Therapy Approach For Patients Research Articles

State-of-the-art therapy and innovative treatment strategies in esophageal squamous cell cancer

SummaryRecent advances in the development of new therapeutic agents and the execution of numerous randomized controlled trials have changed the landscape of systemic therapy approaches in patients with esophageal squamous cell cancer (ESCC). Particularly the inclusion of immunotherapy permits clinicians to improve patient management in multiple settings. This review gives an overview of standard-of-care treatment and sheds light on new therapeutic options, recently approved treatments, and ongoing trials.

Assessing the OPRA trial for surgical oncologists: Safety and feasibility of a total neoadjuvant therapy approach in patients with rectal cancer

The Organ Preservation in patients with Rectal Adenocarcinoma (OPRA) trial is a randomized, non-blinded, phase II prospective study that investigated total neoadjuvant therapy (TNT) and a selective “watch-and-wait” (WW) approach in locally advanced rectal cancer (LARC). It compared two TNT regimens: induction chemotherapy-chemoradiotherapy (INCT-CRT) and chemoradiotherapy-consolidation chemotherapy (CRT-CNCT). Depending on tumor response, patients were offered WW or surgery. The primary endpoint was disease-free survival (DFS), hypothesizing that patients who underwent TNT with selective WW would have improved DFS compared to historical rates. Secondary endpoints included organ preservation (OP) and overall survival, hypothesizing that differences between INCT-CRT and CRT-CNCT could indicate a superior regimen. Results demonstrated treatment of LARC with TNT and selective WW allows for OP in approximately half of patients without negatively impacting oncologic outcomes such as DFS. The data show that a CRT-CNCT regimen had higher rates of OP, lower rates of tumor regrowth, and similar DFS compared to INCT-CRT. Lastly, DFS does not differ between patients who undergo immediate TME versus TME after regrowth. Thus, patients treated with TNT who achieve a clinical complete response (cCR) can safely undergo WW with the potential for OP. Current research to improve TNT and enhance cCR will expand the utility of the WW approach, including the intensification of neoadjuvant chemotherapy (Janus trial), comparing short-course and long-course CRT prior to CNCT (ENSEMBLE and German trials), utilizing fluoropyrimidine-chemotherapy with and without oxaliplatin in the context of WW (CHOW trial), and exploring less invasive operative approaches for early-stage tumors (NEO and NEO-RT trials). SynopsisThe OPRA trial demonstrates treatment of locally advanced rectal cancer using total neoadjuvant therapy with selective “watch-and-wait” allows organ preservation in approximately half of patients without negatively impacting oncologic outcomes. For widespread adoption of “watch-and-wait”, data from accruing prospective trials are needed to demonstrate its viability across diverse clinical settings.

Roles of differently polarized macrophages in the initiation and progressionof pancreatic cancer.

During development of pancreatic cancer macrophage-mediated inflammatory processes and the formation of cancerous lesions are tightly connected. Based on insight from mouse models we provide an overview on the functions of classically-activated pro-inflammatory and alternatively-activated anti-inflammatory macrophages in the initiation and progression of pancreatic cancer. We highlight their roles in earliest events of tumor initiation such as acinar-to-ductal metaplasia (ADM), organization of the fibrotic lesion microenvironment, and growth of low-grade (LG) lesions. We then discuss their roles as tumor-associated macrophages (TAM) in progression to high-grade (HG) lesions with a cancerous invasive phenotype and an immunosuppressive microenvironment. Another focus is on how targeting these macrophage populations can affect immunosuppression, fibrosis and responses to chemotherapy, and eventually how this knowledge could be used for novel therapy approaches for patients with pancreatic ductal adenocarcinoma (PDA).

Physical Therapy Approaches in Ankylosing Spondylitis: A Systematic Review

Background: Ankylosing spondylitis (AS) is a chronic, progressive, inflammatory disorder that mainly affects the axial skeleton with aseptic inflammation of synovial tissue, spinal ligaments, intervertebral discs and facet joints. The purpose of this review is to describe the effectiveness of different physical therapy approaches in patients with AS. Method: This review followed PRISMA guidelines. A search was conducted in electronic databases Google Scholar, PubMed, and Cochrane. Publications were included if the study group included patients with a diagnosis of AS according to the classification system described in the New York criteria. Results: A total of 6 clinical trials and 4 reviews were included in this review. One trial (n=1) had no intervention, most studies (n=4) and all the reviews (n=4) compared a variation in type of exercises, such as aerobic exercise, Pilates, swimming, one trial (n=1) was a follow-up evaluation. Conclusions: The results of this review show that different types of treatment programs improve areas related to the physical health of patients with AS such as pain intensity, mobility, functionality, muscle strength, balance, fatigue, anxiety, depression. The most significant improvement in pain across all research data is noted after aquatic therapy. Supervised physiotherapy is more effective than usual care in improving disease activity, functional capacity and pain in patients with AS.

Longitudinal Omics Data Followed By Preclinical Treatment Studies Identify Proteasome Inhibition As Effective Therapy for Ibrutinib-Resistant Chronic Lymphocytic Leukemia

Resistance to ibrutinib treatment is an increasing problem for patients with chronic lymphocytic leukemia (CLL) as it leads to dismal clinical outcomes. Acquired mutations in the therapy target BTK or its downstream mediator PLCG2 explain only partly the non-responsiveness to this treatment, as merely a subset of patients harbor such mutations, or if so, only in a fraction of the malignant B cells. Besides genetic aberrations, molecular changes both CLL cell-intrinsic and -extrinsic have been associated with ibrutinib resistance. But so far these alterations have not led to the development of novel therapy approaches for patients who are non-responsive to ibrutinib treatment. We have generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1 CLL) continuously with ibrutinib. For a period of several weeks, the leukemic mice respond very well to the treatment, but similarly as observed in patients, relapse under therapy occurs with an aggressive outgrowth of the malignant cells (Figure A), which are non-responsive to ibrutinib upon retransplantation. By whole exome sequencing (WES) of TCL1 CLL cells before treatment and after relapse we did not detect any mutations in Btk or downstream signaling molecules in the resistant cells. In addition, the identified mutations were of low allele frequency and no recurrent mutations were detectable in the relapse samples that could explain the non-responsiveness to ibrutinib. To analyze molecular adaptations that drive resistance to ibrutinib, we performed transcriptome and proteome analyses of TCL1 CLL cells from mice treated with ibrutinib or vehicle at an early responsive time point, and a late time point, when mice got refractory to treatment with ibrutinib (see arrows in Figure A). Comparative analyses of these complex data sets suggested alterations in the proteasome activity as a driver of ibrutinib resistance. By quantifying total ubiquitination of proteins, we further confirmed reduced levels of K48-ubiquitination which suggest an increased proteasomal activity in ibrutinib-resistant tumors. Based on these results, we performed preclinical treatment studies with the proteasome inhibitor carfilzomib, which more efficiently controlled TCL1 CLL in ibrutinib-resistant than in ibrutinib-sensitive tumors. Most interestingly, when carfilzomib was added as salvage therapy at the time of ibrutinib-resistance development in mice, we observed a clear survival benefit compared to mice who continued on ibrutinib monotherapy (Figure B). To verify the relevance of these findings for patients with ibrutinib-resistant CLL, we acquired proteome data of CLL cells from three sequential time points in 3 patients: (1) before start of ibrutinib treatment, (2) during ibrutinib responsiveness (within the first 6 months of treatment), (3) upon ibrutinib refractoriness. This allowed us to identify common dynamic clusters of deregulated proteins that we are currently exploring concerning their role in resistance development. In addition, we treated CLL cells from ibrutinib-resistant patients cultured under lymph node-mimicking conditions ex vivo with several proteasome inhibitors and showed effective responses of these cells comparable to CLL samples of ibrutinib-sensitive patients. Altogether, our omics data approach identified proteasome inhibitors as attractive novel treatment options for CLL patients that do not respond to ibrutinib. Current investigations of proteome data acquired from TCL1 CLL samples before and during carfilzomib treatment aim at identifying the molecular targets of the proteasome with relevance for ibrutinib resistance. Figure:A) Treatment response in mice with TCL1 CLL to ibrutinib (Ibr) and vehicle (Veh) measured as the number of CD5+ CD19+ CLL cells in blood over time. B) Survival curves of mice with TCL1 CLL treated either with vehicle or ibrutinib as monotherapy, or a combination starting with 2 weeks of ibrutinib treatment, followed by the addition of carfilzomib (CFZ). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Efficacy Trial of Escalation of Plerixafor for Mobilization of CD34+ Hematopoietic Progenitor Cells (HPCs) for Globin Gene Transfer in Patients with Sickle Cell Disease

▪There is presently no curative therapy for SCD other than allogeneic hematopoietic progenitor cell (HPC) transplantation. Incoming trials of autologous gene therapy approaches in patients with sickle cell disease (SCD) include the need of HPCs for gene transduction. However, the use of G-CSF for mobilization of HPCs is contraindicated in this patient population, having resulted in sickle crises and death in some patients.Plerixafor is an inhibitor of the CXCR4 chemokine receptor on HPCs and blocks binding of its ligand, stromal cell-derived factor-1α (SDF-1α). It is FDA-approved at doses of 240 μg/kg subcutaneously in combination with G-CSF for autologous HPC mobilization in non- Hodgkin lymphoma and multiple myeloma patients.We designed a multi center 3+3, phase 1 study of dose escalation of plerixafor for mobilization of HPC in patients with SCD. The primary goal of this trial is to evaluate the safety of, and the optimal dose for the mobilization of HPCs with plerixafor alone. The desired optimal peripheral blood CD34 concentration was set at > 30 cells/μl. Plerixafor was supplied by Sanofi following their approval of the protocol. Because of the ethical considerations, and the risks associated with the mobilization of patients with SCD, the protocol was submitted to, and approved by the FDA; IND 122657. It was registered with ClinicalTrials.gov; identifier: NCT02193191.Fourteen patients with SCD were entered on the study to date, and 13 patients were evaluable. Patients' age was 21-41 years (median 30 years). Patients had a history of SCD complications including vaso-occlusive crises, acute chest syndrome, osteomyelitis, cerebral aneurysm, retinal ischemia, and skin ulcers. Nine patients were on, and 4 patients were off hydroxyurea at the time of accrual on study.Six patients were treated at the first dose level of 80 μg/Kg, three patients at the second dose level of 160 μg/Kg, and to date, four patients at the third dose level of 240 μg/Kg. Two patients developed adverse events of vaso-occlusive crisis, 2 and 4 days following completion of plerixafor at the first and third dose level respectively, requiring increasing the first and third dose cohorts to 6 patients.White blood cell counts (WBC), absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC) (x 10^9/L), CD34+ and CD34+CD38- cell counts were measured at the following time points: 0, 6-12 and 20-24 hours post-treatment with Plerixafor, which allowed to identify the optimal CD34 peak time in SCD patients.The results of peak WBC, ANC and ALC, and fold increase for these counts, as well as CD34+ concentrations (cells/μl), and number of patients achieving a CD34+count > 30 cells/μl are shown in Table 1 for patients at the 3 dose levels. There was a 1.8-2.8 fold increase in WBC and 1.0-2.2 fold increase in ANC at the 3 dose levels, and CD34 concentrations were: 7-132 cells/μl, 27-251 cells/μl and 19-95 cells/μl for the 3 respective dose levels. There were no significant variations in the levels of hemoglobin and platelets.In summary, this is the first trial on the use of plerixafor for HPC mobilization in patients with SCD. Our data in 13 patients support the safety of plerixafor administration at doses of 80, 160 μg/Kg, and 240 μg/Kg, which is especially significant, in view of the prior toxicity associated with G-CSF in this patient population. Plerixafor increased WBC, ANC and ALC to acceptable levels (1.8-2.8 fold), and allowed the mobilization of high numbers of CD34+ cells for 8 of 13 patients treated at the 3 dose levels. This study will allow us to define the optimal conditions for effective globin gene transfer after optimization of lentivirus-mediated globin gene transfer with the TNS9.3.55 vector in an upcoming trial. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis.

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.

Goal-directed Therapy and Postcystectomy Ileus: Comment.

We read with interest the recently published study by Arslan-Carlon et al. in Anesthesiology.1 This primary objective of this randomized, controlled trial (N = 283) was to determine whether a goal-directed fluid therapy approach would result in a lower incidence of postoperative ileus compared with a standard fluid therapy approach in patients undergoing open radical cystectomy. All patients had an arterial line coupled to an advanced hemodynamic monitoring device (EV-1000, Edwards Lifesciences, USA) to monitor advanced hemodynamic variables before, during, and immediately after surgery. No statistically significant difference in this primary outcome was found between the two groups. Interestingly, however, the authors identified a relative negative impact of goal-directed fluid therapy on acute kidney injury (AKI) incidence (secondary outcome) with more patients in the goal-directed fluid therapy group who experienced AKI (56% vs. 40%, P = 0.005). We do appreciate the statistical insignificance noted after taking into account Bonferroni adjustments (P = 0.170) because this is rarely done. We congratulate the authors for having performed such a rigorous study. We have, however, two main comments for any interested readers.First, although many clinicians throughout the world may use a similar hemodynamic algorithm that calls for fluid, vasopressor, or inotrope administration if stroke volume variation is greater than 12%, mean arterial pressure (MAP) less than 60 mmHg, or cardiac index less than 2.5 l · min–1 · m–2, there have been at least two large randomized, controlled trials demonstrating that targeting a higher arterial pressure during surgery is associated with less postoperative AKI. The first, from Futier et al.,2 reported a lower incidence of organ dysfunction in the group of patients with a targeted systolic arterial pressure closer to the patient’s baseline value compared with the control group. The second, from Wu et al.,3 demonstrated that targeting a MAP level between 80 and 95 mmHg in chronically hypertensive patients reduces postoperative AKI compared with two other MAP levels (65 to 79 and 96 to 110 mmHg). Additionally, French national guidelines recommend maintenance of a MAP target greater than 70 mmHg to prevent AKI in patients with chronic hypertension (which is the case in more than 60% of the current study population).4 As a result, the MAP level targeted in the current hemodynamic algorithm may have been too low and could be responsible for the higher incidence of AKI.Second, because both groups were monitored with an advanced hemodynamic monitor, we would have greatly appreciated summaries of advanced hemodynamic variables to better understand the results. It would be useful if the authors could provide mean MAP, stroke volume, cardiac index, and stroke volume variation during the case and also the percentage of procedure time the patients were hypotensive as defined using their algorithm of MAP less than 60 mmHg and the percentage of procedure time with a stroke volume variation greater than 12%. It is quite evident that clinicians’ compliance with the application of hemodynamic protocols remains poor, ranging between 62% and 87%, even within ideal study conditions.5,6 Compliance of less than 50% to protocols is reported in daily practice across different medical specialties, but at least 80% adherence is required to observe improved clinical outcomes.7–9 As a result, having hemodynamic data would allow readers to assess protocol compliance and determine whether advanced hemodynamic variables were well optimized throughout the perioperative period.Dr. Joosten has been a consultant for Edwards Lifesciences (Irvine, California), Aguettant Laboratoire (Lyon, France), and Fresenius Kabi GmbH (Bad Homburg, Germany). Dr. Legrand has received consulting fees from Novartis (Bale, Switzerland), lecture fees from Baxter (Lessines, Belgium) and Fresenius Kabi GmbH, and research support from Sphingotec (Hennigsdorf, Germany). The other authors declare no competing interests.

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease.

X-linked severe immunodeficiency disease (SCID-X1) is an inherited, rare, and life-threating disease. The genetic origin is a defect in the interleukin 2 receptor γ chain (IL2RG) gene and patients are classically characterized by absence of T and NK cells, as well as presence of partially-functional B cells. Without any treatment the disease is usually lethal during the first year of life. The treatment of choice for these patients is hematopoietic stem cell transplantation, with an excellent survival rate (>90%) if an HLA-matched sibling donor is available. However, when alternative donors are used, the success and survival rates are often lower. Gene therapy has been developed as an alternative treatment initially using γ-retroviral vectors to correct the defective γ chain in the absence of pre-conditioning treatment. The results were highly promising in SCID-X1 infants, showing long-term T-cell recovery and clinical benefit, although NK and B cell recovery was less robust. However, some infants developed T-cell acute lymphoblastic leukemia after the gene therapy, due to vector-mediated insertional mutagenesis. Consequently, considerable efforts have been made to develop safer vectors. The most recent clinical trials using lentiviral vectors together with a low-dose pre-conditioning regimen have demonstrated excellent sustained T cell recovery, but also B and NK cells, in both children and adults. This review provides an overview about the different gene therapy approaches used over the last 20 years to treat SCID-X1 patients, particularly focusing on lymphoid immune reconstitution, as well as the developments that have improved the process and outcomes.

Sportliche Aktivität und psychische Erkrankungen

Current meta-analyses demonstrate convincing evidence regarding the efficacy of exercise on depression, insomnia, anxiety disorders, schizophrenia and ADHD. However, exercise and sports therapy approaches for patients with psychological disorders are mostly integrated in psychiatric inpatient or rehabilitation settings, but not applied in the outpatient sector. Thus, the German Health sector does not take the advantage of the compelling therapeutic effects of exercise. This review covers the theoretical and empirical fundamentals of the effects of exercise and illustrates practical implications by means of the presentation of the group-therapeutic exercise program ImPuls, that was specifically designed for patients with psychological disorders in outpatient settings. ImPuls integrates current evidence of the effects of exercise (type of sport, duration, frequency, intensity) and the facilitation of motivational and volitional strategies to support patients to integrate exercise in their daily life routines.

Value of the 18F-choline PET/MR hybrid technique on the therapeutic approach in patients with prostate cancer treated with prostatectomy and elevation of prostate specific antigen levels less than 1 ng/ml

ObjectiveTo assess the detection rate of 18F-Choline PET/MRI and subsequent changes in therapy approach for patients with prostate cancer treated by prostatectomy and with rising levels of PSA <1ng/ml. MethodsProspective study with our first 36 patients with prostatectomy for prostate cancer and rising levels of PSA, who were referred for an 18F-Choline PET/MRI study.A dual-phase study was acquired after intravenous administration of 185±10% MBq of 18F-Choline: (1) early imaging (immediately after tracer administration) of prostate area (emission PET/Multiparametric MRI). (2) Whole-body imaging 1h after tracer injection (emission PET/MRI: T1, T2, STIR, diffusion).The therapy approach for patients was decided upon the Oncology Committee consensus based on 18F-Choline PET/MRI findings. ResultsTwenty out of 36 patients (55.6%) were positive for the 18F-Choline PET/MRI study: 8 (22.2%) within the prostatectomy bed, 7 (19.4%) with infradiaphragmatic lymph nodes, 4 (11.1%) with local recurrence and infradiaphragmatic lymph nodes, and 1 (2.8%) with bone metastasis.Sixteen out of the 36 patients (44.4%) were negative for the 18F-Choline PET/MRI study.18F-Choline PET/MRI findings had an impact on the therapy approach to follow: 15 patients (41.6%) showed oligometastatic disease which was treated by imaging-guided radiotherapy, 5 (13.9%) with multiple metastatic disease were treated by androgen deprivation therapy, 16 (44.4%) negative were under active surveillance. ConclusionHybrid 18F-Choline PET/MRI procedure showed a high detection rate for recurrence in prostate cancer patients treated with prostatectomy and rising PSA levels <1ng/ml, and 18F-Choline PET/MRI findings resulted in a better tailored therapy approach delivered to our patients.

Impacto de la tecnología híbrida PET/RM con 18F-colina en la estrategia terapéutica de los pacientes con cáncer de próstata tratados con prostatectomía que presentan elevación del antígeno prostático específico inferior a 1 ng/ml

ObjectiveTo assess the detection rate of 18F-Choline PET/MRI and subsequent changes in therapy approach for patients with prostate cancer treated by prostatectomy and with rising levels of PSA <1 ng/ml. MethodsProspective study with our first 36 patients with prostatectomy for prostate cancer and rising levels of PSA, who were referred for an 18F-Choline PET/MRI study.A dual-phase study was acquired after intravenous administration of 185±10% MBq of 18F-Choline: 1) early imaging (immediately after tracer administration) of prostate area (emission PET/Multiparametric MRI). 2) whole-body imaging 1 h after tracer injection (emission PET/MRI: T1, T2, STIR, diffusion).The therapy approach for patients was decided upon the Oncology Committee consensus based on 18F-Choline PET/MRI findings. ResultsTwenty out of 36 patients (55.6%) were positive for the 18F-Choline PET/MRI study: 8 (22.2%) within the prostatectomy bed, 7 (19.4%) with infradiaphragmatic lymph nodes, 4 (11.1%) with local recurrence and infradiaphragmatic lymph nodes, and 1 (2.8%) with bone metastasis.Sixteen out of the 36 patients (44.4%) were negative for the 18F-Choline PET/MRI study.18F-Choline PET/MRI findings had an impact on the therapy approach to follow: 15 patients (41.6%) showed oligometastatic disease which was treated by imaging-guided radiotherapy, 5 (13.9%) with multiple metastatic disease were treated by androgen deprivation therapy, 16 (44.4%) negative were under active surveillance. ConclusionHybrid 18F-Choline PET/MRI procedure showed a high detection rate for recurrence in prostate cancer patients treated with prostatectomy and rising PSA levels <1 ng/ml, and 18F-Choline PET/MRI findings resulted in a better tailored therapy approach delivered to our patients.

A Rationale for the Use of Clotted Vertebral Bone Marrow to Aid Tissue Regeneration Following Spinal Surgery

Vertebral body bone marrow aspirate (V-BMA), easily accessible simultaneously with the preparation of the site for pedicle screw insertion during spinal procedures, is becoming an increasingly used cell therapy approach in spinal surgery. However, the main drawbacks for V-BMA use are the lack of a standardized procedure and of a structural texture with the possibility of diffusion away from the implant site. The aim of this study was to evaluate, characterize and compare the biological characteristics of MSCs from clotted V-BMA and MSCs from whole and concentrate V-BMAs. MSCs from clotted V-BMA showed the highest cell viability and growth factors expression (TGF-β, VEGF-A, FGF2), the greatest colony forming unit (CFU) potency, cellular homogeneity, ability to differentiate towards the osteogenic (COL1AI, TNFRSF11B, BGLAP) and chondrogenic phenotype (SOX9) and the lowest ability to differentiate toward the adipogenic lineage (ADIPOQ) in comparison to all the other culture conditions. Additionally, results revealed that MSCs, differently isolated, expressed different level of HOX and TALE signatures and that PBX1 and MEIS3 were down-regulated in MSCs from clotted V-BMA in comparison to concentrated one. The study demonstrated for the first time that the cellular source inside the clotted V-BMA showed the best biological properties, representing an alternative and advanced cell therapy approach for patients undergoing spinal surgery.

RAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application.

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.

Noninvasive brain stimulation in the rehabilitation of patients with post-stroke aphasia

Over the past decade, non-invasive brain stimulation, in particular transcranial stimulation by direct electric current (TES), has been increasingly included in the array of methods used for rehabilitation of patients with post-stroke impairments (motor, speech, cognitive). Development of stimulation protocols with determination of the zones of exposure, as well as better understanding of the patterns of restoration of functional systems, became possible due to basic research using functional MRI paradigm. However, the complexity of the organization of the speech system, the variety of forms of aphasia that occur when it is damaged, the individual variability of neuroplastic processes, motivated a search for optimal stimulation protocols that contribute to the personification of the rehabilitation process. Portability, low cost of equipment, a good safety and tolerance profile, as well as a proven effect on neuroplasticity processes, are the undoubted advantages of TES-therapy. There is reason to believe that further study and clinical testing of this technique will turn it into the promising tool for enhancing the effectiveness of classical speech therapy approaches in patients with post-stroke aphasia.

Comparison of motor-phonetic versus phonetic-phonological speech therapy approaches in patients with a cleft (lip and) palate: a study in Uganda

IntroductionAt present, there is growing interest in combined phonetic-phonological approaches to treat active speech errors in children with a cleft (lip and) palate (CP ± L). Unfortunately, evidence for these type of speech interventions in this population is lacking. Therefore, the present study investigated the effectiveness of speech intervention in Ugandan patients with CP ± L. Moreover, a comparison was made between a motor-phonetic and a phonetic-phonological speech intervention. MethodsEight patients (median age: 11.26y) with an isolated CP ± L were assigned into a group receiving motor-phonetic treatment (n = 4) or a group receiving combined phonetic-phonological treatment (n = 4). The participants received 6h of individual speech therapy. In both groups, perceptual and instrumental speech evaluations were performed to evaluate the patients' speech before and after the intervention. ResultsSpeech therapy (irrespective of the used approach) was found to be effective in increasing consonant proficiency and in decreasing the occurrence of non-oral and passive CSCs. No statistically significant differences in outcome variables were found when comparing the two groups pre- and post-treatment. The descriptive results, however, revealed a larger increase in % correctly produced consonants, places and manners after the intervention in the group receiving a combined phonetic-phonological treatment compared to the group receiving a motor-phonetic treatment. ConclusionThis study took a first step in providing evidence concerning the effectiveness of different speech therapy approaches in children with CP ± L. The present study holds some important implications for clinical practice suggesting that an additional phonological approach may be beneficial for the patients with CP ± L. Further research including randomized controlled trials with larger sample sizes is necessary to provide further evidence.

Association of decrease in insula fMRI activation with changes in trait anxiety in patients with craniomandibular disorder (CMD)

Patients with chronic pain and especially with craniomandibular disorder (CMD) show specific psychopathology in trait anxiety. In a previous longitudinal functional imaging study on CMD we found that the anterior insula was modulated by successful therapy intervention and pain relief. We here intended to investigate possible associations between anterior insula fMRI-activation during occlusal movements and trait anxiety over a splint therapy approach in patients with CMD. Three fMRI-investigations of a craniomandibular occlusion task were performed together with pain score evaluations and scoring of trait anxiety (State –Trait Anxiety Inventory; STAI) before, after two weeks and after three months of a DIR-mandibular splint therapy in a small group (n = 9) of CMD patients. Patients showed increased anxiety levels before therapy assessed with the STAI and the depression and anxiety scale (DASS). Besides of relevant reduction in pain the STAI decreased over time. Reduction in STAI was associated with anterior insular fMRI-activation reduction on both hemispheres. We conclude that the anxiety driven anticipation of pain related to occlusal trigger is processed in the anterior insula and might therefore be a main driver of therapeutic intervention by the splint therapy in CMD.

A comparison of adjuvant therapy approaches for patients with early-stage uterine serous carcinoma.

5517 Background: Uterine serous carcinoma is a less common subtype of endometrial cancer that is associated with poorer survival. The optimal post-operative adjuvant treatment strategy for these patients remains uncertain. Methods: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher’s exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free survival (RFS) and overall survival (OS). Results: 634 patients were included. 77% of patients had Stage IA disease, 42% showed no myometrial invasion. The majority had pure serous histology (72%) and LVSI (76%). Adjuvant treatment varied: 12% received no adjuvant therapy, 7% had chemotherapy alone, 51% had cuff brachytherapy, 12% had cuff brachytherapy with chemotherapy (cuff/chemo), and 19% underwent pelvic radiation (EBRT). Complete RFS and OS data were available for 607 and 609 patients, respectively, and the median follow-up time was 58 months. As compared with patients who received no adjuvant therapy, patients who received cuff or cuff/chemo had improved RFS (cuff: HR 0.70, p = 0.02; cuff/chemo HR 0.53, p = 0.01) and OS (cuff HR 0.56, p = 0.001; cuff/chemo HR 0.48, p = 0.01). In a direct comparison, patients with cuff/chemo had better RFS and OS than those with chemotherapy alone (RFS HR 0.52, p = 0.03; OS HR 0.50, p = 0.05). There were no differences in RFS or OS for women who received chemotherapy alone or EBRT. Improved survival with cuff and cuff/chemo persisted on multivariable analyses (included age, stage, LVSI, adjuvant therapy type); additionally, EBRT was also associated with improved OS. In analyses limited to patients without myometrial invasion, patients with cuff or cuff/chemo had improved RFS and OS compared with observation alone. Conclusions: The use of adjuvant cuff brachytherapy with and without chemotherapy was associated with improved RFS and OS in patients with early stage uterine serous carcinoma.

Integral movement therapy versus local movement therapy approach in patients with idiopathic chronic low-back pain: study protocol for a randomized controlled trial

BackgroundChronic low-back pain (CLBP) is one of the most common reasons for seeking medical care and it imposes a significant burden on individuals and society at large. Systematic reviews evaluating the effectiveness of supervised exercise therapies commonly conclude that, to date, there is no evidence to support the superiority of one form of exercise over another. Randomized controlled trials (RCT) to date included mostly trunk strengthening exercises (e.g. bird dog, plank) and there is no evidence about supervised, individually graded integral movement therapy program for patients with CLBP.MethodsThe research design is a RCT with parallel-group design including two intervention groups: integral movement therapy and conventional local movement therapy. Participants in each group will receive 20 supervised sessions in a 10-week period, twice per week, for approximately 1 h per session. Outcome assessments will occur at baseline and immediately after intervention, follow-up will take place at six months and 12 months after the intervention. Prespecified analyses will evaluate the main effects of the treatment.DiscussionThis trial will use a novel, previously unexplored integral approach to CLBP through exercises. In contrast to commonly used exercise programs, the integral program does not include specific local strength exercises for hip and trunk flexors and extensors. However, learning dynamic trunk muscle control in various body positions with added limb movements could be beneficial because of the parallels to everyday work. The study will contribute to clinical practice by providing evidence to guide professionals when deciding for the proper and efficient treatment of patients with CLBP.Trial registrationClinicalTrials.gov, NCT03623802. Registered on 9th August 2018.

Recent developments in the treatment of blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from precursors of dendritic cells and involves most frequently the skin, bone marrow and lymph nodes. Diagnosis depends upon identification of specific tumor markers including CD4, CD56 and CD123. Historically, the median survival has been less than 2 years in most reported series. While for many years, conventional chemotherapy followed by stem cell transplantation was the standard of care, recently tagraxofusp, a cytotoxin directed against CD123, received United States Food and Drug Administration approval specifically for patients with BPDCN. In this review, we will discuss the markers used for diagnosis of BPDCN and focus on the new targeted treatments available. Specifically in BPDCN, tagraxofusp was highly effective with a safety profile found to be acceptable overall, with the noted occurrence of capillary leak syndrome. Future directions in therapy approaches for patients with BPDCN will include the development of other CD123-targeted agents, agents targeting beyond CD123 and investigation of rational combination approaches of CD123-directed therapy with other therapies.