Rucaparib: the past, present, and future of a newly approved PARP inhibitor for ovarian cancer.

Rucaparib camsylate (CO-338, AG-014699, PF-01367338) is a potent PARP-1, PARP-2, and PARP-3 inhibitor. Phase I and II studies demonstrated clinical efficacy in both BRCA-mutated (inclusive of germline and somatic) ovarian tumors and ovarian tumors with homologous recombination deficiency (HRD) loss of heterozygosity (LOH). Rucaparib has received the US Food and Drug Administration (FDA) approval for patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. There is evidence to suggest that rucaparib has clinical efficacy against ovarian tumors with high HRD-LOH. Rucaparib's companion diagnostic FoundationFocus™ CDx BRCA test is the first FDA-approved next-generation sequencing-based companion diagnostic test designed to identify patients likely to respond to rucaparib. This article reviews the mechanisms of action, safety, approval, and indications for use of the PARP inhibitor rucaparib as well as future trials and use of rucaparib's companion diagnostic test.

Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women.

OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials.

Psoriasis: an opportunity to identify cardiovascular risk.

Psoriasis is highly prevalent and is associated with skin-associated complaints as well as arthritis, depression and a lower quality of life. Recently, it has been demonstrated that not only do patients with psoriasis have an increased prevalence of cardiovascular risk factors, but an increased risk of myocardial infarction, and for those with severe disease, increased mortality. Dermatologists and other health professionals need to be cognizant of this association and ensure that cardiovascular risk factors are evaluated and treated appropriately in those patients with psoriasis. We review the association between psoriasis, atherosclerosis and inflammation, as well as some treatable cardiovascular risk factors that may prove beneficial in reducing a patient's cardiovascular risk.

Clostridium difficile colitis in lung transplantation.

PURPOSE: Clostridium difficile colitis (CDC) is the most common nosocomial infection of the gastrointestinal tract in patients with recent antibiotic use or hospitalization. Lung transplant recipients receive aggressive antimicrobial therapy postoperatively for treatment and prophylaxis of respiratory infections. This report describes the epidemiology of CDC in lung recipients from a single center and explores possible associations with bronchiolitis obliterans syndrome (BOS), a surrogate marker of chronic rejection. METHODS: Patients were divided into those with confirmed disease (CDC+) and those without disease (CDC-) based on positive C. difficile toxin assay. Because of a bimodal distribution in the time to develop CDC, the early postoperative CDC+ group was analyzed separately from the late postoperative CDC+ cohort with respect to BOS development. RESULTS: Between 1990 and 2005, 202 consecutive patients underwent 208 lung transplantation procedures. Of these, 15 lung recipients developed 23 episodes of CDC with a median follow-up period of 2.7 years (range, 0-13.6). All patients with confirmed disease had at least 1 of the following 3 risk factors: recent antibiotic use, recent hospitalization, or augmentation of steroid dosage. Of the early CDC+ patients, 100% developed BOS, but only 52% of the late CDC+ patients developed BOS, either preceding or following infection. CONCLUSION: CDC developed in 7.4% of lung transplant patients with identified risk factors, yielding a cumulative incidence of 14.7%. The statistical association of BOS development in early CDC+ patients suggests a relationship between early infections and future chronic lung rejection.

The neurology clerkship core curriculum.

Neurologic symptoms are common in all practice settings, and neurologic diseases comprise a large and increasing proportion of health care expenditures and global disease burden. Consequently, the training of all physicians should prepare them to recognize patients who may have neurologic disease, and to take the initial steps in evaluating and managing those patients. We present a core curriculum outlining the clinical neurology skills and knowledge necessary to achieve that degree of preparation. The curriculum emphasizes general principles and a systematic approach to patients with neurologic symptoms and signs. The ability to perform and interpret the neurologic examination is fundamental to that approach, so the curriculum delineates the essential components of the examination in three different clinical settings. The focus of the curriculum is on symptom-based rather than disease-based learning. The only specific diseases selected for inclusion are conditions that are common or require urgent management. This curriculum has been approved by the national organization of neurology clerkship directors and endorsed by the major national professional organizations of neurologists. It is intended as a template for planning a neurology clerkship and as a benchmark for evaluating existing clerkships. It should be especially helpful to clerkship directors, neurology chairs, deans of medical education, and members of external accreditation groups.

Sensitivity of stomatal and canopy conductance to elevated CO2 concentration - interacting variables and perspectives of scale.

• The hydrological response of forests to rising CO2 is a critical biotic feedback in the study of global climate change. Few studies, however, have investigated this highly dynamic response at relevant temporal and spatial scales. • A combination of leaf and whole-tree measurements and stand-level extrapolations were used to assess how stomatal conductance, canopy transpiration and conductance, and evapotranspiration might be affected by future, higher CO2 concentrations. • Midday measurements of stomatal conductance for leaves sampled in a 12-yr-old sweetgum (Liquidambar styraciflua) stand exposed to free-air CO2 enrichment were up to 44% lower at elevated than at ambient CO2 concentrations, whereas canopy conductance, averaged over the growing season, was only 14% lower in stands exposed to CO2 enrichment. The magnitude of this response was dependent on vapor pressure deficit and soil water potential. Annual estimates of evapotranspiration showed relatively small reductions due to atmospheric CO2 enrichment. • These data illustrate that the hydrological response of a closed-canopy plantation to elevated CO2 depends on the temporal and spatial scale of observation. They emphasize the importance of interacting variables and confirm that integration of measurements over space and time reduce what, at the leaf level, might otherwise appear to be a large and significant response.

Epidemiology of CN IV Palsies.

OBJECTIVE: To examine the etiologies of CN IV palsies based on age and aid the clinician in more effective work-up and treatment. METHODS: Retrospective chart review of 124 patients presenting to Houston Eye Associates between 1968 and January 1999 with superior oblique palsies. Patients were divided into the following age groups: birth to 10 years, 11-20 years, 21-40 years, 41-60 years and over 60 years. Etiologies and treatment were then examined within each age group. Etiologies were categorized as congenital, traumatic, vascular, neoplastic, and idiopathic. Treatment was classified as observation, prisms alone, surgical repair, and surgical repair combined with prisms. Bilateral, unilateral, and masked bilateral palsies were included. RESULTS: Nine of 13 bilateral palsies were due to trauma. The masked bilateral palsy was congenital. Between the ages of birth and 10 years 26 of 37 (70.1%) palsies were congenital. Between the ages of 21 and 40 years 17/35 (48.6%) were due to trauma. Within the remaining age groups 11-20 years, 41-60 years, and over 60 years, the most common etiology was idiopathic 7/13 (53.8%), 11/24 (45.8%), and 7/15 (46.7%) respectively. Surgery was the most common treatment option within all age groups with the exception of the over 60 group. In this age group, prisms alone was most common.

A comparison study of body dysmorphic disorder and obsessive-compulsive disorder.

BACKGROUND: Body dysmorphic disorder, a preoccupation with an imagined or slight defect in appearance, is classified as a somatoform disorder, but has been hypothesized to be related to obsessive-compulsive disorder. A reflection of this hypothesis, body dysmorphic disorder is included in the Yale-Brown Obsessive Compulsive Scale symptom checklist, and its transfer to the anxiety disorders' section was considered for DSM-IV. However, the similarities and differences between body dysmorphic disorder and obsessive-compulsive disorder have received little investigation. METHOD: We compared patients with DSM-IV body dysmorphic disorder (N = 53), obsessive-compulsive disorder (N = 53), or both disorders (N = 33) in terms of demographic features, clinical features, comorbidity, and family history. We also assessed the rate of body dysmorphic disorder among 62 of these subjects initially diagnosed with obsessive-compulsive disorder. RESULTS: 14.5% (9 of 62) of subjects initially diagnosed with obsessive-compulsive disorder had comorbid body dysmorphic disorder. The 2 disorders did not differ significantly in terms of sex ratio; most other demographic, course, and impairment variables; illness severity; or lifetime frequency of most associated disorders in probands or first-degree relatives. However, subjects with body dysmorphic disorder were less likely to be married and more likely to have had suicidal ideation or made a suicide attempt because of their disorder. They also had an earlier onset of major depression and higher lifetime rates of major depression, social phobia, and psychotic disorder diagnoses, as well as higher rates of substance use disorders in first-degree relatives. CONCLUSION: Body dysmorphic disorder appears to be relatively common among patients with obsessive-compulsive disorder. While the 2 disorders have many similarities, they also have some differences and should be differentiated in clinical and research settings.

Corneal coloboma, aphakia and retinal neovascularization with anterior segment dysgenesis (Peters' anomaly).

An infant with bilateral Peters' Anomaly, with corneal opacification in the right eye and an opacification with an axial defect in the left also had an associated hydrocephalus and cardiac anomalies that proved fatal; histopathology of the right eye showed retinal neovascularization in addition to findings consistent with a diagnosis of Peters' Anomaly; in the left eye, pathologic findings were suggestive of a corneal coloboma associated with aphakia.

The impact of new pharmaceutical agents on the cost of neurologic care.

Since the emergence of the specialty, neurologists have worked with a rather restricted list of relatively inexpensive pharmacologic agents. This is rapidly changing with the development of new agents for the treatment of migraine, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and epilepsy, accelerated in part by designation of the 1990s as the "Decade of the Brain." Exciting as these developments are, they are very costly when applied to the large number of patients who may benefit, perhaps exceeding $6.4 billion. Since this cost exceeds the $1.5 billion income of all practicing neurologists, it enhances the value of the neurologic consultation, which can provide more accurate diagnosis and more expertly directed therapy. Our relationships with the drug manufacturers are changing as our prescribing habits become a more likely determinant of profits.

Photosynthetic acclimation in trees to rising atmospheric CO2: A broader perspective.

Analysis of leaf-level photosynthetic responses of 39 tree species grown in elevated concentrations of atmospheric CO2 indicated an average photosynthetic enhancement of 44% when measured at the growth [CO2]. When photosynthesis was measured at a common ambient [CO2], photosynthesis of plants grown at elevated [CO2] was reduced, on average, 21% relative to ambient-grown trees, but variability was high. The evidence linking photosynthetic acclimation in trees with changes at the biochemical level is examined, along with anatomical and morphological changes in trees that impact leaf- and canopy-level photosynthetic response to CO2 enrichment. Nutrient limitations and variations in sink strength appear to influence photosynthetic acclimation, but the evidence in trees for one predominant factor controlling acclimation is lacking. Regardless of the mechanisms that underlie photosynthetic acclimation, it is doubtful that this response will be complete. A new focus on adjustments to rising [CO2] at canopy, stand, and forest scales is needed to predict ecosystem response to a changing environment.

Nerve agents: a review.

Nerve agents produce neuromuscular blockade and convulsions in exposed humans. Military personnel in areas of potential exposure take prophylactic pyridostigmine. They are instructed to self-administer atropine and pralidoxime at the first sign of nerve agent toxicity. The key to treatment of nerve agent poisoning is the administration of atropine in doses larger than is customary in most other disorders, repeated as often as needed. Mechanical ventilation may be required. Convulsions are treated with diazepam, but only after atropine has been administered.

EEG and neuroimaging localization in partial epilepsy.

We have studied cortical localization provided by surface and sphenoidal electroencephalograms (EEGs) and that of computed tomography (CT), magnetic resonance imaging (MR) and single photon emission tomography (SPECT) in 58 patients with partial epilepsy. Each patient had EEG, MR and SPECT during a hospitalization period of 1-2 weeks. CT scans were obtained either during the same period or had been performed in the preceding year. EEG evaluation consisted of 3-5 days of continuous monitoring including video-telemetry and ambulatory recording as well as conventional EEGs with special electrode placements. Additionally 33 of 58 patients (55%) who were potential surgical candidates had sphenoidal recordings. All patients had an abnormal EEG which showed evidence of epileptic hyperexcitability. EEG abnormality was localized in 43 patients (74%). Neuroimaging studies were focally abnormal in 38 patients (66%); 12 CT (21%), 29 MR (50%) and 24 SPECT (41%). Thirty four of 43 patients with localized EEG had at least 1 focally abnormal neuroimaging study (79%), whereas 4 of 15 (27%) patients with non-localized EEG did so. Twenty-eight of 29 patients with focal MR (97%), 11 of 12 patients with focal CT (92%) and 20 of 24 patients with focal SPECT (83%) had a concordant focal EEG. EEG and neuroimaging localization agreed in all 15 patients in whom both MR and SPECT disclosed a concordant focal abnormality. This study demonstrates a significant (P less than 0.005) correlation between surface/sphenoid EEG and neuroimaging localization in partial epilepsy.

Administrative management of the soldier with seizures.

Based on improvement in our understanding of the prognosis of young adults with new onset seizures, and cumulative experience with the rules in effect for the last 30 years, a substantial change in the regulations affecting the fitness and profiling of these soldiers has been made. In general, these liberalize retention and profiling, set limits on the duration of trials of duty, provide for fitness determinations in soldiers with pseudo-seizures, and specify when neurologic consultation is required.

Impact of the new fitness regulation for epilepsy.

In 1983, a new regulation was prepared, based on clinical reports published at that time, redefining the fitness standards for those applicants to the military who had experienced one or more seizures during childhood or early adult life. The most important change admitted those who had been free of seizures and off medications for 5 years or more and who had normal EEGs. Only 2 of 155 soldiers enlisted in 1986 and 1987 meeting these criteria were separated for seizure-related complaints. Both had problems during basic training and the diagnosis of recurrent epilepsy was tenuous in both. We conclude that the regulation change has given many young adults a chance to serve effectively in the Army without appreciable increase in medical or training costs.

Ethylene Directly Inhibits Foliar Gas Exchange in Glycine max.

Gas exchange of individual attached leaves of soybean, Glycine max (L.) Merr cv Davis, was monitored during exposure to exogenous ethylene (C(2)H(4)) to test the hypothesis that the effects of C(2)H(4) on net photosynthesis (P(N)) and stomatal conductance to H(2)O vapor (g(s)) are direct and not mediated by changes in leaf orientation to light. Leaflets were held perpendicular to incident light in a temperature-controlled cuvette throughout a 5.5 hour exposure to 10 microliters per liter C(2)H(4). Declines in both P(N) and g(s) were evident within 2 hours and became more pronounced throughout the exposure period. In C(2)H(4) treated plants, P(N) and g(s) decreased to 80 and 62%, respectively, of the rates in control plants. Because epinastic movement of the leaflets was prohibited by the cuvette, the observed declines in P(N) and g(s) were a direct effect of C(2)H(4) rather than the result of reduced light interception caused by changing leaf angle.

Somatosensory evoked potentials and magnetic resonance imaging in syringomyelia.

Somatosensory evoked potentials (SEPs) to median and posterior tibial stimulation were obtained in 22 patients with syringomyelia. All patients had magnetic resonance imaging (MR) which defined the maximum transverse diameter of the syrinx as well as its longitudinal extension. SEP was abnormal in 16 (72%) patients. Median and posterior tibial SEPs were abnormal in 11 and 15 patients respectively. Both tests were abnormal in 10 patients. Ten patients showed absence of one or more central potentials (P/N13, N20, N22) and 7 patients demonstrated increased conduction times (N9-N20, P/N13-N20, N22-P40). The mean maximum transverse diameter of the syrinx was 7.5 mm in patients with normal SEPs and 16.2 mm in patients with abnormal SEPs. Abnormal SEP was observed in all 5 patients with loss of position sense, in 9 of 13 (69%) with loss of superficial pain and temperature, and 1 of 2 patients with motor deficit only. Central SEP abnormalities were observed in 3 of 5 patients with sensory deficits indistinguishable from a peripheral neuropathy and in 2 patients in the asymptomatic extremity. Three of 4 patients with syringomyelia and Chiari malformation had a normal SEP.

Somatosensory evoked potentials and magnetic resonance imaging in intraspinal neoplasms.

Median and posterior tibial somatosensory evoked potentials (SEPs) were studied on 25 patients with pathologically proven intraspinal neoplasms, and the results were compared and correlated with the details of clinical examination and the information derived from magnetic resonance imaging (MR). MR was abnormal in all cases and in 23 of 25 (92%) demonstrated an intraspinal expansile lesion. SEP was abnormal in 19 of 25 patients (76%). Abnormal SEPs were found in 18 of 19 patients (94%) with cervical or thoracic neoplasms but only in 1 of 6 patients (16%) with the tumor in the thoracolumbar or lumbar region. SEP-MR correlation was significant (P less than 0.05) for thoracic intraspinal neoplasms where all 9 had an abnormal SEP showing a similar pattern of normal median and abnormal posterior tibial study. Clinically, all 7 patients with posterior column sensory deficits had abnormal SEP (100%). Abnormal SEPs were seen in 7 of 11 (63%) patients with spinothalamic deficits and in 4 of 8 (50%) of those with normal sensory examinations. Four of 9 patients (44%) with a normal neurological examination or an examination disclosing ambiguous results indistinguishable from a peripheral pathology had an abnormal SEP strongly suggesting a central sensory disorder. Comparison of preoperative and postoperative SEPs did not disclose useful prognostic information pertaining to the functional recovery.

5-year study of incidence rates of hospitalized cases of head injuries in the US Army.

Incidence rates of hospitalized head injury cases in the US Army were calculated by age, race, and sex. Skull fractures and intracranial diagnoses were found almost exclusively in males. For concussion, white males were at about 1.5 times greater risk compared to black males, and white females were at about 2 to greater than 3 times the risk compared to black females. For other intracranial injury, males were at 1.25 to about 2 times increased risk compared to females, white males were at about 1.5 times risk compared to black males, and white females were at 1.5-2 times greater risk compared to black females. Ten percent of head injury cases had an alcohol-related additional diagnosis and 97% of these were found in males.