Clinical Response Patterns Research Articles

Periodontitis phenotypes and clinical response patterns to non-surgical periodontal therapy: reflections on the new periodontitis classification.

We aimed to identify response patterns to non-surgical periodontal therapy and to investigate whether the new classification system for periodontitis reflects response to treatment after 1yr. At baseline, data on sociodemographic status, smoking, and diabetes were obtained from participants with periodontal disease. Clinical periodontal data and subgingival plaque were also collected. Participants underwent non-surgical periodontal therapy, and after 3 and 12months, clinical data were reassessed. Factor analyses, group-based-trajectory modeling, and mixed-effects regression models were used for data analysis. Factor analysis of the baseline periodontal parameters revealed two different periodontitis dimensions: 'moderate' and 'severe'. Two response patterns for each of these periodontitis dimensions were identified. Periodontal therapy had a beneficial effect on both 'moderate' and 'severe' periodontitis; however, individuals with higher levels of disease at baseline experienced greater treatment effect. Regarding the new classification system, while the staging component distinguished different levels of 'moderate' and 'severe' periodontitis before and after treatment, the grading component did not. This study shows the beneficial effect of non-surgical periodontal therapy on both 'moderate' and 'severe' periodontitis. However, the benefit was limited among individuals with low levels of disease. The new classification system did not adequately reflect the periodontal response to therapy in this patient group.

A study on the clinical profile and treatment outcomes in gallbladder carcinoma from Northern India

Aim: Gallbladder carcinoma (GBC) is a common cancer in women in North India. This prospective observational study aimed at systematically studying the clinical features, treatment response, and survival pattern of GBC patients, in a North Indian population. Materials and Methods: The clinical profile, staging of disease, and treatment outcomes of 116 consecutive patients with histologically confirmed GBC, presenting to a tertiary care hospital in Lucknow from June 2013 to August 2015, with a follow-up period of 2 years till August 2017, were studied. Data were captured on a predesigned study proforma and analyzed with appropriate statistical tools. Results: The median age at presentation was 60 years and 67 patients had coexisting gall stones. Patients were divided into three treatment groups for the analysis. Group A comprised patients who underwent radical cholecystectomy followed by adjuvant chemotherapy. Group B included patients who received the best supportive care and Group C consisted of patients who received palliative chemotherapy. The median overall survival (mOS) was 16, 2, and 9 months for Group A, B, and C patients, respectively. The mOS was 8 months for all patients, irrespective of treatment groups. On univariate analysis, factors having an adverse impact on mOS included obstructive jaundice, elevated liver enzymes, treatment groups, and advanced stage of disease. On multivariate analysis, only factor found significantly associated with mOS was treatment group (P

Unedited pathological recurrent association of palmomental and rooting archaic reflexes in a young woman with severe traumatic brain lesions – case presentation and physiopathological considerations

Introduction. Archaic reflexes are present in infancy, disappear as the brain matures, but reappear in pathological conditions. Case report. A 29-years-old woman has suffered a severe traumatic brain injury. She was admitted to neurorehabilitation 6 months after neurosurgical interventions (ventriculoperitoneal shunt for traumatic hydrocephalus, emerged after decompressive craniectomy). Neurological examination revealed a minimal conscious state, spastic tetraparesis, trismus, central facial palsy, nystagmus, bilateral palm-chin reflex, and a “mitigated” variant of the rooting reflex. The left corneal, snout and glabellar reflexes were absent. Osteotendinous reflexes were brisk, Babinski sign was bilaterally present, palmar and plantar grasp reflexes were absent. The trismus has persisted and chewing remained severely disabled after botulinum toxin injected in the left temporalis muscle and bilaterally in the masseter. The patient was fed by percutaneous endoscopic gastrostomy tube. Neurologic evolution remained stationary after two months of rehabilitative nursing. Discussion. The palmomental reflex described by Marinescu and Radovici, is elicited by scratching the thenar eminence of the palm, and consists of an ipsilateral twitch of the mentalis muscle. Baby rooting for milk is a primitive trigemino-facial reflex found in newborn infants. The lower lip is lowered, and the tongue is moved in the direction where the cheek near the corner of the mouth is brushed. The lockjaw has “mitigated” the classical pattern of clinical response. Repeated stimulation causes a unilateral mentalis muscle response, similar to the palm-chin reflex. The severe traumatic brain lesions have induced pathological reappearance of the palmomental and rooting archaic reflexes, in a unique, unedited pathological association. Key words: palmomental reflex (Marinescu Radovici reflex); rooting reflex; archaic reflexes; botulinum toxin; traumatic brain injury; minimal conscious state,

Antimicrobial usage and its quantification for neonatal sepsis at a tertiary care hospital neonatal intensive care unit

Background: Antimicrobial therapy for neonatal sepsis is challenging as its judicious use can save neonates while its inappropriate use can lead to rapid emergence of resistant strains. Quantification of consumption of antimicrobial agents (AMA) has not been undertaken in Indian neonatal intensive care units (NICU) setting. This prospective observational study evaluated the antimicrobial prescribing pattern and quantified its consumption in clinically suspected neonatal sepsis (NS) cases.Methods: Clinically suspected NS cases admitted over study period of 18 months in a tertiary care level III NICU were enrolled. Data of antimicrobials prescribed, its consumption, culture sensitivity profile of organisms isolated were collected.Consumption was quantified by computing the days of therapy (DOT) per 1000 patient-days (PD).Results: 150 clinically suspected NS cases were enrolled; 37.33% were culture positive. The most common AMA prescribed were netilmicin (94.67%), piperacillin-tazobactam (88.67%). Only 0.67% cases received reserve antimicrobials like colistin, vancomycin and linezolid. 58% received 2 AMA, 39.33% received ≥3 agents. Total antimicrobial consumption was 614.86 DOT/1000 PD and 21.68 DOT/ neonate. Statistically significant difference in total AMA consumption amongst culture positive versus negative cases (p <0.001) was observed but difference was not significant in EOS versus LOS (p=0.95).Conclusion: Usage of antimicrobials for neonatal sepsis was guided by sensitivity pattern of local prevalent flora and clinical response. Usage of reserve antimicrobials were restricted. However, consumption of AB was higher compared to developed countries and we intend to use the study outcome data for antibiotic stewardship program to reduce antibiotic consumption and modify prescribing trends at the study setting.

Leishmania donovani Induced Cutaneous Leishmaniasis: An Insight into Atypical Clinical Variants in Sri Lanka.

Sri Lanka is a recent focus having Leishmania donovani induced cutaneous leishmaniasis (CL) as the main clinical entity. A separate clinical entity within profile of CL was described in this study. Laboratory confirmed cases of CL (n= 950, 2002-2014) were analysed. Most lesions showed known classical developmental stages of CL (CCL) observed in other CL endemic settings while few cases (13%, 122/950) showed atypical skin manifestations (ACL). Clinical, geographical, and treatment response patterns of ACL were different from those of CCL. ACL was mainly found among males (68.0%), in 21-40 year age group (51.6%), and reported delayed treatment seeking (23.5% vs 16.3% in CCL), more nonclassical onset (lesions other than acne form <1cm sized papules), (12.1 vs 2.7%, P<0.05.), more head and neck lesions (41.5%. vs 27.2%), more large lesions (>4cm), (18.6 vs 9.9%), and poor laboratory positivity rates (65.6% vs 88.2%) when compared to CCL. When compared to lesions reporting a typical onset, lesions reporting nonclassical onset were more likely to develop ACL later on (50.1% vs 10.7%). As compared to lesions on limbs, those on head and neck and trunk were more likely to be ACL (7.0%, 16.3%, and 22.8%, respectively, P<0.05). ACL features were not age or gender dependent. Highest proportion within ACL category (32.8%) and small proportion of CCL (10.1%) originated from less leishmaniasis prevalent areas (other regions) (P<0.05). North reported more ACL than South (15.9% vs 7.4%). A total of 95 CL cases with a significant travel history were further analyzed. Residents of other regions when acquired infection from North or South developed more ACL than residents in North or South (60.9% vs 15.9% and 42.9% vs 7.4% respectively). Patients in other regions when travelled to North developed more ACL than when they travelled to South (60.9%, 42.9%). ACL and CCL required an average of 18 doses over 16.7 months and 10 doses over 12 weeks, respectively, to achieve a complete clinical cure. Underlying host immunological factors, parasite strain variations and regional variations of both could be underlying etiologies. Established independent transmission within less leishmaniasis prevalent regions combined with an unusual clinical picture leading to poor clinical suspicion and low laboratory confirmation rate will pose potential difficulties in early case detection in these highly populated and commercialized areas. This in turn will further facilitate silent and high disease transmission.

Prognostic and predictive factors in recurrent and/or metastatic head and neck squamous cell carcinoma: A review of the literature.

The pattern of clinical behaviour and response to treatment of recurrent and/or metastatic head and neck squamous cell carcinoma is heterogeneous. Treatment strategies that can be employed vary from potentially curative salvage surgery and re-irradiation to palliative systemic therapies and best supportive care. The advent of new therapeutic options, in terms of more sophisticated surgical approaches and techniques, highly conformal and precise radiation techniques and immunotherapy may offer improved control of disease and longer survival. Moreover, the epidemiological changes during the last decades, including the increase of human papilloma virus-related oropharyngeal primary tumors, are also reflected in the recurrent and metastatic setting. In this complex context the identification of predictive and prognostic factors is urgently needed to tailor treatment, to increase its efficacy, and to avoid unnecessary toxicities. A better knowledge of prognosis may also help the patients and caregivers in decision making on the optimal choice of care. The purpose of our review is to highlight the current evidence and shortcomings in this field.

Insulin Autoantibody Syndrome: Varying Clinical Presentations and Response Patterns of an Underrecognized Entity.

Context:Insulin autoantibody syndrome (IAAS) is considered to be a rare cause of hyperinsulinaemic hypoglycaemia. Lack of familiarity with the varied clinical manifestations leads to underdiagnosis. Localization techniques aimed at insulin-secreting neoplasms and nesidioblastosis, which are expensive often are ordered when the correct diagnosis is not made.Aims:We describe the myriad of clinical manifestations associated with IAAS based on single centre experience.Settings and Design:Retrospective analysis of patients who got admitted with symptoms suggestive of hypoglycaemia and underwent mixed meal test and prolonged hypoglycaemic test from 2016 to 2019.Subjects and Methods:Retrospective data of 12 patients with IAAS who were diagnosed in the threeyear time period between 2016 and 2019 are included in this analysis. Clinical details, biochemical parameters and imaging modalities were analysed.Statistical Analysis:All analyses were performed with SPSS software (version 17).Results:Total of twelve patients 12 (5 male and 7 females) were identified as IAAS. Median age of presentation was 57 years. Median insulin levels and median C-peptide levels were 300 miu/ml and 18.5 ng/ml respectively. Only 3 (25%) patients had spontaneous resolution. Steroid induced remission occurred by 3 months in the remaining patients. Intermittent hyperglycaemia was seen in 9 (75%) patients. Implicatable drug use preceding the occurrence of the clinical symptoms was observed in five patients.Conclusion:IAAS is not uncommon in India. The diagnosis should be pursued in patients with hyperinsulinaemic hypoglycaemia especially when insulin levels are very high or when there is intermittent hyperglycaemia.

Challenges of evaluating immunotherapy efficacy in solid tumors.

Immunotherapy is one of the most promising treatments for multiple tumor types. The significant clinical benefits and durable responses of immunotherapy have led to the emergence of various immune-related clinical response patterns that extend beyond those achieved with cytotoxic agents. Various studies investigated the efficacy of immunotherapy, including the effect on tumor size, long-term survival benefits, and the ability to overcome the particularly challenging survival curves tailing phenomenon. The current immune-related methods guidelines, such as immune-related Response Criteria (irRC), immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), immune Response Evaluation Criteria in Solid Tumors (iRECIST), and immune-modified Response Evaluation Criteria in Solid Tumors (imRECIST), could be well-adapted to identify the heterogeneity of responses that appear in patients receiving immunotherapy, such as pseudoprogression (PsPD) and hyperprogressive disease (HPD), and to some extent to overcome the limitation of evaluating the efficacy of immunotherapy on tumor size by imaging. Additionally, a second type of evaluation method was proposed based on survival, which includes milestone analysis and restricted mean survival time. Currently, milestone analysis is a complementary tool to summarize and interpret trial results along with more conventional measures of survival and other less established metrics. A golden standard evaluation method to distinguish the efficacy of immunotherapy may improve the process of imaging and aid survival-based efficacy evaluation in patients with solid tumors.

Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST)

BackgroundFebrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000 mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment.MethodsThe FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (≥18 years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3 g every 24 h) or ciprofloxacin (500 mg every 12 h) for a total antibiotic duration of 10 days. The primary endpoint is clinical cure (resolution of symptoms) 6–10 days post-treatment. Secondary endpoints are microbiological cure 6–10 days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30–35 days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of < 0.05 and a power of 80%.DiscussionThe study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI.Trial registrationRegistered at the Nederlands trial register (Dutch trial register) on 4-10-2017. Trial registration number: NTR6449. Secondary ID (national authority): NL60186.041.17.

3D-Tissue Engineered Bone Marrow (3DTEBM) Culture Retrospectively Predicts Treatment Clinical Outcomes of Multiple Myeloma Patients

Background:Multiple Myeloma (MM) is the second most common hematological malignancy, and continues to be a fatal disease even with the development of novel therapies. Despite promising preclinical data in standard tissue culture models, most drugs fail in clinical trials and show lower efficacy in patients. This highlights the discrepancy between the current in vitro models, the pathophysiology of the disease in the patients, and the urgent need for better in vitro models for drug development and improved prediction of efficacy in patients. We have previously developed a patient-derived 3D-Tissue Engineered Bone Marrow (3DTEBM) culture model, which showed superior properties for proliferation of primary MM cells ex vivo, and better recapitulated drug resistance. The long-term goal of this study is to use the 3DTEBM model as a tool to perform drug screens on BM aspirates of MM patients and prospectively predict the efficacy of different therapies in individual patients, and help treatment providers develop personalized treatment plans for each individual patient. In the current study, we used the 3DTEBM model to, retrospectively, predict clinical responses of MM patients to therapy, as a proof of concept.Methods:We used whole-BM, viably frozen tissue banked samples from 20 MM patients with clear clinical response patterns of complete remission, and either very good partial response (sensitive) or progressive disease (non-sensitive). The BM aspirates were used to develop a 3DTEBM that represents each individual patient. The patient-derived 3DTEBM cultures were treated ex vivo with the same therapeutic regimen that the patient received in the clinic for 3 days. The treatment ex vivo was based on combinations at different concentrations which mimic the steady state concentrations (Css) of each drug. The efficacy of the treatment ex vivo was evaluated by digestion of the 3DTEBM matrix, extraction of the cells, and analysis for prevalence of MM cells in the treatment groups compared to the non-treated controls. Patients were defined “sensitive” if the effect reached 50% killing in the range of 10xCss. The ex vivo sensitivity data was then correlated with the clinical response outcomes.Results:We found that the 3DTEBM was predictive in approximately 80% of the cases (in about 85% of the combination therapy cases, and in about 70% of the single therapy cases). Broken down by individual drug, it was predictive in 80% of the cases treated with Bortezomib, 78% Lenalidomide, 84% Dexamethasone, 100% Daratumumab, 50% Carfilzomib, 50% Pomalidomide, and 100% Doxorubicin.Conclusions:The 3DTEBM is a more pathophysiologically relevant model which predicts clinical efficacy of drugs in multiple myeloma patients, retrospectively. This data provides the bases for future studies which will examine the ability of the 3DTEBM model to predict treatment efficacy, prospectively, for development of personalized treatment plans in individual multiple myeloma patients. DisclosuresJeske:Cellatrix LLC: Employment. Azab:Cellatrix LLC: Employment. De La Puente:Cellatrix LLC: Other: Co-founder. Vij:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Azab:Ach Oncology: Research Funding; Cellatrix LLC: Equity Ownership, Other: Founder and owner; Glycomimetics: Research Funding; Targeted Therapeutics LLC: Equity Ownership, Other: Founder and owner.

A Pilot Feasibility Study of Definitive Concurrent Chemoradiation with Pencil Beam Scanning Proton Beam in Combination with 5-fluorouracil and Mitomycin-c for Carcinoma of the Anal Canal

Definitive chemoradiation (CRT) with concurrent 5-fluorouracil (5-FU) and mitomycin-C (MMC) is standard of care for patients with localized squamous cell cancer (SCC) of the anal canal. Treatment, however, can result in significant acute and late toxicity. Pencil beam scanning proton therapy (PBS-PT) holds the potential to improve dose delivery and spare non-target tissues. Preliminary preclinical dosimetric data suggests that treatment with PBS-PT will significantly decrease radiation dose to normal tissue structures compared to conventional 3D treatment planning and IMRT. This is a multi-institutional pilot study evaluating the feasibility of definitive concurrent CRT with PBS-PT in combination with 5-FU and MMC for carcinoma of the anal canal. Patients were enrolled on an NCI sponsored, prospective, multi-institutional, single arm pilot study (NCT 01858025). Key eligibility included: ECOG 0-2, age 18+, histologically confirmed invasive SCC of the anal canal, clinically staged T1-4, N0-3. Pts were treated with PBS proton RT per RTOG 0529 RT dose schema; for T1-2, N0: 50.4 Gy to primary CTV, 42 Gy to elective LNs in 28 fractions; for T3+ or N+: 54 Gy to primary CTV, 50.4-54 Gy to involved LN, and 45 Gy to elective LNs. Pts received concurrent 5-FU/MMC on day 1 and 29. The primary objective of this study was to establish feasibility of PBS-PT with concurrent 5-FU/MMC, which was defined as grade 3+ dermatologic toxicity less than 48% (reported grade 3+ dermatologic toxicity from RTOG 98-11). The secondary objective of this study was to determine the rates of overall grade 3+ toxicities, clinical complete response (cCR) rate and patterns of local regional tumor recurrence. From February 2014 to April 2017, 25 patients were prospectively enrolled between two academic institutions, all of whom were analyzed. 23 pts (92%) completed treatment per protocol, 2 pts died on treatment (1 due to sepsis, 1 due to sudden cardiac death). Median time to completion of treatment was 42 days (range 38-49). The Grade 3+ radiation dermatitis was 24% (Table 1). The clinical complete response rate was 80%. With a median follow-up of 23.7 months (range 11.8-46.4) among the 21 patients still alive, the 2-year local control, colostomy-free survival, progression-free survival, and overall survival are 95%, 75%, 80% and 83%, respectively. In our prospective, multi-institutional pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. While felt to be unrelated to proton radiation therapy, two patient deaths on this small study highlights treatment related risks of this effective yet toxic regimen.Abstract 125; TableCategoryGrade 1Grade 2Grade 3Grade 4Grade 5Hematologic05 (20%)4 (16%)7 (28%)0Gastrointestinal4 (16%)12 (48%)9 (36%)00Radiation dermatitis2 (8%)16 (64%)6 (24%)00Fatigue10 (40%)11 (44%)3 (12%)00Genitourinary12 (48%)4 (16%)1 (4%)00Anorexia8 (32%)6 (24%)000Pulmonary/Respiratory2 (8%)1 (4%)000Worst Overall03 (12%)14 (56%)7 (28%)1 (4%) Open table in a new tab

Immune thrombocytopenia: clinical features and analysis of risk factors to response to the treatment

Introduction: Immune thrombocytopenia (ITP) is an acquired decrease of platelets, caused by autoantibodies against platelets, in the absence of an associated condition. ITP is associated to low morbidity and mortality, however there is reduced quality of life on the patients under treatment. This study has as objectives to describe the clinical features of the patients and the evaluation of risk factors related to the response to treatment. Methods: A retrospective analysis was achieved, regarding the medical records of 99 patients diagnosed with ITP and seen between May of 1992 and August of 2016 in a hospital.Results: 99 patients were analyzed, 71 female (71.7%). Mean age 39 years old to diagnosis (variation 2-84). 83.3% of the patients were chronic ITP and the mean follow up 49.2 months (0,1-289). 74.7% of patients presented bleeding to diagnosis. 76.7% of patients required treatment, and there was remission in 7 (30.4%) of the 23 patients who did not receive any treatment. 37 patients were submitted to splenectomy, 30 (81.1%) of those obtained partial or complete response and 18 (48.6%) presented loss of response. 30% of patients were submitted to posterior treatments. Only two patients had death related to ITP. In bivariate analysis of risk factors to response to the treatment, the only predictors of chronicity were initially the absence of corticosteroid dependence and absence of response to splenectomy, however in multivariate analysis those factors had their significance discarded. Conclusion: The presented results did not confirm a higher progression rate to chronicity in non corticosteroid-dependent patients and in those who did not present response to splenectomy. The clinical features, response pattern and survival of analyzed patients were similar to other studies reported.

Longitudinal assessment of stability of sensory features in children with autism spectrum disorder or other developmental disabilities.

Prior research on the stability of sensory processing problems in children with autism spectrum disorder (ASD) or other developmental disabilities (DD) has produced inconsistent results. We employed a longitudinal study design to assess the stability of three clinical sensory response patterns: hyporesponsiveness; hyperresponsiveness; and sensory interests, repetitions, and seeking behaviors (SIRS). Parents of children with ASD (n = 55) or DD (n = 35) responded to sensory questionnaires at two time points (T1 and T2) separated by 3.3 years on average, with the children aged 2-12 years (M = 5.69 ± 2.46) at the first assessment. For each sensory response pattern, regression analysis revealed that, for both ASD and DD groups, scores at T1 were strong predictors of scores at T2. Over the longitudinal assessment interval, there was a significant mean decline in severity for SIRS in both groups and for hyporesponsiveness in the ASD group. Parental estimates of the amount of therapy services received were positively associated with the severity of sensory features at T2, an outcome that may result from increased intervention dosages being administered to children who fail to improve over time. The results are discussed in terms of person-centered and environmental considerations, which, in combination, have the capacity to affect stability outcomes for sensory features. Autism Research 2019, 12: 100-111. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Children with autism spectrum disorder (ASD) and other developmental disabilities (DD) may process sensory information differently from those who do not have ASD. For example, some children may be over-responsive or under-responsive to sound or touch. In this study, we showed that sensory features in preschool/school-aged children with ASD and DD tend to decrease on average over a several year period. However, individual children tend to retain their ranking (low or high in sensory features) in comparison to other children over time.

Histone deacetylase-mediated regulation of the antimicrobial peptide hBD2 differs in intestinal cell lines and cultured tissue

Histone deacetylase inhibition (HDACi) has been suggested as a promising approach to bolster TLR-mediated induction of antimicrobial peptides such as human β-defensin 2 (hBD2). In inflammatory bowel disease (IBD), Crohn’s disease (CD) patients display an attenuated expression of hBD2 as compared to ulcerative colitis (UC). Here, we aimed to study if combining HDACi with the therapeutic E. coli Nissle 1917 (EcN), a strong hBD2 inducer, might be a feasible strategy to further modify protective immune responses. Monolayer epithelial cell lines versus cultured human biopsies from healthy controls and CD and UC patients showed diverse effects. In mono-cell systems, we observed a strong NF-kB-dependent enhancement of TLR- but also IL1β-mediated hBD2 induction after HDACi. In contrast, multicellular colonic biopsy culture showed the opposite result and HDACi was associated with an abolished TLR-mediated hBD2 induction in all tested patient groups. Of note, CD patients showed an attenuated induction of hBD2 by E. coli Nissle as compared to UC. We conclude that the role of HDACs in hBD2 regulation is context-dependent and likely modified by different cell types. Differential induction in different IBD entities suggests different clinical response patterns based on still unknown hBD2-associated mechanisms.

Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns.

Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy. Latent class analysis identifies mutually exclusive groups of individuals maximizing within-group similarities and between-group differences. In the EMPHASIS-HF trial, 2279 heart failure with reduced ejection fraction patients were randomized to eplerenone or placebo and were characterized according to 18 clinical features. Subgroup definitions were applied to 6472 patients enrolled in the EPHESUS trial to validate observations. Event-free survival and effect of eplerenone on the composite of cardiovascular death and heart failure hospitalization were determined for each subgroup. Four subgroups were identified with significant differences in event-free survival (P=0.002). The subgroup C had the worst event-free survival in both studies and was characterized by older age, lower body mass index, worse renal function, higher baseline potassium levels, high prevalence of anemia, diabetes mellitus, previous revascularization and higher rates of eplerenone discontinuation, and hyperkalemia during follow-up. Two subgroups (B and C) showed a poorer response to eplerenone in both studies and these groups shared common features such as lower body mass index and high prevalence of anemia. Clinical profiles, prognosis, and treatment response patterns of the 4 subgroups applied in EPHESUS trial presented similarities to those observed in EMPHASIS. Using a data-driven approach, we identified heart failure with reduced ejection fraction subgroups with significantly different prognoses and potentially different responses to eplerenone. However, these data should be regarded as hypothesis-generating and prospective validation is warranted, to assess the potential clinical implications of these subgroups. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00232180.

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy

Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab. Case series of C3 glomerulopathy. Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada. Global or partial clinical renal response. Evolution of serum creatinine and proteinuria values. 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders. Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases. Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.

A pilot feasibility study of definitive concurrent chemoradiation with pencil beam scanning proton beam in combination with 5-fluorouracil and mitomycin-c for carcinoma of the anal canal.

733 Background: Definitive chemoradiation (CRT) with concurrent 5-fluorouracil (5-FU)/mitomycin C (MMC) for anal cancer yields high rates of long term survival. However, CRT has significant acute and long term toxicity. Pencil beam scanning proton beam (PBS-PT) may potentially reduce this toxicity. This is a pilot study evaluating the feasibility of definitive concurrent CRT with PBS-PT with 5-FU/MMC for anal cancer. Methods: Pts were enrolled on an NCI sponsored, prospective, multi-institutional, pilot study (NCT 01858025). Key eligibility were ECOG 0-2, age 18+, invasive SCC of the anal canal, clinically staged T1-4, N0-3. Pts were treated per RTOG 0529 RT schema; for T1-2, N0: 50.4 Gy to primary CTV, 42 Gy to elective LNs; for T3+ or N+: 54 Gy to primary CTV, 50.4-54 Gy to involved LN, and 45 Gy to elective LNs. Pts received 5-FU/MMC on day 1 and 29. The primary objective of this study was to determine feasibility of PBS-PT with 5-FU/MMC, determined if grade 3+ dermatologic toxicity is &lt; 48% (grade 3+ dermatologic toxicity from RTOG 98-11). The secondary endpoint was rates of overall grade 3+ toxicities, clinical complete response (cCR) rate and patterns of local regional tumor recurrence. Results: Between February 2014 to April 2017, we enrolled 25 patients into our study, all of whom were analyzed. 23 pts (92%) completed treatment per protocol, 2 pts died on treatment due to underlying comorbidities. Median time to completion of treatment was 42 days (range 38-49). The Grade 3+ radiation dermatitis was 24% (Table 1). With a median follow-up of 17.6 months (range 7.7-42.0) among the 21 patients still alive, the 1 year local control, progression-free survival, and overall survival are 100%, 83% and 87%, respectively. Conclusions: In our prospective, pilot study of PBS-PT with concurrent 5-FU/MMC, PBS-PT was found to be feasible. While felt to be unrelated to the study, the two Grade 5 adverse events on this small study highlights potentially treatment related risks of this effective yet toxic regimen. Clinical trial information: NCT01858025. [Table: see text]

Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.

Abstract 17: In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation

Abstract Immune evasion may facilitate hematologic relapse after allogeneic hematopoietic stem cell transplantation (allo-SCT). We recently demonstrated that CTLA4 blockade with ipilimumab reinvigorates a graft-versus-leukemia effect to induce complete remissions of acute myeloid leukemia (AML) relapsing after allo-SCT. Here, we hypothesized that immune subpopulation dynamics and activation states inferred from in situ gene expression changes within the leukemic microenvironment are informative of clinical outcome. We undertook an in situ transcriptomic characterization of paired, pre/post ipilimumab leukemic biopsies from five samples with relapsed, extramedullary AML. We performed a response-to-treatment expression analysis for each patient and found three immune patterns corresponding to three clinical response patterns following ipilimumab (durable response, relapse, and primary resistance). Durable responses were characterized by a diverse infiltration of activated cytotoxic T lymphocytes, B cells, and macrophages. In contrast, primary resistance was associated with both marked infiltration of CD8 T cells deficient in T-cell receptor signaling, activation, or cytolytic activity and absent infiltration of other immune effectors. Interestingly, the sample with transient response and eventual relapse demonstrated pre- and post-treatment immunologically “inflamed” states that were strongly downregulated during clinical relapse. In situ gene expression analyses of leukemic biopsies before and after ipilimumab therapy suggest that specific patterns of immune population dynamics and activation states underlie diverse clinical outcomes. Citation Format: Pavan Bachireddy, Matthew S. Davids, Michael S. Rooney, Michaela Bowden, Chensheng W. Zhou, Scott J. Rodig, Vincent Ho, Joseph Antin, John Koreth, Edwin Alyea, Robert J. Soiffer, Catherine J. Wu. In situ immune expression signatures before and after ipilimumab therapy for relapsed acute myeloid leukemia after allogeneic stem cell transplantation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 17.

Efficacy of Combined Cognitive-Behavioral Therapy for Insomnia and Pain in Patients with Fibromyalgia: A Randomized Controlled Trial

This controlled trial aims to analyze the efficacy of cognitive-behavioral therapy for insomnia and pain (CBT-IP) compared to cognitive-behavioral therapy for pain (CBT-P) and usual medical care (UMC) at improving sleep and other clinical manifestations (pain, fatigue, impaired functioning, and emotional distress) in women with fibromyalgia (FM). One hundred and twenty-six patients with FM were randomly assigned to different treatment groups and 113 completed the treatments (38 in the CBT-IP group, 34 in the CBT-P group and 41 in the UMC group) and a number of self-reports at pre-treatment, post-treatment, and 3 months of follow-up. The CBT-IP group showed significant improvements at post-treatment in several sleep variables (i.e., subjective sleep quality, sleep latency, sleep efficiency, and use of sleeping medication) that were not observed in the CBT-P and UMC groups. The CBT-IP and CBT-P groups reported significant improvements at post-treatment in FM impact and self-efficacy for coping with pain; the CBT-IP group reported improvements at follow-up in pain intensity, and the CBT-P reported improvements at post-treatment in pain catastrophizing and pain acceptance. Clinical improvements are also described. The findings revealed differential responses between groups regarding sleep and other adjustment parameters and the CBT-IP group exhibited the best clinical response pattern overall. More research in the area of FM treatment is needed to enhance the efficacy of the CBT and identify which patients are likely to benefit from each modality of CBT.