A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

BACKGROUND: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). RESULTS: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. CONCLUSIONS: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer.

BACKGROUND: This was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization. METHODS: Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375-1000 mg/m(2) b.i.d.) for 14 days every 21 days. Radioembolization with (90)Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine. RESULTS: Twenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m(2). The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively. CONCLUSIONS: This combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m(2) b.i.d. is recommended for phase II study with sequential lobar radioembolization.

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer.

BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.

Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND: Increased Aurora kinase A gene copy number (AURKA-CN) has been reported in metastatic colorectal cancer (mCRC), with unknown relationship to clinical outcome. We correlated increased AURKA-CN in mCRC tumours with KRAS mutation status, overall and progression-free survival (OS, PFS). METHODS: Sixty-one mCRC tumours were analysed for AURKA-CN using q-PCR, and KRAS mutation status by direct sequencing. Expression of AURKA protein was analysed by immunohistochemistry. Cox-proportional hazard method, Kaplan-Meier curves and log-rank statistics were used to estimate and compare the hazard ratios and median survival between the groups. RESULTS: In all, 68% of tumour exhibited high AURKA-CN, and 29% had a KRAS mutation, without correlation between the two. Patients with high AURKA-CN tumours had longer median OS (48.6 vs 18.8 months, P=0.01), with stronger trend among KRAS wild-type tumours (median OS not reached vs 18.8 months, P=0.003). Progression-free survival was longer on first-line or second-line chemotherapy among patients with KRAS wild-type and high vs low AURKA-CN (first: 17.6 vs 5.13 months, P=0.04; second: 10.4 vs 5.1 months, P=0.01). AURKA-CN level did not affect outcomes among patients with KRAS mutant tumours. CONCLUSION: Increased AURKA-CN is common in mCRC tumours and is associated with longer OS and longer PFS during chemotherapy, particularly in KRAS wild-type tumours.

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Factors influencing use of the prostate-specific antigen screening test in primary care.

OBJECTIVE: To evaluate the use of the prostate-specific antigen (PSA) test and digital rectal examination (DRE) in prostate cancer screening by primary care physicians. STUDY DESIGN: Physician survey and retrospective medical record review. METHODS: We randomly selected and reviewed the medical records of 3 cross-sectional samples of male patients and surveyed their primary care physicians at 1-year intervals. All the physicians practiced in Colorado. The study spanned 3 years, including late 1992, when the American Cancer Society recommended the use of PSA in a prostate cancer screening guideline. RESULTS: We reviewed the medical records of 4772 male patients and surveyed 109 primary care physicians. We found that PSA testing for men aged 50 or older increased significantly from 1992 to 1994, from 24% in 1992 to 35% in 1993 and 40% in 1994 (overall odds ratio, 2.94; P < .05). Over the same time period, the DRE rate remained relatively unchanged (39% in 1992, 41% in 1993, and 36% in 1994). Overall PSA use was positively associated with patient age greater than 59 years, patient non-smoking status, physician "readiness to change cancer screening behavior," private insurance status, and nonsolo practice. Before the release of a prostate cancer screening guideline, participating physicians cited the American Cancer Society as the organization that most influenced their practice with respect to cancer screening. The magnitude of the reported influence of the American Cancer Society was correlated with the subsequent use of PSA in 1994 by primary care physicians after adjustment for change in DRE and baseline PSA rates, although the association did not reach statistical significance in multivariable regression models. CONCLUSIONS: Primary care physicians in Colorado significantly increased their use of the PSA test from 1992 to 1994, during which time the American Cancer Society issued a guideline recommending the use of PSA for prostate cancer screening. The reported influence of the American Cancer Society on cancer screening practices correlated with the subsequent increase in PSA testing.

Pancreatic cancer.

Optimal therapy for pancreatic adenocarcinoma requires surgical removal with tumor-free margins. Superior outcomes have been reported for high-volume centers incorporating a multidisciplinary approach. Postoperative ("adjuvant") chemotherapy and radiation should be considered in patients with successfully resected primary tumors. Combined modality treatment with chemotherapy and radiation should be considered for locally advanced, unresectable tumors. Gemcitabine can provide symptom relief and a modest improvement in survival for patients with metastatic disease. Strict attention to relief of symptoms such as pain, depression, anorexia/cachexia, and jaundice is essential in all patients with pancreatic cancer. All patients with pancreatic cancer should be encouraged to enter clinical trials of new therapies, given that long-term survival for all stages remains poor.

Communication between older adults and their physicians about urinary incontinence.

BACKGROUND: Urinary incontinence (UI) is a common but undertreated condition in older adults. The study objective was to determine older patients' characteristics related to communication patterns with their physicians about UI. METHODS: Telephone surveys of a sample of patients age 60 and older who visited a primary care provider (PCP) for any reason within the past 2 months were conducted. Participating physicians included general internists and family physicians from 41 primary care practices located in the 17 counties of northwest North Carolina whose 435 incontinent and 711 continent patients completed the surveys. The main outcome measures were patients' frequency and amount of urinary leakage, being asked about incontinence, and initiating a discussion of incontinence if not asked by their PCP. RESULTS: Age and gender were significant independent predictors of incontinence. PCPs were significantly more likely to assess incontinent women than incontinent men (21% vs 10%, p = .053). The older cohorts of older adults were significantly more likely to be symptomatic for UI than their younger counterparts. However, the younger cohorts were more likely to be screened for incontinence by their physicians. CONCLUSIONS: Despite the publication of guidelines on improving the screening and management of UI, the problem remains common and underdetected in older adults. Physicians don't ask and patients don't tell. Interventions are needed to remind physicians to screen high risk patients and to encourage patients with UI to communicate with their physicians.

Physician and patient predictors of health maintenance visits.

BACKGROUND: Because of a strong association between health maintenance visits (HMVs) and cancer screening, knowledge of the predictors of an HMV have implications for screening. OBJECTIVE: To examine the association of an HMV with patient, physician, and practice characteristics in the primary care setting. DESIGN: A statewide study of cancer screening was conducted in Colorado to determine concordance with the National Cancer Institute's guidelines for screening for breast, cervical, prostate, and skin cancer. Medical records form patients were randomly chosen from primary care practices. Predictors of an HMV were determined by fitting a logistic model to baseline data, adjusting for the cluster sampling of patients within practices. SETTING: Nonacademic primary care practices in Colorado. PARTICIPANTS: A total of 5746 patients aged 42 to 74 years from 132 primary care practices. MAIN OUTCOME MEASURE: Whether a patient had an HMV in the previous year. RESULTS: Of all patients, 31% had an HMV in the previous year. Patient characteristics associated with having HMVs included nonsmoking status, odds ratio (OR) (95% confidence interval [CI]) of 1.27 (1.11-1.46), age, and sex. Women aged 50 to 69 years were significantly more likely to have an HMV than men aged 50 to 69 years (OR, 1.30; 95% CI, 1.10-1.54). Among adults aged 70 years and older, there were no significant sex differences in receiving HMVs. Physician and practice characteristics associated with providing HMVs included practice size (> or = 3 full-time physicians) (OR, 1.34; 95% CI, 1.01-1.77), physician contemplation of changing approaches to cancer screening (OR, 1.33; 95% CI, 1.04-1.70), and physician female sex (OR, 1.33; 95% CI, 1.04-1.70). Physician age and specialty (general internist or family physician) were not associated with the level of health maintenance delivery. CONCLUSION: Certain subgroups, such as smokers, patients in smaller practices, and physicians not yet considering changing their approach to cancer screening, could be targeted in future intervention studies designed to provide preventive services in primary care settings.

Hepatitis E virus in Nepal: similarities with the Burmese and Indian variants.

Hepatitis E has been the predominant type of acute hepatitis in Nepal both in adults and children, in sporadic and epidemic forms. We examined six hepatitis E virus (HEV) isolates obtained during an 8-year period, from 1987 to 1995, in the Kathmandu valley of Nepal. Analysis of portions of the putative helicase, polymerase and capsid genes demonstrated close genetic relatedness among themselves (> 96.4% identity) and with the Burmese (> 95.5%) and Indian (> 95.3%) isolates, and less so with the African (> 94.4%) and the Chinese (> 91%) isolates within the Asian genotype. Phylogenetic analysis placed the Nepali isolates in the Burma-India evolutionary branch and showed that the oldest isolate, TK78/87 was more similar to the Burmese isolates whereas the most recent isolates were closer to the Indian ones. Assuming no frameshifts, the Nepali isolates showed high amino acid conservation, but also unique changes when compared to other HEV isolates. Amino acid residue 614 of the capsid protein was identified as a possible marker to distinguish the Burma-Nepal-India from the China-Central Asian Republics subgenotype, and the Mexico genotype.

Cross-reactive epitope among proteins in Plasmodium falciparum Maurer's clefts and primate leukocytes and platelets.

Erythrocytes infected with malaria parasites often contain membranous vesicles that are presumed to facilitate macromolecule traffic between the parasite and erythrocyte membranes. One such vesicle network, called Maurer's clefts, is expressed in Plasmodium falciparum-infected erythrocytes and contains a 50-kD polypeptide. Using a monoclonal antibody reactive with this polypeptide, we show that hepatic stages of P. falciparum express an epitope common to this blood-stage antigen. In addition, this epitope is cross-reactive with antigens expressed by primate leukocytes and platelets. Such epitopes may induce autoantibodies commonly seen in patients with malaria.

Human immunodeficiency virus type 2 glycoprotein enhancement of particle budding: role of the cytoplasmic domain.

Previous studies have shown that the glycoprotein cytoplasmic domains of human immunodeficiency virus type 2 (HIV-2) or simian immunodeficiency virus of macaques modulate biological activities of the viral glycoprotein complex, including syncytium formation, exterior glycoprotein conformation, and glycoprotein incorporation into budding virus particles. We have now utilized a recombinant expression system to study interactions of full-length or truncated HIV-2 glycoproteins with coexpressed HIV-2 Gag proteins which self-assemble and bud as virus-like particles. Interestingly, budding of HIV-2 virus-like particles from cells was enhanced 5- to 24-fold when Gag was coexpressed with the full-length HIV-2 glycoprotein, compared with Gag expressed either alone or with a truncated HIV-2 glycoprotein. The results obtained in this model system indicate that an additional effect of the lengthy cytoplasmic domain of the glycoprotein of HIV-2 is enhancement of particle budding. We speculate that the cytoplasmic domain of the viral glycoprotein of HIV-2 enhances budding by (i) potentiation of Gag structure or function or (ii) membrane modulation.

Measuring physician readiness to change cancer screening: preliminary results.

Our objective was to describe the development and validation of an instrument for measuring physician readiness to change cancer screening and counseling. We designed a cross-sectional survey of primary care physicians. Participants were 745 enrollees in the Copic Insurance Company, a physician liability insurer of more than 80% of Colorado's physicians. A large percentage of physicians do not perceive a need to change their screening patterns for eligible patients in both mammography and Pap tests. Approximately one third of the physicians are contemplating screening more of their patients within the next six months for sigmoidoscopy, clinical skin, and oral cavity exams and counseling more of their patients on skin protection and dietary fat. Few physicians are planning significant changes in cancer screening and counseling within the next month. Scales of readiness to change screening and counseling, as well as an overall readiness-to-change scale, had high internal consistency: .81, .65, .84, for screening, counseling, and overall, respectively. We conclude that readiness to change may be a useful construct for determining if and when physicians may be willing to make behavior changes. Moreover, the assessment of physician readiness to change may facilitate the tailoring of interventions designed to foster physician behavior change and improve patient care.

Changing physician behavior to improve disease prevention.

Physicians often fail to provide nationally recommended preventive services for their patients. Addressing this, we have reviewed selected literature on changing physician behavior using the organizational construct of the "readiness for change" transtheoretical model. This model suggests that behavior evolves through stages from precontemplation, to contemplation, to preparation, to initiation, and to maintenance of change. Traditional continuing medical education may affect knowledge and beliefs, but rarely results in behavior change. However, motivational strategies such as practice feedback reports and influential peers can foster stage change. Successful interventions aimed at physicians preparing for change frequently use an office-system approach that targets not only physicians, but office staff and patients as well. Illustrating how the readiness to change model can guide the design and implementation of interventions, we describe strategies being used in a statewide randomized controlled trial to improve cancer prevention counseling and early detection by primary care physicians. The multistage interventions of Partners for Prevention include support from a medical liability carrier, a motivational videotape, a task-delineated office manual, chart flowsheets, patient activation forms, practice feedback reports, a designated prevention coordinator within each practice and regular telephone calls and office visits by project staff.

Process evaluation of a system (Partners for Prevention) for prevention-oriented primary care.

Process evaluation can identify program components that are related to success, that are generalizable to other settings, and that improve future applications of the program. The Partners for Prevention pilot project tested an office-based system aimed at increasing cancer prevention and screening in primary care offices and involving 17 physicians in private practice. Process evaluation techniques included monitoring systems, satisfaction surveys, and focus groups with the program participants. Each evaluation technique provided different information concerning strategies. The program was difficult to implement on busy days, the materials were useful but needed more flexibility, communication between patient and physician was facilitated, and the office coordinator was a crucial person. Program philosophy was acceptable, but materials needed refinement. The flow sheet and patient health check have been dramatically simplified and customized. New strategies are being tested in a randomized control trial.