Course Of Treatments Research Articles

NMDA receptor antibodies associated with distinct white matter syndromes.

Objective:To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders.Method:Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody–positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated.Results:Three distinct clinicoradiologic phenotypes were recognized: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers.Conclusion:Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.

Personalizing medicine: a review of adaptive treatment strategies

Much of current pharmacological practice focuses on identifying the single 'best' treatment (or course of treatments) for a particular disease. Recently, however, focus has begun to shift towards a more patient-centric rather than disease-centric approach, where personal characteristics are used to identify the optimal treatment for an individual. Adaptive treatment strategies (also known as dynamic treatment regimes) are part of a rapidly expanding area of research whereby such personalized treatments can be identified. These methods can lead to improved results over standard 'one size fits all' approaches, as well as provide a route to formalizing a common practice of using ad hoc approaches when deciding or updating management plans. Here, we provide an introduction to adaptive treatment strategies, explaining their background, their purpose, and how they can be employed in practice.

Changes in implementation of two evidence-based psychotherapies for PTSD in VA residential treatment programs: a national investigation.

There has been little investigation of the natural course of evidence-based treatments (EBTs) over time following the draw-down of initial implementation efforts. Thus, we undertook qualitative interviews with the providers at 38 U.S. Department of Veterans Affairs' residential treatment programs for posttraumatic stress disorder (PTSD) to understand implementation and adaptation of 2 EBTs, prolonged exposure (PE), and cognitive processing therapy (CPT), at 2 time points over a 4-year period. The number of providers trained in the therapies and level of training improved over time. At baseline, of the 179 providers eligible per VA training requirements, 65 (36.4%) had received VA training in PE and 111 (62.0%) in CPT with 17 (9.5%) completing case consultation or becoming national trainers in both PE and CPT. By follow-up, of the increased number of 190 eligible providers, 87 (45.8%) had received VA training in PE and 135 (71.1%) in CPT, with 69 (36.3%) and 81 (42.6%) achieving certification, respectively. Twenty-two programs (57.9%) reported no change in PE use between baseline and follow-up, whereas 16 (42.1%) reported an increase. Twenty-four (63.2%) programs reported no change in their use of CPT between baseline and follow-up, 12 (31.6%) programs experienced an increase, and 2 (5.2%) programs experienced a decrease in use. A significant number of providers indicated that they made modifications to the manuals (e.g., tailoring, lengthening). Reasons for adaptations are discussed. The need to dedicate time and resources toward the implementation of EBTs is noted.

Stem Cells – A Promise to Elixir

Stem cells are pluripotent cells which are having properties to differentiate into different lineages of cells types. Recently stem cells have been doubted in regards of their curative abilities of several diseases. The increasing number of difficulties to treat diseases versus the wait for promising cures creates restlessness among clinicians and patients. However we need to envisage the fact that stem cell research is bound by many ethical concerns and other limitations and, despite of its boundaries, staggering achievements have been made in this field of regenerative medicine. Evidential results have been obtained for treatment of cancer, organogenesis, cardiology, neurological disorders, genetical disorders, HIV, diabetes, obesity, vision impairment and even cosmetic applications. Many of these health conditions do not have a cure till date due to the intricacy in understanding their causes. The ones which have a cure have to bear considerable side effects during the course of medical treatments. Stem cell therapy is riveting because of its ability to cure complicated diseases rather than just controlling the health condition of the patients. It has not only shown promising curative possibilities but also proven itself with many successful cases, some of which have been discussed. Upon regular establishment of this therapy a lot of medical limitations will be resolved. Patients which are underage, overage or suboptimal for other tortuous medical treatments could also benefit from such simpler cures. They are a natural cure and can be practiced with fundamental techniques. This editorial emphasises on such marvels of stem cell therapy which show the brighter side of this dilemma.

Insight into the WNT system and its drug related response

The WNT signalling pathway is a complex system for transferring information for DNA expression from the cell surface receptors to cytoplasm and then to the nucleus. It is based on several proteins that work together as agonists and antagonists in order to maintain homeostasys and to promote anabolic processes. The WNT system acts on all cellular lines involved in bone resorption and formation. WNT pathway can mainly be triggered by two different signalling cascades. The first is well known and is the so-called WNT-beta catenin system (or the canonical pathway), the second is known as the non canonical WNT pathway. WNT proteins form a superfamily of secreted glycoproteins. The association with surface receptors, called Frizzled, that are members of the G protein-coupled receptors superfamily and co receptors like low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) complete the WNT system. LRP5/6 show high affinity for WNT antagonists that modulate the activity of this pathway: DKK1 and sclerostin (SCL), that play a crucial role in modulating the WNT system. The WNT-pathway and in particular its antagonists SCL and DKK1 seems to play a key role in the regulation of bone remodeling during treatment with bone active agents such as bisphosphonates, but not only. Their effects become relevant especially in the course of long-term treatments.

Mycobacterium fortuitum Infection following Reconstructive Breast Surgery: Differentiation from Classically Described Red Breast Syndrome.

Background:Red breast syndrome (RBS) has been described as an erythema that may be associated with 2-stage prosthetic reconstructive breast surgery using biologic mesh. RBS is differentiated from infectious cellulitis through absence of fever and laboratory abnormalities and usually has a self-limiting course. There have been no clinical reports on etiology, risk factors, or management of RBS. This report describes patient data that raise the need to rule out mycobacterial infection when RBS is being considered as a diagnosis.Methods:We present 6 cases of Mycobacterium fortuitum infection occurring after prosthetic breast reconstruction performed with a human-derived acellular dermal matrix, including the timing and course of erythema, laboratory results, treatments used, and long-term outcomes. We also describe the differential diagnoses of RBS in the context of these cases, including emergence of acid-fast bacilli and diagnostic and treatment considerations. Exact two-tailed 95% confidence intervals based on the F-distribution are provided with estimates of the incidence rates of infection.Results:The 6 cases presented here do not fit the typical description of RBS and were caused by mycobacterium infection. Statistical evaluation of the estimated incidence rate of M. fortuitum infection in a patient thought to have RBS, which occurred 100% of the time in this series, revealed a 95% confidence interval of 54.1–100%.Conclusions:When presented with possible RBS, surgeons must rule out cellulitis, culture for acid-fast bacilli such as mycobacterium species, and then determine the best course of treatment. Patient counseling regarding potential household sources of infection is warranted to minimize postoperative infection risk.

Childhood mitochondrial encephalomyopathies: clinical course, diagnosis, neuroimaging findings, mtDNA mutations and outcome in six children

Mitochondrial dysfunction manifests in many forms during childhood. There is no effective therapy for the condition; hence symptomatic therapy is the only option. The effect of symptomatic therapy are not well known. We present clinical course, diagnosis and effect of current treatments for six children suffering from mitochondrial encephalomyopathy identified by clinical demonstrations, brain MRI findings and DNA mutations. Two were male and four were female. Their age ranged between 2 and 17 years. Skeletal muscle biopsies were obtained in three and one showed misshaped and enlarged mitochondria under electron microscope. mtDNA mutation frequency was >30%. Five children were diagnosed with MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) and one with Leigh’s syndrome (LS). All were given cocktail and symptomatic treatments. One of the five MELAS children died from severe complications. The other four MELAS children remain alive; four showed improvement, and one remained unresponsive. Of the four who showed improvement, two do not have any abnormal signs and the other two have some degree of motor developmental delay and myotrophy. The LS child is doing well except for ataxia. Until better therapy such as mitochondrial gene therapy is available, cocktail and symptomatic treatments could at least stabilize these children.

A Double-blind, Placebo-Controlled Study of the Impact of Galantamine on Anterograde Memory Impairment During Electroconvulsive Therapy

Electroconvulsive therapy (ECT) continues to be an effective treatment option for patients who fail to respond to pharmacological interventions, are unable to tolerate medications, and show a suboptimal response to behavioral and psychotherapeutic treatments. However, risks for cognitive impairment may contribute to some patients' refusal of ECT. The present study examined galantamine as a pharmacological intervention to reduce cognitive adverse effects from ECT. Thirty-nine inpatients diagnosed with major depressive disorder; bipolar disorder, depressed type; or schizoaffective disorder, depressed type and admitted for ECT were randomized to galantamine or placebo. Study drugs were initiated 24 to 48 hours before starting ECT and continued throughout the course of ECT. A neuropsychological test battery was administered at baseline and 24 to 48 hours after completing a course of ECT treatments. Depression severity was monitored using the 17-item Hamilton Rating Scale for Depression and Clinical Global Impression Scale at baseline, weekly, and end point. Self-rated adverse effects were monitored weekly. Thirty participants (12 patients in the galantamine group, 18 patients in the placebo group) had both pretreatment and posttreatment neuropsychological ratings. Those in the galantamine group scored significantly higher at discharge for delayed memory (t28 = 2.44, P < 0.05). Hierarchical regressions examined if treatment condition predicted changes in delayed memory scores from baseline to discharge. Inclusion of the treatment condition in the final model made a significant incremental improvement in prediction (ΔR = 0.12, F1,27 change = 4.65, P < 0.05; β = 0.37, t = 2.16, P < 0.05). Galantamine was well tolerated with no clinically significant bradycardia or prolonged paralysis when administered with ECT. Galantamine may be protective against impairment in retention of new learning. Galantamine exhibited minimal adverse effects and was safe when administered during ECT. The present findings require replication by future researchers using larger samples before broad conclusions can be drawn.

Administration of 17α-hydroxyprogesterone into mature male Japanese eel reduces sperm motility by decreasing potassium ion concentrations in the seminal plasma

Our objective was to evaluate the effects of hormonal treatments on the milt quality during the induction of spontaneous spawning in male eels. We measured the changes in milt characteristics (sperm motility, milt pH, seminal plasma ionic concentration) during the course of hormonal treatments intended to induce spontaneous spawning, and before and after spawning. Male eels received weekly injections of hCG (1IU/gBW/wk) to maintain spermiation. To induce spontaneous spawning, males received another priming injection of hCG (1IU/gBW) two days before spawning, followed 24h later by an injection of 17α-hydroxyprogesterone (OHP: 1μg/gBW). Three males, treated as described above, and one female, that had received hormonal injections to induce vitellogenesis and final maturation, were transferred to a tank to spawn. In Experiment 1, we measured the characteristics of milt (1) before administering the priming dose (1–2days after the weekly injection of hCG), (2) before injection with OHP, (3) after spawning (24h after the OHP injection), and (4) before weekly injections with hCG (4–5days after OHP injection). To evaluate the effects of hormonal treatment on the characteristics of milt we administered the same treatments but did not allow spawning (Experiment 2). In both experiments, the percent motility remained high prior to OHP injection, decreased significantly 24h after OHP injection, then recovered by the beginning of weekly hCG injection. The changes in potassium ion concentration were similar to those in sperm motility (%) but there was no change in pH and sodium ion concentrations. When the results were analyzed by individual in Experiment 1 (n=34), the relationship between sperm motility (%) and milt pH showed significant correlations without 24h after the OHP injection. The relationship between sperm motility (%) and potassium ion concentration showed a highly significant correlation 24h after the OHP injection. Thus, both pH and potassium ion concentration regulate motility in Japanese eel spermatozoa during hormonal treatment. Furthermore, administration of OHP into spermiating males reduced motility by decreasing the potassium ion concentration in the seminal plasma.

The Role of Regularization in Deformable Image Registration for Head and Neck Adaptive Radiotherapy

Deformable image registration provides a robust mathematical framework to quantify morphological changes that occur along the course of external beam radiotherapy treatments. As clinical reliability of deformable image registration is not always guaranteed, algorithm regularization is commonly introduced to prevent sharp discontinuities in the quantified deformation and achieve anatomically consistent results. In this work we analyzed the influence of regularization on two different registration methods, i.e. B-Splines and Log Domain Diffeomorphic Demons, implemented in an open-source platform. We retrospectively analyzed the simulation computed tomography (CTsim) and the corresponding re-planning computed tomography (CTrepl) scans in 30 head and neck cancer patients. First, we investigated the influence of regularization levels on hounsfield units (HU) information in 10 test patients for each considered method. Then, we compared the registration results of the open-source implementation at selected best performing regularization levels with a clinical commercial software on the remaining 20 patients in terms of mean volume overlap, surface and center of mass distances between manual outlines and propagated structures. The regularized B-Splines method was not statistically different from the commercial software. The tuning of the regularization parameters allowed open-source algorithms to achieve better results in deformable image registration for head and neck patients, with the additional benefit of a framework where regularization can be tuned on a patient specific basis.

Effect of hyperbaric pressure and temperature on respiration rates and quality attributes of tomato

Previous work with hyperbaric treatment of tomato focused on application at lower temperature (13°C). In this work, hyperbaric treatment at varying pressure levels (i.e., 0.1, 0.3, 0.5, 0.7 and 0.9MPa) at ambient temperature (20°C) was tested as a potential alternative to conventional refrigerated storage (0.1MPa at 13°C) to preserve tomato quality. The experiments were divided into 3 phases: (1) 4 day of hyperbaric treatment, (2) 5 day of post-treatment ripening, and (3) 10 day of post-treatment ripening. Respiration rate (RR) of the tomatoes was continuously monitored during the course of the hyperbaric treatments. Quality attributes were assessed immediately after removal from the hyperbaric treatments and after 5 and 10 day ripening at 20°C after removal from the treatments. Hyperbaric treatments at ≥0.3MPa resulted in RR equal or higher than the RR in control fruit (0.1MPa at 20°C). The lowest RR was obtained from tomato stored at 0.1MPa at 13°C. Hyperbaric treatment at 0.5, 0.7 and 0.9MPa significantly reduced weight loss, retained color, firmness, total soluble solid (TSS), titratable acidity (TA) and TSS:TA ratio at similar levels as the tomato treated at 13°C and 0.1MPa. Firmness after treatment was highest for fruit from 0.1MPa at 13°C and from 0.5, 0.7 and 0.9MPa at 20°C. The higher firmness advantage declined by 5 day of ripening after treatment, with higher firmness only being retained for fruit from the 0.9MPa at 20°C and the 0.1MPa at 13°C treatments. After 10 day ripening, firmness was similar for all treatments. Lightness (L*) and hue angle were greater for all treatments compared with the 0.1MPa at 20°C treatment. However, only the greater hue angle difference was maintained after 5 day of ripening. After 10 day ripening, no significant differences were found in color attributes. Only 0.1MPa at 13°C retained higher soluble solids, lower titratable acidity and higher TSS:TA ratios after treatment and after 5 day ripening. At 10 day of ripening none of the quality attribute differences noted were retained for any of the treatments. These results show that the only consistent effect of hyperbaric treatment at 0.5, 0.7 and 0.9MPa was to reduce weight loss and enhance firmness retention up to 5 day ripening after treatment.

Urticaria and Autoimmunity: Where Are We Now?

There is considerable debate whether chronic urticaria is an autoimmune disease or whether its features suggestive of autoimmunity are epiphenomena. A plethora of circumstantial evidence suggests that chronic urticaria is an autoimmune disease, but criteria to establish autoimmunity require direct proof and indirect evidence, and these are lacking in chronic urticaria. Current approaches to assessing for autoimmunity in vivo via the autologous serum skin test, and in vitro via either basophil histamine release or the basophil activation test are widely utilized, but the results of these tests have limited impact on prediction of the clinical course and efficacy of treatments. Recent guidelines for diagnosing autoimmune urticaria have been proposed, but further investigation is needed.

Change in Defense Mechanisms and Coping Patterns During the Course of 2-Year–Long Psychotherapy and Psychoanalysis for Recurrent Depression

Very little research has been conducted so far to study the potential mechanisms of change in long-term active psychological treatments of recurrent depression. The present pilot randomized controlled trial aimed to determine the feasibility of studying the change process occurring in patients during the course of 2-year-long dynamic psychotherapy, psychoanalysis, and cognitive therapy, as compared with clinical management. In total, eight outpatients presenting with recurrent depression, two patients per treatment arm, were included. All patients were randomly assigned to one of the four treatment conditions. Defense mechanisms and coping patterns were assessed using validated observer-rated methodology based on transcribed, semistructured follow-along independent dynamic interviews. The results indicated that, whereas some patients in the active treatments changed on the symptomatic levels, some others remained unchanged during the course of their 2-year-long treatment. However, with regard to potential mechanisms of change in these patients, changes in defense mechanisms and coping patterns were revealed to be important processes over time in successful therapies and, to a lesser extent, in less successful treatments. No change was found either on outcome or on the process measure for the control condition, that is, clinical management. These results are discussed along with previous data comparing change in defense mechanisms and coping during the course of treatments.

Response shifts in mental health interventions: An illustration of longitudinal measurement invariance.

The efficacy of treatments for depression is often measured by comparing observed total scores on self-report inventories, in both clinical practice and research. However, the occurrence of response shifts (changes in subjects' values, or their standards for measurement) may limit the validity of such comparisons. As most psychological treatments for depression are aimed at changing patients' values and frame of reference, response shifts are likely to occur over the course of such treatments. In this article, we tested whether response shifts occurred over the course of treatment in an influential randomized clinical trial. Using confirmatory factor analysis, measurement models underlying item scores on the Beck Depression Inventory (Beck & Beamesderfer, 1974) of the National Institute of Mental Health Treatment of Depression Collaborative Research Program (Elkin, Parloff, Hadley, & Autry, 1985) were analyzed. Compared with before treatment, after-treatment item scores appeared to overestimate depressive symptomatology, measurement errors were smaller, and correlations between constructs were stronger. These findings indicate a response shift, in the sense that participants seem to get better at assessing their level of depressive symptomatology. Comparing measurement models of patients receiving psychotherapy and medication suggested that the aforementioned effects were more apparent in the psychotherapy groups. Consequently, comparisons of observed total scores on self-report inventories may yield confounded measures of treatment efficacy.

DNA damage response in peripheral nervous system: Coping with cancer therapy-induced DNA lesions

In the absence of blood brain barrier (BBB) the DNA of peripheral nervous system (PNS) neurons is exposed to a broader spectrum of endogenous and exogenous threats compared to that of the central nervous system (CNS). Hence, while CNS and PNS neurons cope with many similar challenges inherent to their high oxygen consumption and vigorous metabolism, PNS neurons are also exposed to circulating toxins and inflammatory mediators due to relative permeability of PNS blood nerve barrier (BNB). Consequently, genomes of PNS neurons incur greater damage and the question awaiting investigation is whether specialized repair mechanisms for maintenance of DNA integrity have evolved to meet the additional needs of PNS neurons. Here, I review data showing how PNS neurons manage collateral DNA damage incurred in the course of different anti-cancer treatments designed to block DNA replication in proliferating tumor cells. Importantly, while PNS neurotoxicity and concomitant chemotherapy-induced peripheral neuropathy (CIPN) are among major dose limiting barriers in achieving therapy goals, CIPN is partially reversible during post-treatment nerve recovery. Clearly, cell recovery necessitates mobilization of the DNA damage response and underscores the need for systematic investigation of the scope of DNA repair capacities in the PNS to help predict post-treatment risks to recovering neurons.

Combined Use of Electroconvulsive Therapy and Amantadine in Adolescent Catatonia Precipitated by Cyber-Bullying

Catatonia is a unique motor dysregulation syndrome characterized by identifiable signs such as immobility, sometimes alternating with excessive motor activity, that is apparently purposeless and not influenced by external stimuli, extreme negativism or muteness, peculiarities of voluntary movement, echolalia, or echopraxia (Fink and Taylor 2009). Catatonia accompanies a number of general medical and neurologic conditions (Dhossche and Wachtel 2010), with acute or insidious onset. In its most severe forms, catatonia may become life threatening, especially when aggravated by autonomic dysfunction and fever. Although previously considered to be rare in children and adolescents (Cohen et al. 1999), recent reports suggest that the prevalence of catatonic symptoms in these age groups is in fact similar to that reported in adults (Ghaziuddin et al. 2012). Overwhelming stress and trauma may trigger catatonia in children and adolescents (Dhossche et al. 2012). Benzodiazepines and electroconvulsive therapy (ECT) are considered first-line treatments (Weiss et al. 2012); however, the literature offers little guidance in cases that do not respond or that respond slowly to a course of these primary treatments. We present an adolescent case with close temporal relationship between onset of catatonia and cyber-bullying, a severe but common stressor nowadays for many adolescents, which resolved with daily ECT and adjunctive amantadine. We did not find any prior published accounts of these features in adolescents.

Finite element analysis of thermal and acoustic processes during laser tattoo removal

Q-switched laser therapy is commonly used for the removal of tattoos. However, despite ever increasing demand for this intervention, a better understanding of the mechanisms that result in pigment reduction is required in order to optimise outcomes and reduce the number of treatment episodes. A finite element analysis computer simulation was developed to model the fragmentation response of ink granules during irradiation of a professional black tattoo using a Q-switched Nd:YAG laser. Thermal and acoustic mechanisms were considered, allowing the optimal laser settings to be predicted throughout the course of treatment. Changes in the thermal properties of the ink during heating were taken into account to improve the reliability of the results obtained. The simulated results are in close agreement with clinical observations. Thermal fragmentation was shown to be the dominant mechanism in pigment reduction when using a 6 nanoseconds pulse at 1,064 nm. In order to provide maximum clearance whilst maintaining acceptable levels of tissue thermal damage, later treatments were shown to benefit from higher fluence levels than initial treatments. Larger spot diameters were also preferable throughout the course of treatment. The results from the simulation build upon previous work carried out in the field, applying ink thermal coefficients which vary with temperature for the first time. These results compliment clinical knowledge, suggesting that a proactive increase in fluence during a course of treatments is likely to improve the response to laser therapy.

Senescence as A Consequence of Ginsenoside Rg1Response on K562 Human Leukemia Cell Line

Traditional chemotherapy strategies for human leukemia commonly use drugs based on cytotoxicity to eradicate cancer cells. One predicament is that substantial damage to normal tissues is likely to occur in the course of standard treatments. Obviously, it is urgent to explore therapies that can effectively eliminate malignant cells without affecting normal cells. Our previous studies indicated that ginsenoside Rg1 (Rg1), a major active pharmacological ingredient of ginseng, could delay normal hematopoietic stem cell senescence. However, whether Rg1 can induce cancer cell senescence is still unclear. In the current study, human leukemia K562 cells were subjected to Rg1 exposure. The optimal drug concentration and duration with K562 cells was obtained by MTT colorimetric test. Effects of Rg1 on cell cycle were analyzed using flow cytometry and by SA-β-Gal staining. Colony-forming ability was measured by colony-assay. Telomere lengths were assessed by Southern blotting and expression of senescence-associated proteins P21, P16 and RB by Western blotting. Ultrastructural morphology changes were observed by transmission electron microscopy. K562 cells demonstrated a maximum proliferation inhibition rate with an Rg1 concentration of 20 μ molL-1 for 48h, the cells exhibiting dramatic morphological alterations including an enlarged and flat cellular morphology, larger mitochondria and increased number of lysosomes. Senescence associated-β-galactosidase (SA-β-Gal) activity was increased. K562 cells also had decreased ability for colony formation, and shortened telomere length as well as reduction of proliferating potential and arrestin G2/M phase after Rg1 interaction. The senescence associated proteins P21, P16 and RB were significantly up-regulated. Ginsenoside Rg1 can induce a state of senescence in human leukemia K562 cells, which is associated with p21-Rb and p16-Rb pathways.

Endoscopic Stapled Marsupialisation of Chronic Presacral Sinus following Low Anterior Resection: A Simple Option in Selected Cases

Chronic presacral sinus (CPS) following anastomose leakage is one of the most serious complications after restorative colorectal surgery. CPS is associated with long course of treatments and can prevent stoma closure. We present our experience with endoscopic stapled marsupialisation (ESM) of CPS. Seven patients underwent ESM. All patients had developed a CPS after clinical anastomotic leakage following low anterior resection with diverting ileostomy. Initially the patients were treated conservatively and with endoscopic vacuum-assisted closure (Endo-VAC). ESM procedure was successful for six patients, resulted in good healing in four patients and no sinus recurrence of the CPS. In two patients the stoma was re-versed. Two patients were treated with neo-adjuvant chemoradiotherapy, who also developed small bowel fistulae. ESM is a simple treatment for CPS and can accelerate healing of chronic presacral cavity, reduce complications and enable to reverse the stoma in selected cases.

A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

AbstractAbstract 55 Background:Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods:The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results:A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion:In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures:Off Label Use:PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.