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.

Osmotically induced electrical changes in isolated bullfrog small intestine.

1. Steady state values of cell water, intracellular Na+ and K+ concentrations, and the electrical parameters ETr, Em, and Isc in the mucosa of isolated bullfrog small intestine were determined following immersion in sodium sulfate Ringer solutions with identical ionic composition but different osmolalities. 2. Cell water and intracellular K+ concentration were inversely related to the osmolality of the bathing medium. During 1 h immersion, intracellular Na+ concentration was not significantly affected by an increase or decrease in external osmolality. 3. Replacement of a hypotonic or an approximately isotonic (normal) medium by a medium of greater osmolality caused statistically significant decreases in ETr, Isc and the (inside negative) magnitude of Em. Conversely, when a hypertonic or a normal medium was replaced by one of lower osmolality, significant increases in the magnitude of these parameters were observed. 4. An equivalent circuit model for the epithelial cell layer, in which the resistance of a relatively highly conducting extracellular shunt pathway is assumed to be the major determinant of the electrical responses of the small intestine to external osmolality, has been shown to account satisfactorily for the observed changes in ETr and Em. In terms of this model, the experimentally observed dependence of Isc on external osmolality requires that, even when both the mucosal and the serosal sides of the tissue are bathed by identical media, isolated bullfrog small intestine maintains a finite diffusion potential across the shunt pathway. This is consistent with current views concerning transepithelial ionic transfer mechanisms.

Influence of home monitoring on compliance with a reduced sodium intake diet.

To test the utility of a qualitative chloride titrator strip in facilitating compliance with a reduced sodium intake diet, we enrolled 32 patients into a randomized crossover trial comprising two study periods of four weeks each. The study periods were begun after the patients had undergone extensive instruction in the diet and the use of the strip. A high degree of correlation between the patient's and the laboratory's interpretation of the strip result was identified in 29 of the subjects. Ability to use the strip was not related to level of education. A total of 12 patients achieved compliance with the diet when using the strips. Of these, nine were able to achieve compliance without the strips. Ten patients (30%) had significantly lower sodium intake when using the strips than when they did not use them. We conclude that the use of the chloride titrator strip can be mastered by most patients and, in conjunction with dietary counseling, can facilitate compliance with a reduced sodium intake diet.

Potential barriers to diabetes care.

To examine a potential reason why physicians sometimes fail to adhere to standards of care with which they are in agreement, 103 consecutive patients with diabetes mellitus were interviewed immediately after their doctor's appointment in a general medicine clinic of a city/county hospital. The mean age of the patients was 57 yr and the average duration of diabetes was 9 yr. Sixty percent of these patients had their feet examined. A major factor in determining the physicians behavior was whether the nurse or aide had the patient remove his shoes and socks before being seen by the physician. Physicians were more than three times as likely to perform foot examinations when patients were presented barefoot than when presented wearing shoes and socks. Rarely in medical and continuing medical education do we consider how clinic routines can influence physician's behavior in the management of diabetes.

The diabetes education study: a controlled trial of the effects of diabetes patient education.

The Diabetes Education Study (DIABEDS) was a randomized, controlled trial of the effects of patient and physician education. This article describes a systematic education program for diabetes patients and its effects on patient knowledge, skills, self-care behaviors, and relevant physiologic outcomes. The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center. Patients were predominantly elderly, black women with non-insulin-dependent diabetes mellitus of long duration. Patients randomly assigned to experimental groups (N = 263) were offered up to seven modules of patient education. Each content area module contained didactic instruction (lecture, discussion, audio-visual presentation), skill exercises (demonstration, practice, feedback), and behavioral modification techniques (goal setting, contracting, regular follow-up). Two hundred seventy-five patients remained in the study throughout baseline, intervention, and postintervention periods (August 1978 to July 1982). Despite the requirement that patients demonstrate mastery of educational objectives for each module, postintervention assessment 11-14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge. However, statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous. Experimental group patients experienced significantly greater reductions in fasting blood glucose (-27.5 mg/dl versus -2.8 mg/dl, P less than 0.05) and glycosylated hemoglobin (-0.43% versus + 0.35%, P less than 0.05) as compared with control subjects. Patient education also had similar effects on body weight, blood pressure, and serum creatinine. Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization.

Binding of Plasmodium falciparum 175-kilodalton erythrocyte binding antigen and invasion of murine erythrocytes requires N-acetylneuraminic acid but not its O-acetylated form.

Sialic acid on human erythrocytes is involved in invasion by the human malaria parasite, Plasmodium falciparum. Mouse erythrocytes were used as a reagent to explore the question of whether erythrocyte sialic acid functions as a nonspecific negative charge or whether the sialic acid is a necessary structural part of the receptor for merozoites. Human erythrocytes contain N-acetylneuraminic acid (Neu5Ac), whereas mouse erythrocytes, which are also invaded by P. falciparum merozoites, contain 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2) and N-glycoloylneuraminic acid (Neu5Gc), in addition to Neu5Ac. We compared the effects of sialidase and influenza C virus esterase treatments of mouse erythrocytes on invasion and the binding of a 175-kDa P. falciparum protein (EBA-175), a sialic acid-dependent malaria ligand implicated in the invasion process. Sialidase-treated mouse erythrocytes were refractory to invasion by P. falciparum merozoites and failed to bind EBA-175. Influenza C virus esterase, which converts Neu5,9Ac2 to Neu5Ac, increased both invasion efficiency and EBA-175 binding to mouse erythrocytes. Thus, the parasite and EBA-175 discriminate between Neu5Ac and Neu5,9Ac2, that is, the C-9 acetyl group interferes with EBA-175 binding and invasion by P. falciparum merozoites. This indicates that sialic acid is part of a receptor for invasion.

Acute hemiplegia and cortical blindness due to moya moya disease: report of a case in a child with Down's syndrome.

We are reporting what we believe to be the first case of moya moya disease (hemiplegia associated with supraclinoid carotid stenosis and multiple cerebral telangiectasia) in a child with Down's syndrome. On cerebral angiography, multiple collateral vessels and rete mirabile (anastomosis of meningeal vessels with internal cerebral vessels) were noted, in addition to the supraclinoid carotid stenosis. Computerized tomography revealed nonobstructive hydrocephalus and findings consistent with multiple vascular insults or infarcts. It is not clear whether moya moya disease represents a true disease entity (congenital arterial dysplasia) or is a syndrome caused by nonspecific vascular reaction. Since abnormal vascular morphology has previously been described in children with trisomy 21, we suggest that the presence of these two disease entities may not be coincidental. It may represent a genetic predisposition in Down's syndrome toward vascular abnormalities, with variable expressivity which manifested itself in this case by abnormalities in the cerebral circulation.

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.

Heritable aspects of salt sensitivity.

Dietary salt reduction is an important nonpharmacologic remedy for mild hypertension as well as a useful adjunct to drug treatment. However, a reduced salt intake diet is not effective in reducing the blood pressure of all hypertensive patients. Several lines of evidence indicate that some patients are salt-sensitive whereas others are salt-resistant. A series of investigations have been conducted showing that the blood pressure responses to either acute salt and volume loading or to a reduced dietary salt intake are normally distributed. Blood pressure, humoral regulators of blood pressure and renal sodium handling are each found to be influenced by genetic variance. The change in blood pressure from dietary salt reduction is influenced by genetic variance as well. Definitions of salt sensitivity and resistance were formulated, and salt sensitivity of blood pressure was found to occur significantly more often in black than in white Americans. Furthermore, preliminary data suggest that measurement of phenotypes of haptoglobin in blood may assist in identifying salt-sensitive and salt-resistant subjects. Trials of a reduced salt intake diet in pharmacologically treated hypertensive patients are currently being conducted. The data suggest that at least half of the patients are salt-sensitive and that their medications may be reduced in response to the intervention. Results of this study may be of relevance to many of the 60 million Americans with hypertension, particularly to those who are black and elderly.

The association of depressive symptoms and urinary incontinence among older adults.

OBJECTIVES: To examine the relationship of urinary incontinence (UI) and depressive symptoms (DS) in older adults. DESIGN: A randomized, controlled trial to determine the effects of clinical practice guideline implementation on provider attitudes and behavior, and patients' UI, health status, quality of life, and satisfaction with care. Baseline and endpoint data were collected from patients via computer-assisted telephone interviewing. SETTING: Forty-one nonacademic primary care practices (PCP) in North Carolina. PARTICIPANTS: A total of 668 community-dwelling adults (age > 60) who had visited the one of the selected PCPs. INTERVENTION: PCPs in the intervention group were given instruction in the detection and management of UI, educational materials for providers and patients, office system supports, and academic detailing. MEASUREMENTS: The dependent measure was assessed using an eight-item screener for DS. UI (status, frequency, amount), health (physical, mental), and demographic (age, gender, marital status) and self-report information about bladder control served as predictors. RESULTS: Wilcoxon rank sum tests showed that UI status was associated with moderate to severe DS (43% vs 30%, P = .05). Multivariate analyses showed that UI status, physical and mental health, and gender were significant predictors of DS. Among UI adults (n = 230), physical and mental health, life satisfaction, and the perception that UI interfered with daily life were significant predictors of DS. CONCLUSIONS: This study provides clear evidence that UI is related to DS in older adults.

Why older community-dwelling adults do not discuss urinary incontinence with their primary care physicians.

OBJECTIVES: This study explored reasons why older adults with urinary incontinence (UI) do not initiate discussions with or seek treatment for UI from their primary care provider. DESIGN: A randomized, prospective controlled trial involving 41 primary care sites. SETTING: Primary care practice sites. PARTICIPANTS: 49 older adults age 60 and older not previously screened for UI by their primary care doctor. MEASUREMENTS: Demographic data, self-reported bladder-control information using questionnaires, and health status. RESULTS: Adults who did not discuss UI were older, had less-frequent leaking accidents and fewer nighttime voids and were less bothered by UI than those who did. The two main reasons why patients did not seek help were the perceptions that UI was not a big problem (45%) and was a normal part of aging (19%). CONCLUSIONS: Embarrassment or lack of awareness of treatment options were not significant barriers to discussing UI. Adults with a fairly high frequency of UI (average of 1.7 episodes per day) did not view UI as abnormal or a serious medical condition.

Ovarian teratoma with peritoneal gliomatosis and elevated serum alpha-fetoprotein.

An adolescent girl, had a grade 1 immature teratoma combined with a rare manifestation of glial peritoneal implants of grade 0. A unilateral salpingo-oophorectomy was performed. Alpha-fetoprotein levels, which were elevated before the operation, returned to normal. The patient has been symptom-free for more than three years after the surgical treatment. Repeated normal assays for alpha-fetoproteins can serve as a guide to a projected favorable course. The World Health Organization grading of the teratoma is listed and pertinent medical literature is briefly discussed.

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.

Relationship between patient reports of urinary incontinence symptoms and quality of life measures.

OBJECTIVE: To determine if patient reports of urinary incontinence symptoms can predict quality of life as measured by the short forms of the Incontinence Impact Questionnaire and the Urogenital Distress Inventory, two standardized, disease-specific instruments. METHODS: Telephone surveys were conducted of 384 community dwelling incontinent women, aged 60 years and older, who admitted to at least one episode of incontinence per week during the previous 3 months. Subjects were asked if they considered the incontinence a problem, as well as questions regarding volume and frequency of voids and urine loss. Each subject completed both standardized quality of life questionnaires. Responses to incontinence symptom questions were correlated with the standardized measures. RESULTS: The question, "Do you consider this accidental loss of urine a problem that interferes with your day-to-day activities or bothers you in other ways?" was the best predictor of the subject's responses to both quality-of-life measures, with a correlation coefficient of 0.69 for the Incontinence Impact Questionnaire and 0.67 for the Urogenital Distress Inventory. The patients' symptoms that best correlated with both quality of life measures and the report of bothersome incontinence were frequent episodes of incontinence (0.40-0.58), greater amounts of urine loss (0.26-0.54), and more frequent voids (0.24-0.41). CONCLUSION: Primary care practitioners may screen for problematic incontinence by asking if patients' incontinence is bothersome to them and by obtaining simple historic information on voiding and leaking patterns. These questions may provide an efficient tool to detect bothersome incontinence in older women.