC (40 patients) or HBT (45 patients) by 2 surgeons proficient in all procedures. Using the overall score and the obstructive subscale (OAUA) of the AUASS, the RP group showed a posttreatment decrease in scores compared with both HBTC and HBT groups. OAUA scores of HBTC and HBT groups were significantly greater than scores in RP patients over the course of the study. HBTC patients had increased irritative symptoms initially when compared with RP patients, and, although not statistically significant, the magnitude of the difference persisted over the course of the study. Total AUASS and subscale scores for the RP group returned to near baseline levels within 12 months. The use of incontinence pads was a criterion for urinary incontinence, and the proportion of patients returning to baseline continence was lower in RP patients over the course of the study. No notable differences in Voiding Bother (VB) scores were found. Initially RP patients experienced worse Sexual Function (SF) scores; however, scores for RP patients changed over time and approached the levels seen in HBTC patients at 18 months. The Sexual Function Bother (SFB) scores also were higher initially in the RP group but then decreased to similar levels observed for HBTC patients by 18 months. None of the treatment groups returned to near baseline SF or SFB scores during the course of this study. CONCLUSIONS: Comparison of voiding function indicated that HBTC and HBT patients initially have more obstructive voiding symptoms, whereas urinary incon- tinence is initially worse in RP patients. Initially RP patients demonstrated worse SF and SFB scores, but RP patients returned to HBTC levels within 18 months.

Surgical and postoperative factors affecting length of hospital stay after radical prostatectomy.

BACKGROUND: Radical prostatectomy continues to comprise the mainstay of therapy for localized prostate carcinoma. However, caring for radical prostatectomy patients accounts for approximately half of the $1.7 billion annual cost of prostate carcinoma treatment. Length of stay (LOS) after surgery appears to be one of the main components of this cost. The first step in reducing cost is to identify those variables associated with LOS. Radical prostatectomy can be performed using two very different surgical techniques and with each technique different costs are incurred. The objective of the current study was to identify factors associated with LOS as a function of surgical approach. To reduce potential biases due to patient requests for longer hospitalization or physician preferences in that regard, secondary objectives were to identify factors associated with time to fluid intake (TTF) and time to consume solid foods (TTS). METHODS: An institutional-based, retrospective chart review of 313 men with clinically localized prostate carcinoma who underwent either a perineal (RPP) or retropubic (RRP) prostatectomy at a single university center from March 1988 to October 1996 was undertaken. Information regarding LOS was available for 311 patients. Linear regression models were used to assess the association between covariables and LOS. Poisson regression models for count data were used to assess associations between covariables and the secondary endpoints of TTF and TTS. Covariables included: preoperative (age, race, prostate specific antigen, Gleason score, clinical stage, lymph node resection, comorbidity, and admission time), intraoperative (surgical approach, surgeon, operative time, estimated blood loss, transfusion requirement, anesthetic approach, and American Society of Anesthesiologists score), and postoperative (pain management complications and transfusions) parameters. RESULTS: The median LOS was 4 days (range, 1-19 days) for RPP and 5 days (range, 3-16 days) for RRP approaches. The final model included six main effects and three interaction terms. Overall, LOS decreased over time with LOS decreasing at a faster rate in patients who underwent RPP. In general, patients who underwent RRP had an increased LOS compared with patients who underwent RPP. Complications from surgery and age increased the LOS for all patients; however, the increase was greater in patients who underwent RPP. In addition, the use of intraoperative epidural anesthesia and the increased use of postoperative narcotics were associated with increased LOS for patients undergoing both surgical approaches. TTF and TTS were significantly longer for patients who underwent the retropubic approach compared with those patients who underwent the perineal approach. After adjustment for surgical approach no other covariables were found to be associated with TTF. After adjustment for surgical approach, the occurrence of complications was found to be associated with TTS, indicating that patients who experienced complications took longer before they could tolerate solid foods. CONCLUSIONS: In view of the importance of clinical care pathways in reducing medical expenditures from radical prostatectomy, the results of the current study may contribute to the further refining of these pathways by highlighting the differences and similarities among the variables affecting LOS as a function of surgical approach.

Quality-of-life comparison of radical prostatectomy and interstitial brachytherapy in the treatment of clinically localized prostate cancer.

OBJECTIVES: Interstitial brachytherapy (BT) is increasingly utilized as a curative treatment for localized prostate cancer because it is perceived as less morbid than surgical alternatives. However, to date no studies have directly compared the quality of life and symptoms of patients with localized prostate cancer treated with curative intent by radical prostatectomy with those treated by either BT alone or BT combined with external beam radiation. METHODS: On June 1, 1998, 242 men with clinically localized Stage T1c to T3 adenocarcinoma of the prostate, treated at our institution with curative intent from January 1, 1997 to June 1, 1998, were mailed a questionnaire. Cross-sectional analysis of returned questionnaires was carried out. Patients were treated with either radical prostatectomy (RP), palladium-103 (Pd(103)) brachytherapy (115 Gy) monotherapy (BTM), or Pd(103) combined brachytherapy (90 Gy) and external beam radiation (40 to 45 Gy) (BTC). The primary outcome measures were the Functional Assessment of Cancer Therapy scale (FACT-G), American Urological Association (AUA)/international prostate symptom score (IPSS), "Urinary Function Questionnaire for Men after Radical Prostatectomy," and Brief Sexual Function Inventory. RESULTS: Data from 138 patients were included in the analysis; 27 had RP, 70 had BTM, and 41 had BTC. Total FACT-G and personal well-being scores were significantly lower in the BTC group. Brachytherapy monotherapy and RP had similar scores on the FACT-G, with surgical patients having the lowest IPSS scores. Correlations were noted between total FACT-G and urinary symptom score, degree of sexual function, frequency of diarrhea, and frequency of hot flashes. Bothersomeness of urinary function correlated with the degree of urinary control. The radical prostatectomy and BTM groups had improvement in quality of life, voiding, diarrhea, and sexual function with time, whereas the BTC group experienced a decline. CONCLUSIONS: Patients treated with BTC had an overall lower quality of life compared with those treated by RP and BTM, and RP patients reported fewer irritative or obstructive voiding complaints. Although the consistency and magnitude of these trends require further study, our data suggest that RP remains a well-tolerated and accepted option.

Microvessel density, p53, retinoblastoma, and chromogranin A immunohistochemistry as predictors of disease-specific survival following radical prostatectomy for carcinoma of the prostate.

OBJECTIVES: Angiogenesis has been shown to be related to p53 and retinoblastoma gene function as well as to neuroendocrine differentiation (as measured by chromogranin A staining) in prostate tumors. Studies have indicated that immunohistochemical assessment of p53, retinoblastoma, and chromogranin A in prostate cancers treated by radical prostatectomy can be useful in predicting disease-specific survival, whereas the degree of microvessel density (MVD), a measure of angiogenesis, correlates with disease recurrence. The ability of MVD, however, to predict disease-specific survival either alone or in conjunction with other prognostic factors has not yet been evaluated. The purpose of our study was to determine the relative importance of p53, retinoblastoma, and chromogranin A as well as MVD in the prediction of disease-specific survival following radical prostatectomy in conjunction with classical pathologic assessment. METHODS: From 1970 to 1984, radical prostatectomy was performed on 75 patients with clinical Stage A2 to B2 adenocarcinoma of the prostate. No neoadjuvant or adjuvant treatments were given, and patients were followed until death. Prostatectomy specimens were examined to evaluate conventional pathologic parameters. In addition, the tissue was immunohistochemically stained for p53, retinoblastoma, chromogranin A, and endothelial cells. A previously described computerized imaging system analyzed the microvessels and computed both "optimized" and "area-weighted" MVD scores. Proportional hazard models were used to investigate the simultaneous association of these variables with disease-specific survival. RESULTS: Of the 75 patients, 4 had follow-up of less than 3 months, and 29 patients had inadequate tissue for analysis of all immunohistochemical markers. The analyzed subset of 42 patients was found to be representative of the cohort of 71 patients. Multivariate analysis revealed that p53 and retinoblastoma have the greatest prognostic importance regarding disease-specific survival. Chromogranin A and optimized or area-weighted MVD scores were of no additional value when p53 and retinoblastoma were assessed. CONCLUSIONS: Microvessel density, as a determinant of angiogenesis and chromogranin A, does not seem to add significantly to the prognostic disease-specific survival information provided by conventional pathology combined with p53 and retinoblastoma assessment.

Sequential chemotherapy (etoposide, vinblastine, and doxorubicin) and subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features: A phase II Cancer and Leukemia Group B Study (9051).

BACKGROUND: The aim of this study was to evaluate a regimen of sequential chemotherapy and radiotherapy for patients with Hodgkin disease. METHODS: The Cancer and Leukemia Group B conducted a Phase II study of three cycles of etoposide, vinblastine, and doxorubicin (EVA) chemotherapy followed by subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features. Fifty-nine patients were enrolled in the study. Fifty-three patients met all study eligibility criteria; 48 of them (91%) had mediastinal disease and 29 (55%) had bulky mediastinal disease. RESULTS: A complete response (CR) occurred in 35 of the patients (66%). Of all patients who had CR, 26% had the CR after the chemotherapy and before the radiation, and 74% after the chemotherapy and radiation. Twenty percent of the patients who had CR experienced disease progression; in these patients, the progression was outside the radiotherapy field in the lung and involved widespread disease. CONCLUSIONS: EVA offers a nonbleomycin-containing alternative for patients in whom preexisting pulmonary disease may be exacerbated by bleomycin and radiation therapy. EVA, as given in this study (in three cycles), was insufficient chemotherapy for patients who had disease in areas outside the radiation fields (occult disease).

Origin of microsatellite instability in gastric cancer.

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma.

Urinary function after radical prostatectomy: a comparison of the retropubic and perineal approaches.

OBJECTIVES: Urinary continence is one of the most significant outcomes after radical surgery for prostate cancer. Although both retropubic and perineal approaches to radical prostatectomy are commonly used, they have not yet been compared with respect to urinary continence and voiding function in a single-institution study using a validated patient-administered instrument. This study had two primary objectives: first, to assess whether differences exist between these two procedures with respect to the overall prevalence and resolution of postoperative urinary incontinence, and second, to determine the impact of the urinary incontinence on patient lifestyle in this patient population. METHODS: A written instrument composed of the Urinary Function Questionnaire for Men after Radical Prostatectomy, the American Urological Association (AUA) Symptom Score, and seven items querying urinary retention and urinary function bother were mailed in February 1996 to 209 men who underwent radical prostatectomy by either the perineal (43%) or retropubic (57%) approach between January 1990 and December 1995. Descriptive statistics were used to summarize the prevalence of urinary incontinence and urinary function bother as reported from this cross-sectional questionnaire. Logistic regression models were used to assess the association between reported urinary incontinence and surgical approach, AUA symptom scores, and treatment of incontinence after adjusting for possible confounders (eg, the time between surgery and questionnaire, and patient age). RESULTS: One hundred sixty-seven men (80%) responded to the questionnaire. The median age of the participants at questionnaire administration was 68 years (range 43 to 80). Overall, 57% (95% confidence interval [CI] 50% to 63%) of the responders reported complete urinary continence at the time of the questionnaire, with a median time between surgery and the questionnaire of 2.7 years (range 0.3 to 5.4). When continence was defined as either complete dryness or minimal urinary leakage, 75% (95% CI 69% to 81%) of the responders reported being continent. In men who responded to the questionnaire within 2 years of surgery, the probability of experiencing complete urinary continence was similar between the two surgical approaches. In men who responded to the questionnaire more than 2 years after surgery, patients who had undergone perineal prostatectomy were more likely to report complete continence than those who underwent retropubic surgery. However, this observed difference disappears when continence was defined as either complete dryness or minimal urinary leakage. The major impact of urinary incontinence on patient lifestyle was observed in patients with more than just minimal leakage. CONCLUSIONS: Radical perineal and radical retropubic prostatectomy have similar outcomes when patients with minor degrees of incontinence are grouped together with continent patients. Since the impact of a minimal degree of urinary incontinence on the patient's lifestyle after radical prostatectomy seems to be minor, currently we do not believe that postoperative continence status is a major factor in choosing one procedure over the other.

Allelotype of gastric adenocarcinoma.

Gastric adenocarcinoma is a leading cause of cancer mortality world-wide. Yet, the underlying molecular events important in the development of this cancer are largely undefined. Thus, we performed a comprehensive survey for allelic loss on our panel of xenografted human gastric carcinomas. Contaminating normal stromal cells of primary cancers often limit mutational analyses. Xenografted samples of our gastric carcinomas provided optimally enriched tumors for neoplasia that clearly and sensitively demonstrated genetic alterations. Additionally, total absence of allelic signals in these xenografted samples confirmed true loss of alleles rather than just allelic imbalance. Analysis of at least two highly polymorphic microsatellite markers per nonacrocentric chromosomal arm in our xenografted human gastric carcinomas demonstrated significant loss of heterozygosity well above background levels at 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q. Several of these loci represent novel findings of significant loss in gastric cancers. On chromosome 17p, p53 is known to be inactivated either by mutation or deletion in a majority of gastric carcinomas. The critical target(s) of inactivation in gastric cancers at these other loci remain to be characterized.